Therapeutic Response To The Angiogenesis Inhibitor Sunitinib In Ovarian Clear Cell Cancer

A group of international researchers reported sustained responses in two ovarian clear cell cancer (OCCC) patients with chemotherapy-resistant disease, who were treated with the anti-angiogenesis inhibitor sunitinib (Sutent®). The researchers emphasize the growing realization that OCCC is molecularly and clinically distinct as compared to other forms of ovarian cancer, and note significant common scientific characteristics possessed by both OCCC and renal clear cell cancer.

Clear Cell Carcinoma of the Ovary

Ovarian clear cell cancer (OCCC) is a rare form or subtype of epithelial ovarian cancer that is generally refractory to platinum-based chemotherapy. A group of international researchers from the United Kingdom, Australia, Japan, Canada and the United States recently reported results from comprehensive OCCC tumor gene expression and copy number testing, which was designed to identify potential therapeutic targets of OCCC.

Gene expression and DNA copy number testing was performed using primary human OCCC tumor samples, and the test findings were confirmed by immunohistochemistry (IHC) on tissue microarrays. Based on this testing, the researchers identified specific over-expression of the IL6 (interleukin-6)-STAT3 (signal transducer and activator of transcription 3)-HIF (hypoxia-inducible factors) cellular pathway in OCCC tumors, as compared with high-grade serous ovarian cancers. Expression of PTHLH (parathyroid hormone-like hormone) and high levels of circulating IL6 were also found in OCCC patients, and the researchers believe that this finding may explain the frequent occurrence of hypercalcemia and thromboembolic events in OCCC. Notably, the study results set forth a description of amplification of several RTKs (receptor tyrosine kinases), most notably MET (met proto-oncogene [hepatocyte growth factor receptor]), which certainly suggests other potential therapeutic targets for this hard-to-treat subtype of ovarian cancer.

Circulating IL6 levels were measured in the blood serum from patients with OCCC or high-grade serous ovarian cancers and corresponded to progression-free and overall survival. Two OCCC patients were treated with sunitinib and their therapeutic responses were measured clinically and by positron emission tomography (PET). The researchers reported sustained clinical and functional imaging responses in two OCCC patients with chemotherapy-resistant disease who were treated with sunitinib, thereby showing  significant scientific parallels with renal clear cell cancer.

Based upon the findings above, the researchers highlighted the importance of specific therapeutic targets in the treatment of OCCC, and suggested that more extensive clinical trials with sunitinib in OCCC patients are warranted.  The overarching findings of this study provide significant impetus to the growing realization that OCCC is molecularly and clinically distinct as compared to other forms of ovarian cancer.

Source: Anglesio MS, George J, Kulbe H, et. al. IL6-STAT3-HIF Signalling and Therapeutic Response To The Angiogenesis Inhibitor, Sunitinib, In Ovarian Clear Cell Cancer. Clin Cancer Res. 2011 Feb 22. [Epub ahead of print] PubMed PMID: 21343371.

Additional Information:

  • Dedicated Ovarian Clear Cell Cancer Clinical Trials (currently recruiting as of 3/25/11).

A Phase II Evaluation of SU11248 (Sunitinib Malate) (IND #74019, NSC #736511) in the Treatment of Persistent or Recurrent Clear Cell Ovarian Carcinoma, Clinical Trial Summary, NCT00979992, ClinicalTrials.gov.

A Phase II Evaluation of Temsirolimus (CCI-779) [Torisel®] (NCI Supplied Agent: NSC# 683864, IND# 61010) in Combination With Carboplatin and Paclitaxel Followed by Temsirolimus (CCI-779) Consolidation as First-Line Therapy in the Treatment of Stage III-IV Clear Cell Carcinoma of the Ovary, Clinical Trial Summary, NCT01196429, ClinicalTrials.gov.

  • Open Ovarian Cancer and Solid Tumor Clinical Trials Testing MET Inhibitors (as of 3/25/11)

We provide below a list of MET inhibitors that are currently available through open ovarian cancer and solid tumor clinical trials.  A few caveats are noteworthy.

First, the association between MET inhibiton and ovarian clear cell cancer inhibition has NOT been established as a form of treatment in large randomized, prospective clinical trials.

Second, most of the clinical trials listed below are phase I studies designed to test the biological activity and safety of the drug — not the effectiveness.  Patients enrolled in a phase I trial are generally the first humans to receive the study drug.

Third, all patients should seek advice from their doctor in advance of deciding to enroll in a clinical trial. Many of the clinical drugs listed below inhibit one or more cellular functions in addition to MET.

List of open solid tumor clinical trials testing AMG 208.

List of open solid tumor clinical trials testing MGCD-265.

List of open solid tumor clinical trials testing PF-2341066 (crizotinib)(NCT01121588NCT00585195).

List of open ovarian cancer clinical trials testing sunitinib (SU11274)/Sutent®.

List of open solid tumor clinical trials testing sunitinib (SU11274)/Sutent®.

List of open solid tumor clinical trials testing cabozantinib (a/k/a XL184 or BMS-907351).

List of open solid tumor clinical trials testing ARQ197.

List of open solid tumor clinical trials testing INCB28060.

List of open solid tumor clinical trials testing E7050.

List of open solid tumor clinical trials testing MGCD265.

  • Genetic Similarity Between Ovarian Clear Cell Cancer & Renal Clear Cell Cancer

Yoshida S, Furukawa N, Haruta S, et. al. Theoretical model of treatment strategies for clear cell carcinoma of the ovary: focus on perspectives. Cancer Treat Rev. 2009 Nov;35(7):608-15. Epub 2009 Aug 8. Review. PubMed PMID: 19665848.

Rauh-Hain JA, Penson RT. Potential benefit of Sunitinib in recurrent and refractory ovarian clear cell adenocarcinoma. Int J Gynecol Cancer. 2008 Sep-Oct;18(5):934-6. Epub 2007 Dec 13. PubMed PMID: 18081793.

Zorn KK, Bonome T, Gangi L, et. al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005 Sep 15;11(18):6422-30. PubMed PMID: 16166416.

British Columbian Researchers Make Groundbreaking Genetic Discovery In Endometriosis-Associated Ovarian Cancers

British Columbian researchers discover that approximately one-half of clear-cell ovarian cancers and one-third of endometrioid ovarian cancers possess ARID1A gene mutations, as reported today in the New England Journal of Medicine.

British Columbian researchers discover that approximately one-half of ovarian clear-cell cancers (OCCC) and one-third of endometrioid ovarian cancers possess ARID1A (AT-rich interactive domain 1A (SWI-like)) gene mutations, as reported today in the New England Journal of Medicine (NEJM). The research paper is entitled ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas, and represents, in large part, the collaborative work of Drs. David Hunstman and Marco Marra.

Dr. David Huntsman, Co-Founder & Acting Director, Ovarian Cancer Research Program of British Columbia

Dr. Marco Marra, Director, Michael Smith Genome Sciences Centre, British Columbia Cancer Agency

David Huntsman, M.D., FRCPC, FCCMG, is a world-renowned genetic pathologist, and the Co-Founder and Acting Director of the Ovarian Cancer Research Program of British Columbia (OvCaRe). He also heads the Centre for Translational and Applied Genomics, located in the British Columbia (BC) Cancer Agency’s Vancouver Centre.  Dr. Huntsman is the Co-Director of the Genetic Pathology Evaluation Centre, Vancouver General Hospital, and the Associate Director of the Hereditary Cancer Program, BC Cancer Agency. He is involved in a broad range of translational cancer research and, as the OvCaRe team leader, has studied the genetic and molecular structure of ovarian cancer for many years. In June 2009, the NEJM published one of Dr. Huntsman’s most recent groundbreaking discoveries:  the identification of  mutations in the FOXL2 gene as the molecular basis of adult granulosa cell ovarian cancer tumors.

Marco Marra, Ph.D. is the Director of the BC Cancer Agency’s Michael Smith* Genome Sciences Centre (GSC) , one of eight BC Cancer Agency specialty laboratories. Dr. Marra is internationally recognized as a preeminent leader in the field of genetics.  His leadership has helped transform the GSC into one of the world’s most advanced and productive centers for development and application of genomics, bioinformatics and related technologies. The work of the GSC , along with collaborations involving the BC Cancer Agency and other local, national and international researchers and organizations, have led to several major scientific breakthroughs over the past decade.

*Dr. Michael Smith won the 1993 Nobel Prize in chemistry for his development of oligonucleotide-based site-directed mutagenesis, a technique which allows the DNA sequence of any gene to be altered in a designated manner. His technique created an groundbreaking method for studying complex protein functions, the basis underlying a protein’s three-dimensional structure, and a protein’s interaction with other molecules inside the cell.

Tackling Ovarian Cancer, “One Subtype At a Time”

In December 2008, the OvCaRe team announced an important discovery about the genetics of ovarian cancer – that instead of being one single disease, it is made up of a spectrum of distinct diseases. “Until now,” says OvCaRe team leader David Huntsman, “ovarian cancer has been treated as a single disease both in the cancer clinic and the research lab.” This may help explain why there have been many fewer advances in ovarian cancer research and treatment than for other cancer types.

On the heels of this important finding, Huntsman says his team decided to tackle ovarian cancers “one subtype at a time.” For its first target, the team chose granulosa cell ovarian tumors, which account for five percent of ovarian tumors and have no known drug treatments. Working with research colleagues at the GSC, Huntsman’s team used the latest genomic sequencing equipment to decipher the genetic code of this ovarian cancer subtype.

“[T]en years ago, ovarian cancer appeared to be an unsolvable problem—the liberating moment came when we established that ovarian cancer is actually a number of distinct diseases … We tailor our research approach to each subtype with the hope of developing effective treatments specific to each disease.”

Dr. David Huntsman, Co-Founder & Acting Director, Ovarian Cancer Research Program of British Columbia.

The genomic sequencing study results were illuminating, says Huntsman, as the research team was able to identify “a single ‘spelling mistake’ in this tumor’s DNA.” Still, Huntsman is buoyed by the promise of this research and its potential to save lives. “We’ve had dozens of letters and emails from women around the world with granulosa cell tumors, who’ve written to thank us saying this discovery has given them hope they never thought they would have. Reading these letters has been both incredibly humbling and inspiring for our team.” Libby’s H*O*P*E*™ reported Dr. Huntsman’s critical ovarian cancer discovery on June 10, 2009.

The OvCaRe team’s research findings have already been used to advance the care of BC patient Barbara Johns, a fourth grade teacher whose granulosa cell tumor was surgically removed in February 2009. “This could lead to new non-surgical treatment options for patients with this type of cancer,” says Johns, who was the first patient to benefit from the new diagnostic test. “It’s definitely a step in the right direction.”

Listen to a brief audio excerpt taken from an interview with Dr. David Huntsman, in which he explains why this is an exciting time for ovarian cancer research.

The Ovarian Cancer Research Program of British Columbia

Select NEJM Article Authors (left to right): Drs. Sohrab Shah, David Huntsman, Dianne Miller, C. Blake Gilks

OvCaRe, a multi-institutional and multi-disciplinary ovarian cancer research group, was developed as a collaboration between the BC Cancer Agency, the Vancouver Coastal Health Research Institute, and the University of British Columbia.  The OvCaRe program includes clinicians and research scientists from Vancouver General Hospital (VGH) and the BC Cancer Agency, who specialize in gynecology, pathology, and medical oncology. As noted above, Dr. Huntsman leads the OvCaRe team as its Co-Founder and Acting Director.

A team approach has ensured the building of translational research platforms, accessible to all OvCaRe team members regardless of institutional affiliation or medical/scientific discipline. The OvCaRe program research platforms include a gynecologic cancer tumor bank, the Cheryl Brown Ovarian Cancer Outcomes Unit, a tissue microarray core facility for biomarker studies, a xenograft core facility for testing experimental therapeutics, and a genomics informatics core facility. OvCaRe is developing two additional core facilities to improve knowledge dissemination and clinical trials capacity.

Although OvCaRe was formed less than ten years ago, the team has been recognized for several groundbreaking medical and scientific discoveries related to the understanding and management of ovarian cancer. The significant discoveries reported within the past two years are listed below.

  • Proved that various subtypes of ovarian ovarian are distinct diseases, and reported that potential treatment advances depend on both clinically managing and researching these subtypes as separate entities (2008)( PMID: 19053170).
  • Identified mutations in the FOXL2 gene as the molecular basis of adult granulosa cell ovarian cancer tumors using next generation sequencing – the first clinically relevant discovery made with this new technology (2009)(PMID: 19516027).
  • Discovered that women with earlier stage ovarian clear-cell cancer may benefit from lower abdominal radiation therapy (2010)(PMID: 20693298).

In many cases, these contributions have already led to changes in clinical practice in British Columbia. The international reputation of Vancouver’s OvCaRe team ensures that the positive impact of these changes is felt immediately throughout British Columbia, while also being emulated in other jurisdictions worldwide.  These contributions were made possible due to the population-based cancer system in British Columbia and strong support from the BC Cancer Foundation and the Vancouver General Hospital (VGH) & University of British Columbia (UBC) Hospital Foundation.

Background:  Ovarian Clear-Cell Cancer

Ovarian cancer ranks as the 5th deadliest cancer among U.S. women.[1] There are four general subtypes of epithelial ovarian cancer — serous, clear-cell, endometrioid, and mucinous.[2] High-grade serous ovarian cancer is the most common and represent approximately 70% of all cases of epithelial ovarian cancer in North America. [3]

The OCCC subtype represents 12 percent of ovarian cancers in North America; however, it represents up to 20 percent of ovarian cancers diagnosed in Japan and other East Asian countries. [3,4] OCCC possesses unique clinical features such as a high incidence of stage I disease, a large pelvic mass, an increased incidence of vascular thromboembolic complications, and hypercalcemia. [4-6] Both OCCC and endometrioid ovarian cancer are frequently associated with endometriosis. [4-6] The genetic events associated with the transformation of endometriosis into ovarian clear-cell cancer and endometrioid cancer are unknown.

Clear cell carcinoma of the ovary

OCCC does not respond well to the standard platinum and taxane-based ovarian cancer chemotherapy: response rates are 15 per cent compared to 80 per cent for the most common type of ovarian cancer, high-grade serous ovarian cancer. [4-6] However, the exact mechanisms underlying OCCC’s resistance to chemotherapy is not fully understood. Although several mechanisms involved in drug resistance exist in OCCC, including decreased drug accumulation, increased drug detoxification, increased DNA repair activity [4-6], and low proliferation activity[4]; no particular chemoresistance system has been identified. Due to the general chemoresistant nature of OCCC, it is generally stated that the prognosis for advanced-stage or recurrent OCCC is poor. [3, 7-8] The prognosis for OCCC that is diagnosed in Stage I, and treated by complete cytoreduction that results in little or no residual disease, is usually good. [8-10]

Although OCCC is the second leading cause of death from ovarian cancer, it is relatively understudied by the medical and research community. Despite this fact, there have been a few important studies involving this subtype of ovarian cancer.

Various researchers have long noted that OCCC has a distinct genetic profile, as compared to other types of epithelial ovarian cancer.[6, 11-14] Gene expression profiling can serve as a powerful tool to determine biological relationships, if any, between tumors.  In fact, National Cancer Institute (NCI) and Memorial Sloan-Kettering Cancer Center (MSKCC) researchers observed that clear-cell cancers share similarity in gene expression profiles, regardless of the human organ of origin (including kidney), and could not be statistically distinguished from one another. [13] The researchers found that the same was not true for the non-OCCC forms of epithelial ovarian cancer.  Several investigators have made similar observations. [14-16] It is important to note, however, that there are significant genetic differences between OCCC and renal clear-cell cancer (RCCC).  For example, abnormalities of the VHL (Von Hippel-Lindau)/HIF1-α (Hypoxia-inducible factor 1-alphapathway have been identified in the majority of RCCC cases, but not in OCCC cases. [17, 18]

The basic finding that clear-cell tumors show remarkably similar gene expression patterns regardless of their organ of origin is provocative.  This NCI/MSKCC study finding raises the question of whether therapies used to treat RCCC would be effective against OCCC.  Targeted-therapies such as VEGFR inhibitors (e.g., sunitinib (Sutent®)), PDGFR inhibitors (e.g., sorafenib (Nexavar®)), m-TOR inhibitors (e.g., temsirolimus (Torisel®) & everolimus (Afinitor®)), and anti-angiogenesis drugs (e.g., bevacizumab (Avastin®)) are used to treat RCCC. Notably, Fox Chase Cancer Center researchers performed preclinical testing of everolimus on ovarian cancer cell lines and xenografted mice and observed significant anti-tumor activity. [19, 20] The Division of Clinical Gynecologic Oncology at the Massachusetts General Hospital also observed the anti-tumor effect of sunitinib in one refractory OCCC patient that recurred after nine years and four prior treatment lines. [21] Japanese researchers have also highlighted this potential approach to fighting OCCC. [22-25]

All of the above-mentioned drugs used to treat RCCC are currently being tested in ovarian cancer and solid tumor clinical studies.  Accordingly, these drugs are generally available to advanced-stage and recurrent OCCC patients who do not respond to prior taxane/platinum therapy and other standard lines of treatment, assuming such patients satisfy all clinical study enrollment criteria. [26-30]

In a 2009 study conducted by researchers at Johns Hopkins and University of California, Los Angeles (UCLA), it was discovered that approximately one-third of OCCCs contained PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) gene mutations. [31] Testing patients with cancer for PIK3CA gene mutations may be feasible and allow targeted treatment of the PI3K-AKTmTOR cellular signaling pathway, according to the results of a University of Texas, M.D. Anderson Cancer Center study presented at the 2009 AACR (American Association for Cancer Research)-NCI-EORTC (European Organization For Research & Treatment of Cancer) International Conference on Molecular Targets and Cancer Therapeutics. [31] The M.D. Anderson study results may carry great significance in the future because there are several PI3K signaling pathway targeting drugs in clinical development for use against ovarian cancer and solid tumors. [32]

Also in 2009, researchers affiliated with UCLA, the Mayo Clinic, and Harvard Medical School announced that they established a biological rationale to support the clinical study of the U.S. Food & Drug Administration (FDA)-approved leukemia drug dasatinib (Sprycel®), either alone or in combination with chemotherapy, in patients with ovarian cancer (including OCCC). [33]

In August 2010, Dr. Ken Swenerton, a senior OvCaRe team member and co-leader of OvCaRe’s Cheryl Brown Ovarian Cancer Outcomes Unit, reported provocative findings relating to the use of adjuvant radiotherapy to fight OCCC. [34] Dr. Swenerton is also a co-chair of the NCI Gynecologic Cancer Steering Committee (GCSC) Ovarian Cancer Task Force.  The NCI GCSC determines all phase III clinical trials for gynecologic cancers in the U.S. and other jurisdictions. The population-based, retrospective study conducted by OvCaRe reported that a 40 percent decrease in disease specific mortality was associated with adjuvant radiotherapy administered to women with stage I (other than grade 1 tumors), II, & III clear-cell, endometrioid, and mucinous ovarian cancers, who possessed no residual (macroscopic) disease following complete cytoreductive surgery. Although the study dataset was too small to discriminate effects among the clear-cell, endometrioid and mucinous ovarian cancer histologies, the overall results highlight the curative potential of adjuvant radiotherapy in select non-serous ovarian cancer patients.  Moreover, there is limited scientific and anecdotal evidence set forth in past studies that supports the select use of radiotherapy against OCCC. [35-38]

BRCA 1 (BReast CAncer gene 1) & BRCA 2 (BReast CAncer gene 2) mutations increase a woman’s lifetime risk of breast and ovarian cancer. [39] In at least one small study, BRCA2 germline (inherited) and somatic (non-inherited) gene mutations were identified in 46 percent of the OCCC samples tested. [40] This provocative study brings into question the potential use of PARP (Poly (ADP-ribose) polymerase) inhibitors against OCCC in select patients. [41] PARP inhibitors have shown effectiveness against germline BRCA gene mutated ovarian cancers, [42, 43] and may be effective against somatic BRCA gene mutated ovarian cancers. [44, 45]

International researchers continue to identify theoretical therapeutic drug targets for OCCC. These targets include:  IGF2BP3 (insulin-like growth factor 2 mRNA-binding protein 3) [46], HNF-1beta (hepatocyte nuclear factor-1beta) [47], annexin A4  [48], GPC3(Glypican-3) [49], osteopontin [50], sFRP5 (secreted frizzled-related protein 5) [51], VCAN (versican) [52], transcription factor POU6F1 (POU class 6 homeobox 1) [53], and microRNA mir-100 [54].

Although researchers have identified that OCCC is distinct from high-grade serous carcinoma, OCCC-specific biomarkers and treatments have not been broadly adopted. Despite the theoretical approaches and study results highlighted above, there are no definitive (i.e., clinically-proven) anti-cancer agents for OCCC, and without understanding the molecular basis of this ovarian cancer subtype in much greater detail, the development of more targeted therapies is unlikely.

NEJM ARID1A Study Methodology

The OvCaRe team research consisted of four major analyses as described below.

  • RNA Sequencing of OCCC Tumor Samples and Cell Line (Discovery Cohort)

By way of background, DNA (deoxyribonucleic acid) is the genetic material that contains the instructions used in the development and functioning of our cells. DNA is generally stored in the nucleus of our cells. The primary purpose of DNA molecules is the long-term storage of information. Often compared to a recipe or a code, DNA is a set of blueprints that contains the instructions our cells require to construct other cell components, such as proteins and RNA (ribonucleic acid) molecules. The DNA segments that carry this genetic information are called genes.

RNA is the genetic material that transcribes (i.e., copies) DNA instructions and translates them into proteins.  It is RNA’s job to transport the genetic information out of the cell’s nucleus and use it as instructions for building proteins.  The so-called “transcriptome” consists of all RNA molecules within our cells, including messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). The sequence of RNA mirrors the sequence of the DNA from which it was transcribed or copied. Consequently, by analyzing the entire collection of RNAs (i.e., the transcriptome) in a cell, researchers can determine when and where each gene is turned on or off in our cells and tissues.  Unlike DNA, the transcriptome can vary with external environmental conditions. Because it includes all mRNA transcripts in the cell, the transcriptome reflects the genes that are being actively expressed at any given time.

A gene is essentially a sentence made up of the bases A (adenine), T (thymine), G (guanine), and C (cytosine) that describes how to make a protein.  Any change in the sequence of bases — and therefore in the protein instructions — is a mutation. Just like changing a letter in a sentence can change the sentence’s meaning, a mutation can change the instruction contained in the gene.  Any changes to those instructions can alter the gene’s meaning and change the protein that is made, or how or when a cell makes that protein.

Gene mutations can (i) result in a protein that cannot carry out its normal function in the cell, (ii) prevent the protein from being made at all, or (iii) cause too much or too little of a normal protein to be made.

The first study analysis involved the RNA sequencing of 18 patient OCCC tumors and 1 OCCC cell line.  The primary purpose of this step was to discover any prevalent genetic mutations within the sample tested.  Specifically, the research team sequenced the whole transcriptomes of the OCCC tumors and the single OCCC cell line and discovered  a variety of somatic (non-inherited) mutations in the ARID1A gene.  The researchers also found mutations in CTNNB1(catenin beta-1 gene), KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue gene), and PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide gene).

ARID1A encodes the BAF250a protein, a key component of the SWI-GNF chromatin remodeling complex which regulates many cellular processes, including development, differentiation, proliferation, DNA repair, and tumor suppression. [55] The BAF250a protein encoded by ARID1A is believed to confer specificity in regulation of gene expression.

To date, mutations or other aberrations in ARID1A have not been identified in ovarian cancer, but have been identified in breast and lung cancer cell lines. [56] Other researchers have suggested that ARID1A is a tumor-suppressor gene. [56]

  • DNA Sequencing of OCCC Tumor Samples and Cell Lines (Discovery Cohort + Mutation Validation Cohort)

The finding of multiple types of mutations in a single gene, ARID1A, within the discovery cohort, led researchers to perform a mutation validation analysis.  The researchers only conducted analyses with respect to ARID1A, because it was already known that mutations in CTNNB1, KRAS, and PIK3CA are recurrent in ovarian cancer. [31, 57]

This step of the research involved DNA sequencing of 210 samples of various subtypes of ovarian cancer and one OCCC cell line, along with the 18 OCCC tumor samples and one OCCC cell line used in the discovery cohort. Upon completion of the DNA sequencing, the researchers identified ARID1A mutations in 55 of 119 (46%) OCCCs, 10 of 33 (30%) endometrioid cancers, and none of the 76 high-grade serous cancers. Also, the researchers found primarly somatic (non-inherited) truncating mutations.

Based on the second study analysis, the researchers report that the presence of ARID1A mutations are strongly associated with OCCCs and endometrioid cancers.  These two subtypes of ovarian cancer, as noted above, are associated with endometriosis.

  • Testing For BAF250a Protein Expression

In the third study analysis, the researchers used immunohistochemical analysis (IHC) to measure BAF250a protein expression in 450 ovarian cancers.

The first round of IHC testing involved 182 ovarian cancers which were available from the discovery cohorts and the mutation-validation cohorts: 73 OCCCs, 33 endometrioid cancers, and 76 high-grade serous ovarian cancers.  The goal of the first IHC analysis was to compare the loss of BAF250a protein expression in OCCCs and endometrioid cancers, with and without ARID1A mutations. Upon completion, the researchers identified loss of BAF250a protein expression in 27 of 37 (73%) OCCCs, and 5 of 10 (50%) endometrioid cancers, which possessed ARID1A mutations. In contrast, loss of BAF250a protein expression was identified in only 4 of 36 (11%) OCCCs, and 2 of 23  (9%) endometrioid cancers, which did not possess ARID1A mutations. Thus, the loss of BAF250a protein expression was much greater in OCCCs and endometrioid cancers with ARID1A mutations.

The goal of the second IHC analysis was to compare loss of BAF250a protein expression among all OCCCs, endometrioid cancers, and high-grade serous cancers. The researchers identified loss of BAF250a protein expression in 31 of 73 (42%) OCCCs, and 7 of 33 (21%) endometrioid cancers, as compared to 1 of 76 (1%) high-grade serous cancers. Thus, the loss of BAF250a protein expression was much greater in the OCCCs and endometrioid cancers, as compared to high-grade serous cancers, regardless of ARID1A mutation status.

The second round of IHC testing measured loss of BAF250a protein expression within the IHC validation cohort. This analysis revealed that 55 of 132 (42%) OCCCs, 39 of 125 (31%) endometrioid cancers, and 12 of 198 (6%) high-grade serous cancers, lost BAF250a protein expression.

By the end of IHC testing, the researchers established that the loss of BAF250a protein expression was consistently more common in OCCCs and endometrioid cancers than in high-grade serous cancers, when assessed in the discovery and mutation-validation cohorts, and again in the IHC cohort.

The researchers also reported that no significant associations with loss of BAF250a protein expression were noted on the basis of age at disease presentation, disease stage, or disease-specific survival within any of the ovarian cancer subtypes.

  • Analysis of ARID1A Gene Mutations & BAF250a Protein Expression In Continguous Atypical Endometriosis

The fourth study analysis evaluated samples taken from two OCCC patients who had ARID1A mutations and contiguous atypical endometriosis. In both instances, the patient sample included the primary OCCC tumor, clones derived from contiguous atypical endometriosis, and clones derived from a distant endometriotic lesion.

In the first patient, ARID1A mutations were identified in the OCCC tumor, and 17 of 42 clones derived from contiguous atypical endometriosis, but in none of the 52 clones derived from a distant endometriotic lesion. The samples taken from this patient’s OCCC tumor and atypical endometriosis revealed loss of BAF250a protein expression; however, expression was maintained in the distant endometriotic lesion. HNF-1beta was expressed in the OCCC tumor, but not in the contiguous atypical or distant endometriosis. Estrogen receptor expression tested positive in both the contiguous atypical and distant endometriosis, but not in the OCCC tumor.

In the second patient, ARID1A mutations and a CTNNB1 mutation were identified in the OCCC tumor and contiguous atypical endometriosis, but not in a distant endometriotic lesion.

Results Summary

Based on the foregoing discussion, the major OvCaRe study findings are summarized below.

  • 46% of patients with OCCC and 30% of those with endometrioid cancers had somatic (non-inherited) truncating or missense mutation in the ARID1A gene.
  • No ARID1A mutations were identified in the 76 high-grade serous cancers analyzed.
  • Loss of BAF250a protein expression was identified in 36% of OCCCs and endometrioid cancers, but in only 1% of high-grade serous cancers.
  • Loss of BAF250a protein expression was seen in 73% and 50% of OCCCs and endometrioid cancers with an ARID1A mutation, respectively, and in only 11% and 9% of samples without ARID1A mutations, respectively.
  • The majority of cancers possessing somatic ARID1A mutations and loss of BAF250a expression appear to have a normal (also known as “wild-type”) allele present.
  • DNA and RNA sequencing data reveals that the ratio of abnormal (mutant) to normal (wild-type) alleles at both the DNA and RNA levels is consistent, thereby suggesting that epigenetic silencing is not a significant factor.
  • In two patients, ARID1A mutations and loss of BAF250a protein expression were identified in the OCCC tumor and contiguous atypical endometriosis, but not in distant endometriotic lesions.

Conclusions

The researchers note in the study that ARID1A is located at chromosome 1p36.11. Although this fact carries little meaning for a layperson, the researchers explain that this chromosomal region is commonly deleted in tumors, and that such deletions could contain tumor-suppressor genes. Based upon the totality of the data, the OvCaRe team believes that ARID1A is a tumor-suppressor gene which is frequently disrupted in OCCCs and endometrioid cancers.  Although a bit speculative due to small sample size, the researchers also believe that because ARID1A mutation and loss of BAF250a protein expression were identified in precancerous endometriotic lesions, such events represent a transformation of endometriosis into cancer.

“The finding that ARID1A is the most frequently mutated gene described thus far in endometrioid and clear cell ovarian cancers represents a major scientific breakthrough. This discovery also sheds light on how endometriosis predisposes to the development of these cancers. The novel insights provided by this work have the exciting potential to facilitate advances in early diagnosis, treatment and prevention of endometrioid and clear cell cancers, which account for over 20 per cent of ovarian cancer cases.”

Dr. Andrew Berchuck, Director, Division of Gynecologic Oncology, Duke University Medical Center

Inaugural Ovarian Clear-Cell Carcinoma Symposium

International Clear-Cell Carcinoma of the Ovary Symposium (June 24, 2010)

On June 24, 2010, a group of preeminent clinicians and cancer research scientists from around the world gathered for the Clear Cell Carcinoma of the Ovary Symposium (the Symposium), which was held at the University of British Columbia. To my knowledge, the Symposium is the first global scientific meeting dedicated to a specific subtype of ovarian cancer, namely OCCC.

At the invitation of Dr. David Huntsman, the founder of the Symposium, I had the distinct pleasure and honor of attending this prestigious and informative meeting as an observer. Dr. Huntsman was aware that my 26-year old cousin, Libby, died from OCCC, and he thought that the Libby’s H*O*P*E*™ community would benefit from the information presented at the Symposium.

The stated goal of the Symposium was to empower the international clinical and research community interested in OCCC, and allow that community to focus on the major barriers to improving OCCC outcomes. Moreover, the Symposium speakers and attendees were charged with presenting unpublished data and providing provocative OCCC questions for group discussion. The countries represented at that Symposium included Australia, Canada, Italy, Japan, the United Kingdom, and the U.S.

The 1-day event was presented through three major sessions.  The first session addressed issues that challenge the clinical dogma relating to OCCC, and covered topic areas such as epidemiology, surgery, pathology, systemic oncology, and radiation oncology. The second session addressed OCCC molecular pathology and genomics.  The third session addressed global OCCC translational research and covered topic areas including OCCC outcomes from conventional clinical trials, current OCCC clinical trials, and novel approaches to OCCC treatment and the testing of new agents.

The international Symposium presenters, included the following individuals:

  • David Bowtell, Group Leader, Cancer Genetics & Genomics Research Laboratory, Peter MacCallum Cancer Centre; Program Head, Cancer Genetics & Genomics, Peter MacCallum Cancer Centre, Melbourne (Australia).
  • Michael A. Quinn, MB ChB Glas. MGO Melb. MRCP FRCOG FRANZCOG CGO, Director of Oncology/Dysplasia, Royal Women’s Hospital, Melbourne, Australia; Professor, Department of Obstetrics and Gynecology, University of Melbourne; Chair, National Cancer Control Initiative; Chair, Education Committee, International Gynecological Cancer Society; Chair, Ovarian Cancer Research Group, Cancer Council; Member, National Expert Advisory Group on Ovarian Cancer. (Australia)
  • C. Blake Gilks, M.D., FRCPC,  Co-Founder, Ovarian Cancer Research Program of BC; Professor & Acting Head, Department of Pathology and Laboratory Medicine, University of British Columbia; Head of Anatomic Pathology, Vancouver General Hospital; Member, Vancouver Coastal Health Research Institute; Co-Founder & Co-Director, Genetic Pathology Evaluation Centre, Vancouver General Hospital. (Canada)
  • Paul Hoskins, MA, M.B. B. CHIR, MRCP., FRCPC, Clinical Professor, University of British Columbia. (Canada)
  • David Huntsman, M.D., FRCPC, FCCMG, Co-Founder & Acting Director, Ovarian Cancer Research Program of British Columbia; Director, Centre for Translational and Applied Genomics, BC Cancer Agency; Co-Director, Genetic Pathology Evaluation Centre, Vancouver General Hospital; Associate Director, Hereditary Cancer Program, BC Cancer Agency. (Canada)
  • Helen MacKay, M.D., Staff Physician, Division of Medical Oncology and Hematology, Princess Margaret Hospital; Assistant Professor, University of Toronto; Member: (i) ICON 7 Translational Committee (representing NCIC CTG),  (ii) Study Committee of the TFRI Ovarian Cancer Biomarker Program, (iii) Gynecologic Cancer Steering Committee Cervical Cancer Task Force: Intergroup/NCI/National Institutes of Health, (iv) Cervix Working Group (NCIC CTG), (v) Gynecologic Disease Site Group (Cancer Care Ontario), and (vi) the GOC CPD Committee. (Canada)
  • Amit M. Oza, Bsc, MBBS, M.D., FRCPC, FRCP, Senior Staff Physician & Professor of Medicine, Princess Margaret Hospital, University of Toronto; Clinical Studies Resource Centre Member, Ontario Cancer Institute. (Canada)
  • Ken Swenerton, M.D., Co-Leader, Cheryl Brown Ovarian Cancer Outcomes Unit, Ovarian Cancer Research Program of BC; Clinical Professor, Medical Oncology, University of British Columbia; Department of Pathology, Vancouver Coastal Health Research Institute;  Genetic Pathology Evaluation Centre,Vancouver General Hospital; Co-Chair, NCI Gynecologic Cancer Steering Committee Ovarian Cancer Task Force. (Canada).
  • Anna Tinker, M.D., FRCPC, Clinical Assistant Professor, University of British Columbia, Department of Medicine; Medical Oncologist, Oncology, British Columbia Cancer Agency (Canada).
  • Gillian Thomas, M.D., FRCPC, Professor, Department of Radiation Oncology & Obstetrics and Gynecology, University of Toronto; Radiation Oncologist, Odette Cancer Centre; Co-Chair, NCI Gynecologic Cancer Steering Committee; Member, ACRIN Gynecologic Committee; Member, Cervix Committee and Executive Committee, Gynecologic Cancer Intergroup (GCIG); Member, Cervix Committee – Gynecologic Oncology Group (GOG); Associate Editor, International Journal of Gynecologic Cancer. (Canada)
  • Aikou Okamoto, M.D., Department of Obstetrics & Gynecology, Jikei University School of Medicine, Tokyo (Japan).
  • Ian McNeish, MA, Ph.D., MRCP, MRC, Senior Clinical Fellow, Professor of Gynecological Oncology & Honorary Consultant in Medical Oncology, Deputy Director of the Barts Experimental Cancer Medicine Centre, Institute of Cancer, Barts and the London School of Medicine. (United Kingdom) (See Libby’s H*O*P*E*™, April 7, 2009)
  • Michael J. Birrer, M.D., Ph.D., Director of GYN/Medical Oncology at the Massachusetts General Hospital Cancer Center; Professor, Department of Medicine, Harvard Medical School; Co-Chair, NCI Gynecologic Cancer Steering Committee; formerly, Chief of the Molecular Mechanisms Section, Cell and Cancer Biology Branch, NCI Center for Cancer Research; formerly official representative from NCI Center for Cancer Research to the Gynecological Cancer Steering Committee. (United States)(See Libby’s H*O*P*E*™, December 8, 2009)

OvCaRe Ovarian Clear-Cell Carcinoma Research Initiative

As noted above, OCCC has been identified as distinct subtype of ovarian cancer.  OCCC-specific biomarkers or treatments have not been broadly adopted. Moreover, there are currently no clinically proven anti-cancer agents for OCCCs. For this reason, the OvCaRe team and other BC Cancer Agency scientists, have initiated a pioneering OCCC research initiative that consists of six separate, but interrelated projects.

The project will begin with the most fundamental research, the large scale sequencing of RNA and DNA derived from OCCC tumors. In the second, concurrent project, the vast quantities of genome sequence data will be transformed into usable knowledge that will be evaluated for clinical relevance by local and international experts. Identifying and validating novel biomarkers from the data obtained will be the focus of the third project, and the fourth project will permit scientists to specifically target those cellular biochemical signaling pathways that are considered to be useful tools for future drug development. The development and testing of the therapeutic targets and new drugs or new combinations of drugs in animal and human testing will complete this initiative.

The OvCaRe and the BC Cancer Agency scientists have a unique opportunity to completely reshape the scientific and medical understanding of OCCC and impact the way patients with this rare form of cancer are treated. The strength of their research initiative is based on linking the clinical research resources developed through OvCaRe with the genomic sequencing capacity of the BC Cancer Agency’s Genome Sciences Centre, and the drug development capacity of the Centre for Drug Research and Development and the NanoMedicine Research Group.

“This pioneering discovery by Dr. Huntsman and his dedicated ovarian cancer research team will allow the international research community to take the genomic ‘high ground’ in the battle against these formidable subtypes of epithelial ovarian cancer. The Ovarian Cancer Research Program of BC’s reported findings represent a critical first step towards development of one or more personalized targeted therapies to combat these lethal forms of ovarian cancer.”

Paul Cacciatore, Founder, Libby’s H*O*P*E*™

The impact of this research may not be experienced by women diagnosed with OCCC today, but this foundational research must begin immediately so as to impact outcomes in the years to come. Ably led by Dr. David Huntsman, this team of dedicated individuals represents a depth and breadth of medical and scientific expertise not often found in a single geographic location.

The hope is that through the identification of therapeutic targets for OCCC, this team will yield a powerful “superstar” drug such as Herceptin (used successfully for HER-2 positive breast cancer) or Gleevec (used successfully for chronic myelogenous leukemia (CML)). These drugs are examples of therapeutics that were created based on a direct match of an identified genetic target to the therapeutic solution.

This project is of utmost importance as it will define the unique aspects of OCCC and lead to the development of more effective therapies for women diagnosed with this rare subtype of ovarian cancer.

Special Acknowledgments

First and foremost, I want to thank Dr. Huntsman for his intelligence, creative vision and compassion, which he utilizes to great effect each day, in conducting scientific research designed to ultimately benefit all women with OCCC. I also want to thank Dr. Huntsman for the generous invitation to attend the OCCC Symposium in June. It was a privilege and honor to attend and listen to international OCCC experts discuss and debate the merits of various approaches to beating this subtype of epithelial ovarian cancer. In sum, Dr. Huntsman has been extremely generous to me with respect to his time and expertise during my recent trip to Vancouver and throughout my preparation of this article.

Prior to today’s ARID1A gene mutation discovery announcement, women with OCCC did not have a “voice” in the cancer research scientific community. Dr. Huntsman has not only given these women a voice, he has given them hope for the future.  As the late Christopher Reeve said: “Once you choose hope, anything is possible.”

I also want to thank the OvCaRe team members and BC Cancer Agency scientists that I met in Vancouver during my June trip, including Ken Swenerton, M.D., Sohrab Shah, Ph.D., Dianne Miller, M.D., Sam Aparicio, Ph.D., and Blake Gilks, M.D., for taking the time to answer all of my novice questions with a great understanding and passion.

Simply stated, this article would not have been possible without the substantial assistance provided to me by Sharon Kennedy, a Senior Director of Development with the BC Cancer Foundation. Sharon exemplifies the “heart and soul” behind the BC Cancer Foundation’s philanthropic activities.

Last, but certainly not least, I want to thank Mr. Douglas Gray, a highly successful entrepreneur and attorney, for introducing me to the BC scientific cancer research community. Doug is a tireless supporter of all women with OCCC, through his compassion, caring, and philanthropic generosity.

The Talmud says: “And whoever saves a life, it is considered as if he saved an entire world.” Doug Gray is in the business of saving women’s lives.

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References:

1/Jemal A, Siegel R, Xu J, Ward E. Cancer Statistics, 2010. CA Cancer J Clin 2010 July 7 (Epub ahead of print).

2/Cellular Classification of Ovarian Epithelial Cancer, Ovarian Epithelial Cancer Treatment (PDQ®)(Health Professional Version), National Cancer Institute, July 9, 2010.

3/Köbel M, Kalloger SE, Huntsman DG, et al. Differences in tumor type in lowstage versus high-stage ovarian carcinomas. Int J Gynecol Pathol 2010;29:203-11.

4/Itamochi H, Kigawa J, Terakawa N. Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma. Cancer Sci 2008;99:653-8.

5/Schwartz DR, Kardia SL, Shedden KA, Kuick R, Michailidis G, Taylor JM, et. al.  Gene Expression in Ovarian Cancer Reflects Both Morphology and Biological Behavior, Distinguishing Clear Cell from Other Poor-Prognosis Ovarian CarcinomasCan Res 2002 Aug; 62, 4722-4729.

6/Sugiyama T & Fujiwara K.  Clear Cell Tumors of the Ovary – Rare Subtype of Ovarian Cancer, Gynecologic Cancer, ASCO Educational Book, 2007 ASCO Annual Meeting, June 2, 2007 (Microsoft Powerpoint presentation).

7/Chan JK, Teoh D, Hu JM, Shin JY, Osann K, Kapp DS. Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancersGynecol Oncol. 2008 Jun;109(3):370-6. [Epub 2008 Apr 18].

8/Ma SK, Zhang HT, Wu LY, Liu LY. Prognostic analysis of 88 patients with ovarian clear cell carcinomaZhonghua Zhong Liu Za Zhi. 2007 Oct;29(10):784-8.

9/Takano M, Sasaki N, Kita T, Kudoh K, Fujii K, Yoshikawa T et. alSurvival analysis of ovarian clear cell carcinoma confined to the ovary with or without comprehensive surgical staging; Oncol Rep. 2008 May;19(5):1259-64.

10/Takano M, Kikuchi Y, Yaegashi N, Kuzuya K, Ueki M, Tsuda H et. al.  Clear cell carcinoma of the ovary: a retrospective multicentre experience of 254 patients with complete surgical stagingBr J Cancer. 2006 May 22;94(10):1369-74.

11/Sugiyama T, Kumagai S, & Hatayama S. Treatments of epithelial ovarian cancer by histologic subtype. Gan To Kagaku Ryoho. 2009 Feb;36(2):187-92.

12/Pectasides D, Pectasides E, Psyrri A, Economopoulos T. Treatment Issues in Clear Cell Carcinoma of the Ovary: A Different Entity?Oncologist. 2006 Nov-Dec;11(10):1089-94.

13/Zorn KK, Bonome T, Gangi L, Chandramouli GV, Awtrey CS, Gardner GJ et. al.  Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer; Clin Cancer Res. 2005 Sep 15;11(18):6422-30.

14/Schaner ME, Ross DT, Ciaravino G, Sorlie T, Troyanskaya O, Diehn M, et. alGene Expression Patterns in Ovarian CarcinomasMol. Bio. Cell 2003 Dec.; 14(11):4376-4386.

15/Tan DS, Kaye S.  Ovarian clear cell adenocarcinoma: a continuing enigma.  J Clin Pathol. 2007 Apr;60(4):355-60. Epub 2006 Oct 3.

16/ Dent J, Hall GD, Wilkinson N, Perren TJ, Richmond I, Markham AF, et. alCytogenetic alterations in ovarian clear cell carcinoma detected by comparative genomic hybridisation. Br J Cancer. 2003 May 19;88(10):1578-83.

17/Costa LJ, Drabkin HA. Renal cell carcinoma: new developments in molecular biology and potential for targeted therapiesOncologist 2007;12:1404-1415.

18/Köbel M, Xu H, Bourne PA, Spaulding BO, Shih IM; Mao TL et. alIGF2BP3 (IMP3) Expression Is a Marker of Unfavorable Prognosis in Ovarian Carcinoma of Clear Cell Subtype. Modern Pathology. 2009;22(3):469-475. [Epub 2009 Jan 9].

19/Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, et. alRAD001[everolimus] inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model.  Clin. Cancer. Res. 2007 Jul; 13, 4261-4270.

20/Mabuchi S, Altomare DA, Connolly DC, Klein-Szanto A, Litwin S, Hoelzle MK, et. al. RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer.  Cancer Res. 2007 Mar 15;67(6):2408-13.

21/Rauh-Hain JA, Penson RT. Potential benefit of Sunitinib in recurrent and refractory ovarian clear cell adenocarcinoma. Int J Gynecol Cancer. 2008 Sep-Oct;18(5):934-6. Epub 2007 Dec 13.

22/Yoshida S, Furukawa N, Haruta S, et. al. Theoretical model of treatment strategies for clear cell carcinoma of the ovary: focus on perspectives. Cancer Treat Rev. 2009 Nov;35(7):608-15. Epub 2009 Aug 8. Review.

23/Mabuchi S, Kawase C, Altomare DA, et. al.  mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary. Clin Cancer Res. 2009 Sep 1;15(17):5404-13. Epub 2009 Aug 18.

24/Miyazawa M, Yasuda M, Fujita M, et. al. Therapeutic strategy targeting the mTOR-HIF-1alpha-VEGF pathway in ovarian clear cell adenocarcinoma. Pathol Int. 2009 Jan;59(1):19-27.

25/Mabuchi S, Kawase C, Altomare DA, et. al.  Vascular endothelial growth factor is a promising therapeutic target for the treatment of clear cell carcinoma of the ovary. Mol Cancer Ther. 2010 Aug;9(8):2411-22. Epub 2010 Jul 27.

26/For open ovarian cancer clinical trials using sunitinib, CLICK HERE; For open solid tumor clinical trials using sunitinib, CLICK HERE.

27/For open ovarian cancer clinical trials using sorafenib CLICK HERE; For open solid tumor clinical trials using sorafenib, CLICK HERE.

28/For open ovarian cancer clinical trials using temsirolimus, CLICK HERE; For open solid tumor clinical trials using temsirolimus, CLICK HERE.

29/For open ovarian cancer clinical trials using everolimus, CLICK HERE; For open solid tumor clinical trials using everolimus, CLICK HERE.

30/For open ovarian cancer clinical trials using bevacizumab, CLICK HERE; For open solid tumor clinical trials using bevacizumab, CLICK HERE.

31/PI3K Pathway: A Potential Ovarian Cancer Therapeutic Target?, by Paul Cacciatore, Libby’s H*O*P*E*™, November 30, 2009.

32/For open ovarian cancer clinical trials using a phosphoinositide 3′-kinase (PI3K)-targeted therapy; CLICK HERE; For open solid tumor clinical trials using a phosphoinositide 3′-kinase (PI3K)-targeted therapy, CLICK HERE.

33/UCLA Researchers Significantly Inhibit Growth of Ovarian Cancer Cell Lines With FDA-Approved Leukemia Drug Dasatinib (Sprycel®),by Paul Cacciatore, Libby’s H*O*P*E*™, November 30, 2009.

34/Swenerton KD, Santos JL, Gilks CB, et. al. Histotype predicts the curative potential of radiotherapy: the example of ovarian cancers. Ann Oncol. 2010 Aug 6. [Epub ahead of print]

35/Nagai Y, Inamine M, Hirakawa M, et. al. Postoperative whole abdominal radiotherapy in clear cell adenocarcinoma of the ovary. Gynecol Oncol. 2007 Dec;107(3):469-73. Epub 2007 Aug 31.

36/Skirnisdottir I, Nordqvist S, Sorbe B. Is adjuvant radiotherapy in early stages (FIGO I-II) of epithelial ovarian cancer a treatment of the past? Oncol Rep. 2005 Aug;14(2):521-9. PubMed PMID: 16012740.

37/Takai N, Utsunomiya H, Kawano Y, et. al. Complete response to radiation therapy in a patient with chemotherapy-resistant ovarian clear cell adenocarcinoma. Arch Gynecol Obstet. 2002 Dec;267(2):98-100.

38/Suzuki M, Saga Y, Tsukagoshi S, et. al. Recurrent ovarian clear cell carcinoma: complete remission after radiation in combination with hyperthermia; a case study and in vitro study. Cancer Biother Radiopharm. 2000 Dec;15(6):625-8.

39/BRCA1 and BRCA2: Cancer Risk and Genetic Testing, National Cancer Institute Fact Sheet, Cancer Topic, National Cancer Institute, May 29, 2009.

40/Goodheart MJ, Rose SL, Hattermann-Zogg M, et. al. BRCA2 alteration is important in clear cell carcinoma of the ovary. Clin Genet. 2009 Aug;76(2):161-7. Epub 2009 Jul 28.

41/For open ovarian cancer clinical trials using PARP inhibitors, CLICK HERE; For open solid tumor clinical trials using PARP inhibitors, CLICK HERE.

42/Audeh MW, Carmichael J, Penson RT, et. al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010 Jul 24;376(9737):245-51. Epub 2010 Jul 6.

43/PARP Inhibitor Olaparib Benefits Women With Inherited Ovarian Cancer Based Upon Platinum Drug Sensitivity, by Paul Cacciatore, Libby’s H*O*P*E*™, April 23, 2010.

44/Konstantinopoulos PA, Spentzos D, Karlan BY, et. al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol. 2010 Aug 1;28(22):3555-61. Epub 2010 Jun 14.

45/Bast RC Jr, Mills GB. Personalizing therapy for ovarian cancer: BRCAness and beyond. J Clin Oncol. 2010 Aug 1;28(22):3545-8. Epub 2010 Jun 14.

46/Köbel M, Xu H, Bourne PA, et. al. IGF2BP3 (IMP3) expression is a marker of unfavorable prognosis in ovarian carcinoma of clear cell subtype. Mod Pathol. 2009 Mar;22(3):469-75. Epub 2009 Jan 9.

47/Köbel M, Kalloger SE, Carrick J, Huntsman D, et. al. A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary. Am J Surg Pathol. 2009 Jan;33(1):14-21.

48/Kim A, Serada S, Enomoto T, Naka T. Targeting annexin A4 to counteract chemoresistance in clear cell carcinoma of the ovary. Expert Opin Ther Targets. 2010 Sep;14(9):963-71.

49/Maeda D, Ota S, Takazawa Y, et. al. Glypican-3 expression in clear cell adenocarcinoma of the ovary. Mod Pathol. 2009 Jun;22(6):824-32. Epub 2009 Mar 27.

50/Matsuura M, Suzuki T, Saito T. Osteopontin is a new target molecule for ovarian clear cell carcinoma therapy. Cancer Sci. 2010 Aug;101(8):1828-33. Epub 2010 May 12.

51/Ho CM, Lai HC, Huang SH, et. al. Promoter methylation of sFRP5 in patients with ovarian clear cell adenocarcinoma. Eur J Clin Invest. 2010 Apr;40(4):310-8.

52/Yamaguchi K, Mandai M, Oura T, et. al. Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes.  Oncogene. 2010 Mar 25;29(12):1741-52. Epub 2010 Jan 11.

53/Yoshioka N, Suzuki N, Uekawa A, et. al. POU6F1 is the transcription factor that might be involved in cell proliferation of clear cell adenocarcinoma of the ovary. Hum Cell. 2009 Nov;22(4):94-100.

54/Nagaraja AK, Creighton CJ, Yu Z, et. al. A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer. Mol Endocrinol. 2010 Feb;24(2):447-63. Epub 2010 Jan 15.

55/Reisman D, Glaros S, Thompson EA. The SWI/SNF complex and cancer. Oncogene 2009;28:1653-68.

56/Huang J, Zhao YL, Li Y, et. al.  Genomic and functional evidence for an ARID1A tumor suppressor role.  Genes Chromosomes Cancer 2007;46:745-50.

57/Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results, by Paul Cacciatore, Libby’s H*O*P*E*™, August 3, 2010.

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Sources:

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Genetics 101

The information hyperlinked above was obtained from GeneticHealth & the BC Cancer Agency’s Michael Smith Genome Sciences Centre.

About David Huntsman, M.D., FRCPC, FCCMG

David Huntsman, M.D., FRCPC, FCCMG, is a world-renowned genetic pathologist, and the Co-Founder and Director of the Ovarian Cancer Research Program of British Columbia(OvCaRe). He also heads the Centre for Translational and Applied Genomics, located in the British Columbia (BC) Cancer Agency’s Vancouver Centre.  Dr. Huntsman is also the Co-Director of the Genetic Pathology Evaluation Centre, Vancouver General Hospital, and the Associate Director of the Hereditary Cancer Program, BC Cancer Agency. He is involved in a broad range of translational cancer research and, as the OvCaRe team leader, has studied the genetic and molecular structure of ovarian cancer for many years.

His recent retrospective assessment of 21 candidate tissue-based biomarkers implicated that ovarian cancer subtypes are different diseases, contributing to the view that contemplation of disease subtype is crucial to the study of ovarian cancer. To ultimately beat ovarian cancer, Huntsman and his dedicated OvCaRe team believe that ovarian cancer must be genetically tackled “one subtype at a time.”  In June 2009, the NEJM published one of Dr. Huntsman’s most recent groundbreaking discoveries:  the identification of  mutations in the FOXL2 gene as the molecular basis of adult granulosa cell ovarian cancer tumors.  As of today, Dr. Huntsman and his OvCaRe team can add to their groundbreaking discoveries, the identification of frequent ARID1A gene mutations in endometriosis-associated ovarian cancers (i.e., the clear-cell and endometrioid ovarian cancer subtypes).

About Marco Marra, Ph.D.

Marco Marra, Ph.D. is the Director of the BC Cancer Agency’s Michael Smith Genome Sciences Centre (GSC), one of eight BC Cancer Agency specialty laboratories. Dr. Marra is internationally recognized as a preeminent leader in the field of genetics.  His leadership has helped transform the GSC into one of the world’s most advanced and productive centers for development and application of genomics, bioinformatics and related technologies.

The work of the GSC , along with collaborations involving the BC Cancer Agency and other local, national and international researchers and organizations, have led to several major scientific breakthroughs over the past decade.  These breakthroughs include the rapid genome sequencing of the SARS Coronavirus, and the sequencing and genome analysis of the avian flu (H7N3).

About the Ovarian Cancer Research Program of British Columbia (OvCaRe)

The Ovarian Cancer Research Program of BC was formed in late 2000 when a group of Vancouver-based physicians and scientists joined with the common vision of enhancing ovarian cancer research in British Columbia and the explicit goal of improving outcomes for ovarian cancer patients. OvCaRe was developed as a collaboration between the BC Cancer Agency, the Vancouver Coastal Health Research Institute, and the University of British Columbia.  The OvCaRe program includes clinicians and research scientists from the Vancouver General Hospital (VGH) and the British Columbia (BC) Cancer Agency, who specialize in gynecology, pathology, and medical oncology.

OvCaRe is currently focused on three major goals.

1. To improve ovarian cancer survival through early detection of disease. OvCaRe researchers are working to identify proteins that are produced in the early stages of ovarian cancer. Detection of these proteins can then be developed into diagnostic tests to allow for earlier diagnosis of ovarian cancer.

2. To develop new therapies for ovarian cancer treatment. This is being achieved through research aimed at identifying the cause of ovarian cancer at the cellular level and then directly and specifically targeting that defect. OvCaRe is using a similar strategy to develop treatments to prevent ovarian cancer recurrence.

3. To develop individualized ovarian cancer treatments. Ovarian cancer can be subdivided into several groups based on their pathological appearance, however these groups are currently all treated in the same manner, though their responses are quite variable. OvCaRe is working to determine what is responsible for division between ovarian cancers subtypes and developing subtype specific treatments.

OvCaRe is funded through generous donations to the VGH & UBC Hospital Foundation and BC Cancer Foundation. The OvCaRe team is considered a leader in ovarian cancer research, breaking new ground to improve the identification, understanding, and treatment of this disease.

About the British Columbia (BC) Cancer Agency

The BC Cancer Agency provides a comprehensive province-wide, population-based cancer control program for the people of British Columbia, Canada, including prevention, screening and early detection programs, translational research and education, and care and treatment.

The BC Cancer Agency’s mandate covers the spectrum of cancer care, from prevention and screening, to diagnosis, treatment, and rehabilitation. The BC Cancer Agency’s mandate is driven by a three-fold mission: (1) reduce the incidence of cancer, (2)  reduce the mortality rate of people with cancer, and (3) improve the quality of life of people living with cancer. This mission includes providing screening, diagnosis and care, setting treatment standards, and conducting research into causes of, and cures for, cancer.

The BC Cancer Agency operates five regional cancer centres, providing assessment and diagnostic services, chemotherapy, radiation therapy, and supportive care.  Each of the BC Cancer Agency’s centres delivers cancer treatment based on provincial standards and guidelines established by the Agency.

Research is an essential part of the BC Cancer Agency’s mission to not only find the causes of cancer, but to find better treatments for prolonged life and better quality of life. With direct links between the BC Cancer Agency’s physicians and researchers at its five centres (including the Deeley Research Centre (located in Victoria) and the BC Cancer Agency’s Research Centre (located in Vancouver)), the BC Cancer Agency can quickly translate new discoveries into clinical applications. The BC Cancer Agency’s Research Centre includes eight specialty laboratories including the Michael Smith Genome Sciences Centre, and the Terry Fox Laboratory.

The BC Cancer Agency includes the following among its many accomplishments:

  • Canada’s largest fully integrated cancer and research treatment organization;
  • the best cancer incidence and survival rates in Canada as a result of the unique and longstanding population-based cancer control system;
  • leadership in cancer control with world-renowned programs in lymphoid, lung, breast, ovarian and oral cancer research and care; and
  • a unique set of research platforms that form the basis of research and care, including one of the world’s top four genome sciences centres.

About the Vancouver General Hospital (VGH)

The Vancouver General Hospital (VGH) is a 955 bed hospital that offers specialized services to residents in Vancouver and across the province.  VGH is also a teaching hospital, affiliated with the University of British Columbia and home to one of the largest research institutes in Canada.

About the British Columbia (BC) Cancer Foundation

The BC Cancer Foundation is an independent charitable organization that raises funds to support breakthrough cancer research and care at the BC Cancer Agency.

Over 70 years ago, the BC Cancer Foundation, led by a group of prominent BC citizens, created what is today the BC Cancer Agency. The Foundation has offices in all five of the BC Cancer’s Agency’s treatment centres – Abbotsford, Fraser Valley, Southern Interior, Vancouver Island and Vancouver.

About the Vancouver General Hospital (VGH) & University of British Columbia (UBC) Hospital Foundation

The VGH & UBC Hospital Foundation is a registered charity that raises funding for the latest, most sophisticated medical equipment, world-class research and improvements to patient care for VGH, UBC Hospital, GF Strong Rehab Centre and Vancouver Coastal Health Research Institute. For more than 25 years, the Foundation and its donors have been a bridge between the essential health care governments provide and the most advanced health care possible.


Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results

The largest study to correlate genetics with response to anticancer drugs released its first results on July 15. The researchers behind the study, based at Massachusetts General Hospital Cancer Center and the Wellcome Trust Sanger Institute, describe in this initial dataset the responses of 350 cancer samples (including ovarian cancer) to 18 anticancer therapeutics.

U.K.–U.S. Collaboration Builds a Database For “Personalized” Cancer Treatment

The Genomics of Drug Sensitivity in Cancer project released its first results on July 15th. Researchers released a first dataset from a study that will expose 1,000 cancer cell lines (including ovarian) to 400 anticancer treatments.

The largest study to correlate genetics with response to anticancer drugs released its first results on July 15. The researchers behind the study, based at Massachusetts General Hospital Cancer Center and the Wellcome Trust Sanger Institute, describe in this initial dataset the responses of 350 cancer samples (including ovarian cancer) to 18 anticancer therapeutics.

These first results, made freely available on the Genomics of Drug Sensitivity in Cancer website, will help cancer researchers around the world to obtain a better understanding of cancer genetics and could help to improve treatment regimens.

Dr. Andy Futreal, co-leader of the Cancer Genome Project at the Wellcome Trust Sanger Institute, said:

Today is our first glimpse of this complex interface, where genomes meet cancer medicine. We will, over the course of this work, add to this picture, identifying genetic changes that can inform clinical decisions, with the hope of improving treatment.  By producing a carefully curated set of data to serve the cancer research community, we hope to produce a database for improving patient response during cancer treatment.

How a patient responds to anticancer treatment is determined in large part by the combination of gene mutations in her or his cancer cells. The better this relationship is understood, the better treatment can be targeted to the particular tumor.

The aim of the five-year, international drug-sensitivity study is to find the best combinations of treatments for a wide range of cancer types: roughly 1000 cancer cell lines will be exposed to 400 anticancer treatments, alone or in combination, to determine the most effective drug or combination of drugs in the lab.

The therapies include known anticancer drugs as well as others in preclinical development.

To make the study as comprehensive as possible, the researchers have selected 1000 genetically characterized cell lines that include common cancers such as breast, colorectal and lung. Each cell line has been genetically fingerprinted and this data will also be publicly available on the website. Importantly, the researchers will take promising leads from the cancer samples in the lab to be verified in clinical specimens: the findings will be used to design clinical studies in which treatment will be selected based on a patient’s cancer mutation spectrum.

The new data released today draws on large-scale analyses of cancer genomes to identify genomic markers of sensitivity to anticancer drugs.

The first data release confirms several genes that predict therapeutic response in different cancer types. These include sensitivity of melanoma, a deadly form of skin cancer, with activating mutations in the gene BRAF to molecular therapeutics targeting this protein, a therapeutic strategy that is currently being exploited in the clinical setting. These first results provide a striking example of the power of this approach to identify genetic factors that determine drug response.

Dr. Ultan McDermott, Faculty Investigator at the Wellcome Trust Sanger Institute, said:

It is very encouraging that we are able to clearly identify drug–gene interactions that are known to have clinical impact at an early stage in the study. It suggests that we will discover many novel interactions even before we have the full complement of cancer cell lines and drugs screened. We have already studied more gene mutation-drug interactions than any previous work but, more importantly, we are putting in place a mechanism to ensure rapid dissemination of our results to enable worldwide collaborative research. By ensuring that all the drug sensitivity data and correlative analysis is freely available in an easy-to-use website, we hope to enable and support the important work of the wider community of cancer researchers.

Further results from this study should, over its five-year term, identify interactions between mutations and drug sensitivities most likely to translate into benefit for patients: at the moment we do not have sufficient understanding of the complexity of cancer drug response to optimize treatment based on a person’s genome.

Professor Daniel Haber, Director of the Cancer Center at Massachusetts General Hospital and Harvard Medical School, said:

We need better information linking tumor genotypes to drug sensitivities across the broad spectrum of cancer heterogeneity, and then we need to be in position to apply that research foundation to improve patient care.  The effectiveness of novel targeted cancer agents could be substantially improved by directing treatment towards those patients that genetic study suggests are most likely to benefit, thus “personalizing” cancer treatment.

The comprehensive results include correlating drug sensitivity with measurements of mutations in key cancer genes, structural changes in the cancer cells (copy number information) and differences in gene activity, making this the largest project of its type and a unique resource for cancer researchers around the world.

Professor Michael Stratton, co-leader of the Cancer Genome Project and Director of the Wellcome Trust Sanger Institute, said:

“This is one of the Sanger Institute’s first large-scale explorations into the therapeutics of human disease.  I am delighted to see the early results from our partnership with the team at Massachusetts General Hospital. Collaboration is essential in cancer research: this important project is part of wider efforts to bring international expertise to bear on cancer.”

Ovarian Cancer Sample Gene Mutation Prevalence

As part of the Cancer Genome Project, researchers identified gene mutations found in 20 ovarian cancer cell lines and the associated prevalence of such mutations within the sample population tested. For purposes of this project, a mutation — referred to by researchers as a “genetic event” in the project analyses description — is defined as (i) a coding sequence variant in a cancer gene, or (ii) a gene copy number equal to zero (i.e., a gene deletion) or greater than or equal to 8 (i.e., gene amplification).  The ovarian cancer sample analysis thus far, indicates the presence of mutations in twelve genes. The genes that are mutated and the accompanying mutation prevalence percentage are as follows:  APC (5%), CDKN2A (24%), CTNNB1 (5%), ERBB2/HER-2 (5%), KRAS (10% ), MAP2K4 (5%), MSH2 (5%), NRAS (10%), PIK3CA (10%), PTEN (14%), STK11 (5%), and TP53 (62%). Accordingly, as of date, the top five ovarian cancer gene mutations occurred in TP53, CDKN2A, CDKN2a(p14)(see below), PTEN, and KRAS.

Click here to view the Ovary Tissue Overview.  Click here to download a Microsoft Excel spreadsheet listing the mutations in 52 cancer genes across tissue types. Based upon the Ovary Tissue Overview chart, the Microsoft Excel Chart has not been updated to include the following additional ovarian cancer sample mutations and associated prevalence percentages: CDKN2a(p14)(24%), FAM123B (5%), FBXW7 (5%), MLH1 (10%), MSH6 (5%).

18 AntiCancer Therapies Tested; Next 9 Therapies To Be Tested Identified

As presented in the initial study results, 18 drugs/preclinical compounds were tested against various cancer cell lines, including ovarian. The list of drugs/preclinical compounds that were tested for sensitivity are as follows:  imatinib (brand name: Gleevec),  AZ628 (C-Raf inhibitor)MG132 (proteasome inhibitor), TAE684 (ALK inhibitor), MK-0457 (Aurora kinase inhibitor)sorafenib (C-Raf kinase & angiogenesis inhibitor) (brand name: Nexavar), Go 6976 (protein kinase C (PKC) inhibitor), paclitaxel (brand name: Taxol), rapamycin (mTOR inhibitor)(brand name: Rapamune), erlotinib (EGFR inhibitor)(brand name: Tarceva), HKI-272 (a/k/a neratinib) (HER-2 inhibitor), Geldanamycin (Heat Shock Protein 90 inhibitor), cyclopamine (Hedgehog pathway inhibitor), AZD-0530 (Src and Abl inhibitor), sunitinib (angiogenesis & c-kit inhibitor)(brand name:  Sutent), PHA665752 (c-Met inhibitor), PF-2341066 (c-Met inhibitor), and PD173074 (FGFR1 & angiogenesis inhibitor).

Click here to view the project drug/preclinical compound sensitivity data chart.

The additional drugs/compounds that will be screened by researchers in the near future are metformin (insulin)(brand name:  Glucophage), AICAR (AMP inhibitor), docetaxel (platinum drug)(brand name: Taxotere), cisplatin (platinum drug)(brand name: Platinol), gefitinib (EGFR inhibitor)(brand name:  Iressa), BIBW 2992 (EGFR/HER-2 inhibitor)(brand name:  Tovok), PLX4720 (B-Raf [V600E] inhibitor), axitinib (angiogenesis inhibitor)(a/k/a AG-013736), and CI-1040 (PD184352)(MEK inhibitor).

Ovarian cancer cells dividing. (Source: ecancermedia)

Ovarian Cancer Therapy Sensitivity

Targeted molecular therapies that disrupt specific intracellular signaling pathways are increasingly used for the treatment of cancer. The rational for this approach is based on our ever increasing understanding of the genes that are causally implicated in cancer and the clinical observation that the genetic features of a cancer can be predictive of a patient’s response to targeted therapies. As noted above, the goal of the Cancer Genome Project is to discover new cancer biomarkers that define subsets of drug-sensitive patients. Towards this aim, the researchers are (i) screening a wide range of anti-cancer therapeutics against a large number of genetically characterized human cancer cell lines (including ovarian), and (ii) correlating drug sensitivity with extensive genetic data. This information can be used to determine the optimal clinical application of cancer drugs as well as the design of clinical trials involving investigational compounds being developed for the clinic.

When the researchers tested the 18 anticancer therapies against the 20 ovarian cancer cell lines, they determined that the samples were sensitive to many of the drugs/compounds. The initial results of this testing indicate that there are at least six ovarian cancer gene mutations that were sensitive to eight of the anticancer therapies, with such results rising to the level of statistical significance.  We should note that although most (but not all) of the ovarian cancer gene mutations were sensitive to several anticancer therapies, we listed below only those which were sensitive enough to be assigned a green (i.e., sensitive) heatmap code by the researchers.

Click here to download a Microsoft Excel spreadsheet showing the effect of each of the 51 genes on the 18 drugs tested. Statistically significant effects are highlighted in bold and the corresponding p values for each gene/drug interaction are displayed in an adjacent table.  A heatmap overlay for the effect of the gene on drug sensitivity was created, with the color red indicating drug resistance and the color green indicating drug sensitivity.

The mutated genes present within the 20 ovarian cancer cell line sample that were sensitive to anticancer therapies are listed below.  Again, only statistically significant sensitivities are provided.

  • CDKN2A gene mutation was sensitive to TAE684, MK-0457, paclitaxel, and PHA665752.
  • CTNNB1 gene mutation was sensitive to MK-0457.
  • ERBB2/HER-2 gene mutation was sensitive to HKI-272.
  • KRAS gene mutation was sensitive to AZ628.
  • MSH2 gene mutation was sensitive to AZD0530.
  • NRAS gene mutation was sensitive to AZ628.

We will provide you with future updates regarding additional ovarian cancer gene mutation findings, and new anticancer therapies tested, pursuant to the ongoing Cancer Genome Project.

Sources:

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About The Genomics of Drug Sensitivity In Cancer Project

The Genomics of Drug Sensitivity In Cancer Project was launched in December 2008 with funding from a five-year Wellcome Trust strategic award. The U.K.–U.S. collaboration harnesses the experience in experimental molecular therapeutics at Massachusetts General Hospital Cancer Center and the expertise in large scale genomics, sequencing and informatics at the Wellcome Trust Sanger Institute. The scientists will use their skills in high-throughput research to test the sensitivity of 1000 cancer cell samples to hundreds of known and novel molecular anticancer treatments and correlate these responses to the genes known to be driving the cancers. The study makes use of a very large collection of genetically defined cancer cell lines to identify genetic events that predict response to cancer drugs. The results will give a catalogue of the most promising treatments or combinations of treatments for each of the cancer types based on the specific genetic alterations in these cancers. This information will then be used to empower more informative clinical trials thus aiding the use of targeted agents in the clinic and ultimately improvements in patient care.

Project leadership includes Professor Daniel Haber and Dr. Cyril Benes at Massachusetts General Hospital Cancer Center and Professor Mike Stratton and Drs. Andy Futreal and Ultan McDermott at the Wellcome Trust Sanger Institute.

About Massachusetts General Hospital

Massachusetts General Hospital (MGH), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

About The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992 as the focus for U.K. gene sequencing efforts. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms such as mouse and zebrafish, and more than 90 pathogen genomes. In October 2005, new funding was awarded by the Wellcome Trust to enable the Institute to build on its world-class scientific achievements and exploit the wealth of genome data now available to answer important questions about health and disease. These programs are built around a Faculty of more than 30 senior researchers. The Wellcome Trust Sanger Institute is based in Hinxton, Cambridge, U.K.

About The Wellcome Trust

The Wellcome Trust is a global charity dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education, and the application of research to improve health. It is independent of both political and commercial interests.

Required Cancer Genome Project Disclaimer:

The data above was obtained from the Wellcome Trust Sanger Institute Cancer Genome Project web site, http://www.sanger.ac.uk/genetics/CGP. The data is made available before scientific publication with the understanding that the Wellcom Trust Sanger Institute intends to publish the initial large-scale analysis of the dataset. This publication will include a summary detailing the curated data and its key features.  Any redistribution of the original data should carry this notice: Please ensure that you use the latest available version of the data as it is being continually updated.  If you have any questions regarding the sequence or mutation data or their use in publications, please contact cosmic@sanger.ac.uk so as to obtain any updated or additional data.  The Wellcome Trust Sanger Institute provides this data in good faith, but makes no warranty, express or implied, nor assumes any legal liability or responsibility for any purpose for which the data are used.

2008 ASCO Annual Meeting Abtracts Highlight Several Drugs That Show Promise Against Drug Resistant Ovarian Cancer

There were several drugs highlighted in clinical trial abstracts presented at the 2008 American Society of Clinical Oncology (ASCO) Annual Meeting that demonstrated varying degrees of effectiveness against drug resistant (i.e., recurrence within 6 to 12 months after completion of first line treatment) and/or drug refractory (i.e., recurrence within 6 months after completion of first line treatment) ovarian cancer. By “effectiveness,” we mean generally that the drug or drug combination produced a complete response, partial response, and/or disease stabilization (and in a few cases, a significant drop in the CA-125 tumor marker) in ovarian cancer tumors. To better understand how to intrepret a medical study abstract, click here. The 2008 ASCO Annual Meeting was held in Chicago, Illinois on May 30 – June 3, 2008.

A list of the drugs/drug combinations is provided below. Any drug covered in depth through an earlier H*O*P*E*™ weblog post is noted. We also included 2008 ASCO Annual Meeting abstracts that provide “solid tumor” clinical trial results with respect to studies that enrolled patients with ovarian cancer tumors. When evaluating the potential enrollment in a clinical trial at various treatment points, an ovarian cancer survivor should evaluate trials dedicated to ovarian cancer patients in entirety, as well as general “solid tumor” trials that allow enrollment of ovarian cancer patients. Generally, a patient should give first priority to dedicated ovarian cancer trials and use the solid tumor trials as a “backup” to the ovarian cancer trials. All questions regarding the priority assigned to, or proper sequencing of, clinical trials should be discussed in detail with your doctor(s). Treatment priority and sequencing issues arise, for example, when enrollment in one clinical trial potentially disqualifies the patient for a subsequent second clinical trial based upon the protocol (i.e., inclusion/exclusion criteria) of the second trial. This example assumes that both clinical trials are currently enrolling patients when trial enrollment is being evaluated by you and your doctor.

Abbreviation Legend:

ABSTR=2008 American Society of Clinical Oncology Annual Meeting Abtract; ASCO=American Society of Clinical Oncology; CA-125=cancer antigen 125; CEA=Carcinoembryonic Antigen (Tumor Marker); CR=Complete Response; CT=Computed Tomography

CTC=Common Toxicity Criteria; DCE-MRI=Dynamic Contrast Enhanced Magnetic Resonance Imaging; DLT=Dose Limiting Toxicity; DP=Disease Progression; EOC=Epithelial Ovarian Cancer; G=Grade of Adverse Drug Effect;

GCIG=Gynecologic Cancer Intergroup; GOGGynecologic Oncology Group; MTD=Maximum Tolerable Dose; mg/m²=milligrams per metre squared; NCI=National Cancer Institute; OR=Objective Response; OS=Overall Survival;

PET=Positron Emission Tomography Scanning; PK=Pharmacokinetics; PO=Oral Administration; PR=Partial Response; PFS=Progression Free Survival; RECIST=Response Evaluation Criteria in Solid Tumors; RR=Response Rate; SD=Stable Disease

SNS-595 (Voreloxin®):

NOV-002 & Carboplatin (Paraplatin®):

  • NOV-002 plus carboplatin in platinum-resistant ovarian cancer (2008 ASCO Abstract #5593). Patients were heavily pretreated with 11/15 patients having received 3 prior [treatment] lines. Toxicity was mild-moderate with no G4 toxicity. There was no febrile neutropenia. The most common toxicities were nausea and fatigue, as well as abdominal pain and bowel obstruction thought to be related to underlying disease. To date, there is 1 patient with PR, 7 patients with SD and 5 patients with PD, with 1 patient off-trial for patient discretion. PFS is 14 weeks. Patients tolerated this regimen extremely well, with most toxicity attributable to carboplatin alone. Conclusion: The PFS was longer than expected, with a significant proportion of these platinum resistant patients achieving clinical benefit with prolonged stable disease. [61% disease control (CR+PR+SD) rate]

Picoplatin & Pegylated Liposomal Doxorubicin (Doxil®):

  • Final results of a phase I study of picoplatin and pegylated liposomal doxorubicin [e.g. Doxil™] in advanced solid tumor malignancies (2008 ASCO Annual Mtg. Abstr. #2568 ): Picoplatin is a novel, sterically hindered platinum(II) complex designed to circumvent mechanisms of platinum resistance. Given the single agent activity seen in multiple tumor types, we conducted a phase I study of picoplatin in combination with pegylated liposomal doxorubicin (PLD) in patients with advanced solid tumors. The Phase 1 trial enrolled 16 patients with advanced solid tumors who had received up to three prior regimens for metastatic disease. Patients were administered picoplatin followed by liposomal doxorubicin on day one of a 28-day cycle. Four dose levels of picoplatin and pegylated liposomal doxorubicin were tested: 100/20, 100/30, 100/40 and 120/40 (all mg/m2). A total of 62 courses of treatment were delivered to 16 patients with a median number of four cycles per patient. A total of 12 patients were evaluable for response. One patient experienced a CR (primary peritoneal cancer) and four experienced a PR (including three of five patients with ovarian cancer). Hematologic and non-hematologic toxicity were mild. Conclusion: This study suggests that picoplatin and liposomal doxorubicin is an active combination with promising results and can be given at standard dose levels with a minimal increase in toxicity. [41% disease control (CR+PR+SD) rate among evaluable patients]

Weekly Topotecan (Hycamtin™) Monotherapy:

  • Phase II study of weekly topotecan in recurrent ovarian cancer: duration of response based on a prolonged follow-up (ASCO Annual Mtg. Abstr. #16549). Nineteen patients (median age 52 yrs, range 45-72) with EOC who progressed after 3 (11/19 patients = 57.9%), 4 (7/19 patients= 36.8%) or 5 (1/19 patients= 5.3%) previous lines of chemotherapy were treated with Topotecan at the dose of 2.0 mg/m2 via a 30-minute intravenous infusion once every week until disease progression, unacceptable toxicity or when a stability of disease was reached. Results: All patients were evaluable for toxicity and clinical response. 16/19 patients enrolled (84.2%) had stage III-IV disease. Median number of chemotherapy cycles was 7 (range 3 – 12). A total of 107 cycles were administered. Dose reduction was necessary for 13% of the cycles. Main toxicities included anemia (G1-G2=57.9%), leucopenia (G1-G2=15.8%), thrombocytopenia (G1-G2=10.5%) and asthenia (20%). No one showed a CR, while 5/19 patients experienced a PR (26.4%), 6/19 patients experienced SD (31.5%), and 8/19 patients (42.1%) experienced DP. The median PFS was 12 weeks in patients with PR; SD was maintained for a median time of 14 weeks. Conclusion: The rate of patients with ongoing stable disease (31.5%) suggests that the clinical benefit of weekly topotecan may be expected also in patients with no other viable therapeutic options. [57% disease control (CR+PR+SD) rate among evaluable patients]

Azacitidine & Carboplatin:

Combretastatin A4 Phosphate (Zybrestat™) and Bevacizumab (Avastin™):

BSI-201:

Belinostat (PXD101):

SU11248/Sunitinib (Sutent®):

AZD2281 (KU-0059436):

  • AZD2281, a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study (2008 ASCO Annual Mtg. Abstr. #5510) Thirty-two patients with BRCA-deficient ovarian cancer (i.e., patients with BRCA gene mutations) the majority of whom were platinum resistant/refractory are so far evaluable for response. All evaluable patients had either received treatment for at least 8 weeks (2 cycles) or progressed prior to completion of 2 cycles. Fourteen patients have achieved PR, 13 patients meeting GCIG- CA125 criteria and 10 patients meeting RECIST criteria. Of the responders, 1 patient has been on drug > 56 weeks whilst 7 patients have maintained responses for > 24 weeks. SD was seen in an additional 8 patients, 7 of whom continue on drug and 3 patients had SD > 16 weeks. Responses were seen at all dose levels from 100mg bd and above. Conclusion: AZD2281 is well tolerated and has demonstrated compelling activity in patients with BRCA deficient ovarian cancer. Responses were seen in all patient groups including platinum resistant disease. Updated efficacy data, together with a correlation of potential predictive factors including platinum free interval will be presented on a total planned cohort of 46 patients with BRCA-deficient ovarian cancer. A randomised study in BRCA-deficient ovarian cancer has been planned. [68% disease control (CR+PR+SD) rate among evaluable patients]

Gemcitibine (Gemzar™) & Epirubicin (Ellence™):

Belinostat/PXD101, Carboplatin (Paraplatin®) & Paclitaxel (Taxol™):

Pegylated Liposomal Doxorubicin (Doxil®) & Gemcitabine (Gemzar®):

Pemetrexed/LY231514 (Altima®):

Sorafenib (Nexavar™):

  • Phase II trial of sorafenib in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study (2008 ASCO Annual Mtg. Abstr. #5537). Sorafenib is a tyrosine kinase inhibitor targeting raf and other receptor kinases (VEGF-R, PDGF-R, Flt3, c-KIT). Sorafenib may have anti-angiogenic activity through inhibition of VEGF-R. This phase II study was conducted to assess the activity and tolerability of sorafenib in patients with recurrent EOC. Methods: This was an open label multi-institutional phase II study …. Eligible patients had persistent or recurrent EOC/PPC after 1-2 prior cytotoxic regimens, measurable or detectable (e.g. by CA125) disease, and GOG performance status < 2. Patients were required to have progressed within 12 months of completing platinum based therapy. Treatment consisted of sorafenib 400 mg orally bid until disease progression or prohibitive toxicity. Primary endpoints were PFS at 6 months and toxicity by NCI criteria. Secondary endpoints were tumor response and duration of PFS/OS. Results: 73 patients were enrolled from 10/04 to 5/07 and as of 12/2007, 68 patients are evaluable (2 ineligible and 3 too early) for toxicity. Median age was 60 (range 33-80) years and prior treatment consisted of 1 regimen in 40 patients and 2 regimens in 28 patients. Significant G3 and G4 toxicities included: rash (12 patients), metabolic (10 patients), gastrointestinal (3 patients), cardiovascular (2 patients), and pulmonary (2 patients). No treatment related deaths were recorded. Only patients with measurable disease were used to assess efficacy. Among the 59 patients with measurable disease, 12 survived PFS at least 6 months. Three patients are yet to be determined. Two patients had PR; 20 had SD; 30 had DP, and 7 could not have their tumor assessed. Conclusions: Preliminary results suggest that sorafenib is tolerated in patients with recurrent EOC with dermatologic and metabolic abnormalities being the most common toxicities. Efficacy data is expected to reach maturity and be analyzed in the spring of 2007, and comprehensive results will be presented. [42% disease control (CR+PR+SD) rate among evaluable patients]

Topotecan (Hycamtin™) & Bevacizumab (Avastin™):

  • Phase II prospective study of weekly topotecan and bevacizumab in platinum refractory ovarian cancer or peritoneal cancer (OC) (2008 ASCO Annual Mtg. Abstr. #5551). Patients (pts) with platinum refractory OC have limited treatment options. Bevacizumab, an anti-angiogenesis agent has demonstrated efficacy in recurrent ovarian cancer. Bevacizumab combined with chemotherapy in other solid tumors has improved efficacy compared with bevacizumab or chemotherapy alone. Topotecan, an active drug in recurrent OC has been used in a weekly fashion with less toxicity and more acceptability than a standard 5 day regimen. Topotecan and bevacizumab have non-overlapping toxicities. We studied the efficacy and tolerability of weekly topotecan and bevacizumab in patients with platinum refractory OC. Methods: The primary objectives of this study were to evaluate PFS, OS, OR rate and toxicity of this combination regimen. Eligible pts included those with platinum refractory OC (recurrence < 6 months of platinum therapy) who had received a maximum of 2 prior chemotherapy regimens. Results: Twenty-two pts have been enrolled to date, with 11 pts remaining on study and 18 now evaluable. Best responses for the 18 evaluable pts were: 22.2% PR (n=4), 27.8% SD (n=5), and 50% DP (n=9). Eleven pts went off study due to DP (based on CT scan RECIST criteria [n=6] or general deterioration and/or bowel obstruction [n=5]). Median duration on study for the 18 evaluable pts was 15 wks (range 5-63 weeks). Four pts have had PFS >5 months. The 18 evaluable pts received a total of 91 treatment cycles. No pt went off study due to treatment related toxicity or suffered a bowel perforation. Conclusions: Combination bevacizumab and topotecan administered in a weekly fashion demonstrate good activity in platinum refractory OC with acceptable toxicity. G3-G4 Hematologic or Hypertensive Toxicities. [50% disease control (CR+PR+SD) rate among evaluable patients]

Lapatinib (Tykerb™), Carboplatin (Paraplatin®) & Paclitaxel (Taxol™):

  • Phase I/II lapatinib plus carboplatin and paclitaxel in stage III or IV relapsed ovarian cancer patients (2008 ASCO Annual Mtg. Abstr. #5556). The purpose of this study was to establish the MTD and evaluate DLTs and response to therapy of combination therapy with carboplatin/paclitaxel and lapatinib, an oral dual tyrosine kinase inhibitor of both ErbB1 and ErbB2, in Stage III /IV relapsed ovarian cancer. Methods: This was an open-label, multicenter, phase I/II study of carboplatin/paclitaxel in combination with single agent lapatinib in Stage III/IV relapsed ovarian cancer patients. Measurable disease, adequate organ function and ECOG performance status of 0-2 were required. Results: 25 ovarian cancer patients are enrolled and four are too early to be evaluable. The median age is 57 (range 39-81). The median number of prior therapeutic regimens is 4 (range 1-10). GI toxicities were primarily < grade 2 and were successfully treated with aggressive bowel management. 10 patients (pts) experienced G3 toxicities. 4 pts- leukopenia, 2 pts-neutropenia, 2 pts-hyperglycemia, 2 pts-allergic reactions to carboplatin, 1 pt-thrombocytopenia, 1 pt-lymphopenia, 1 pt-hypokalemia, 1 pt-nausea, 1 pt-diarrhea, 1 pt-bowel obstruction. Response to therapy to date is: CR=21%, PR=29%, SD=29%, PD=21%. Two patients who were in complete remission both stopped IV chemotherapy and were maintained only with lapatinib. One is still in remission after six months and one relapsed. Conclusions: Lapatinib, an oral targeted molecular therapy which inhibits both EGFR 1 and 2 tyrosine kinase activity, can be safely administered with a weekly regimen of carboplatin and paclitaxel in heavily pretreated, ovarian cancer patients. The high response rates seen warrant further investigation. [79% disease control (CR+PR+SD) rate among evaluable patients]

Ifomide, Epirubicin, & Cisplatin:

NKTR-102 (Pegylated irinotecan):

  • Phase I dose finding and pharmacokinetic study of NKTR-102 (PEGylated irinotecan): Early evidence of anti-tumor activity (2008 ASCO Annual Mtg. Abstr. #13518 ). NKTR-102 is a novel pegylated form of irinotecan with superior efficacy against a range of xenografts compared with irinotecan. Sustained tumor inhibition is associated with increased SN38 exposure. A phase I trial of NKTR-102 was conducted to establish the MTD and to characterize safety and PK in patients (pts) with refractory solid tumors. No CTC Grade 4 toxicity was observed. G3 diarrhea was dose limiting. Other toxicities included transient uncomplicated G3 neutropenia and transient infusion related visual disturbance. PK data are available for 12 pts. Two partial responses were observed in pts with advanced cervical cancer and small cell lung cancer. Anti-tumor activity was seen in 4 other pts; ovarian: CA-125 decreased from 2557 to 518, Hodgkin’s disease: 28% radiologic improvement with symptomatic benefit, adrenocortical: cortisol levels normalized, metabolic response by PET, esophageal: CEA decreased from 35.5 to 13.6, metabolic response by PET. Conclusions: NKTR-102 shows early evidence of activity in a wide spectrum of tumors. Cumulative SN38 exposure is 1.2 to 6.5 fold higher than that predicted for irinotecan. Toxicity is manageable; diarrhea (not neutropenia) is dose limiting.

ON 01910.Na:

  • Phase I study of ON 01910.Na, a novel polo-like kinase 1 pathway modulator, administered as a weekly 24-hour continuous infusion in patients with advanced cancer (2008 ASCO Annual Mtg. Abstr. #2515). ON 01910.Na induces G2/M cell cycle arrest, apoptosis, and cell death in a broad spectrum of cancer cells, but not in non-neoplastic cells. In vitro, cell killing is dependent on drug exposure time. Based on these preclinical findings, a weekly 24hr continuous infusion (CI) study to determine safety and MTD of ON 01910.Na was initiated. Methods: Patients with advanced cancers received ON 01910.Na as a weekly 24hr CI. Twenty-three pts (7:16 M:F, 45-80 yrs) have received ON 01910.Na. G2 toxicities (2-grade increase over baseline) included fatigue (3 pts) and anorexia (1 pt). Fatigue (11/23 pts) was the most common side effect, with no G3 or greater fatigue observed. Overall, three G3 events occurred, none of which were drug-related. The best response was a pt with advanced ovarian cancer who maintained stable disease for 36 wks of treatment. Conclusions: ON 01910.Na is well tolerated as a weekly 24h continuous infusion. In the dose range studied, the drug exhibited non-linear kinetics with rapid attainment of plasma concentrations that are cytotoxic to cancer cells in vitro, but have limited end-organ toxicity in vivo. Study data continues to accrue, and we expect to recommend a phase II dose shortly. Further analysis and combination phase I studies are planned.

BAY 73-4506:

  • Phase I study of BAY 73-4506, an inhibitor of oncogenic and angiogenic kinases, in patients with advanced solid tumors: Final results of a dose-escalation study (2008 ASCO Annual Mtg. Abstr. #2558 ). BAY 73-4506 is a potent tyrosine kinase inhibitor of receptor tyrosine kinases (VEGFR, PDGF, RET, KIT, FGFR) and serine/threonine kinases (raf and p38MAPK). In tumor xenograft models, BAY 73-4506 demonstrated a broad spectrum antitumor activity. Methods: This phase I study was a dose-escalation trial investigating the safety, PK, and pharmacodynamic (PD) profile of BAY 73-4506, given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers including DCE-MRI, soluble VEGFR-2 (sVEGFR-2) and VEGF plasma levels were assessed at each cycle. Tumor response was evaluated as per RECIST. Results: 52 patients (pts) with solid tumors and progressive disease were enrolled and treated with doses of 10 to 220 mg once daily. Frequent tumor types included colorectal cancer (CRC) (31%), malignant melanoma (10%), and ovarian cancer (10%). The median treatment duration was 49.5 days (min. 3, max. 609). Drug-related adverse events (AEs) of all grades reported in >20% of pts were hoarseness (54%), dermatological toxicities (50%; CTC G3-G4: 13%), mucositis (35%), diarrhea (25%; CTC 3: 2%), fatigue (23%; CTC 3: 2%), and hypertension (23%; CTC 3: 6%). Treatment-related AEs leading to dose reduction, interruption or discontinuation were hand foot skin reaction (15%), diarrhea (8%), and thrombopenia (6%). Of the 33 evaluable pts, 9% achieved a partial response (PR), 64% had stable disease (SD), at least 7 weeks after start of treatment, and 48% had SD or PR for more than 11 weeks. Conclusions: The recommended phase II dose for BAY 73-4506 is 160 mg daily, using the 21 days on/7 days off treatment schedule. Clinical activity (PR+SD) has been demonstrated in 73% of the evaluable pts. An extension cohort (dose level 160 mg) has been started.