PARP Inhibitor MK-4827 Shows Anti-Tumor Activity in First Human Clinical Study

MK-4827, a new drug that targets proteins responsible for helping cancer cells repair their damaged DNA, has shown promising anti-tumor activity in its first human clinical trial.

MK-4827, a new drug that targets proteins responsible for helping cancer cells repair their damaged DNA, has shown promising anti-tumour activity in its first human clinical trial. Some patients with a range of solid tumors, many of whom had been treated unsuccessfully for their cancer with other therapies, have seen their tumors shrink or stabilize for periods of between 46 days to more than a year. The research will be presented today (Thursday) at the 22nd EORTCNCIAACR [1] Symposium on Molecular Targets and Cancer Therapeutics, which is being held in Berlin, Germany.

PARP is a key signaling enzyme involved in triggering the repair of single-strand DNA damage. PARP inhibition has been demonstrated to selectively kill tumor cells lacking components of the homologous recombination (HR) DNA repair pathway while sparing normal cells. Known defects in HR repair include the well-characterized hereditary BRCA1 and BRCA2 mutations in breast and ovarian cancer, as well as nonhereditary BRCA mutations. (Photo Credit: AstraZeneca Oncology)

Laboratory studies of the drug, MK-4827, have shown that it inhibits proteins called PARP1 and PARP2 (poly(ADP)-ribose polymerase). PARP is involved in a number of cellular processes and one of its important functions is to assist in the repair of single-strand breaks in DNA. Notably, if one single-strand DNA break is replicated (replication occurs before cell division), then it results in a double-strand break.  By inhibiting the action of PARP, double-strand breaks occur, which in turn, lead to cell death. Tumors that are caused by a mutation in the BRCA1 or BRCA2 genes are susceptible to cell death through PARP inhibition because correctly functioning BRCA genes assist in repairing double-strand DNA breaks via a process called homologous-recombination-dependent DNA repair, whereas mutated versions are unable to perform this role. Normal cells do not replicate as often as cancer cells and they still have homologous repair operating; this enables them to survive the inhibition of PARP and makes PARP a good target for anti-cancer therapy.

In a Phase I trial [2] conducted at the H. Lee Moffitt Cancer Center (Tampa Florida, USA), University of Wisconsin-Madison (Madison, USA) and the Royal Marsden Hospital (London, UK), MK-4827 was given to 59 patients (46 women, 13 men) with a range of solid tumors such as non-small cell lung cancer (NSCLC), prostate cancer, sarcoma, melanoma and breast and ovarian cancers. Some patients had cancers caused by mutations in the BRCA1/2 genes, such as breast and ovarian cancer, but others had cancers that had arisen sporadically.

Robert M. Wenham, M.D., MS, FACOG, Clinical Director, Gynecologic Oncology, Department of Women's Oncology, H. Lee Moffitt Cancer Center

The drug was given in pill form once a day, and the researchers found that the maximum tolerated dose was 300 mg per day. Dr. Robert Wenham, Clinical Director for Gynecologic Oncology in the Department of Women’s Oncology at the Moffitt Cancer Center, who is presenting data on behalf of the participating investigators, said: “MK-4827 is generally well tolerated, with the main dose-limiting toxicity being thrombocytopenia – an abnormal decrease in the number of platelets in the circulatory blood. The most common side effects are mild nausea, vomiting, anorexia and fatigue.”

The researchers saw anti-tumor responses in both sporadic (non-inherited) and BRCA1/2 mutation-associated cancers [emphasis added]. Ten patients with breast and ovarian cancers had partial responses, with progression-free survival between 51-445 days, and seven of these patients are still responding to treatment. Four patients (two with ovarian cancer and two with NSCLC) had stable disease for between 130-353 days.

Dr. Wenham said: “Most patients in the trial had exhausted standard therapies and those who responded to this drug have benefited. Several patients have been receiving treatment for more than a year. The responses mean that MK-4827 is working as hoped and justify additional studies. Just how well MK-4827 works compared to other treatments is the goal of the next set of studies.”

He gave a possible explanation as to why patients with cancers that were not caused by BRCA1 or BRCA 2 gene mutations also responded to the PARP inhibition. “BRCA is a tumor suppressor gene that assists in repairing double stranded DNA breaks. In BRCA-mutation related cancers, loss of both copies of the gene results in a non-functional protein and thus BRCA deficiency. Because BRCA works with other proteins, BRCA-pathway related deficiency can be seen in the absence of two mutated copies of the BRCA genes. This may explain why responses have been reported for this class of drugs in non-BRCA mutant cancers.”

Dr. Wenham and his colleagues are recruiting more patients for additional studies and an expansion of the existing trial. “We want to understand what types of cancers will respond best to treatment with MK-4827,” he said. “Cohorts are currently open for patients with ovarian cancer, patients without germ-line BRCA mutations, and prostate cancer patients. Cohorts will open soon for patients with T-cell prolymphocytic leukemia, endometrial cancer, breast cancer and colorectal cancer. MK-4827 is also being studied in combination with conventional chemotherapy drugs.”

Sources:

Additional Information:

Related Information:

References:

[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

[2] This study was funded by Merck & Co., Inc. MK-4827 is owned by Merck & Co., Inc.

Dana-Farber Researchers “OncoMap” The Way To Personalized Treatment For Ovarian Cancer

Researchers have shown that point mutations – mis-spellings in a single letter of genetic code – that drive the onset and growth of cancer cells can be detected successfully in advanced ovarian cancer using a technique called OncoMap. The finding opens the way for personalized medicine in which every patient could have their tumor screened, specific mutations identified, and the appropriate drug chosen to target the mutation and halt the growth of their cancer.

Researchers have shown that point mutations – mis-spellings in a single letter of genetic code – that drive the onset and growth of cancer cells can be detected successfully in advanced ovarian cancer using a technique called OncoMap. The finding opens the way for personalized medicine in which every patient could have their tumor screened, specific mutations identified, and the appropriate drug chosen to target the mutation and halt the growth of their cancer.

Using mass spectrometry for identifying the genetic make-up of cancer cells, OncoMap can determine the point mutations in tumors by utilizing a large panel of over 100 known cancer-causing genes (referred to as “oncogenes“). In the work to be presented today (Wednesday) at the 22nd EORTCNCIAACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Berlin, researchers will describe how they used OncoMap to identify oncogene mutations in tumor samples obtained from women with advanced high-grade serous ovarian cancer. [2] Earlier in the year 76 mutations in 26 different genes had been found but, since then, further work in more tumor samples has found more.

Ursula A. Matulonis, M.D., Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute; Associate Professor, Medicine, Harvard Medical School

Dr. Ursula Matulonis, director/program leader in medical gynecologic oncology at the Dana-Farber Cancer Institute located in Boston, Massachusetts (USA) and Associate Professor of Medicine at Harvard Medical School, will tell the meeting:

“Epithelial ovarian cancer is the most lethal of all the gynecologic malignancies, and new treatments are needed for both newly diagnosed patients as well as patients with recurrent cancer. The success of conventional chemotherapy has reached a plateau, and new means of characterizing ovarian cancer so that treatment can be personalized are needed.

We know that many human cancers have point mutations in certain oncogenes, and that these mutations can cause cancer cells to have a dependence on just one overactive gene or signalling pathway for the cancer cell’s growth and survival – a phenomenon known as ‘oncogene addiction’. If the mutation that causes the oncogene addiction can be inhibited, then it seems that this often halts the cancer process. Examples of mutations that are successfully inhibited by targeted drugs are HER2 (for which trastuzumab [Herceptin®] is used in breast cancer), EGFR (erlotinib [Tarceva®] in lung cancer) and c-kit (imatinib [Gleevec®] in chronic myeloid leukemia). So if we know the status of specific genes in a tumor, then this enables us to choose specific treatments that are likely to work successfully against the cancer.”

Dr Matulonis and her colleagues used OncoMap to investigate the mutation status of high-grade serous ovarian tumors that were known not to be caused by inherited mutations in the BRCA 1 and BRCA 2 genes. They found mutations previously identified to be involved in ovarian cancer: KRAS, BRAF, CTNNB1 and PIK3CA. The KRAS and PIK3CA mutations were the most common, while BRAF was more rare. The researchers also identified a low frequency of mutations in many other different oncogenes.

Dr. Matulonis further noted:

“This study shows that it’s feasible to use OncoMap to identify whether a patient’s tumor has a mutation in an oncogene for which a known drug is available to target that specific gene, so as to enable us to place her on a clinical study of that drug; for instance, XL147 or GDC-0941 are inhibitors for the P13kinase mutation that are in clinical trials at present.  In addition, someone’s cancer could harbor a mutation (such as ALK) that is not known to be associated with ovarian cancer or has not yet been studied in ovarian cancer – these patients could be matched with a drug that inhibits that protein too. As new drugs get developed, this information would be used to match future drugs with patients and their cancers.”

The researchers hope that OncoMap will become a clinical test for all cancer patients at the Dana-Farber Cancer Institute before long, so that the genetic information obtained can be used to choose the best treatment for them.

Dr. Matulonis said:

“At present, only a few targeted therapies are being used for newly diagnosed ovarian cancer and most are being used to treat recurrent ovarian cancer, but this will change eventually. I have already referred several of our patients who are either newly diagnosed or have recurrent cancer and who have mutations (one with KRAS and one with PIK3CA) to our phase I program for drugs studies specific to these mutations.  For ovarian cancer, understanding mutational analysis is one piece of the genetic puzzle. Our group will also start looking for chromosomal and gene amplifications and deletions in patients’ tumors, which we know are important for ovarian cancer.”

Matulonis believes that OncoMap and other similar analytical tools will become mainstream practice in all cancer clinics before long. Tools for detecting genes with the incorrect numbers of copies or abnormal expression will also help doctors to choose the best treatment for individual patients.”

Source: Researchers map the way to personalised treatment for ovarian cancer, Abstract no: 35. Oral presentation in plenary session 2.  22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Berlin, Germany, November 16- 19, 2010.

References:

[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

[2] The study was funded by the Madeline Franchi Ovarian Cancer Research Fund, twoAM Fund and the Sally Cooke Ovarian Cancer Research Fund.

Related Information:

Girls with Stage I Ovarian Germ-Cell Tumors Can Safely Skip Chemotherapy Until Recurrence

Researchers from Dana-Farber/Children’s Hospital Cancer Center found that as many as 50 percent of young girls treated for germ-cell ovarian tumors may be safely spared chemotherapy using a “watch and wait” strategy to determine whether follow-up treatment is needed.

Researchers from Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC) found that as many as 50 percent of young girls treated for germ-cell ovarian tumors may be safely spared chemotherapy using a “watch and wait” strategy to determine whether follow-up treatment is needed.

In contrast to the current practice of administering chemotherapy to all patients following removal of these rare tumors, researchers said the study demonstrated that treatment could safely be delayed and given only when the cancer recurred.

Data from the trial involving 25 young women ages 9 to 16 was presented at the 42nd Congress of the International Society of Paediatric Oncology (SIOP) in Boston on Friday, October. 22.

Lindsay Frazier, M.D., Pediatric Oncologist, Dana-Farber / Children's Hospital Cancer Center; Chair, Germ Cell Tumor Committee, Children's Oncology Group

The study was led by Lindsay Frazier, MD, a pediatric oncologist at DF/CHCC and chair of the Germ Cell Tumor Committee of the Children’s Oncology Group.

“I personally think that not giving chemotherapy to half the patients [women with germ cell ovarian tumors] is a good thing,” said Frazier. “The chemotherapy is just as effective given when the disease recurs. I would recommend that parents consider a watching and waiting strategy.”

Germ cell tumors are malignancies that develop in precursors of sperm cells in boys and egg cells in girls. Some forms of the tumors are most often detected immediately following birth; other types are most common between the ages of 10 and 30.

Previous trials had shown that delaying chemotherapy was safe and effective in Stage 1 germ cell testicular tumors in boys. Over time, 30 percent of the patients developed a recurrence, but they were all cured by chemotherapy.

“So instead of giving 100 percent of them chemotherapy, only 30 percent needed it,” explained Frazier, who said it’s been found that the usual three cycles of chemotherapy administered for the tumors doubles the long-term risk of cardiovascular disease or second cancers.

The current study was undertaken to test a similar watch-and-wait approach in female patients. Frazier said 25 girls with Stage 1 germ cell ovarian tumors were recruited from about 100 medical centers — an indication of the cancer’s rarity. In all cases, the tumors had been completely removed by surgery.

Instead of undergoing chemotherapy immediately, the girls were monitored closely for signs of recurrence. Every three weeks their blood was tested for biochemical markers signifying a regrowth of the cancer, and every three months they were scanned with CT or MRI imaging.

“The median time to relapse was two months, and the latest relapse was at 9 months, so the families were not living with uncertainty for a long time,” Frazier said.

The recurrence rate was 50 percent — higher than in the boys with germ cell tumors — but the delayed treatment was similarly effective though one girl died, yielding a survival rate of 96 percent.

Preventing unnecessary chemotherapy treatment for half of girls with such tumors is still desirable, said Frazier, “because there is evidence that girls are even more susceptible to long-term harm from chemo than boys are.”

The study was supported by the National Cancer Institute.

Sources:

PI3K Pathway: A Potential Ovarian Cancer Therapeutic Target?

…[T]here are several PI3K signaling pathway targeting drugs in clinical development for use against ovarian cancer and solid tumors, including GDC-0941, BEZ235, SF1126, XL-147, XL-765, BGT226, and PX-866.  The results of two recent medical studies suggest that the use of PI3K-targeted therapies may offer an effective therapeutic approach for patients with advanced-stage and recurrent ovarian cancer, including a generally chemotherapy-resistant histological subtype of epithelial ovarian cancer known as “ovarian clear cell cancer” (OCCC).  The targeting of the PI3K pathway in endometrial, ovarian, and breast cancer is also being investigated by a Stand Up To Cancer “Dream Team.” …

PI3K Cellular Signaling Pathway — An Overview

PI3K/AKT cellular signaling pathway (Photo: Cell Signaling Technology(R))

In 2004 and 2005, multiple researchers identified mutations in the PIK3CA  gene with respect to multiple cancers.[1]  The PIK3CA gene encodes the PI3K catalytic subunit p110α. PI3K (phosphoinositide 3- kinase) proteins have been identified in crucial signaling pathways of ovarian cancer cells. PI3Ks are also part of the PI3K-AKT-mTOR signaling pathway which promotes cellular glucose metabolism, proliferation, growth, survival, and invasion and metastasis in many cancers. PIK3CA gene mutations can increase PI3K signaling, thereby activating the PI3K-AKT-mTOR pathway within cancer cells.

As of this writing, there are several PI3K signaling pathway targeting drugs in clinical development for use against ovarian cancer and solid tumors, including GDC-0941, BEZ235, SF1126, XL-147, XL-765, BGT226, and PX-866. [2]  The results of two recent medical studies suggest that the use of PI3K-targeted therapies may offer an effective therapeutic approach for patients with advanced-stage and recurrent ovarian cancer, including a generally chemotherapy-resistant histological subtype of epithelial ovarian cancer known as “ovarian clear cell cancer” (OCCC).  The targeting of the PI3K pathway in endometrial, ovarian, and breast cancer is also being investigated by a Stand Up To CancerDream Team.”

Frequent Mutation of PIK3CA Gene In Recurrent & Advanced Clear Cell Ovarian Cancer

OCCC is one of the five major subtypes of epithelial ovarian cancer. OCCC accounts for only 4% to 12% of epithelial ovarian cancer in Western countries and, for unknown reasons, it comprises more than 20% of such cancers in Japan [3,4,5]. OCCC possesses unique clinical features such as a high incidence of stage I disease, a large pelvic mass, an increased incidence of venous thromboembolic complications, and hypercalcemia. It is frequently associated with endometriosis.  Compared to serous ovarian cancer, OCCC is relatively resistant to conventional platinum and taxane-based chemotherapy. For these reasons, new effective therapies are desperately needed for OCCC.

Researchers from Johns Hopkins and the University of California, Los Angeles (UCLA) analyzed 97 OCCC tumors for genetic sequence mutations in KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), BRAF (v-raf murine sarcoma viral oncogene homolog B1), PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide), TP53 (tumor protein p53), PTEN (phosphatase and tensin homolog), and CTNNB1 (Catenin, Beta-1) as these mutations frequently occur in other major types of ovarian cancers.[6] The samples tested included the following:

  • 18 OCCCs for which affinity-purified tumor cells from fresh specimens were available;
  • 10 OCCC tumor cell lines.

Upon test completion, the researchers discovered that sequence mutations of PIK3CA, TP53, KRAS, PTEN, CTNNB1, and BRAF occurred in 33%, 15%, 7%, 5%, 3%, and 1% of OCCC cases, respectively.

Clear cell carcinoma of the ovary (Photo: Geneva Foundation For Medical Education & Research)

The sequence analysis of the 18 affinity purified OCCC tumors and the 10 OCCC cell lines showed a PIK3CA mutation frequency of 46%. Based upon these findings the researchers concluded that the use of PIK3CA-targeting drugs may offer a more effective therapeutic approach compared with current chemotherapeutic agents for patients with advanced-stage and recurrent OCCC. As noted above, there are several PI3K-targeting drugs in clinical development for use against ovarian cancer and solid tumors.[2]

Notably, one of the researchers involved with this OCCC study is Dennis J. Slamon, M.D., Ph.D. Dr. Slamon serves as the Director of Clinical/Translational Research, and as Director of the Revlon/UCLA Women’s Cancer Research Program at the Jonsson Comprehensive Cancer Center. Dr. Slamon is also a professor of medicine, chief of the Division of Hematology/Oncology and Executive Vice Chair of Research for UCLA’s Department of Medicine. Dr. Slamon is a co-discoverer of the breast cancer drug Herceptin®. Herceptin is a monoclonal antibody targeted therapy used against HER-2 breast cancer, an aggressive breast cancer subtype that affects 20% to 30% of women with the disease. Herceptin’s development was based, in part, upon the unique genetic profile of HER-2 breast cancer as compared to other forms of breast cancer. Herceptin® revolutionized the treatment of HER-2 postive breast cancer and is recognized worldwide as the standard of care for that subtype of breast cancer.  The approach taken by Johns Hopkins and UCLA researchers in this study — the identification of  a subtype within a specific form of cancer that may be susceptible to a targeted therapy —  bears a striking similarity to the overarching approach taken in the development of Herceptin®.

Ovarian Cancer & Other Solid Tumors With PIK3CA Gene Mutations Respond To PI3K-AKT-mTOR Pathway Inhibitors In Phase I Clinical Testing.

Testing patients with cancer for PIK3CA gene mutations is feasible and may allow targeted treatment of the PI3K-AKT-mTOR cellular signaling pathway, according to the results of a University of  Texas, M.D. Anderson Cancer Center study presented on November 17, 2009 at the 2009 AACR (American Association for Cancer Research)-NCI (National Cancer Institute)-EORTC (European Organization For Research & Treatment of Cancer) International Conference on Molecular Targets and Cancer Therapeutics.[7]

mTOR cellular signaling pathway (Photo: Cell Signaling Technology(R))

Filip Janku, M.D., Ph.D, a clinical research fellow with the M.D. Anderson Cancer Center’s department of investigational cancer therapeutics, and colleagues conducted a mutational analysis of exon 9 and exon 20 of the PI3KCA gene using DNA from the tumors of patients referred to targeted therapy clinical trials. Patients with PIK3CA mutations were preferably treated whenever possible with regimens utilizing PI3K-AKT-mTOR signaling pathway inhibitors.

As part of this study 117 tumor samples were analyzed. PIK3CA mutations were detected in 14 (12%) patients.  In tumor types with more than 5 patients tested, PIK3CA mutations were identified in endometrial cancer (43%, 3 out of 7 patients), ovarian cancer (22%, 5 out of 23 patients), squamous head and neck cancer (14%, 1 out of 7 patients), breast cancer (18%, 2 out of 11 patients), and colon cancer (15%, 2 out of 13 patients). No mutations were identified in patients with melanoma or cervical cancer.

Of the 14 patients found to possess PIK3CA mutations, 10 were treated based upon a clinical trial protocol that included a drug targeting the PI3K-AKT-mTOR pathway.  A partial response to treatment was experienced by 4 (40%) patients. Although the total number of patients is small, there were 2 (67%) patient responses in 3 endometrial cancer cases, 1 (25%) patient response in 4 ovarian cancer cases, 1 (100%) patient response in 1 breast cancer, and no patient response in 1 colorectal cancer case.  Although the total number of study patients is small, the researchers conclude that the response rate appears high (40%) in tumors with PIK3CA mutations treated with PI3K-AKT-mTOR pathway inhibitors.

“The implications of this study are twofold,” said Dr. Janku.  “We demonstrated that PIK3CA testing is feasible and may contribute to the decision-making process when offering a patient a clinical trial. Although this study suffers from low numbers, the response rate observed in patients treated with inhibitors of PI3K/AKT/mTOR pathway based on their mutational status was well above what we usually see in phase-1 clinical trials.”  “These results are intriguing but at this point should be interpreted with caution,” said Janku. “The promising response rate needs to be confirmed in larger groups of patients. We expect to learn more as this project continues to offer PIK3CA screening to patients considering a phase-1 clinical trial.”

Stand Up 2 Cancer Dream Team: Targeting the PI3K Pathway in Women’s Cancers

The potential importance of the PI3K pathway in the treatment of ovarian cancer is emphasized by the two medical studies above.  This issue is also receiving considerable attention from one of the Stand Up 2 Cancer (SU2C) “Dream Teams,” which is going to evalute  the potential for targeting the PI3K pathway in women’s cancer.  SU2C assigned $15 million of cancer research funding to this critical issue.  The scientists involved in this SU2C Dream Team are the pioneers who discovered the PI3K pathway and validated its role in human cancers, and they will focus on breast, ovarian and endometrial cancers, all of which possess the PI3K mutation.

The leader and co-leaders of the PI3K pathway SU2C team are set forth below.

Leader:

Lewis C. Cantley, Ph.D., Director, Cancer Center at Beth Israel Deaconess Medical Center.

Co-Leaders:

Charles L. Sawyers, M.D., Director, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center.

Gordon B. Mills, M.D., Ph.D., Chair, Department of Systems Biology, University of Texas, M.D. Anderson Cancer Center.

The specific SU2C Dream Team research goal with respect to targeting the PI3K pathway in women’s cancers is stated as follows:

The PI3K pathway is mutated in more cancer patients than any other, and these mutations are the most frequent events in women’s cancers, making it an attractive molecular target for agents that inhibit these genetic aberrations. If successful, this project will allow clinicians to use biomarkers and imaging techniques to predict which patients will benefit from PI3K pathway inhibitors and lead to the development of therapeutic combinations that will hit multiple targets in the complex pathways that contribute to cancer cell growth.  This work will help assure that these therapies are given to patients who will benefit from them, and it will also increase the overall pace of clinical trials targeting PI3K inhibitors.

Based upon the two studies discussed, and the creation and funding of the SU2C Dream Team for the purpose of targeting the PI3K pathway in women’s cancer, the future holds great promise in the battle against ovarian cancer (including OCCC).  It is our hope that more clinical study investigators will offer PI3K pathway mutation screening to all ovarian cancer patient volunteers.  Libby’s H*O*P*E*™ will continue to monitor the clinical development of PI3K pathway inhibitors, and make our readers aware of all future developments.

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References:

1/Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008 Sep 18;27(41):5497-510. PubMed PMID: 18794884
Samuels Y, Ericson K. Oncogenic PI3K and its role in cancer. Curr Opin Oncol. 2006 Jan;18(1):77-82. PubMed PMID: 16357568.
Levine DA, Bogomolniy F, Yee CJ, et. al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res. 2005 Apr 15;11(8):2875-8. PubMed PMID: 15837735.
Samuels Y, Wang Z, Bardelli A, et. al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004 Apr 23;304(5670):554. Epub 2004 Mar 11. PubMed PMID: 15016963.

2/For open ovarian cancer clinical trials using a PI3K-targeted therapy; CLICK HERE; For open solid tumor clinical trials using a PI3K-targeted therapy, CLICK HERE.

3/ Itamochi H, Kigawa J & Terakawa N.  Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma. Can Sci 2008 Apr;99(4):653-658. [PDF Document]

4/Schwartz DR, Kardia SL, Shedden KA, et. alGene 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.

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

6/Kuo KT, Mao TL, Jones S, et. al. Frequent Activating Mutations of PIK3CA in Ovarian Clear Cell Carcinoma. Am J Pathol. 2009 Apr 6. [Epub ahead of print]

7/Janku F, Garrido-Laguna I, Hong D.S.  PIK3CA mutations in patients with advanced cancers treated in phase I clinical trials, Abstract #B134, Molecular Classification of Tumors, Poster Session B, 2009 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference. [PDF Document].

2009 ASCO Annual Meeting Highlights: Ovarian Cancer & Select General Issues

The 2009 American Society of Clinical Oncology (ASCO) Annual Meeting was held in Orlando, Florida from May 29 through June 2, 2009.  We provide below select highlights from the 2009 ASCO Annual Meeting that relate to ovarian cancer and other general issues.

The 2009 American Society of Clinical Oncology (ASCO) Annual Meeting was held in Orlando, Florida from May 29 through June 2, 2009.  We provide below select highlights from the 2009 ASCO Annual Meeting that relate to ovarian cancer and other general issues. Learn more about How to Read a Medical Abstract in a Research Study.

Development Time of Cancer Clinical Trials Linked to Accrual Goals.

Physicians Need to Address Prescription Costs With Patients Who Participate In Clinical Trials.

Availability of Experimental Therapy Outside of Randomized Clinical Trials In Oncology.

ASCO Fertility Preservation Guidelines For Cancer Patients Not Widely Followed By Oncologists.

Ginger (Zindol®) Quells Cancer Patients’ Chemotherapy-Related Nausea.

Early Treatment of Recurrent Ovarian Cancer Based Upon Rising CA-125 Levels Does Not Increase Survival.

Body Mass Index (BMI) Should Be Taken Into Account When Assessing A Cancer Patient’s Vitamin D Status.

Extreme Drug Resistance (EDR) Assay Results Do Not Independently Predict Or Alter The Outcomes of Patients With Epithelial Ovarian Cancer Who Are Treated With Optimal Cytoreductive Surgery Followed By Platinum & Taxane Combination Chemotherapy in Either a Primary or Recurrent Setting.

Systematic Review Of Past Study Results For Use of Cytoreductive Surgery Combined With Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

Preliminary Results From Phase II Study of Oxaliplatin+Docetaxel+Bevacizumab As First Line Treatment of Advanced Ovarian Cancer Show 62% Overall Response Rate & 70% One-Year Progression Free Survival.

Combined Weekly Docetaxel + Gemcitabine In Relapsed Ovarian Cancer & Peritoneal Cancer Produces 59% Overall Response Rate.

A Phase II Trial of Irinotecan & Oral Etoposide Chemotherapy in Recurrent Ovarian Cancer Patients Produces 47% Overall Response Rate & 81% Clinical Benefit Rate.

Weekly Bevacizumab & Pegylated Liposomal Doxorubicin Produce 55% Clinical Benefit Rate In Progressing/Recurrent Ovarian Cancer Patients.

Phase II Study of Belotecan (CKD-602)+ Carboplatin Demonstrates 53% Overall Response Rate in Recurrent Ovarian Cancer Patients.

Single Agent Voreloxin Produces 11% Overall Response Rate & 52% Disease Control Rate in Phase II Study Involving Women with Platinum-Resistant Ovarian Cancer.

A Phase II Study of Patupilone In Patients With Platinum Refractory/Resistant Ovarian, Primary Fallopian, or Peritoneal Cancer Produces 48% Clinical Benefit Rate.

Trabectedin (Yondelis®) + Pegylated Liposomal Doxorubicin (PLD) Produces Better Response Than PLD Alone.

M.D. Anderson Cancer Center Finds Anti-VEGF Therapy Is Highly Effective In Patients With Ovarian Granulosa Cell Tumors.

M.D. Anderson Cancer Center Finds That Increased Angiogenesis Is A Significant Predictor Of Poor Clinical Outcome In Patients With Sex-Cord Stromal Tumors; Suggests Anti-Angiogenesis Therapy is Warranted For This Subtype of Ovarian Cancer.

ZYBRESTAT™ (Combretastatin A-4 phosphate) Produces 32% Confirmed Partial Response Rate (RR) in Evaluable Patients With Platinum Resistant Ovarian Cancer (25% RR if total enrolled patients used as denominator).

ASSIST-5 Trial of TELCYTA® + Pegylated Liposomal Doxorubicin Produces 12% Response Rate (With One Complete Response) in Patients With Platinum Refractory and Resistant Ovarian Cancer.

Two Studies Provide Contradictory Data for Use of Carboplatin + Pegylated Liposomal Doxorubicin in Ovarian Cancer

OGX-427 Treatment Demonstrates Safety, Evidence of Declines in Circulating Tumor Cells and Reductions in Tumor Markers in a Phase I Cancer Trial, Including 60% Response Rate (Based Upon Declining CA125) For Ovarian Cancer Patients.

Maintenance BIBF 1120 Could Delay Disease Progression in Recurrent Ovarian Cancer.

Oral PARP Inhibitor Olaparib (AZD2281) Effective Against BRCA-Deficient Advanced Ovarian Cancer.

Carfilzomib (PX-171-007) Produces Stable Disease For 4+ Months In One Ovarian Cancer Patient Who Failed Under Four Previous Treatment Lines – Phase II Solid Tumor Trial.

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About The American Society of Clinical Oncology

The American Society of Clinical Oncology is a non-profit organization founded in 1964 with the overarching goals of improving cancer care and prevention. More than 27,000 oncology practitioners belong to ASCO, representing all oncology disciplines and subspecialties. Members include physicians and health-care professionals in all levels of the practice of oncology. To view 2009 ASCO Annual Meeting presentation abstracts, click here.  To view 2009 ASCO Annual Meeting presentation abstracts regarding ovarian cancer, click here.  To view ASCO ovarian cancer information, click here.

About Cancer.Net

Cancer.Net, formerly People Living With Cancer (PLWC), brings the expertise and resources of the American Society of Clinical Oncology (ASCO), the voice of the world’s cancer physicians, to people living with cancer and those who care for and care about them. ASCO is composed of more than 27,000 oncologists globally who are the leaders in advancing cancer care. All the information and content on Cancer.Net was developed and approved by the cancer doctors who are members of ASCO, making Cancer.Net the most up-to-date and trusted resource for cancer information on the Internet. Cancer.Net is made possible by The ASCO Cancer Foundation, which provides support for cutting-edge cancer research, professional education, and patient information.

Cancer.Net provides timely, oncologist-approved information to help patients and families make informed health-care decisions. All content is subject to a formal peer-review process by the Cancer.Net Editorial Board, composed of more than 150 medical, surgical, radiation, and pediatric oncologists, oncology nurses, social workers, and patient advocates. In addition, ASCO editorial staff reviews the content for easy readability. Cancer.Net content is reviewed on an annual basis or as needed.

To view Cancer.Net ovarian cancer information, click here.

Learn more about How to Read a Medical Abstract in a Research Study, Cancer.Net.

Early Treatment of Recurrent Ovarian Cancer Based Upon Rising CA-125 Levels Does Not Increase Survival

“European researchers report [at the 2009 American Society of Clinical Oncology Annual Meeting being held in Orlando, Florida from May 29 through June 2nd] that starting treatment early for an ovarian cancer relapse based on CA125 blood levels alone does not improve overall survival, compared with delaying treatment until symptoms arise.”

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Researchers Are On The TRAIL To Killing Cancer With Genetically-Engineered Adult Stem Cells

“Researchers in London have demonstrated the ability of adult stem cells from bone marrow (mesenchymal stem cells, or MSCs) to deliver a cancer-killing protein to tumors.  The genetically engineered stem cells are able to home to the cancer cells, both in culture and in mouse models, and deliver TNF-related apoptosis-inducing ligand (TRAIL), destroying the tumor cells while sparing normal cells. …”

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Ginger Quells Cancer Patients’ Chemotherapy-Related Nausea

“People with cancer can reduce post-chemotherapy nausea by 40 percent by using ginger supplements, along with standard anti-vomiting drugs, before undergoing treatment, according to scientists at the University of Rochester Medical Center. …”

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2009 ASCO Annual Meeting Abstracts Now Available Online

2009 ASCO Annual Mtg Logo

The 2009 Annual Meeting of the American Society of Clinical Oncology (ASCO) will be held in Orlando, Florida from May 29 through June 2, 2009. The ASCO Annual Meeting will be a forum for cutting-edge scientific and educational developments in oncology with a focus on personalizing cancer care.  The medical abstracts that will be presented at the 2009 ASCO Annual Meeting were made available for online viewing today at 6:00 P.M. EDT/3:00 P.M. PDT.  Late breaking medical abstracts will be available for viewing no later than 12:00 P.M. EDT on May 31st. Continue reading

Preclinical Results Validate Lpathomab As A Potential Future Treatment for Ovarian Cancer

“Lpath, Inc. … , the category leader in bioactive-lipid-targeted therapeutics, reported compelling new in vivo and in vitro results relating to its preclinical drug candidate, Lpathomab, in various ovarian cancer studies …”

“Lpath Presents Compelling New Preclinical Results of Its Anti-Cancer Drug Candidate, Lpathomab(TM), at the AACR 100th Annual Meeting –

New In Vivo and In Vitro Results Provide Further Validation of Lpathomab as Potential Treatment for Cancer

SAN DIEGO, CA, Apr 20, 2009 (MARKET WIRE via COMTEX)Lpath, Inc. (OTCBB: LPTN), the category leader in bioactivelipid-targeted therapeutics, reported compelling new in vivo and in vitro results relating to its preclinical drug candidate, Lpathomab, in various ovarian cancer studies. The results were presented today by Lpath scientists at the 100th Annual Meeting of the American Association for Cancer Research (AACR) in Denver, Colorado.

Lpathomab is a monoclonal antibody that binds to the bioactive lipid lysophosphatidic acid (LPA) and acts as a molecular sponge to absorb LPA, thereby neutralizing LPA-mediated biological effects on tumor growth, angiogenesis, and metastasis. LPA has been associated with a variety of cancer types, but the correlation with ovarian cancer and breast cancer has been particularly strong.

Using the human ovarian cell line called SKOV3, Lpath’s preclinical studies demonstrated Lpathomab significantly reduced IL-8 and IL-6 cytokine release in SKOV3-conditioned media and blocked tumor-cell migration triggered by LPA (both IL-8 and IL-6 promote tumor angiogenesis and metastasis). More important, Lpathomab inhibited the progression of SKOV3 tumor cells when injected into the peritoneal cavity of mice and reduced levels of pro-metastatic factors in these animals.

Lpathomab also reduced neovascularization (new blood-vessel growth) in two classical angiogenic models and showed preliminary anti-metastatic activity when tested in a classical experimental metastasis model.

According to Roger Sabbadini, Ph.D., Lpath’s founder and chief scientific officer, ‘In view of these promising preclinical results, we believe Lpathomab has the potential to augment the efficacy of current ovarian cancer therapy by blocking the growth-promoting, angiogenic, and metastatic effects of LPA.’

About Lpath

San-Diego-based Lpath, Inc. is the category leader in bioactive-lipid-targeted therapeutics, an emerging field of medical science whereby bioactive signaling lipids are targeted for treating important human diseases. ASONEP(TM), an antibody against Sphingosine-1-Phosphate (S1P), is currently in a Phase 1 clinical trial in cancer patients and also holds promise against multiple sclerosis and various other disorders. ASONEP is being developed with the support of partner Merck-Serono as part of a worldwide exclusive license. A second product candidate, iSONEP(TM) (the ocular formulation of the S1P antibody), has demonstrated superior results in various preclinical models of age-related macular degeneration (AMD) and retinopathy and is in a Phase 1 clinical trial in wet-AMD patients. Lpath’s third product candidate, Lpathomab(TM), is an antibody against lysophosphatidic acid (LPA), a key bioactive lipid that has been long recognized as a valid disease target (cancer, neuropathic pain, fibrosis). The company’s unique ability to generate novel antibodies against bioactive lipids is based on its ImmuneY2(TM) drug-discovery engine, which the company is leveraging as a means to expand its pipeline. For more information, visit www.Lpath.com …”

Sources:

Personalized Medicine Helps Breast, Colorectal & Ovarian Cancer Patients Survive

“Cancer patients can survive longer under treatments based on their individual genetic profiles, according to a nationwide study released jointly today by Phoenix-area healthcare organizations. The study shows that molecular profiling of patients can identify specific treatments for individuals, helping keep their cancer in check for significantly longer periods, and in some cases even shrinking tumors. Study results were released today at the 100th annual meeting of the American Association for Cancer Research in Denver by Dr. Daniel Von Hoff, Physician-In-Chief of the Phoenix-based Translational Genomics Research Institute (TGen), and the study’s Principal Investigator. … Patients experienced varying levels of improvement. Among those with breast cancer, the period of progression-free survival increased for 44 percent of patients; for colorectal, 36 percent of patients; for ovarian, 20 percent of patients; and for miscellaneous cancers the improvement was seen in 16 percent of patients. …” [Emphasis added by Libby’s H*O*P*E*™]


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“Personalized medicine helps cancer patients survive – TGen, Scottsdale Healthcare and Caris Dx clinical trial shows molecular profiling can result in specific treatments for individual patients that significantly limit the growth and spread of tumors

PHOENIX, Ariz. – April 19, 2009 – Cancer patients can survive longer under treatments based on their individual genetic profiles, according to a nationwide study released jointly today by Phoenix-area healthcare organizations.

The study shows that molecular profiling of patients can identify specific treatments for individuals, helping keep their cancer in check for significantly longer periods, and in some cases even shrinking tumors.

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Daniel Von Hoff, M.D., F.A.C.P., Physician in Chief & Senior Investigator, The Translational Genomics Research Institute; Chief Scientific Officer, TGen Clinical Research Services, Scottsdale Healthcare; Clinical Professor of Medicine, University of Arizona Department of Medicine

Study results were released today at the 100th annual meeting of the American Association for Cancer Research in Denver by Dr. Daniel Von Hoff, Physician-In-Chief of the Phoenix-based Translational Genomics Research Institute (TGen), and the study’s Principal Investigator.

The study included 66 patients at nine centers across the United States, including Scottsdale Heathcare. Dr. Von Hoff also is the Chief Scientific Officer of TGen Clinical Research Services (TCRS) at Scottsdale Healthcare, a partnership between TGen and Scottsdale Healthcare that is administered by the Scottsdale Clinical Research Institute (SCRI) at Scottsdale Healthcare.

All of the patients had previously experienced growth of their tumors while undergoing as many as two to six prior cancer treatments, including conventional chemotherapy.

However, after molecular profiling identified precise targets, new treatments were administered that resulted in patients experiencing significant periods of time when there was no progression of their cancer.

This clinical trial was unique because patients acted as their own control,’ said Dr. Von Hoff. ‘We compared each patient’s progression-free survival, following treatment based on molecular profiling, to how their tumors progressed under their prior treatment regimens, before molecular profiling.’

In a significant number of patients, the targeted treatments provided significantly longer periods when tumors did not progress, or even shrunk, said Dr. Von Hoff, who also is a Medical Director of US Oncology and a former Director of the Arizona Cancer Center at the University of Arizona.

Dr. Von Hoff said the new study was done in a way that avoided issues surrounding tumor subtypes and differences in individual biology, which have confounded other clinical trials.

He said this clinical trial demonstrated the value of personalized medicine, in which treatments are prescribed based on an individual’s specific genetic makeup. The type of drugs, dosages, their delivery and other treatment aspects – all are based on each patient’s individual medical needs.

Among the patients, 27 percent had breast cancer, 17 percent had colorectal cancer, 8 percent had ovarian cancer and 48 percent had cancers that were classified as miscellaneous.

Patients experienced varying levels of improvement. Among those with breast cancer, the period of progression-free survival increased for 44 percent of patients; for colorectal, 36 percent of patients; for ovarian, 20 percent of patients; and for miscellaneous cancers the improvement was seen in 16 percent of patients.

‘With this trial, we are showing the power of personalized medicine using the tools we already have available to us. As these tools become more precise and more effective, the value of personalized medicine will increase,’ Dr. Von Hoff said.

The molecular profiling for this research study was performed by Caris Diagnostics (Caris Dx) in Phoenix.

These results are the first in a series of studies in support of Target NowTM, a commercially-available oncology testing service offered exclusively by Caris Dx. Target Now uses cutting-edge molecular profiling techniques, including both DNA microarray and immunohistochemical (IHC) analysis, to provide individualized information about a patient’s tumor as an aid to the treating oncologist.

‘This trial is evidence of an important breakthrough in the treatment of cancer. We are excited to work with Dr. Von Hoff and TGen as we make this important molecular diagnostic information available to physicians to aid in therapy-selection decision making,’ said David D. Halbert, Chairman and CEO of Caris Diagnostics. ‘The valuable information provided through the Target Now panel of tests improves patient care while reducing costs for the payer.’

Clinical studies were conducted by TCRS at the Virginia G. Piper Cancer Center at Scottsdale Healthcare Shea Medical Center. Scottsdale Healthcare is a primary clinical research site for TGen.

‘Patients in our community have access to ground-breaking, world-class research right in their own backyard thanks to this collaboration,’ said Tom Sadvary, president and CEO of Scottsdale Healthcare. ‘Our goal is reducing the time it takes to get new treatment discoveries from the research lab to the patient. We are thrilled to see these advances in personalized medicine taking place right here in Scottsdale.’

The recent clinical study was dubbed the Bisgrove Trial, after longtime Scottsdale Healthcare supporter Jerry Bisgrove. The trial was funded through a $5 million grant from Mr. Bisgrove’s Stardust Foundation to the Scottsdale Healthcare Foundation. Mr. Bisgrove has been a patient at Scottsdale Healthcare and is a member of the Scottsdale Healthcare Foundation Board of Trustees. In honor of the Stardust gift, the research building at the Virginia G. Piper Cancer Center at Scottsdale Healthcare Shea Medical Center is named the Debi and Jerry Bisgrove Research Pavilion.

‘The Stardust Foundation is proud to have played a key role in the advancements in cancer research represented by Dr. Von Hoff’s clinical trial. We believe we are closer than ever to finding a cure for this devastating disease that affects so many millions,’ Mr. Bisgrove said.

*          *          *

About Scottsdale Healthcare
Scottsdale Healthcare is a primary clinical research site for TGen. TGen Clinical Research Services (TCRS) at Scottsdale Healthcare is housed in the Virginia G. Piper Cancer Center at Scottsdale Healthcare, located on the Scottsdale Healthcare Shea medical campus. Scottsdale Healthcare is the not-for-profit parent organization of the Scottsdale Healthcare Shea, Scottsdale Healthcare Osborn and Scottsdale Healthcare Thompson Peak hospitals, Virginia G. Piper Cancer Center, Scottsdale Clinical Research Institute, TGen Clinical Research Services at Scottsdale Healthcare, Scottsdale Healthcare Home Health Services, Scottsdale Healthcare Community Health Services, and Scottsdale Healthcare Foundation. For additional information, visit www.shc.org.

About Scottsdale Clinical Research Institute (SCRI)
SCRI, established in 2005, provides infrastructure and support for the clinical research at Scottsdale Healthcare. Start-up funding for SCRI was provided by a lead gift of $4.5 million from the Virginia G. Piper Charitable Trust in 2005. An additional $5 million was provided by the Stardust Foundation to support this multi-site molecular profiling study of targeted therapies for treatment refractory cancers coordinated by SCRI. A defining feature of SCRI is a focus on genomics and personalized medicine as well as clinical and translational research. The basic science arm of SCRI is provided by a partnership with the Translational Genomics Research Institute (TGen). Innovations from TGen’s laboratory are taken to the bedside at SHC by our joint clinical research program, TGen Clinical Research Services (TCRS) at Scottsdale Healthcare. Additional research collaborations include the University of Arizona, Arizona State University, other local health care delivery systems and participation in the Arizona NIH Clinical and Translational Science Award (CTSA) program initiative. Areas of study at SCRI include Cancer, Cardiovascular, Trauma, Metabolic and Nanomedicine.

Press Contact:
Keith Jones
Public Relations Director
Scottsdale Healthcare
480-882-4412
kjones@shc.org

About TGen
The Translational Genomics Research Institute (TGen) is a non-profit organization dedicated to conducting groundbreaking research with life changing results. Research at TGen is focused on helping patients with diseases such as cancer, neurological disorders and diabetes. TGen is on the cutting edge of translational research where investigators are able to unravel the genetic components of common and complex diseases. Working with collaborators in the scientific and medical communities, TGen believes it can make a substantial contribution to the efficiency and effectiveness of the translational process. For more information, visit: www.tgen.org.

Press Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
syozwiak@tgen.org

About Caris Diagnostics
Caris Diagnostics (Caris Dx) is a leading provider of the highest quality diagnostic, translational development and pharmaceutical services encompassing anatomic pathology and molecular testing. Caris Diagnostics provides world-class pathology services to physicians who treat patients in the community setting. The company provides academic-caliber medical consults through its industry-leading team of subspecialty fellowship and expert-trained pathologists in gastrointestinal and liver pathology, dermatopathology and hematopathology. Caris Diagnostics provides the highest levels of service to its customers and their patients through its state-of-the-art laboratories; proprietary, advanced clinical and technology solutions; and rigorous quality assurance programs. Through the molecular testing expertise of the Caris Molecular Profiling Institute (Caris MPI) at Caris Dx, the company also offers advanced molecular analyses of patient samples through prognostic testing services and genomic and proteomic profiling to provide critical information to physicians treating cancer and other complex diseases. In addition, Caris MPI supports pharmaceutical companies and other researchers in their clinical trials for targeted therapeutics with custom genomic and proteomic analyses, analyte preservation, tissue procurement and comprehensive reporting services. The company has strategic relationships with the International Genomics Consortium, US Oncology, the Translational Genomics Research Institute, and the Biodesign Institute of Arizona State University. More than 2,000 physicians nationally use Caris Diagnostics. Formed in 1996, the company is headquartered in Irving, Texas and operates four laboratories: Irving, Texas; Phoenix, Arizona (2 sites); Newton, Massachusetts. Additional information is available at www.carisdx.com.

Press Contact:
Brian Wright
Caris Dx
(602) 358-8916
bwright@carismpi.com”

Sources:

Genetic Variations In miRNA Processing Pathway & Binding Sites Help Predict Ovarian Cancer Risk

“Genetic variations in the micro-RNA (miRNA) processing pathway genes and miRNA binding sites predict a woman’s risk for developing ovarian cancer and her prospects for survival, researchers from The University of Texas M. D. Anderson Cancer Center reported at the 100th annual meeting of the American Association for Cancer Research. … The unique study was the first to examine the association of genetic variants related to miRNA with ovarian cancer risk, overall survival for ovarian cancer patients, and platinum-based chemotherapy response. …”

Genetic variations in miRNA processing pathway and binding sites help predict ovarian cancer risk – Several variations indicate likelihood of response to platinum-based chemotherapy

DENVER – Genetic variations in the micro-RNA (miRNA) processing pathway genes and miRNA binding sites predict a woman’s risk for developing ovarian cancer and her prospects for survival, researchers from The University of Texas M. D. Anderson Cancer Center reported at the 100th annual meeting of the American Association for Cancer Research.

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Xifeng Wu, M.D., Ph.D., Professor, Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center

‘We found a gene dosage effect, the more unfavorable variations a woman has, the greater her ovarian cancer risk and the shorter her survival time,’ said senior author Xifeng Wu, M.D., Ph.D., professor in M. D. Anderson’s Department of Epidemiology. Median survival, for example, ranged from 151 months for women with fewest unfavorable variations to 24 months for those with the most.

Several variations also indicate likely response to platinum-based chemotherapy.

‘Our findings have the potential clinical application of indicating a patient’s prognosis and showing who will respond to different therapies by analyzing a single blood sample,’ Wu said. ‘We also will incorporate this genetic information with epidemiological information to build a comprehensive model to predict susceptibility to ovarian cancer.’

The team chose the miRNA processing pathway because it is crucial to production of miRNAs, the small molecules that regulate between one third and half of all genes. The researchers also chose the binding sites on host genes where miRNAs exert their effects on gene expression.

They analyzed 219 potential functional single nucleotide polymorphisms (SNPs) – variations of a single DNA building block in a gene – in eight genes that process miRNA and at the miRNA binding sites of 129 cancer-relevant genes. The study examined genetic information from 417 cancer patients and 417 healthy controls. To minimize the possible confounding effects of ethnicity, 339 Caucasian cases and 349 controls were analyzed.

They discovered 12 SNPs to be significantly associated with ovarian cancer risk. Moreover, compared to women with five or fewer unfavorable genotypes, women with eight or more of these unfavorable genotypes were 4.5 times more likely to develop ovarian cancer and women with six to eight unfavorable SNPs were at twice the risk.

The team also found 21 SNPs significantly associated with overall survival. Median survival was 151 months for women with six or fewer unfavorable variations; 42 months for those with seven to nine unfavorable variations; and 24 months for those with 10 or more. One of the outcome risk SNPs also was strongly associated with platinum-based chemotherapy response, with those having the SNP 3.4 times less likely to respond to chemotherapy.

Wu collaborated with Dong Liang, Ph.D, in the College of Pharmacy and Health Sciences, Texas Southern University, and Karen Lu, M.D., professor in M. D. Anderson’s Department of Gynecologic Oncology, on this study.

The unique study was the first to examine the association of genetic variants related to miRNA with ovarian cancer risk, overall survival for ovarian cancer patients, and platinum-based chemotherapy response. Such a wide-ranging inquiry was made possible by M. D. Anderson’s extensive clinical and genetic data sets, Wu said.

Co-authors with Wu, first author Liang, Ph.D., and Lu are; Jie Lin, Ph.D., Xia Pu, Yuanqing Ye, Ph.D., all in the Department of Epidemiology; and Larissa Meyer, M.D., in the Department of Gynecologic Oncology at M. D. Anderson Cancer Center. Pu is a graduate student at The University of Texas Graduate School of Biomedical Sciences at Houston, which is a joint effort of M. D. Anderson and The University of Texas Health Science Center at Houston.

This research was supported by an award by the Department of Defense Ovarian Cancer Research Program.”

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including 2008, M. D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.

Sources:

Tumor-Promoting Protein COX-2 Is The Target Of First Joint Symposium Between AACR & ASCO

An inflammatory protein implicated in a variety of cancers is the target of the first joint symposium between the nation’s two premier cancer research organizations.  The presidents of the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) organized the session focused on the COX-2 enzyme and cancer treatment Monday afternoon — April 20, 2:30-4:30 p.m., in rooms 205-207 of the Colorado Convention Center — at the AACR’s 100th Annual Meeting 2009 in Denver.  A similar symposium on new molecular targets will be conducted at ASCO’s annual meeting in May 29- June 2 in Orlando.  COX-2 is best known as a target for preventing dangerous polyps that lead to colorectal cancer, but it is also advancing as a target for treatment of many solid tumors. …

“Leading cancer organizations team up on tumor-promoting protein – AACR and ASCO begin joint symposia at annual meetings with focus on COX-2

An inflammatory protein implicated in a variety of cancers is the target of the first joint symposium between the nation’s two premier cancer research organizations.

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Raymond DuBois, M.D., Ph.D., President, AACR; Provost and Executive Vice President, The University of Texas M. D. Anderson Cancer Center

The presidents of the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) organized the session focused on the COX-2 enzyme and cancer treatment Monday afternoon — April 20, 2:30-4:30 p.m., in rooms 205-207 of the Colorado Convention Center — at the AACR’s 100th Annual Meeting 2009 in Denver. A similar symposium on new molecular targets will be conducted at ASCO’s annual meeting in May 29- June 2 in Orlando.

COX-2 is best known as a target for preventing dangerous polyps that lead to colorectal cancer, but it is also advancing as a target for treatment of many solid tumors.

‘Our symposium is timely because we are starting to see data from Phase II and Phase III clinical trials about COX-2 inhibition following post-surgical chemotherapy in colon cancer patients,’ said Raymond DuBois, M.D., Ph.D., president of AACR and provost and executive vice president at The University of Texas M. D. Anderson Cancer Center.

‘There’s been a great deal of preclinical and translational research addressing COX-2 overexpression in tumors and its role in cancer growth and survival. In prevention, inhibiting this enzyme reduces the number of high-risk precancerous polyps by 66 percent,’ DuBois said. ‘The time is ripe to combine basic science and clinical expertise to advance the therapeutic potential of this approach.’

Joint efforts are critical to the development of new approaches against cancer, said ASCO President Richard L. Schilsky, M.D., professor of medicine at the University of Chicago Medical Center.

‘The development of targeted therapies for cancer prevention and treatment requires the close collaboration and combined resources of basic scientists and clinical investigators,’ Schilsky said. ‘The success of targeted therapy for cancer depends first and foremost on a comprehensive understanding of the biology of the drug target coupled with a robust assay to assess target inhibition and a drug that hits the target. With these ingredients in place, clinical trials can be designed to assess the impact of treatment in the population most likely to benefit.’

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Richard L. Schilsky, M.D., President, ASCO; Associate Dean for Clinical Research, Professor of Medicine at the University of Chicago Medical Center.

‘The AACR/ASCO Symposium illustrates these core principles and demonstrates that continued progress against cancer requires the partnership of all investigators and practitioners represented by these two great organizations,’ Schilsky said.

The idea for joint symposia at each organization’s annual meeting has been discussed for years and was advanced by immediate past presidents William Hait, M.D., Ph.D., of AACR and Nancy Davidson, M.D., of ASCO.

DuBois and Schilsky co-chair the symposium. Scheduled presentations are:

  • COX-2 and Cancer Biology by DuBois, who discovered the enzyme’s overexpression in tumors.
  • Overview of COX-2 as a Target for Cancer Treatment, by Schilsky.

*          *          *

AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. ASCO is the world’s leading professional organization representing physicians who care for people with cancer. Many scientists and physicians are members of both organizations.”

Source: Leading Cancer Organizations Team Up on Tumor-Promoting Protein – AACR and ASCO begin joint symposia at annual meetings with focus on COX-2, M.D. Anderson News Release, The University of Texas M.D. Anderson Cancer Center, April 17, 2009.

Comment:  The relationship between ovarian cancer and COX-2 remains unclear.  Some in vitro and in vivo studies make a connection between ovarian cancer and COX-2, while others suggest that COX-1 is more relevant to current ovarian cancer research.  It is an area that warrants further investigation.

Recent Studies Re Ovarian Cancer and COX-2:

Early Detection Remains Key in Updated National Comprehensive Cancer Network (NCCN) Guidelines for Ovarian Cancer

New updates to the NCCN Clinical Practice Guidelines in Oncology™ for Ovarian Cancer were presented at the NCCN 14th Annual Conference on March 14. Notable additions to the NCCN Guidelines are a section on managing allergic reactions to chemotherapy agents and new agents for recurrence therapy. Robert J. Morgan Jr., M.D., F.A.C.P. of  the City of Hope Comprehensive Cancer Center presented the updated NCCN Guidelines that continue to stress early detection of ovarian cancer and the enrollment of patients in clinical trials.

“Early Detection Remains Key in Updated NCCN Guidelines for Ovarian Cancer


New updates to the NCCN Clinical Practice Guidelines in Oncology™ for Ovarian Cancer were presented at the NCCN 14th Annual Conference on March 14. Notable additions to the NCCN Guidelines are a section on managing allergic reactions to chemotherapy agents and new agents for recurrence therapy. Robert J. Morgan, MD, of City of Hope Comprehensive Cancer Center presented the updated NCCN Guidelines that continue to stress early detection of ovarian cancer and the enrollment of patients in clinical trials.


March 16, 2009

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Robert J. Morgan Jr., M.D., F.A.C.P., Professor of Medical Oncology, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA & Chair of the NCCN Guidelines Panel for Ovarian Cancer

HOLLYWOOD, FL — Improvements in screening and early detection remains the key for women with ovarian cancer according to Robert J. Morgan, MD, of City of Hope Comprehensive Cancer Center and chair of the NCCN Guidelines Panel for Ovarian Cancer. Dr. Morgan discussed the future of ovarian cancer and notable changes to the recently updated NCCN Ovarian Cancer Guidelines at the NCCN Annual Conference on Saturday, March 14.

Dr. Morgan began by explaining that the major challenge in treating ovarian cancer is that by the time the majority of patients (70 percent) are diagnosed with the disease, it has already progressed to stage III or IV. ‘We have not yet found a good way to screen the general population or even the high-risk population of women for ovarian cancer,’ he said.

New to the NCCN Guidelines is a section on the management of allergic reactions in patients receiving chemotherapy for ovarian cancer. Dr. Morgan explained the need for this section as ovarian cancer tends to respond to the same treatment repeatedly. Combined with the fact that recurrence rates of ovarian cancer are high, this can result in patients often being retreated with the same chemotherapeutic agent. Given that virtually all chemotherapy drugs have the potential to cause infusion reactions, including agents commonly used in ovarian cancer, the NCCN Guidelines Panel felt it was important to provide information on allergic reactions and recommendations on desensitization regimens.

‘Most patients experiencing allergic reactions are able to be desensitized allowing for continued chemotherapeutic treatment, which is vital to the management of ovarian cancer,’ said Dr. Morgan.

Also new to the updated NCCN Guidelines is the addition of new agents for recurrence therapy, most notably pemetrexed (Alimta®, Eli Lilly and Company) as well as recommendations for therapies based on the timing of recurrence.

‘Seventy-five to 80 percent of patients with stage III or IV ovarian cancer will experience recurrence and this recurrence can occur at any time – during treatment, within 6 months of completing treatment, or more than a year after completing treatment,’ Dr. Morgan noted. ‘In the updated NCCN Guidelines, we differentiated appropriate therapy for recurrence based upon the time frame on which it occurs.’

Additionally, Dr. Morgan referred to a clinical trial suggesting that pemetrexed is active in recurrent ovarian cancer, to support the new recommendation in the updated NCCN Guidelines.

Dr. Morgan described new updates to the Principles of Primary Surgery section in the updated NCCN Guidelines that included the recommendation to consider completion surgery for patients responsive to chemotherapy with initially unresectable residual disease, as well as recommendations relating to special circumstances including minimally-invasive procedures, and fertility sparing procedures.

Dr. Morgan also discussed recent clinical studies conducted abroad that studied the effect of chemotherapy as an up-front therapy in patients with ovarian cancer, and concluded that ‘in the United States, up-front debulking surgery remains the recommendation for the best overall survival.’

Another addition to the updated NCCN Guidelines is a section on the Principles of Chemotherapy. This section emphasizes the encouragement of patients participating in clinical trials during all aspects of their treatment course as well as noting that patients with newly diagnosed tumors should be informed about the different options available, particularly IV [intravenous] vs. IV/IP chemotherapy and the risks and benefits of each regimen.

‘The future of ovarian cancer lies in early detection and improvements in screening,’ Dr. Morgan noted as he discussed potential biomarkers for the detection, prediction and prognostication of ovarian cancer.

He concluded that steady progress is being made in the treatment of ovarian cancer, but further trials are necessary to investigate the role of targeted agents alone and in combination in newly diagnosed and recurrent ovarian cancer. Finally, he again stressed the need for physicians to encourage their patients to participate in clinical trials.

For questions about NCCN or for interview information, please contact Megan Martin 215.690.0576.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. For more information, visit www.nccn.org.

The NCCN Member Institutions are

Cited SourceEarly Detection Remains Key in Updated NCCN Guidelines for Ovarian Cancer, News, National Comprehensive Cancer Network (NCCN), March 16, 2009.

Libby’s H*O*P*E*(tm) Adds New Cancer Video Archive Courtesy of Vodpod.com

Yesterday, Libby’s H*O*P*E* added a new cancer video archive to the weblog courtesy of Vodpod.com.  Currently, the archive contains approximately 90 videos that address many general cancer and ovarian cancer issues, as well as the personal voices of those affected by cancer. The new video archive is located on the homepage right sidebar.  All you have to do is “click and play.”

vodpod-logoYesterday, Libby’s H*O*P*E* added a new cancer video archive to the weblog courtesy of Vodpod.com.  Currently, the archive contains approximately 90 videos that address many general cancer and ovarian cancer issues, as well as the personal voices of those affected by cancer. The new video archive is located on the homepage right sidebar.  All you have to do is “click and play.”  The video arrangement is set to “random order” so that new videos appear on the homepage sidebar each time you visit Libby’s H*O*P*E*.

If you are aware of a general cancer/ovarian cancer video that is educational, heartfelt, inspirational, humorous, poignant, or is simply dedicated to the one you love, please provide us with the URL address of the video.  The URL video address can be sent to us by email (click on the “contact” button located at the top of the homepage), or by comment (post a comment under this post).  Upon receipt of the video URL address, we will add the referenced video to the new archive.  We appreciate your participation in adding to our video archive and hope you find the archive helpful.