2009

The MRA awarded seven teams pursing multidisciplinary translational research.

Proposal Title: Developing Melanoma Screening in Primary Care
Principal Investigators:

• Team Lead: Martin A. Weinstock, M.D., Ph.D., Rhode Island Hospital and Brown University
   (image below)
  
• Maryam Asgari, M.D., M.P.H., Kaiser Foundation Research Institute
• Melody Eide, M.D., M.P.H., Henry Ford Health System
• Suzanne Fletcher, M.D., M.Sc., Harvard Pilgrim Health Care and Harvard Medical School
• Alan Geller, R.N., M.P.H., Harvard School of Public Health
• Allan Halpern, M.D., M.S., Memorial Sloan-Kettering Cancer Center

Weinstock

Summary: An increasing body of evidence indicates that effective early detection is our best hope for cutting melanoma deaths by at least half in the near future. Conventional education programs have had the effect of stabilizing mortality rates despite steadily increasing incidence trends, but we need to change our methods to get a substantial reduction in deaths. Today, knowledge and skills for melanoma screening remains low in primary care, performance of thorough skin self-examination remains low, and education of clinicians remains focused on teaching variations of the “ABCD”s of melanoma in conventional formats. We propose to develop an early detection training program that is web-based for widespread use, grounded in the realities of primary care delivery, and which includes a deeper image database and web-based format that together will allow a quantum leap in interactivity compared to prior efforts in melanoma, both to engage the learner and to improve the training achieved upon completion. Further, this training will incorporate dermoscopy (epiluminescence microscopy) which today is rarely used in primary care despite its proven ability to improve accuracy of the clinical examination. We have assembled a diverse team from multiple institutions with expertise and experience in melanoma early detection, medical education for cancer prevention, interventions with a variety of clinicians, and in large health systems, screening, and web-based instruction. We will measure both improvement in skills and effect on the health delivery system. This will provide a key exportable tool for mortality reduction efforts, including large definitive trials and health campaigns.


Proposal Title: Manipulating Immune Regulation in Adoptive T-cell Therapy for Melanoma
Principal Investigators:

• Team Lead: Jeffrey Weber, M.D., Ph.D., H. Lee Moffitt Cancer Center and Research Institute (image below)
• Patrick Hwu, M.D., M.D. Anderson Cancer Center

Weber

Summary: In this Team Science proposal, two institutions with extensive experience in immunotherapy and adoptive cell therapy for cancer will test the toxicities and feasibility of a cell therapy approach  using tumor infiltrating lymphocytes (TIL) and high dose IL-2 after lymphoid depletion with fludarabine and cytoxan to treat patients with stage IV melanoma. This pilot feasibility trial will be followed by a phase I trial to improve the anti-tumor activity of the transferred cells so that the approach becomes more practical. The phase I trial will evaluate the utility of using an immune modulating antibody that stimulates 41BB/CD137 to increase effector cell proliferation, longevity and anti-tumor activity in vivo so that higher avidity and more effective TIL may expand in vivo after adoptive transfer. The anti-41BB antibody will be administered intravenously in escalating doses after lymphoid depletion and adoptive transfer of TIL to test whether it can be safely administered and to define a maximal tolerated dose of the antibody after lymphoid depletion and adoptive transfer of TIL with IL-2.  We wish to also define a dose of the antibody that optimally increases the growth of long lived tumor specific memory TIL in the circulation, a correlate of known benefit of TIL therapy. The overall goals of this proposal are to show that TIL therapy after lymphoid depletion is practical and has clinical activity in metastatic melanoma, and to use a newly developed immune modulatory antibody to improve upon those results.


Proposal Title: Identification and Validation of Combination Therapies for Melanomas
Principal Investigators:

• Team Lead: Michael J. Weber, Ph.D., University of Virginia (image below)
• Levi Garraway, M.D., Ph.D., Dana-Farber Cancer Institute (image below)
• Dan Gioeli, Ph.D., University of Virginia

Weber	Garraway

Summary: The pharmaceutical pipeline is filled with potential cancer therapies targeting genetically altered proteins that drive malignancy. However, it is already becoming clear that cancer cells have multiple mechanisms for escaping the toxic effects of these therapies. In particular, cancer cells develop compensatory signaling mechanisms that can bypass the effects of single drugs.  This suggests that we need to develop combinations of therapies that target not only the primary mutated regulatory pathway, but that also block the compensatory responses. This need is particularly evident in melanoma, where we have targeted therapies against the major genetic alterations, and yet the effects of these drugs are partial and temporary. Drs Levi Garraway and Michael Weber have pooled their complementary expertise to search for the most effective combinations that can kill melanoma cells. Dr. Garraway is using gene silencing techniques and Dr. Weber is using small molecule inhibitors of regulatory pathways to identify combinations of drugs and targets that will synergistically be lethal to cancer cells. Because many of the relevant targets and small molecules are already being developed for cancer therapy, this work should move rapidly into the preclinical and clinical setting.


Proposal Title: Sequencing of the Melanoma Exome, Transcriptome and Epigenome
Principal Investigators:

• Team Lead: Ruth Halaban, Ph.D., Yale University (image below)
• Marcus Bosenberg, M.D., Ph.D., Yale University
• Michael Krauthammer, M.D., Ph.D., Yale University
• David Stern, Ph.D., Yale University

Halaban

Summary: The major objectives of the team research are to identify novel genetic and epigenetic abnormalities in melanomas in order to discover new cancer susceptibility genes and new targets for therapy. Indeed, it has been shown already that treatment of cancer patients can be more effective when guided by evidence-based test(s) that match a specific drug to a specific “driving force” in the tumor. This concept is particularly relevant to melanoma, because of its highly heterogeneous nature, being composed of different origins (cutaneous, mucosal, acral, ocular), with different etiological factors and signature alterations. In addition, tumors often change their characteristics in response to treatment. This can lead to recurrence, due to the accumulation of additional changes that activate escape pathways and confer drug resistance. Currently, only a small number of “driving forces” that can be targeted by drugs have been identified in melanomas, including activated BRAF or c-KIT kinases. For this reason, the team is focused on advancing therapeutic intervention by addressing the issue of melanoma heterogeneity employing deep sequencing of specific regions of DNA that encode genes and transcriptional elements responsible for normal functions of cells that become aberrant in cancer cells. New generation DNA sequencing tools will be employed to reveal novel mutations, gene fusion, translocations, novel transcripts and isoforms, recurrent copy-number alterations (gains and losses), and regions of DNA methylation/demethylation. The team research is embedded in the Yale SPORE in Skin Cancer and will use the large collection of clinically annotated melanoma tumors and matching normal cells. The results will be correlated with patient outcome, family and clinical history and with additional on going studies on melanoma kinases, global gene expression, miRNA, and genomic abnormalities interrogated by array technology (SNP/CNV). Novel observations will be validated by functional studies using current and new drugs in cultured tumor cells, and in animal models, by constructing mice carrying the mutation in the gene of interest. The results will provide the basis for melanoma reclassification at the molecular level that can be used to select patients for targeted therapy.

The team is composed of researches with different expertise, such as basic science, bioinformatics, pathology, mouse genetics, kinases, oncology and surgery. Dr. Ruth Halaban, PhD, is the Principal Investigator and Drs. Michael Krauthammer, Marcus Bosenberg, and David Stern are co-investigators. In addition, there is strong collaboration with clinical investigators in the Yale SPORE in Skin Cancer program, that include Drs. Mario Sznol, Harriet Kluger, Stephan Ariyan and Deepak Narayan who are deeply engaged in these studies.


Proposal Title: Combinatorial Immunotherapy for Melanoma with B7-H1/PD-1 Checkpoint Blockade
Principal Investigators:

• Team Lead: Drew Pardoll, M.D., Ph.D., Johns Hopkins University
• Lieping Chen, M.D., Ph.D., Johns Hopkins University
• Suzanne Topalian, M.D., Johns Hopkins University

Pardoll, Topalian and Chen

Summary: Melanoma is a unique human cancer in its response to immune-based therapies. Immunotherapy is currently the only form of therapy that can cure melanoma, though this occurs very rarely. The team is exploring a novel therapeutic strategy of blocking a specific pathway that melanoma cells use to turn off immune responses that could otherwise kill the tumor. This pathway, discovered by Dr. Chen, involves expression by melanoma cells of a molecule, termed B7-H1, which binds to a receptor on anti-melanoma T lymphocytes, termed PD-1. This interaction turns off the immune response in a reversible fashion. Dr. Topalian is leading a clinical effort to test therapeutic monoclonal antibodies directed to both PD-1 and B7-H1 that block this interaction and thus reactivates anti-melanoma immunity. Preliminary results in patients have demonstrated regression of some melanomas after a single administration of the anti-PD-1 antibody. Dr. Pardoll has developed a genetically engineered melanoma vaccine, which he has shown can greatly enhance anti-melanoma immune responses. This team is exploring a combination therapy utilizing the melanoma vaccine to boost the number of anti-melanoma T cells together with the antibodies that block the melanoma from turning off those vaccine-induced anti-tumor immune responses.


Proposal Title: Identification of Novel Melanoma Risk Genes Using High-throughput Genomics
Principal Investigators:

• Team Lead: Jeffrey Trent, Ph.D., Translational Genomics Research Institute
• Nicolas Hayward, Ph.D., Queensland Institute of Medical Research
• Goran Jonsson, Ph.D., Lund University
• Graham Mann, Ph.D., The University of Sydney

Trent	Hayward	Jonsson	Mann

Summary: Other than primary prevention, early detection of cutaneous malignant melanoma offers the best form of cure. Characterization of the genes influencing melanoma risk is critical towards efforts aimed at disease prevention and early detection. Studies of families with multiple melanoma patients have identified mutations in two genes that strongly predispose to the disease, but the mutations are found only in a minority of families. To identify additional genes, the International Melanoma Genetics Consortium (GenoMEL) recently completed the largest genetic study of melanoma families to date, comprising 174 families with three or more melanoma patients. This study identified two chromosome positions likely to harbor melanoma susceptibility genes, while a separate smaller study by a GenoMEL member group has identified a third. We propose here to extend this collaborative effort by screening all genes at these three chromosomal locations for disease-predisposing mutations in melanoma families. We will also work towards identifying additional susceptibility genes by sequencing the entire genomes of patients from five of the largest melanoma families. The identification of novel predisposition genes is a major first step towards accurately estimating individualized disease risk and ultimately implementing disease prevention and early-detection strategies for at-risk individuals. Further, characterization of the molecular mechanisms underlying melanoma susceptibility may lead to a better understanding of the processes underlying melanoma development and progression, and ultimately to novel strategies for melanoma treatment.


Proposal Title: Defining the Importance of Immunity to NY-ESO-1 in Melanoma
(Co-funded by the Cancer Research Institute)
Principal Investigators:

• Team Lead: Jedd D. Wolchok, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center
• James P. Allison, Ph.D., Memorial Sloan-Kettering Cancer Center
• Jonathan Cebon, Ph.D., Ludwig Institute for Cancer Research
• Alexander Eggermont, M.D., Ph.D., Daniel den Hoed Cancer Center
• Sacha Gnjatic, Ph.D., Ludwig Institute for Cancer Research
• Dirk Jäger, M.D., University Hospital Heidelberg
• Elke Jäger, Ph.D., Goethe University Frankfurt
• Alexander Knuth, M.D., University of Zurich
• Lloyd J. Old, M.D., Ludwig Institute for Cancer Research