Novel “Jantibody Fusion Protein” Cancer Vaccine Holds Promise Against Ovarian Cancer

A novel approach to cancer immunotherapy – strategies designed to induce the immune system to attack cancer cells – may provide a new and cost-effective weapon against some of the most deadly tumors, including ovarian cancer and mesothelioma.

A novel approach to cancer immunotherapy – strategies designed to induce the immune system to attack cancer cells – may provide a new and cost-effective weapon against some of the most deadly tumors, including ovarian cancer and mesothelioma. Investigators from the Massachusetts General Hospital (MGH) Vaccine and Immunotherapy Center (VIC) report in the Journal of Hematology & Oncology that a protein engineered to combine a molecule targeting a tumor-cell-surface antigen with another protein that stimulates several immune functions prolonged survival in animal models of both tumors.

“Some approaches to creating cancer vaccines begin by extracting a patient’s own immune cells, priming them with tumor antigens and returning them to the patient, a process that is complex and expensive,” says Mark Poznansky, M.D., Ph.D., director of the MGH Vaccine and Immunotherapy Center and senior author of the report. “Our study describes a very practical, potentially broadly applicable and low-cost approach that could be used by oncologists everywhere, not just in facilities able to harvest and handle patient’s cells.”

The MGH team’s vaccine stimulates the patient’s own dendritic cells, a type of immune cell that monitors an organism’s internal environment for the presence of viruses or bacteria, ingests and digests pathogens encountered, and displays antigens from those pathogens on their surface to direct the activity of other immune cells. As noted above, existing cancer vaccines that use dendritic cells require extracting cells from a patient’s blood, treating them with an engineered protein or nucleic acid that combines tumor antigens with immune-stimulating molecules, and returning the activated dendritic cells to the patient.

Fusion protein activates immune cells against tumors. The Jantibody fusion protein, combining an antibody fragment targeting an antigen found on tumor cells with an immune-response-inducing protein (MTBhsp70), activates dendritic cells against several tumor antigens and induces a number of T-cell-based immune responses. (Jianping Yuan, PhD, MGH Vaccine and Immunotherapy Center)

The approach developed by the MGH team starts with the engineered protein, which in this case fuses an antibody fragment targeting a protein called mesothelin – expressed on the surface of such tumors as mesothelioma, ovarian cancer and pancreatic cancer – to a protein from the tuberculosis bacteria that stimulates the activity of dendritic and other immune cells. In this system, the dendritic cells are activated and targeted against tumor cells while remaining inside the patient’s body.

In the experiments described in the paper, the MGH team confirmed that their mesothelin-targeting fusion protein binds to mesothelin on either ovarian cancer or mesothelioma cells, activates dendritic cells, and enhances the cells’ processing and presentation of several different tumor antigens, inducing a number of T-cell-based immune responses. In mouse models of both tumors, treatment with the fusion protein significantly slowed tumor growth and extended survival, probably through the activity of cytotoxic CD8 T cells.

“Many patients with advanced cancers don’t have enough functioning immune cells to be harvested to make a vaccine, but our protein can be made in unlimited amounts to work with the immune cells patients have remaining,” explains study co-author Jeffrey Gelfand, MD, senior scientist at the Vaccine and Immunotherapy Center. “We have created a potentially much less expensive approach to making a therapeutic cancer vaccine that, while targeting a single tumor antigen, generates an immune response against multiple antigens. Now if we can combine this with newly-described ways to remove the immune system’s “brakes” – regulatory functions that normally suppress persistent T-cell activity – the combination could dramatically enhance cancer immunotherapy.”

Poznansky adds that the tumors that might be treated with the mesothelin-targeting vaccine – ovarian cancer, pancreatic cancer and mesothelioma – all have poor survival rates. “Immunotherapy is generally nontoxic, so this vaccine has the potential of safely extending survival and reducing the effects of these tumors, possibly even cutting the risk of recurrence. We believe that this approach could ultimately be used to target any type of cancer and are currently investigating an improved targeting approach using personalized antigens.” The MGH team just received a two-year grant from the Department of Defense Congressionally Directed Medical Research Program to continue their research.

Poznansky is an associate professor of Medicine, and Gelfand is a clinical professor of Medicine at Harvard Medical School. Jianping Yuan, Ph.D., of the MGH Vaccine and Immunotherapy Center (VIC) is the lead author of the Journal of Hematology and Oncology report. Additional co-authors include Pierre LeBlanc, Ph.D., Satoshi Kashiwagi M.D., Ph.D., Timothy Brauns, and Svetlana Korochkina, Ph.D., MGH VIC; and Nathalie Scholler, M.D., Ph.D., University of Pennsylvania School of Medicine.

The authors dedicate their report to Janet Gelfand, the wife of Jeffrey Gelfand, who died of ovarian cancer in 2006 and inspired their investigation. In her honor they named their tumor-targeting fusion protein “Jantibody.” Support for the study includes grants from the Edmund Lynch Jr. Cancer Fund, Arthur Luxenberg Esq., Perry Weitz Esq., the VIC Mesothelioma Research and Resource Program, and the Friends of VIC Fund.

Massachusetts General Hospital, founded 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 $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

Sources:

• Novel cancer vaccine holds promise against ovarian cancer, mesothelioma — Antigen-targeting fusion protein should be less expensive, more accessible than current approaches, Massachusetts General Hospital, Press Release, March 5, 2014.

• Yuan J et al., A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma. J Hematol Oncol. 2014 Feb 24;7(1):15. doi: 10.1186/1756-8722-7-15. (Abstract – PMID: 24565018; Full Text – PMCID: PMC3943805)

Caris Life Sciences Launches Molecular Profiling Service For Ovarian Cancer Patients

Caris Life Sciences announces the launch of a new molecular profiling service for ovarian cancer patients

Caris Life Sciences, Inc. (Caris), a leading biosciences company focused on enabling precise and personalized healthcare through the highest quality anatomic pathology, molecular profiling, and blood-based diagnostic services, announced the launch of a new, Caris Target Now™ molecular profile for ovarian cancer patients. This expansion of the Caris Target Now™ offering provides individualized molecular information to treating physicians, relevant to the selection of therapies to treat this highly-lethal cancer. Ovarian cancer affects more than 20,000 women annually and produces some of the highest five-year mortality rates found among the 200+ types of cancer.

Caris Target Now™ molecular profiling examines the unique genetic and molecular make-up of each patient’s tumor so that treatment options may be matched to each patient individually.  Caris Target Now™ helps patients and their treating physicians create a cancer treatment plan based on the tumor tested. By comparing the tumor’s information with data from published clinical studies by thousands of the world’s leading cancer researchers, Caris can help determine which treatments are likely to be most effective and, just as important, which treatments are likely to be ineffective.

The Caris Target Now™ test is performed after a cancer diagnosis has been established and the patient has exhausted standard of care therapies or if questions in therapeutic management exist. Using tumor samples obtained from a biopsy, the tumor is examined to identify biomarkers that may have an influence on therapy. Using this information, Caris Target Now™ provides valuable information on the drugs that will be more likely to produce a positive response. Caris Target Now™ can be used with any solid cancer such as lung cancer, breast cancer, prostate cancer, and now, ovarian cancer.

Evidence Behind Caris Target Now™

Daniel D. Von Hoff, M.D., F.A.C.P., is the Executive Director of Caris Life Sciences' Clinical Research

A multi-center, prospective, pilot study first published in The Journal of Clinical Oncology (JCO) in October 2010 [1] — along with an accompanying editorial [2] —  determined that personalized cancer treatment tailored to a tumor’s unique genetic make-up identified therapies that increased progression free survival (PFS) over previous therapies in 27% of patients with advanced disease.

The purpose of the study was to compare PFS using a treatment regimen based on the molecular profiling (MP) of a patient’s tumor with the PFS determined for the most recent regimen on which the patient had experienced progression after taking that regimen for 6 weeks.  Unlike a typical control study, each patient was his or her own study control.  Tissue samples from patients with refractory metastatic cancer were submitted for MP in two formats including:

• formalin-fixed tissue for immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) assays; and
• immediately frozen tissue for oligonucleotidemicroarray (MA) gene expression assays.

In many of these refractory tumors, targets for conventional therapies were identified, which was “a surprise finding,” according to Dr. Daniel Von Hoff, the Executive Director of Caris’ Clinical Research.  But the profiling also suggested therapies in cases where the treating physician was unsure regarding the next line of treatment. The MP approach was found to have clinical benefit for the individual patient who had a PFS ratio (PFS on MP selected therapy/PFS on prior therapy) of ≥ 1.3.  Among the 86 patient tumors that were profiled with Caris Target Now™:

• 
  84 (98%) had a detected molecular target;
• 
  66 of the 84 patients were treated with therapies that were linked to their MP results; and
• 18 (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38% range; one-sided, one-sample P = .007).

The study investigators concluded that it is possible to identify molecular targets in patients’ tumors. In 27% of the patients, the MP approach resulted in a longer PFS on a MP-based regimen than on the regimen that was based on physician’s choice.  “It was also encouraging to see that the overall survival in these 18 patients was better than that for the whole group of 66 patients (9.7 vs. 5 months),” said Von Hoff.

Of the 66 participants, 27% had breast cancer, 17% had colorectal cancer, and 8% had ovarian cancer; the remainder were classified as miscellaneous.  The improvement in PFS among the various types of cancer patients was as follows: 44% in patients with breast cancer, 36% in those with colorectal cancer, 20% in those with ovarian cancer, and 16% in the miscellaneous group.

The investigators in the study utilized Caris Target Now™ molecular profiling, which is currently available to oncologists and their patients.

“Oncologists commonly expect a 1-in-20 chance of patient response in 3rd- and 4th-line therapies.  This recent study suggests those odds can be improved to 1-in-4 when using therapeutic guidance provided by Caris Target Now™.”

— Dr. Jeff Edenfield, a practicing oncologist with US Oncology, and routine user of Caris Target Now™

Since 2008, more than 15,000 cancer patients have received a Caris Target Now™ molecular profile. Caris Target Now™ has been designed to provide treating physicians with therapeutic options, often identifying anti-tumor agents that may not have been considered before. The Caris Target Now™ report is based on the genetic make-up of an individual patient’s tumor cross-referenced with a vast and growing proprietary database of clinical literature, correlating genetic tumor information to therapeutic response. Using biomarker-based therapies has been linked to the likelihood of a positive patient response.

James H. Doroshow, M.D., Director, Division of Cancer Treatment & Diagnosis, National Cancer Institute

In the accompanying JCO editorial, James H. Doroshow, M.D., the Director of the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis, commented that the study by Von Hoff et. al. possessed several limitations. [2] The stated limitations of the study include (i) uncertainty surrounding the achievement of the study’s primary end point based upon use of the time-to-disease progression (TTP) index; (ii) limited prior experience with patients as their own controls, and (iii) lack of study randomization.  Despite these limitations, Dr. Doroshow noted that important lessons can be learned from the study conducted by Von Hoff et. al.

“First and foremost, this study vividly reminds us that the need for therapeutic intervention arises one patient at a time. When we sit with an individual who is trying to live with an advanced solid tumor after having already received several different chemotherapy regimens, it is unlikely that any published prognostic index or gene signature, as currently implemented, will be of much help in decision making—for physicians or for patients. [citation omitted]. Thus, a truly urgent need exists to move past the empiric therapeutic paradigm that launched the first half century of systemic oncologic treatment. [citation omitted]. Von Hoff et al have taken a noteworthy, albeit somewhat flawed, first step in this direction in their attempt to imagine a novel paradigm for cancer therapy, using the techniques of molecular tumor characterization on an individual patient basis. Future investigators of new cancer therapies should learn from this initial effort and focus on how these rapidly evolving molecular tools can be used in the development of an entirely new investigative model for the systemic treatment of cancer.”

Caris is currently conducting and initiating additional studies of Caris Target Now™ molecular tumor profiling through collaboration with leading institutions and cancer centers.

With 300% growth in utilization in 2010, medical oncologists are recognizing the utility and value of this novel approach in providing improved care to patients. Physician adoption is rapidly accelerating, as Caris recently reached the threshold of providing Caris Target Now™ services to more than 1,000 patients per month. This new introduction for ovarian cancer is most relevant for physicians treating women who have progressed on platinum-based therapy and/or who need guidance for third-line treatment options. Caris Target Now™ for ovarian cancer offers the opportunity for these women to benefit from personalized and targeted therapy guidance based upon molecular profiling.

“Ovarian cancer is a highly-lethal cancer that presents distinct diagnostic and therapeutic challenges, often presenting no major symptoms until the cancer has metastasized,” said Dr. Les Paul, Caris’ Senior Vice President for Medical Affairs. “Choosing the optimal therapeutic intervention at the earliest possible stage is critical to extending progression free survival in ovarian cancer patients. With the introduction of the Caris Target Now™ ovarian profile, we are able to support physicians with as much information as possible, including the latest relevant clinical literature citations to aid them in making the best therapeutic decision possible for each patient.”

Examples of the potential use of an existing clinical trial drug to target a specific molecular characteristic possessed by an ovarian cancer include:

• dasatinib (Sprycel) for Src positive ovarian cancer; [3-5]
• PARP inhibitors for BRCA gene-mutated (hereditary) ovarian cancer; [6-9]
• PI3K inhibitors for PIK3CA gene-mutated ovarian cancer; [10] and
• EC145 for folate-receptor positive ovarian cancer. [11]

Use of Molecular Profiling By Leading Medical Institutions; Sponsorship By A Charitable Foundation

It should be noted that molecular profiling is already being used in clinical practice at several leading cancer institutions.  At Massachusetts General Hospital, (MGH), The MGH Cancer Centre uses a PCR-based mutation-detection assay and state-of-the-art robotic technology, called “SNaPshot,” to look for 130 known gene mutations in tumor tissue. “We are already using molecular profiling for all our lung cancer patients,” said Jeffrey Settleman, Ph.D., scientific director at the MGH Cancer Center, to Medscape Oncology in 2009. [12] “This has already had an impact on treatment decisions, and it appears to be improving treatment. We have seen better response rates and we hope that this will translate into better survival.”  In fact, MGH is engaged currently in the largest study aimed at matching tumor genomes to potential anticancer treatments. [13] It is our understanding that MGH performs molecular profiling currently on melanoma, leukemia, brain and metastatic breast cancer, and metastatic adenocarcinoma that start in the lung, colon or rectum.

Several other institutions are in the process of developing or have developed their own systems, including the University of Texas M.D. Anderson Cancer Center [14], and the Dana-Farber Cancer Institute [15].  All are striving to profile individual tumors so that therapy can be personalized, which means that it has a better chance of working because it targets specific mutations found in a patient’s tumor. The MP approach also prevents patients from being exposed to drugs that have a limited chance of success, eliminating toxicity and improving quality of life.

We should also note the Clearity Foundation sponsors molecular profiling services on behalf of ovarian cancer patients at no cost. The Clearity Foundation is a 501(c)(3) not-for-profit, founded by Laura Shawver, Ph.D., who is an ovarian cancer survivor and research scientist.  The Clearity Foundation seeks to improve treatment outcomes in recurrent and progressive ovarian cancer patients by providing diagnostic services that determine the molecular profile of the individual patient with the belief that a molecular “blueprint” is crucial to finding appropriate treatments.

About Caris Target Now™

Caris Target Now™ is a comprehensive tumor analysis coupled with an exhaustive clinical literature search, which matches appropriate therapies to patient-specific biomarker information to generate an evidence-based treatment approach. Caris Target Now™ testing provides information that may help when considering potential treatment options.

Caris Target Now™ begins with an immunohistochemistry (IHC) analysis. An IHC test measures the level of important proteins in cancer cells providing clues about which therapies are likely to have clinical benefit and then what additional tests should be run.

If there is access to a frozen sample of patient tissue available, Caris may also run a gene expression analysis by microarray. The microarray test looks for genes in the tumor that are associated with specific treatment options.

As deemed appropriate based on each patient, Caris will run additional tests. Fluorescent In-Situ Hybridization (FISH) is used to examine gene copy number variation (i.e., gene amplification) in the tumor. Polymerase Chain Reaction (PCR) or DNA sequencing is used to determine gene mutations in the tumor DNA.

Caris takes the results from each test and applies the published findings from thousands of the world’s leading cancer researchers. Based on this analysis, Caris Target Now™ identifies potential therapies for patients and their treating physicians to discuss.

Caris Target Now™ was developed and its performance characteristics were determined by Caris, a CLIA-certified medical laboratory in compliance with the U.S. Clinical Laboratory Amendment Act of 1988 and all relevant U.S. state regulations. It has not been approved by the United States Food and Drug Administration.

About Caris Life Sciences

Caris Life Sciences, a leading biosciences company, specializes in the development and commercialization of the highest quality anatomic pathology, molecular profiling, and blood-based diagnostic technologies, in the fields of oncology, dermatopathology, hematopathology, gastrointestinal pathology and urologic pathology. The company provides academic-caliber consultations for patients every day, through its industry-leading team of expert, subspecialty pathologists. Caris also offers advanced molecular analyses of patient samples through prognostic testing services and genomic, transcriptomic, and proteomic profiling to assist physicians in their treatment of cancer. Currently, Caris is developing the Carisome™ platform, a proprietary, blood-based technology for diagnosis, prognosis, and theranosis of cancer and other complex diseases. The company is headquartered in the Dallas metroplex, and operates laboratories at the headquarters, as well as in the Phoenix and Boston metro areas.

About Daniel Von Hoff, M.D., FACP, Executive Director, Caris Life Sciences Clinical Research

Daniel D. Von Hoff, M.D., is currently physician-in-chief and director of translational research at Translational Genomics Research Institute (TGen) in Phoenix, Arizona. He is also chief scientific officer for US Oncology and the Scottsdale Healthcare’s Clinical Research Institute.  He holds an appointment as clinical professor of medicine at the University of Arizona College of Medicine.

Dr. Von Hoff’s major interest is in the development of new anticancer agents, both in the clinic and in the laboratory. He and his colleagues were involved in the beginning of the development of many of the agents now in routine use, including: mitoxantrone, fludarabine, paclitaxel, docetaxel, gemcitabine, irinotecan, nelarabine, capecitabine, lapatinib and others.

At present, Von Hoff and his colleagues are concentrating on the development of molecularly targeted therapies particularly for patients with advanced pancreatic cancer. Dr. Von Hoff’s laboratory interests and contributions have been in the area of in vitro drug sensitivity testing to individualize treatment for the patient, mechanisms of gene amplification, particularly of extrachromosomal DNA, and understanding of and targeting telomere maintenance mechanisms. His laboratory work now concentrates on the discovery of new targets in pancreatic cancer.

Dr. Von Hoff has published more than 543 papers, 133 book chapters, and more than 956 abstracts. Dr. Von Hoff  also served on President Bush’s National Cancer Advisory Board from June 2004 through March 2010.

Dr. Von Hoff is the past president of the American Association for Cancer Research(AACR) (the world’s largest cancer research organization), a fellow of the American College of Physicians, and a member and past board member of the American Society of Clinical Oncology (ASCO). He is a founder of ILEX™ Oncology, Inc. (acquired by Genzyme after Ilex had 2 agents, alemtuzumab and clofarabine approved for patients with leukemia). He is founder and the editor emeritus of Investigational New Drugs – The Journal of New Anticancer Agents; and, editor-in-chief of Molecular Cancer Therapeutics. He is also proud to have been a mentor and teacher for multiple medical students, medical oncology fellows, graduate students, and post-doctoral fellows. He is a co-founder of the AACR/ASCO Methods in Clinical Cancer Research Workshop.

References:

1/ Von Hoff DD, Stephenson JJ Jr, Rosen P, et. al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010 Nov 20;28(33):4877-83. Epub 2010 Oct 4. PubMed PMID: 20921468.

2/ Doroshow JH. Selecting systemic cancer therapy one patient at a time: Is there a role for molecular profiling of individual patients with advanced solid tumors? J Clin Oncol. 2010 Nov 20; 28(33):4869-71. Epub 2010 Oct 4. PMID: 20921466.

3/Addition of Dasatinib (Sprycel) to Standard Chemo Cocktail May Enhance Effect in Certain Ovarian Cancers, by Paul Cacciatore, Libby’s H*O*P*E*™, April 19, 2009.

4/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 11, 2009.

5/BMS-345541 + Dasatinib Resensitizes Carboplatin-Resistant, Recurrent Ovarian Cancer Cells, by Paul Cacciatore, Libby’s H*O*P*E*™, July 1, 2010.

6/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.

7/ Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009 Jul 9;361(2):123-34. Epub 2009 Jun 24. PMID: 19553641.

8/Audeh MW, Penson RT, Friedlander M, et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol 2009;27(supplement):p. 15S.

9/PARP Inhibitor MK-4827 Shows Anti-Tumor Activity in First Human Clinical Study, by Paul Cacciatore, Libby’s H*O*P*E*™,  November 17, 2010.

10/PI3K Pathway: A Potential Ovarian Cancer Therapeutic Target?, by Paul Cacciatore, Libby’s H*O*P*E*™,  November 20, 2009.

11/Endocyte’s EC145 Produces Significant Anti-Tumor Activity In Advanced Stage Chemoresistant Ovarian Cancer Patients, by Paul Cacciatore, Libby’s H*O*P*E*™, October 21, 2009.

12/Massachusetts General Hospital Cancer Center To Genetically Profile All Patient Tumors, by Paul Cacciatore, Libby’s H*O*P*E*™, March 14, 2009.

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

14/An Initiative for Molecular Profiling in Advanced Cancer Therapy (IMPACT) Trial. A Molecular Profile-Based Study in Patients With Advanced Cancer Treated in the Investigational Cancer Therapeutics Program, University of Texas M.D. Anderson Cancer Center, ClinicalTrials.gov Identifier: NCT00851032.

15/Dana-Farber Researchers “OncoMap” The Way To Personalized Treatment For Ovarian Cancer, by Paul Cacciatore, Libby’s H*O*P*E*™, November 16, 2010.

Sources:

• Caris Life Sciences Launches Caris Target Now™ Ovarian Profile, Press Release, Caris Life Sciences, January 12, 2011.

• AACR 2009: Molecular Profiling of Tumors Improves Cancer Treatment, written by Zosia Chustecka, American Association for Cancer Research (AACR) 100th Annual Meeting (2009), Medscape Medical News, Medscape Today, April 21, 2009.

Additional Information:

• Caris Target Now Test List [Adobe Reader PDF doc.] & Information For Ordering Physicians.
• The Clearity Foundation (www.clearityfoundation.org)

Lab-On-A-Chip: Veridex & MGH Collaborate On Next-Generation Circulating Tumor Cell Test

Veridex, LLC announces a collaboration with Massachusetts General Hospital to develop and commercialize a next-generation circulating tumor cell technology for capturing, counting and characterizing tumor cells found in patients’ blood.

Yesterday, Veridex, LLC (Veridex) announced a collaboration with Massachusetts General Hospital (MGH) to develop and commercialize a next-generation circulating tumor cell (CTC) technology for capturing, counting and characterizing tumor cells found in patients’ blood. The collaboration will involve Ortho Biotech Oncology Research & Development (ORD), a unit of Johnson & Johnson Pharmaceutical Research & Development. It focuses on the development of a next-generation system that will enable CTCs to be used both by oncologists as a diagnostic tool for personalizing patient care, as well as by researchers to accelerate and improve the process of drug discovery and development.

The collaboration will rely on the collective scientific, technical, clinical, and commercial expertise between the partners: MGH’s experience in clinical research and novel CTC technologies; the experience of Veridex as the only diagnostics company to have brought CTC technology to the U.S. market as an FDA-cleared in vitro diagnostic (IVD) assay ( “CellSearch® CTC Test”) for capturing and counting the number of tumor cells in the blood to help inform patients and their physicians about prognosis and overall survival in certain types of metastatic cancers; and ORD’s expertise in oncology therapeutics, biomarkers and companion diagnostics.  The platform to be developed will be a bench-top system to specifically isolate and explore the biology of rare cells at the protein, RNA and DNA levels.

“This new technology has the potential to facilitate an easy-to-administer, non-invasive blood test that would allow us to count tumor cells, and to characterize the biology of the cells,” said Robert McCormack, Head of Technology Innovation and Strategy, Veridex. “Harnessing the information contained in these cells in an in vitro clinical setting could enable tools to help select treatment and monitor how patients are responding.”

“The role of CTCs in drug discovery and development is growing as new technologies allow us to use CTCs for the first time as templates for novel DNA, RNA and protein biomarkers,” said Nicholas Dracopoli, Vice President, Biomarkers, ORD. “Given the demand for actionable data to guide personalized medicine for patients with cancer, there is a rapidly growing need for advanced, automated non-invasive technologies that can aid in selection of treatment and monitor response throughout the course of their disease.”

Mehmet Toner, Ph.D., Professor of Surgery, Massachusetts General Hospital (MGH) & Harvard Medical School; Director, MGH BioMicro- ElectroMechanical Systems Resource Center

“The challenging goal of sorting extremely rare circulating tumor cells from blood requires continuous technological, biological and clinical innovation to fully explore the utility of these precious cells in clinical oncology,” said Mehmet Toner, Ph.D., director of the BioMicroElectroMechanical Systems Resource Center in the MGH Center for Engineering in Medicine. “We have developed and continue to develop a broad range of technologies that are evolving what we know about cancer and cancer care. This collaboration is an opportunity to apply our past learning to the advancement of a platform that will ultimately benefit patients with cancer.”

Building on its successful development and evolution of CTC technology, as well as contributions to the body of science in the CTC field, MGH aims to revolutionize how oncologists detect, monitor and potentially treat cancers.  The MGH team has already developed two generations of a microfluidic chip capable of capturing CTCs with a high rate of efficiency. However the third generation technology now being developed with the companies is based on a new technological platform and will aim for even higher sensitivity, as well as suitability for broad applications and ready dissemination.

In the above demonstration of the first generation CTC-Chip, circulating tumor cells (fluorescent labeled, shown in white) mixed with blood (not labeled) are captured on nano-scale posts as they flow through the chip. The chip is the size of a microscope slide with 78,000 posts, which are coated with antibodies to epithelial cell adhesion molecules in tumor cells. (Video courtesy of Dr. Sunitha Nagrath, Massachusetts General Hospital/Harvard Medical School)

“This agreement is quite different from the usual academic-industrial agreement because we will be working together to bring new MGH-invented technology from its current, very early stage, through prototype and scale-up, to our ultimate goals of FDA approval and clinical adoption,” says Dr. Toner. “Our innovation team will be dedicated to developing this technology from its basic scientific principles all the way to initial prototyping within the biological research and clinical environments. Veridex has the knowledge required to translate early-stage technology into a product that can be reliably manufactured and meet regulatory requirements.

“Applying data gathered from CTCs to the care of cancer patients is a complex problem, and our strategy is to diversify technological approaches to find the best solutions for specific applications,” Toner adds. “We may find that different technologies work better for diagnosis, for prognosis and for the long-term goal of early detection; so we don’t want to confine ourselves to a single option.” His team is continuing to develop the microfluidic chip technology, with the support of Stand Up to Cancer.

Daniel A. Haber, M.D., Ph.D., Director, Massachusetts General Hospital Cancer Center

Daniel Haber, MD, PhD, director of the MGH Cancer Center, says, “The ability to establish a dedicated MGH research center focused on the intersection of bioengineering, molecular biology and clinical oncology presents an opportunity to develop a next-generation platform that will help us detect, define and monitor cancer cells more effectively – which should make an enormous difference in the lives of so many patients and their families.”

About Circulating Tumor Cells

Circulating tumor cells are cancer cells that have detached from the tumor and are found at extremely low levels in the bloodstream. The value of capturing and counting CTCs is evolving as more research data is gathered about the utility of these markers in monitoring disease progression and potentially guiding personalized cancer therapy.

About Veridex, LLC

Veridex, LLC, a Johnson & Johnson company, is an organization dedicated to providing physicians with high-value diagnostic oncology products. Veridex’s IVD products may significantly benefit patients by helping physicians make more informed decisions that enable better patient care. Veridex’s Clinical Research Solutions provide tools and services that may be used for the selection, identification and enumeration of targeted rare cells in peripheral blood for the identification of biomarkers, aiding scientists in their search for new, targeted therapies. For more information, visit www.veridex.com.

About Ortho Biotech Oncology Research & Development

Ortho Biotech Oncology Research & Development, a unit of Johnson & Johnson Pharmaceutical Research & Development, is a research and development organization that strives to transform cancer to a preventable, chronic or curable disease by delivering extraordinary and accessible diagnostic and therapeutic solutions that prolong and improve patients’ lives.

About Massachusetts General Hospital

Celebrating the 200th anniversary of its founding in 1811, Massachusetts General Hospital 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. For more information visit http://www.mgh.harvard.edu/.

Sources:

• Veridex, LLC Announces Collaboration to Develop Next-Generation Circulating Tumor Cell (CTC) Technology with Massachusetts General Hospital, News Release, Johnson & Johnson, January 3, 2011.

• MGH has entered into a collaborative agreement with Veridex LLC to establish a center of excellence in research on circulating tumor cell technologies, News Release, Massachusetts General Hospital, January 3, 2011.

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:

• Largest study of genomes and cancer treatments releases first results, Press Release, The Wellcome Trust Sanger Institute, July 15, 2010.

• Cancer Genome Project website, The Wellcome Trust Sanger Institute.

• Genomics of Drug Sensitivity in Cancer website, The Wellcome Trust Sanger Institute.

_____________________________________________________________

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.

2010-2011 U.S. News & World Report “Best Hospitals” List

This week, U.S. News & World Report issued its 2010-2011 rankings of the best U.S. hospitals for adults. The University of Texas, M.D. Anderson Cancer Center is rated #1 in cancer treatment, and Johns Hopkins is rated #1 in gynecology and #1 overall based upon all medical specialties.

If you would like more information regarding the 2010-2011 U.S. News & World Report best U.S. hospital rankings, click here. To better understand how U.S. News & World Report ranked the hospitals in each specialty, read Best Hospitals 2010-11: The Methodology, written by U.S. News & World Report’s Avery Comarow.  If you would like to review the current U.S. News & World Report America’s Best Children’s Hospitals list, click here.

Top 10 U.S. Hospitals: Cancer	Top 10 U.S. Hospitals: Gynecology	Top 10 U.S. Hospitals (highest scores in at least six medical specialties)
1. Univ. of Texas M.D. Anderson Cancer Center, Houston, Texas	Johns Hopkins Hospital, Baltimore, Maryland	Johns Hopkins Hospital, Baltimore, Maryland
2. Memorial Sloan-Kettering Cancer Center, New York, New York	Mayo Clinic, Rochester, Minnesota	Mayo Clinic, Rochester, Minnesota
3. Mayo Clinic, Rochester, Minnesota	Brigham and Women’s Hospital,Boston, Massachusetts	Massachusetts General Hospital, Boston, Massachusetts
4. Johns Hopkins Hospital, Baltimore, Maryland	Cleveland Clinic, Cleveland, OH	Cleveland Clinic, Cleveland, Ohio
5. University of Washington Medical Center, Seattle, Washington	Massachusetts General Hospital, Boston, Massachusetts	Ronald Reagan UCLA Medical Center, Los Angeles
6. Dana-Farber Cancer Institute, Boston, Massachusetts	Magee-Womens Hospital of Univ. of Pittsburgh Medical Center, Pittsburgh, Pennsylvania	New York-Presbyterian Univ. Hospital of Columbia & Cornell, New York, New York
7. Massachusetts General Hospital, Boston, Massachusetts	Duke University Medical Center, Durham, North Carolina	Univ. of California, San Francisco (UCSF) Medical Center
8. Univ. of California, San Francisco (UCSF) Medical Center	Univ. of California, San Francisco (UCSF) Medical Center	Barnes-Jewish Hospital/Washington University, St. Louis
9. Cleveland Clinic, Cleveland, Ohio	New York-Presbyterian Univ. Hospital of Columbia & Cornell, New York, New York	Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
10. Ronald Reagan UCLA Medical Center, Los Angeles	Memorial Sloan-Kettering Cancer Center, New York, New York	Duke University Medical Center, Durham, North Carolina

MAGP2 Gene Expression Signature: A Potential Ovarian Cancer Personalized Treatment Target

A multi-institutional study has identified a potential personalized treatment target for the most common form of ovarian cancer. In the December 8 issue of Cancer Cell, the research team describes finding that a gene called MAGP2 – not previously associated with any type of cancer – was overexpressed in papillary serous ovarian tumors of patients who died more quickly. They also found evidence suggesting possible mechanisms by which MAGP2 may promote tumor growth.

A multi-institutional study has identified a potential personalized treatment target for the most common form of ovarian cancer. In the December 8 issue of Cancer Cell, the research team describes finding that a gene called MAGP2 (microfibril-associated glycoprotein 2) – not previously associated with any type of cancer – was overexpressed in papillary serous ovarian tumors of patients who died more quickly. They also found evidence suggesting possible mechanisms by which MAGP2 may promote tumor growth.

Michael Birrer, MD, Ph.D., Professor, Department of Medicine, Harvard Medical School; Director GYN/Medical Oncology, Medicine, Massachusetts General Hospital

“Ovarian cancer is typically diagnosed at an advanced stage when it is incurable, and the same treatments have been used for virtually all patients,” says Michael Birrer, MD, PhD, director of medical gynecologic oncology in the Massachusetts General Hospital (MGH) Cancer Center, and the study’s corresponding author. “Previous research from my lab indicated that different types and grades of ovarian tumors should be treated differently, and this paper now shows that even papillary serous tumors have differences that impact patient prognosis.” Birrer was with the National Institutes of Health when this study began but later joined the MGH Cancer Center.

The fifth most common malignancy among U.S. women, ovarian cancer is expected to cause approximately 15,000 deaths during 2009. Accounting for 60 percent of ovarian cancers, papillary serous tumors are typically diagnosed after spreading beyond the ovaries. The tumors typically return after initial treatment with surgery and chemotherapy, but while some patients die a few months after diagnosis, others may survive five years or longer while receiving treatment.

To search for genes expressed at different levels in ovarian cancer patients with different survival histories, which could be targets for new treatments, the researchers conducted whole-genome profiling of tissue samples that had been microdissected – reducing the presence of non-tumor cells – from 53 advanced papillary serous ovarian cancer tumors. Of 16 genes that appeared to have tumor-associated expression levels, MAGP2 had the strongest correlation with reduced patient survival.

Further analysis confirmed that MAGP2 expression was elevated in another group of malignant ovarian cancer tumors but not in normal tissue. MAGP2 gene expression was also reduced in patients whose tumors responded to chemotherapy. Recombinant expression of MAGP2 in samples of the endothelial cells that line blood vessels caused the cells to migrate and invade normal tissue.  In addition, MAGP2 gene overexpression increased microvessel density — a measurement used to determine the extent of tumor angiogenesis. The latter two observations suggest a potential role for MAGP2 gene overexpression in the growth of an ovarian cancer tumor’s blood supply.

“By confirming that different ovarian tumors have distinctive gene signatures that can predict patient prognosis, this study marks the beginning of individualized care for ovarian cancer,” says Birrer, a professor of Medicine at Harvard Medical School. “MAGP2 and the biochemical pathways it contributes to are definitely targets for new types of therapies, and we plan to pursue several strategies to interfere with tumor-associated pathways. But first we need to validate these findings in samples from patients treated in clinical trials.”

About The Study

Co-lead authors of the Cancer Cell paper are Samuel Mok, M.D., M.D. Anderson Cancer Center, and Tomas Bonome, National Cancer Institute (NCI). Additional co-authors are Kwong-Kowk Wong, M.D. Anderson; Vinod Vathipadiekal, Aaron Bell, Howard Donninger, Laurent Ozbun, Goli Samimi, John Brady, Mike Randonovich, Cindy Pise-Masison, and Carl Barrett, NCI; Michael Johnson, Dong-Choon Park, William Welch and Ross Berkowitz, Brigham and Women’s Hospital; Ke Hao and Wing Wong, Harvard School of Public Health; and Daniel Yip, University of South Florida. The study was supported by grants from the National Institutes of Health, the Ovarian Cancer Research Fund and the National Cancer Institute.

About Massachusetts General Hospital

Massachusetts General Hospital, 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.

Sources:

• Possible ovarian cancer treatment target identified – Genetic signature associated with poor prognosis could lead to improved therapies, Press Release, Massachusetts General Hospital (via EurekAlert), December 8, 2009.

• Mok SC, Bonome T, Vathipadiekal V, Bell A, Johnson ME, Wong KK, et. al. A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: microfibril-associated glycoprotein 2. Cancer Cell. 2009 Dec 8;16(6):521-32. PubMed PMID: 19962670.

• Farley J, Ozbun LL, Birrer MJ. Genomic analysis of epithelial ovarian cancer. Cell Res. 2008 May;18(5):538-48. Review. PubMed PMID: 18427574.

2009-2010 U.S. News & World Report Best U.S. Hospital Rankings

Today, U.S. News & World Report issued its 2009-2010 rankings of the best U.S. hospitals for adults. The University of Texas, M.D. Anderson Cancer Center is rated #1 in cancer treatment; Brigham and Women’s Hospital is rated #1 in gynecology; and Johns Hopkins is rated #1 overall based upon all medical specialties.

If you would like more information regarding the 2009-2010 U.S. News & World Report best U.S. hospital rankings, click here. To better understand how U.S. News & World Report ranked the hospitals in each specialty, read America’s Best Hospitals: Here’s How We Selected Them – Deaths, reputation, and patient safety were among the factors the rankings took into account, written by U.S. News & World Report’s Avery Comarow.  If you would like to review the current U.S. News & World Report America’s Best Children’s Hospitals list, click here.

Top 10 U.S. Hospitals: Cancer	Top 10 U.S. Hospitals: Gynecology	Top 10 U.S. Hospitals (highest scores in at least six medical specialties)
1. Univ. of Texas M.D. Anderson Cancer Center, Houston, Texas	Brigham and Women’s Hospital, Boston, Massachusetts	Johns Hopkins Hospital, Baltimore, Maryland
2. Memorial Sloan-Kettering Cancer Center, New York, New York	Johns Hopkins Hospital, Baltimore, Maryland	Mayo Clinic, Rochester, Minnesota
3. Johns Hopkins Hospital, Baltimore, Maryland	Mayo Clinic, Rochester, Minnesota	Ronald Reagan UCLA Medical Center, Los Angeles
4. Mayo Clinic, Rochester, Minnesota	Duke University Medical Center, Durham, North Carolina	Cleveland Clinic, Cleveland, Ohio
5. Dana-Farber Cancer Institute, Boston, Massachusetts	Univ. of California, San Francisco (UCSF) Medical Center	Massachusetts General Hospital, Boston, Massachusetts
6. University of Washington Medical Center, Seattle, Washington	Cleveland Clinic, Cleveland, Ohio	New York-Presbyterian Univ. Hospital of Columbia & Cornell, New York, New York
7. Massachusetts General Hospital, Boston, Massachusetts	Magee-Womens Hospital of Univ. of Pittsburgh Medical Center, Pittsburgh, Pennsylvania	Univ. of California, San Francisco (UCSF) Medical Center
8. Univ. of California, San Francisco (UCSF) Medical Center	New York-Presbyterian Univ. Hospital of Columbia & Cornell, New York, New York	Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
9. Duke University Medical Center, Durham, North Carolina	Massachusetts General Hospital, Boston, Massachusetts	Barnes-Jewish Hospital/Washington University, St. Louis
10. Stanford Hospital and Clinics, Stanford, California	Ronald Reagan UCLA Medical Center, Los Angeles	Brigham and Women’s Hospital, Boston, Massachusetts

One In Three Billion Found: Single Mutation In FOXL2 Gene May Cause Granulosa Cell Ovarian Cancer

“… Vancouver scientists from the Ovarian Cancer Research (OvCaRe) Program at BC Cancer Agency and Vancouver Coastal Health Research Institute have discovered that there appears to be a single spelling mistake in the genetic code of granulosa cell tumours, a rare and often untreatable form of ovarian cancer. This means that out of the three billion nucleotide pairs that make up the genetic code of the tumour, one – the same one in every tumour sample – is incorrect. The discovery, published online June 10th in the New England Journal of Medicine, marks the beginning of a new era of cancer genomics, where the complete genetic sequence of cancers can be unravelled and the mutations that cause them exposed. For women with granulosa cell tumours it represents the first specific diagnostic tool and clear path to develop much needed treatments for this cancer. …”

Found: One in Three Billion

The spelling mistake in the genetic code that causes a type of Ovarian Cancer

Eureka! Vancouver scientists from the Ovarian Cancer Research (OvCaRe) Program at BC Cancer Agency and Vancouver Coastal Health Research Institute have discovered that there appears to be a single spelling mistake in the genetic code of granulosa cell tumours, a rare and often untreatable form of ovarian cancer. This means that out of the three billion nucleotide pairs that make up the genetic code of the tumour, one – the same one in every tumour sample – is incorrect. The discovery, published online June 10th in the New England Journal of Medicine, marks the beginning of a new era of cancer genomics, where the complete genetic sequence of cancers can be unravelled and the mutations that cause them exposed. For women with granulosa cell tumours it represents the first specific diagnostic tool and clear path to develop much needed treatments for this cancer.

David Huntsman, M.D. (Nfld.), Associate Professor, Department of Pathology & Laboratory Medicine, University of British Columbia; Genetic Pathologist, BC Cancer Agency

“This is really a two-fold discovery,” says Dr. David Huntsman, lead author and genetic pathologist at the BC Cancer Agency and Vancouver General Hospital and associate professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia. “It clearly shows the power of the new generation of DNA sequencing technologies to impact clinical medicine, and for those of us in the area of ovarian cancer research and care, by identifying the singular mutation that causes granulosa cell tumours, we can now more easily identify them and develop news ways to treat them.”

In the past when scientists wanted to look at the sequence of a tumour, it was a laborious process, with each gene individually decoded into thousands of nucleotides and all data accumulated and sorted. Most studies could only look at one or at most a few of the 20,000 genes in the human genome whereas the new sequencing technologies allow scientists to look at everything at once. Through a collaboration between OvCaRe and the BC Cancer Agency’s Genome Sciences Centre, the research team used “next generation” sequencing machines that are able to decode billions of nucleotides at rapid speed and new computer techniques to quickly assemble the data. “This task would have been unfathomable in terms of both cost and complexity even two years ago,” says Dr. Marco Marra, Director of the BC Cancer Agency’s Genome Sciences Centre.

The OvCaRe team decoded four tumour samples of the relatively rare granulosa cell tumour, which affects five percent of ovarian cancer patients. Using the new sequencing technology and bioinformatics, they discovered a single nucleotide located in the FOXL2 gene was mutated in every sample. The research team further validated their work by examining a large number [95 samples] of additional tumour samples from across Canada and around the world, and are satisfied they have been able to validate that this mutation is present in almost all granulosa cell tumours and not in unrelated cancers. Most types of cancers, including ovarian cancers, have a broad range of genetic abnormalities. This finding shows that granulosa cell tumours have a characteristic single DNA spelling mistake that can serve as an easy to read identity tag for this cancer type.

“Although it has been suggested that hundreds of any cancer type would have to be sequenced at great depth to make clinically useful discoveries,” says Huntsman, “we had hypothesized that knowledge could be gained from much smaller studies if the cancers were carefully selected and represented clinically homogenous diseases. There are many rarer cancer types, like granulosa cell tumours that fit that bill and based upon our success in decoding granulosa cell tumours we are focusing on other rare tumours in what could be described as a guerrilla war on cancer. We hope that these studies will not only help future patients with rare tumours but will also teach us about more common ones as well.”

“This cancer is unique,” says Dr. Dianne Miller, gynecologic oncologist at BC Cancer Agency and Vancouver General Hospital. “For patients with this tumour type, it means they should all have the same response to the same treatment. And now that we have this pathway, we can look for existing cancer drugs that might work on this particular gene mutation to make the cancer disappear.”

The OvCaRe team was able to make this discovery because of the multidisciplinary nature of the group, which crosses two provincial health authorities and is made up of gynaecologists, pathologists, bioinformatics specialists, and oncologists. Further enhancing the team’s success is the centralization of patient treatment and record keeping.

“We are excited by this paper,” says Dr. Michael Birrer, professor, Department of Medicine, Harvard Medical School and director GYN/Medical Oncology, Medicine, Massachusetts General Hospital. “The ovarian cancer research and care community now has new biologic insights into this poorly understood tumour and a potential therapeutic target. More importantly, this tour de force study reveals the power of genomic approaches to cancer, particularly rare tumours.”

Ovarian cancer affects about one in 70 Canadian women. Approximately 2500 new cases are diagnosed each year and the five-year survival rate is only 30 per cent.

This study was supported by donors to VGH & UBC Hospital Foundation and the BC Cancer Foundation, and Genome BC for the development of Illumina sequencing at the BC Cancer Agency’s Genome Sciences Centre. OvCaRe and the BC Cancer Agency’s Genome Sciences Centre are also supported by the Michael Smith Foundation for Health Research.

Ovarian Cancer Research Program (OvCaRe) is a multidisciplinary research program involving clinicians and research scientists in gynaecology, pathology, and medical oncology. OvCaRe is a unique collaboration between the BC Cancer Agency, Vancouver Coastal Health Research Institute, and the University of British Columbia. Funding is provided through donations to VGH & UBC Hospital Foundation and the BC Cancer Foundation, who, in a joint partnership created a campaign to raise funds to make OvCaRe possible. The OvCaRe team is considered a leader in ovarian cancer research, breaking new ground in better identifying, understanding, and treating this disease. Earlier this year, the team discovered that ovarian cancer was not just one disease, but rather made up of several distinct subtypes.

Primary Sources:

• Found: One in Three Billion – The spelling mistake in the genetic code that causes a type of Ovarian Cancer, News Release, BC Cancer Agency, June 10, 2009.

• Shah SP, Köbel M, Senz J, et. al.  Mutation of FOXL2 in Granulosa-Cell Tumors of the Ovary. N Engl J Med 2009 0: NEJMoa0902542 (Full Text).

Related N Engl J Med Editorial:  Shendure J, Stewart, CJ. Cancer Genomes on a Shoestring Budget. N Engl J Med 2009 0: NEJMe0903433 (Full Text).

Additional Reference:  Köbel M, Kalloger SE, Boyd N,et. al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med. 2008 Dec 2;5(12):e232. PubMed PMID: 19053170; PubMed Central PMCID: PMC2592352.

Additional Resources:

• Granulosa Cell Tumor of the Ovary Foundation (San Diego, California).
• Granulosa Cell Tumour Foundation New Zealand

Stand Up To Cancer Funded Research Dream Team Takes Aim At Women’s Cancers

Stand Up To Cancer (SU2C), the Entertainment Industry Foundation’s charitable initiative supporting groundbreaking research aimed at getting new cancer treatments to patients in an accelerated timeframe, has reached a significant milestone, awarding the first round of three-year grants — that total $73.6 million — to five multi-disciplinary, multi-institutional research Dream Teams. … Each Dream Team’s project, funded for three years pending satisfactory achievement of stated milestones, is “translational” in nature, geared toward moving science from “bench to bedside” where it can benefit patients as quickly as possible. …

A Dream Team of leading cancer researchers will accelerate development of drugs to attack a mutated [PI3K] molecular pathway that fuels endometrial, breast and ovarian cancers, funded by a three-year $15 million grant awarded today by [SU2C] … Genetic aberrations in the network, known as the PI3K pathway, are found in half of all breast cancer patients, 60 percent of all cases of endometrial cancer and 20 percent of ovarian cancer patients. Other cancers that include a mutationally activated PI3K pathway include melanoma, colon and prostate cancers, brain tumors, and leukemia.

Massachusetts General Hospital Cancer Center To Genetically Profile All Patient Tumors

“The Massachusetts General Hospital Cancer Center has recently opened a new Translational Research Laboratory that will uncover the genetic codes and gene mutations from almost all of its cancer patients. … By embarking on such an ambitious approach, Cancer Center pathologists and oncologists hope to gather specific information about tumor properties that will lead to targeted therapies and better personalized treatments. Mass General will be the first and only cancer center to conduct molecular profiling of positive biopsies and tumors from all patients as part of basic patient care. …”

“Genetic profiling

09/Mar/2009

Massachusetts General Hospital Cancer Center Opens Molecular Pathology Lab to Genetically Profile All Patient Tumors

The Massachusetts General Hospital Cancer Center has recently opened a new Translational Research Laboratory that will uncover the genetic codes and gene mutations from almost all of its cancer patients. Previously only a sampling of patients had their tumors analyzed in such a comprehensive fashion.

By embarking on such an ambitious approach, Cancer Center pathologists and oncologists hope to gather specific information about tumor properties that will lead to targeted therapies and better personalized treatments. Mass General will be the first and only cancer center to conduct molecular profiling of positive biopsies and tumors from all patients as part of basic patient care.

Scientists and researchers have already identified over 110 genetic mutations responsible for causing tumor growth, many of which are involved in several different types of cancers. Codirectors of the Transplational Research Laboratory, Leif Ellisen, MD, PhD, and A. John Iafrate, MD, PhD, have equipped the lab with state-of-the-art robotic technology, which will make it possible to quickly genotype tumor specimens within a short period of time.

‘This new and improved classification of cancers that we are doing is intended to give our oncologists more information about a individual patient’s cancer, so they can treat it in a very specific way, thereby significantly increasing the odds of success,’ says Iafrate.

Several new cancer drugs that are currently available or in development are able to block some of the mutations and pathways that cause tumor cells to proliferate. By targeting tumor gene mutations with these smart drugs, doctors may be able to eradicate malignant cells without using traditional treatments like chemotherapy and radiation, which have significant side effects.

The lab’s new tumor genotyping initiative should also expedite the time it takes to find the right drug for the right patient. According to Ellisen, ‘If we are able to identify a mutation in, say, a case of lung cancer, and we know that a particular drug has been successful in treating colon cancer patients with the same mutation, then we have good reason to believe that drug will work turning off the cancer-causing mutation in the lung cancer patient as well.’

The lab will start with the genotyping of Mass General’s lung cancer patients and phase in different disease groups over the next few weeks. It is anticipated that the profiling of all possible patient tumors will occur gradually over the coming months.

Learn more about research at the Cancer Center ”

Cited Source:  Massachusetts General Hospital Cancer Center opens molecular pathology lab to genetically profile all patient tumors, News, Massachusetts General Hospital, Mar. 9, 2009.

Update:

• Making Personalized Cancer Care Routine, In Depth, NCI Cancer Bulletin, Volume 6 / Number 11, National Cancer Institute, June 2, 2009 (noting that Massachusetts General Hospital & Memorial Sloan-Kettering Cancer Center are performing genetic profiling of all lung cancer tumors).

Infinity Announces Hedgehog Pathway Ovarian Cancer Preclinical Data; Results Indicate Significant Inhibition of Tumor Growth in Primary Ovarian Cancer

Infinity Pharmaceuticals, Inc. (Nasdaq:INFI), an innovative cancer drug discovery and development company, … announced the presentation of preclinical data from the natural product foundation of IPI-926, Infinity’s orally-available inhibitor of the Hedgehog pathway, demonstrating significant inhibition of tumor growth in a primary ovarian cancer model.

“CAMBRIDGE, Mass., Feb. 9, 2009 (GLOBE NEWSWIRE) — Infinity Pharmaceuticals, Inc. (Nasdaq:INFI), an innovative cancer drug discovery and development company, today announced the presentation of preclinical data from the natural product foundation of IPI-926, Infinity’s orally-available inhibitor of the Hedgehog pathway [see “Hedgehog Structure & Function,’ and ‘Hedgehog Inhibition’ Animations below under ‘Additional Resources’] demonstrating significant inhibition of tumor growth in a primary ovarian cancer model.

Data from the laboratory of Bo Rueda, Ph.D., Associate Professor, Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School and Associate Director, Vincent Center for Reproductive Biology, Massachusetts General Hospital, was introduced in an oral presentation entitled, Hedgehog inhibitor cyclopamine suppresses Gli1expression and inhibits serous ovarian cancer xenograft growth last week at the 40th Annual Meeting on Women’s Cancer of the Society of Gynecologic Oncologists. The data show that treatment with cyclopamine, the natural product foundation of IPI-926, in animals bearing grafts of primary ovarian cancer resulted in significant tumor growth inhibition compared to vehicle treated animals. Dr. Rueda’s models of ovarian cancer are derived from patient specimens that have not undergone prior tissue culture, and are believed to reflect the clinical presentation of ovarian cancer.

Infinity’s novel, oral, Hedgehog pathway inhibitor, IPI-926, is semi-synthetic derivative of the natural product cyclopamine with superior drug-like properties, including being 30 to 50 times more potent. In addition, IPI-926 has demonstrated significant anti-tumor activity and excellent pharmaceutical properties, including oral bioavailability, long plasma half-life and duration of action, and dose-dependent inhibition of tumor growth, in a number of preclinical models including pancreatic cancer, small cell lung cancer, and medulloblastoma.

IPI-926 is currently being evaluated in a Phase 1 trial in patients with advanced and/or metastatic solid tumors. The study is designed to evaluate the safety, tolerability and pharmacokinetics of IPI-926, and to determine a recommended dose and schedule for subsequent studies. Infinity will also evaluate potential anti-tumor activity of IPI-926 and examine pharmacodynamic markers of its biological activity.

Infinity anticipates publishing additional preclinical data with IPI-926 at the 2009 Annual Meeting of the American Association for Cancer Research (AACR) in April 2009.

About IPI-926

IPI-926 is a novel, proprietary inhibitor of the Hedgehog signaling pathway being evaluated in a Phase 1 clinical trial in patients with advanced solid tumors. IPI-926 is a derivative of the natural product cyclopamine that binds to and inhibits a key regulator of this pathway, the Smoothened receptor. The Hedgehog signaling pathway is normally active in regulating tissue and organ formation during embryonic development. However, abnormal activation of the Hedgehog pathway can lead to cancer and is believed to play a central role in allowing the proliferation and survival of several types of cancers, including pancreatic, prostate, lung, breast, and certain brain cancers. In preclinical models, IPI-926 has demonstrated significant anti-tumor activity and excellent pharmaceutical properties, including oral bioavailability, long plasma and tumor half-life, and dose-dependent inhibition of tumor growth, in a number of preclinical models.

About Infinity Pharmaceuticals, Inc.

Infinity is an innovative cancer drug discovery and development company seeking to discover, develop, and deliver to patients best-in-class medicines for the treatment of cancer and related conditions. Infinity combines proven scientific expertise with a passion for developing novel small molecule drugs that target emerging cancer pathways. Infinity’s two most advanced programs in Hsp90 inhibition and Hedgehog signaling pathway inhibition are evidence of its innovative approach to oncology drug discovery and development. For more information on Infinity, please refer to the company’s website at http://www.infi.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding the utility of Hedgehog inhibitors, including IPI-926, in treating various types of cancer; future clinical trial activity of IPI-926; and the presentation of additional preclinical data on IPI-926. Such statements are subject to numerous factors, risks and uncertainties that may cause actual events or results to differ materially from the company’s current expectations. For example, there can be no guarantee that IPI-926 will successfully complete necessary preclinical and clinical development phases. In particular, management’s expectations could be affected by risks and uncertainties relating to: results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, investigational review boards at clinical trial sites, and publication review bodies; Infinity’s ability to enroll patients in its clinical trials; decisions made by EORTC and other organizations evaluating data for presentation or publication; Infinity’s ability to obtain additional funding required to conduct its research, development and commercialization activities; unplanned cash requirements and expenditures; and Infinity’s ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing. These and other risks which may impact management’s expectations are described in greater detail under the caption “Risk Factors” included in Infinity’s registration statement on Form S-3 filed with the Securities and Exchange Commission on January 9, 2009. Further, any forward-looking statements contained in this press release speak only as of the date hereof, and Infinity expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

CONTACT: Infinity Pharmaceuticals, Inc.
Monique Allaire
617-453-1105
Monique.Allaire@infi.com
http://www.infi.com”

Quoted Source:  Infinity Announces Hedgehog Pathway Preclinical Data in Ovarian Cancer – Data Demonstrate Significant Inhibition of Tumor Growth in Primary Ovarian Cancer, Press Release, Infinity Pharmaceuticals, Inc., Feb. 9, 2009.

Additional Resources:

• A Phase 1 Study of IPI-926 in Patients With Advanced and/or Metastatic Solid Tumor Malignancies, Phase I Clinical Trial Description & Entry Criteria, ClinicalTrials.gov (ID:  NCT00761696).

• IPI-926 Preclinical Results, Hedgehog Pathway, Publication Archive, Infinity Pharmaceuticals, Inc.

• Hedgehog Function & Structure Animation, Pipeline, IPI-926, Hedgehog Pathway, Infinity Pharmaceuticals, Inc.

• Hedgehog Inhibition Animation, Pipeline, IPI-926, Hedgehog Pathway, Infinity Pharmaceuticals, Inc.