The Team Science Award Program is the centerpiece of the MRA research funding portfolio. This program fulfills one of MRA's primary goals: to foster a collaborative research process. Multidisciplinary teams consist of Principal Investigators with complementary expertise who may be from the same institution, inter-institutional, and/or international. Team science projects promote transformational melanoma research advances with the potential for rapid clinical translation.
Maximal immune checkpoint inhibition for leptomeningeal melanoma
BMS-MRA Team Science Award in Immunotherapy
• Ryan Sullivan, M.D., Massachusetts General Hospital
• Arlene Sharpe, Ph.D., Harvard Medical School
• Young Investigator: Priscilla Brastianos, M.D., Massachusetts General Hospital
The treatment for melanoma has revolutionized over the past 5 years. As a result, our patients are living longer and better than ever before. Unfortunately, one group of patients, those with disease that involves the lining of the brain and spinal cord (known as the leptomeninges), have devastating complications from disease and have a dismal survival of 4-6 weeks. Treatment options are limited and may be associated with significant toxicities to the brain and spine. Importantly, these patients have been excluded all the clinical trials, and we do not know how well any of the new immune therapies (ipilimumab, pembrolizumab, nivolumab) or the so-called targeted therapies (such as vemurafenib, dabrafenib, trametinib) work for these patients. At MGH Cancer Center we have treated approximately 10 patients who had melanoma and leptomeningeal disease (LMD) using immune therapy, with two patients exhibiting a response, and one patient alive two years after starting treatment. While it was gratifying to see responses, we would like to offer even more effective therapy for these patients and have designed a clinical trial to maximize immune therapy for patients with melanoma and leptomeningeal disease. In this proposal, we propose a clinical trial to study the activity of the immunotherapy combination of ipilimumab and nivolumab in leptomeningeal disease from melanoma. We will use cutting edge technology to study the genetic changes that lead to leptomeningeal disease involvement. Understanding the genetic changes in cancer can lead to the discovery of new drug targets. We will also perform studies to understand the characteristics of the immune system of patients with leptomeningeal disease. Our objectives are to identify tests on either blood or spinal fluid that predict response to immunotherapy, as well as identify other targets that may lead to novel therapies for this terrible disease.
Radiation and immune checkpoint blockade from mechanism to patients
The Rising Tide Foundation - Tara Miller Foundation - MRA Team Science Award
• Robert Vonderheide, M.D., University of Pennsylvania
• E. John Wherry, Ph.D., University of Pennsylvania
• Andy Minn, M.D., Ph.D., University of Pennsylvania
• Young Investigator: Tara Gangadhar, M.D., University of Pennsylvania
• Young Investigator: Christina Twyman-Saint Victor, M.D., University of Pennsylvania
Melanoma can suppress the immune system through receptors that act as brakes for T cell activation. Immune checkpoint blockade (ICB) can reverse this process and has resulted in unprecedented improvement in survival. Unfortunately, the majority of patients still relapse, making the elucidation of resistance mechanisms and combination therapies high priority. We have assembled a multi-disciplinary melanoma research team dedicated to rapid discovery and clinical impact. Members include experts in cancer immunology, immune checkpoint biology, discovery of resistance mechanisms, and melanoma clinical trials. Our goal is to simultaneously use mouse models and clinical trials to discover resistance mechanisms and ways to improve ICB that are readily deployable in the clinic. We are investigating if radiation (RT) and other therapies can diversify T cells with potential to attack melanoma, and then unleash this potential with ICB combinations that minimizes resistance. As a first step, we initiated a clinical trial of ICB combined with RT for stage IV melanoma, which was led by young investigators supported by the MRA, and used mouse models to mimic the clinical trial. Remarkable responses occurred; however, improvement was still needed. Using mice and patients, we discovered resistance mechanisms, insight into how RT cooperates with ICB, and biomarkers consistent with the translational potential of our findings. We used this information to design second-generation clinical trials, which will soon start. This proposal will iterate this bench-to-bedside approach by 1) testing ways to enhance RT and further improve ICB, 2) discover additional resistance mechanisms and how to reverse them, and 3) use biospecimens from our second-generation clinical trials to examine biomarkers and mechanisms revealed by mouse studies. We anticipate these efforts will have rapid clinical impact, allowing us to design third-generation clinical trials to reduce the mortality of melanoma.
Reducing Melanoma Deaths with INFORMED: Consequences of Screening
MRA Team Science Award
- Martin Weinstock, M.D., Ph.D., Rhode Island Hospital
- John Kirkwood, M.D., University of Pittsburgh
- Patricia Risica, DrPH, Brown University
Melanoma mortality in the US is nearly 10,000 per year and unlike most other common cancers the melanoma death rate is not dropping. Screening offers potential for cutting melanoma deaths nearly in half within a decade. Widespread screening will not occur, however, unless the scientific evidence is sufficient to convince authoritative evidence-based medicine groups that such screening saves lives and its benefits outweigh the associated risks of harm. The past few years produced key evidence that melanoma screening may save lives. The most important evidence of this comes from an initiative in one state in Germany where a screening program was associated with a 48% drop in mortality, despite little change in the surrounding states where there was no screening program. Inspired by that program, the University of Pittsburgh Medical Center Physician Services Division (UPMC-PSD) has launched a new program to screen patients in its largest primary care practices. This is the first time a major US Health Care System has undertaken such an effort. The program aims to train over 500 primary care physicians using an on-line program developed by our team with a grant from the MRA. The physician leadership of the UPMC-PSD has organized and led the screening program and publicized it to the patients of its major practices. They have systems in place to allow our experienced multidisciplinary research team to use routine data and special interviews conducted for this study to measure many possible effects on melanoma diagnoses, skin surgeries, health care visits, emotional reactions, and positive health effects. This grant’s purpose is to scientifically evaluate key aspects of the UPMC-PSD program and gather evidence of benefits and harms to establish the basis for gaining endorsement for melanoma screening from evidence-based medicine groups. This will help lead to the widespread use of melanoma screening that would have potential to save thousands of lives each year.
Development of AMPK Activators for Treatment of Melanoma
Weill Cornell-MGH-MRA Team Science Award with generous support from Elizabeth and Oliver Stanton
- Lewis Cantley, Ph.D., Weill Cornell Medical College
-Bin Zheng, Ph.D., Massachusetts General Hospital
-Ellen and Gary Davis-MRA Young Investigator: Jonathan Zippin, M.D., Ph.D., Weill Cornell Medical College
Over 8,000 deaths from melanoma occur in the United States per year. Its incidence has risen sharply over past few decades, making melanoma the sixth most common cancer, and the incidence is predicted to increase. The discovery of proteins called “oncogenes,” which are essential for the growth of melanoma, sparked the development of therapeutic agents that target these proteins. While initial clinical results appeared promising, researchers realized that melanoma cells eventually become resistant to these drugs and are able to circumvent their anti-tumor effects, highlighting the need for additional agents. We have found that cells, when stressed for energy, activate an enzyme called AMP-activated protein kinase (AMPK). AMPK blocks important oncogenes from functioning properly; suggesting that activation of AMPK might provide a novel melanoma therapy. AMPK activators are already used for patient care in diabetes treatments. We now demonstrate activators of AMPK, when combined with melanoma therapies, lead to more melanoma cell death in mice. AMPK activators may provide a new option for melanomas that currently suffer from a paucity of available therapeutics. We propose to explore the use of AMPK activators in multiple melanoma subtypes and melanomas that have become resistant to standard therapies. Finally, in collaboration with physicians at MGH and MSKCC, we will perform a clinical trial to determine the safety and biological activity of AMPK activators in combination with standard therapy in patients with late stage melanoma. During this trial, we will perform a biomarker analysis to determine which patients will benefit from this combination therapy.
Targeting BFL-1/A1-mediated Chemoresistance in Melanoma
MRA Team Science Award with generous support from Susan and John Hess
- David E. Fisher, M.D., Ph.D., Massachusetts General Hospital
-Loren Walensky, M.D., Ph.D., Dana-Farber Cancer Institute
-Stewart Rahr-MRA Young Investigator: Adriano Piris, M.D., Brigham and Women’s Hospital
This proposal builds on the recent development of a novel and potent new drug family aimed at disarming a cancer-causing protein that blocks the ability of melanoma cells to die. This protein, called BFL-1/A1, is known to promote malignant behavior and resistance to current treatments for melanoma. BFL-1/A1 appears to be uniquely present in melanomas, making it a further attractive drug target. This Team Proposal brings together 3 experts in drug development, melanoma biology, and melanoma diagnostics. Loren D. Walensky, MD, PhD specializes in development of new drugs that antagonize a key family of “cell death” regulating proteins, which includes BFL-1/A1. David E. Fisher, MD, PhD of Massachusetts General Hospital is a melanoma physician scientist, who studies melanoma formation and treatment resistance. Young Investigator Adriano Piris, MD, also of MGH is a dermatopathologist and junior faculty member, whose combined clinical and research efforts focus on identifying the features that sub classify melanoma into the multiple disease sub-types that are important for optimizing treatments. For this proposal, Dr. Walensky is synthesizing BFL-1/A1 targeting drugs, Dr. Fisher will study the activity and mechanism of action of these inhibitors in melanoma cells, and Dr. Piris will characterize the melanoma subgroup (~30%) whose malignant behavior is driven by BFL-1/A1 --- the subgroup likeliest to benefit from this therapy. We believe that this fusion of chemical biology, melanoma biology, dermatopathology, and developmental therapeutics will enable us to advance a next-generation targeted therapy to overcome treatment resistance in a significant portion of melanomas.
Developing Salvage Therapeutics for RAF/MEK Inhibitor-Resistant Melanoma
MRA Team Science Award with generous support from Anonymous Donor
- Levi A Garraway, M.D., Ph.D., Dana-Farber Cancer Institute
-James Bradner, M.D., Dana-Farber Cancer Institute
-Denise and Michael Kellen-MRA Young Investigator: Jason Luke, M.D., Dana-Farber Cancer Institute
Recent years have witnessed major advances in the treatment of metastatic melanoma. For example, treatment with new targeted drugs known as RAF and MEK inhibitors can yield dramatic response for patients whose tumors harbor cancer-causing mutations in the gene called BRAF. Unfortunately, the tumors inevitably relapse after several months to ~2 years of clinical benefit—once they relapse, they show resistance to further treatment with these drugs. Unfortunately, few effective treatments exist for melanoma patients whose tumors reach this point. Clearly, the development of new therapies for these drug-resistant forms of melanoma represents a major medical need. The goal of this project is to exploit a new set of drug targets for BRAF-mutant melanoma identified by the Garraway laboratory, and to search for inhibitory molecules that could eventually provide new therapeutic options for these patients. Specifically, we have identified a protein called EIF5A1 that is required for growth of drug-resistant BRAF-mutant melanomas. In this study, we will use both new types of melanoma tumor model systems and a “proof-of-concept” study in melanoma patients to determine whether drug-resistant melanomas can be treated effectively by extinguishing the activity of this protein in several ways. In addition, we will test a collection of over 65,000 diverse chemical compounds to identify specific and potent new inhibitors of EIF5A1, with the ultimate goal of bringing these new compounds to the clinic. Upon completion of this research, we expect to identify new therapies that may benefit many patients with drug-resistant, BRAF-mutant melanoma.
Cell-type Specific Delivery of Small Molecules for Immunotherapy of Cancer
MRA Team Science Award
- Darrell J Irvine, Ph.D., Massachusetts Institute of Technology
-Kai Wucherpfennig, Ph.D., Dana-Farber Cancer Institute
-Bristol-Myers Squibb-MRA Young Investigator: Michael Goldberg, Ph.D., Dana-Farber Cancer Institute
Therapies that boost the immune system’s ability to attack tumor cells are showing substantial promise in the treatment of melanoma. In particular, treatments that enhance the ability of patients’ T-cells to recognize and destroy tumor cells have been shown in recent clinical trials to provide a means for large burdens of metastatic disease to be eliminated, without recurrence. Unfortunately, such dramatic responses are still observed in only 20-30% of patients, and thus new strategies to increase further the efficacy of tumor immunity are needed. A key limitation of current therapies is thought to be the ability of tumors to suppress the function of anti-tumor T-cells directly. Employing a novel strategy to discover signals involved in immunosuppression, we have discovered a set of previously unexamined proteins that are directly involved in hindering anti-tumor immune function, thereby helping tumors evade elimination by the immune system. Using this set of candidate genes, we will test an approach to enhance the tumor-killing capacity of the immune system by using nanoparticles to target drugs that inhibit these proteins specifically to T-cells that are being held in check by growing tumors. By targeting these drugs to T-cells, we expect to enhance the anti-tumor activity of the immune system dramatically while avoiding toxic side effects.
Mechanisms of Acquired Resistance to Combined BRAF/MEK Targeting
MRA Team Science Award with generous support from Amanda and Jonathan Eilian
-Stewart Rahr-MRA Investigator: Roger Lo, M.D., Ph.D., University of California, Los Angeles
-Alain Algazi, M.D., University of California, San Francisco
Today, we are armed with a precision drug (called BRAF inhibitors) which targets a specific molecular alteration found among 50% of advanced melanomas. These BRAF inhibitors can reliably and impressively shrink melanoma tumors in the majority of patients and even provide a potential cure for a small fraction of patients. The central problem is that the average survival benefit from BRAF inhibitors for most treated patients is measured only in months. This problem stems from the issue of drug resistance, the process by which melanoma adapts and evolves around BRAF inhibitors. Our knowledge of how melanomas resist or evade BRAF inhibitors has led to an innovative clinical strategy to effectively curtail such resistance. This strategy combines the BRAF inhibitors with another precision drug, the MEK inhibitors. However, the combination of BRAF and MEK inhibitors still leads to drug resistance. Understanding the mechanisms by which melanomas acquire resistance to BRAF and MEK inhibitors should engender novel clinical strategies aimed at dramatically extending patient survival. Here, we hypothesize that comprehensively profiling both genetic and non-genetic alterations repeatedly detected in drug-resistant tumors but not in tumors prior to treatment would efficiently allow us to zero in on common drivers of drug resistance. Genetic alterations change the DNA or hardware of the tumor cells. What we have uncovered in preliminary work is that perhaps as much as half of all melanomas which escape from BRAF and MEK inhibitors do so by a non-genetic mechanism. This “epigenetic” mode of drug resistance involves not hardware (DNA) but software alterations, or different ways by which the melanoma interprets the hardwired genetic code. We emphasize the highly translational nature of this study, as we extract large-scaled information directly from the precious tumors of treated patients and have the capacity to extend laboratory findings into clinical trial testing.
Crossroads of Genetic and Immunologic Heterogeneity of Melanoma Metastasis
The Johns Hopkins Kimmel Cancer Center-Memorial Sloan Kettering-MRA Team Science Award with generous support from Judy and Russ Carson
- Suzanne L. Topalian, M.D., Johns Hopkins University School of Medicine
-Christine Iacobuzio-Donahue, M.D., Memorial Sloan Kettering Cancer Center
Complex interactions between the immune system and melanoma influence tumor invasion, metastasis, and survival outcomes, but they are incompletely understood. Abnormalities in DNA, the genetic material in melanoma cells, create opportunities for immune recognition, but melanomas can exert suppressive mechanisms to thwart immune attack. In addition to genetic diversity, different sites of melanoma in individual patients may be immunologically diverse; both kinds of diversity create pathways for melanomas to evade therapeutic interventions. A deeper knowledge of how genetic and immunologic factors interact is central to understanding why melanoma progresses and to developing more effective therapies including treatment combinations. To date, studies in this area have been hampered by the limited availability of tumor tissue for laboratory investigations. However, our team has developed a robust rapid autopsy program to study complex biological behavior in cancer, in a way that is otherwise not possible with small tumor needle biopsies. In our previous work in pancreatic cancer, genetic analysis allowed us to characterize how tumors grew and spread, and revealed some unexpected features. We now propose to build on this experience to study melanoma, in ways that will illuminate interacting genetic and immune factors driving melanoma progression and metastasis in patients who have undergone various forms of therapy. We aim to 1) establish a tumor bank from 8-10 autopsies, representing the diversity of melanoma metastasis; 2) characterize genetic features of tumor evolution, using sophisticated sequencing technologies; 3) explore immunological diversity within melanoma metastases; and 4) correlate genetic and immunological melanoma signatures in order to better understand factors driving tumor progression. Such knowledge is needed to guide the development of more effective therapies for melanoma patients, including combinations of molecular and immune-based drugs.
Mutational Density and Response to Immunotherapy with Checkpoint Blockade
Leveraged Finance Fights Melanoma-MRA Team Science Award
- Bert Vogelstein, M.D., Johns Hopkins University
-Drew Pardoll, M.D., Ph.D., Johns Hopkins University
Mary Jo and Brian Rogers Young Investigator: Evan Lipson, M.D., Johns Hopkins University
Recently, new immunotherapies have led to significant clinical benefit in patients with melanoma. In particular, antibodies that block an immune-inhibitory pathway, termed PD-1, induce longterm regression or disease stabilization in 40-45% of melanoma patients with significant toxicity in less than 5% of patients. They work because melanomas engage this pathway as a mechanism to evade immune attack; antibodies that block the PD-1 pathway therefore unleash anti-cancer immunity within the tumor itself. There is much evidence that the major component of the immune system unleashed by anti-PD-1 antibodies is the killer T cell. We hypothesize that melanomas are particularly susceptible to immune attack once PD-1 is blocked because they possess many mutations, each of which can result in a unique piece of a protein that T cells can use to distinguish the tumor cell from normal cells and thus, specifically target the cancer cells. However, not all melanomas possess such large numbers of mutations. We propose to determine whether the number of mutations in a melanoma correlates with the magnitude of the anti-melanoma immune response in a patient and, in turn, the clinical response to PD-1 blockade. In addition to marrying the fields of cancer genetics and cancer immunology, these studies will potentially lay the groundwork for a biomarker to predict response to anti-PD-1 antibodies and also for the generation of personalized melanoma vaccines that could be used in combination with anti-PD-1 therapy.
Discovery of Novel Immune Checkpoints in Melanoma
Saban Family Foundation-MRA Team Science Award
- Gal Markel, MD, PhD, Sheba Medical Center
-Tamar Geiger, PhD, Tel Aviv University: Young Investigator, Generously Supported by Jill & Jay Bernstein
-Noam Shomron, PhD, Tel Aviv University
The recent success in melanoma immunotherapy has positioned the field of immuno-oncology as one of the pillars of oncological treatments. Conceptually, forceful stimulation of the immune system against the already immune-resistant tumors, changed to disarming the tumor immune evasion mechanisms to render it sensitive to the patient's own immune response. We propose focusing on discovery of new melanoma immune evasion mechanisms, and develop specific inhibitors as lead compounds that would become the basis for novel drugs. For that purpose, we formed a synergistic team led by a melanoma clinician from the largest melanoma center in Israel, who is also an expert tumor immunologist, and two experts in genetics and proteomics who are also experts in bioinformatics and computerized algorithms. The strategy is to conduct two-layered mega-scan of many thousands of proteins and their potential regulators. The ability to perform these scans and analyze these amounts of data have become possible only very recently with technological advents. The unique aspect of our proposal is that the discovery process is based on robust clinical outcome, as the test samples would be obtained from patients treated with a robust immunotherapy available only in our institution (outside the US). Comparative data from patients who responded to treatment and those who did not will highlight immune-relevant differences. These differences will be scrutinized mechanistically to positively identify novel immune evasion mechanisms. Specific inhibitors would be developed against them to abrogate their suppressive function. These inhibitors could become leads for facilitated drug development.
TAMs in Melanoma: Mechanisms and Therapeutic Efficacy of Novel Inhibitors
Saban Family Foundation-MRA Team Science Award
- Rotem Karni, PhD, Hebrew University of Jerusalem
-Tal Burstyn-Cohen, PhD, Hebrew University of Jerusalem: Young Investigator
-H. Shelton Earp, III, MD, University of North Carolina Lineberger Comprehensive Cancer Center
-S. Gail Eckhardt, MD, University of Colorado Anschutz Medical Campus
-Stephen Frye, PhD, University of North Carolina Lineberger Comprehensive Cancer Center
-Douglas Graham, MD, PhD, University of Colorado Anschutz Medical Campus
Our group and others have identified a role for a protein called Mer in various cancers including melanoma. Mer is a signaling molecule shown to mediate cell growth, migration and invasiveness in many cancers, but the role of Mer in melanoma is still unclear. We have recently found that Mer is overexpressed in approximately 50% of melanoma cell lines, with highest expression in metastatic melanomas. Studies on a specific inhibition of Mer by a novel small molecule inhibitor suggested it may be a new therapeutic strategy for melanoma patients, and warrants further study. We propose to test novel small-molecule inhibitors of Mer as a possible therapy for melanoma and to determine their efficacy when combined with standard therapies currently in clinical use. Additionally, we aim to investigate how Mer is activated in melanoma cells. Identifying new activators of Mer will allow the development of additional novel agents. This team consists of experts in cancer cell signaling, cell biology/biochemistry, and drug discovery and development. Taken together, these studies are expected to provide necessary new information on this pathway in melanoma, and pre-clinical data to enable rational design of a Phase 1 clinical trial for patients with metastatic melanoma.
Nanomedicine co-targeting of neuroinflammation in melanoma brain metastases
Saban Family Foundation-MRA Team Science Award
- Ronit Satchi-Fainaro, PhD, Tel Aviv University
-Neta Erez, PhD, Tel Aviv University: Young Investigator
-Zvi Ram, MD, Tel Aviv University
The major cause of melanoma mortality is metastasis to distant organs, most frequently to the brain. In order for tumor cells to be able to survive and colonize there, they need to recruit and be supported by non-cancerous cells in the brain microenvironment. The role of the brain microenvironment in facilitating this metastatic growth is poorly understood. Astrocytes are cells in the brain that function to maintain brain homeostasis (equilibrium). These cells play a principal role in the repair, scarring, and inflammation process of the brain following injury, and their abnormal regulation is thought to contribute to the development of brain cancer and metastasis. However, the role of astrocytes in supporting and facilitating melanoma brain metastasis is largely unknown as is their role in inflammation. In this project, we will determine the interactions of melanoma cells with astrocytes and identify potential drug targets. Furthermore, we will design novel medicines based on nano-particles that allow for attachment of a combination of several drugs enabling enhanced efficacy and decreased toxicity. This team consists of experts in drug development, neurology, and tumor biology. If successful, this project will result in novel therapeutic approaches for co-targeting melanoma cells and astrocytes, paving the road for clinical translation for the treatment of melanoma brain metastases, which represents a serious and unmet medical need.
Using Genomic Technologies to Comprehensively Characterize Acral Melanomas
Hidary Foundation-MRA Team Science Award
-Maryam Asgari, MD, MPH, Kaiser Permanente Research Institute
-Boris Bastian, MD, PhD, University of California, San Francisco
-Eric Jorgenson, PhD, Kaiser Permanente Research Institute
-Pui-Yan Kwok, MD, PhD, University of California, San Francisco
Acral melanoma is a rare type of melanoma that occurs mostly on the palms and soles whose characteristics, epidemiology and survival differ from other melanoma types. The changes in the complete set of DNA (genome) of acral melanomas, and understanding how such genomic changes interact to drive the disease, has not been studied in detail. This proposal seeks to use multiple-pronged state-of-the-art technologies to study the genomics of acral melanoma using tumor specimens and associated clinical data from Kaiser Permanente Northern California databases. Our aim is to expand the knowledge of acral melanoma, to lay the foundation for improving cancer prevention and early detection, and to identify new targets for treatment.
Comprehensive Genomic Characterization of Acral Melanoma: Characterizing Established and Identifying Therapeutic Molecular Targets
Hidary Foundation-MRA Team Science Award
- Jeffrey Sosman, MD, Vanderbilt University
-Charlotte Ariyan, MD, PhD, Memorial-Sloan Kettering Cancer Center
-Jeffrey Trent, PhD, Translational Genomics Research Institute
This proposal involves a consortium formed by melanoma clinicians and melanoma surgeons expert in acral melanoma (AM) from Memorial Sloan-Kettering Cancer Center (MSKCC) and Vanderbilt-Ingram Cancer Center (VICC), combined with proven scientific expertise in state-of-the-art genetic technologies at the Translational Genomics Research Institute (TGen). The remarkably robust collection of fresh tumor specimens from a large number of AM patients present at MSKCC and VICC combined with the depth of critically important clinical information on the characteristics of these patients is a major strength of this project. By analyzing the tumor specimens and normal tissue from patients, this team will define both the genetic variations of each tumor in detail and provide an overall frequency and significance of recognized genetic changes for AM. Through this process, the team will better understand molecular therapeutic targets that are already known (e.g., BRAF and CKIT) and identify new therapeutic molecular targets.
Epigenetics in Melanoma: Mechanistic Evaluation and Novel Therapies
Sokoloff Family-MRA Team Science Award
-Marcus Bosenberg, M.D., Ph.D., Yale University
-Frank Slack, Ph.D., Beth Israel Deaconess Medical Center
-Young Investigator: Narendra Wajapeyee, Ph.D., Yale University
Mentor: Marcus Bosenberg
Although recent treatment advances including BRAF inhibitor therapy and immunotherapy approaches are promising, most advanced melanoma patients still have a bad prognosis. Much progress has been made in the identification of key genetic changes in melanoma, however despite the observation that non-genetic alterations, including DNA methylation, appear to be nearly universal in human melanoma, the specific functional contribution of these changes to melanoma formation is largely unknown. DNA methyltransferases (DNMTs) modify DNA and alter the expression of individual genes, but do not alter the DNA coding sequence. We evaluated the effects of inactivation of specific DNMTs in melanoma. Interestingly, while inactivation of the Dnmt1 DNA methyltransferase did not prevent melanoma formation, inactivation of Dnmt3b markedly reduced melanoma formation. Dnmt3b in part appears to control the levels of specific micro RNAs (miRNAs) to regulate melanoma growth. These findings demonstrate that DNMT3B and specific miRNAs play a critical role in melanoma formation and are promising targets for new melanoma treatments. We propose to: 1). Determine the mechanism of requirement for DNA methylation in melanoma, 2). Determine the functional role of miRNAs in melanoma formation and progression, and 3). Discover new specific DNA methyltransferase inhibitors that can eventually be used to treat melanoma patients. We anticipate that the proposed experiments will identify the cascade of signaling changes brought about by altered DNA methylation and miRNA expression that are needed for melanoma formation and progression. Within the period of the grant, we also expect to produce new DNMT inhibitors that are suitable for clinical trials. These drugs could have a major and rapid impact in treating melanoma and other forms of cancer.
Targeting BRAF-mutant melanoma brain metastases
Generously supported by the Hess Foundation
-Michael Davies, M.D., Ph.D., University of Texas M.D. Anderson Cancer Center
-Erik Sulman, M.D., Ph.D., University of Texas M.D. Anderson Cancer Center
-Hussein Tawbi, M.D., Ph.D., University of Pittsburgh
-GlaxoSmithKline-MRAYoung Investigator: Georgina Long, Ph.D., Melanoma Institute Australia
Mentor: Richard Scolyer, Co-Director of Research, Melanoma Institute Australia
Brain metastases are diagnosed in ~60% of patients with stage IV melanoma, and the average survival for these patients is only 4 months. Recently, the investigators in this grant proposal helped to design and lead the BREAK-MB trial, which tested the safety and efficacy of the selective BRAF inhibitor dabrafenib in melanoma patients with brain metastases. This trial demonstrated that dabrafenib treatment was safe in these patients and the majority achieved clinical responses. However, similar to patients with extracranial (non-brain) metastases, most of the clinical responses were relatively short. Studies of tissue samples from other types of metastases have identified a number of molecular changes that occur with BRAF inhibitor treatment, including several that cause resistance and disease progression, which have been used to design more effective therapeutic approaches. However, no such studies have been performed in patients with brain metastases. Research in multiple cancer types, including melanoma, has demonstrated that brain metastases harbor many molecular differences compared to metastases in other sites. Thus, understanding the effects of BRAF inhibitor treatment in brain metastases may identify specific strategies to improve clinical outcomes in these patients. In order to test the hypothesis that the molecular effects of approved doses of BRAF inhibitors differ in brain and extracranial metastases, we are conducting a clinical trial in patients with at least 1 brain metastasis that can be cured with surgery. The patients will be treated with the BRAF inhibitor (dabrafenib) for ~1 week prior to surgical removal of the brain metastasis and at least one extracranial metastasis. In this grant we will use our combined resources and expertise to compare the molecular and immunological effects of dabrafenib treatment on the brain and extracranial metastases in order to identify rational new treatment strategies for brain metastasis patients.
Human anti-MICA Monoclonal Antibodies for Melanoma Immunotherapy
-Glenn Dranoff, M.D., Dana-Farber Cancer Institute
-Kai Wucherpfennig, M.D., Ph.D., Dana-Farber Cancer Institute
-Helman Family-MRA Young Investigator: Michael Goldberg, Ph.D., Dana-Farber Cancer Institute
Mentors: Glenn Dranoff and Kai Wucherpfennig
We demonstrated that some metastatic melanoma patients who are treated with vaccines composed of their own tumor cells and/or an antibody that improves immune function (anti-CTLA-4) achieve long-lasting benefits. Our analysis of these long-term responding patients uncovered an important aspect of the immune response to melanoma. This characteristic involves an immune reaction that is directed to a target called MICA, which is a protein expressed at high levels on the surface of many melanomas (and also other cancers), but not on healthy tissues. Unfortunately, melanoma cells devise ways to release some of the MICA from the surface, and the shed form of MICA inhibits the immune response. We found, however, that melanoma vaccines and CTLA-4 treatment can stimulate some patients to make a strong antibody response to MICA. These antibodies can overcome the suppressive effects of soluble MICA, and in turn promote the destruction of melanoma cells. We developed a new experimental strategy that allows us to isolate from patients who respond to these immunotherapies specific antibodies against the factors that are involved in melanoma destruction. We used this technique to isolate a panel of human antibodies to MICA. Our work to date has indicated that one of these antibodies is a compelling candidate for therapeutic testing in melanoma patients. This antibody reacts with all forms of MICA tested, suggesting that it might be applicable to a wide range of melanoma patients. Our preliminary studies also show that the antibody is able to overcome the immune suppressive effects of shed MICA that is present in the blood of different melanoma patients and to promote immune responses to melanomas growing in mice. In this application, we propose to learn more about the properties of this antibody and develop techniques to monitor the effects of administering the antibody in planned clinical trials in melanoma patients.
Molecular mechanisms of T cell inflamed melanoma to identify new targets
-Thomas Gajewski, M.D., Ph.D, University of Chicago
-Eugene Chang, M.D., University of Chicago
-Kenan Onel, M.D., Ph.D., University of Chicago
Significant advances using immune-based therapies for melanoma have generated great enthusiasm both for researchers and for patients. A key feature of immunotherapies is the ability to induce a durable clinical benefit, with some patients likely being cured of their disease. However, despite this great promise, clinical responses are still seen in a minority of patients. We need to determine why some patients fail to respond to immunotherapies so that we can develop new strategies that expand the subset of patients who can benefit from these treatments. We recently have characterized the tumors in melanoma patients and have found a gene expression pattern and set of biologic features that appear to predict clinical response to immunotherapies. This biology is characterized by a pre-existing attempt of the host immune system to attack the tumor, with inflammatory features in the tumor site. The goal of this proposal is to determine why some patients generate this spontaneous smoldering immune response while some do not. Correlations are proposed using patient samples, and mechanisms will be evaluated in animal models. Our preliminary data are already encouraging. Knowledge of these mechanisms will provide a foundation to develop next-generation immunotherapies for melanoma.
Chromatin-based therapeutic combinations for the treatment of melanoma
Christie's-MRA Team Science Award
-Levi A Garraway, M.D., Ph.D., Dana-Farber Cancer Institute
-Leonard Zon, M.D., Children’s Hospital Boston
Although there have been major treatment advances in the treatment of melanomas that carry mutations in the BRAF gene, responses are still short-lived (several months to a year). This is because the cancer cells eventually develop drug resistance: ways to avoid being killed by cancer drugs in current use (these drugs are called RAF and MEK inhibitors). The goal of this project is to identify new drugs that might be combined with RAF and MEK inhibitors to prevent or delay the emergence of such resistance mechanisms and ultimately achieve long-term control of this subtype of melanoma. Using powerful new technologies that can test each human gene for its ability to cause drug resistance, the laboratory of Dr. Levi Garraway identified over 100 genes able to drive resistance to RAF+MEK inhibitors in cultured melanoma cells. In parallel, Dr. Leonard Zon has used a fish model of melanoma (zebrafish) as a high-throughput means to identify biological processes that are operant in human melanoma. In this project, we will use both human melanoma cells and zebrafish to study an exciting new class of drugs called “chromatin-modifying factors” for their ability to kill BRAF-mutant melanoma cells in combination with RAF+MEK inhibitors in human melanoma cells and zebrafish melanoma tumors. So-called “chromatin-based” therapeutics show immense promise in cancer treatment. Once drugs targeting chromatin-modifying factors are identified and verified, we will design a clinical study that can test the feasibility of combining inhibitors of chromatin with RAF/MEK inhibitors in patients with BRAF-mutant melanoma. In summary, this research combines state of the art basic science with new drug discovery avenues to speed the development of novel cancer drug combinations aimed at further extending the survival of many melanoma patients.
Drivers in melanoma susceptibility, development and progression
L'Oreal Paris-MRA Team Science Award
-Meenhard Herlyn, D.V.M., D.Sci., The Wistar Institute
-Vivi Ann Florenes, Ph.D., Oslo University Hospital
-Julia Newton-Bishop, M.D., Leeds University
-Young Investigator: Todd Ridky, M.D., Ph.D., University of Pennsylvania
Mentor: Meenhard Herlyn
Individuals with genetically determined phenotypes such as light skin color which tans poorly, red hair, blue eyes or many moles are generally considered susceptible to melanoma compared to those with none of these attributes. However, only a few of these individuals contract the disease suggesting that both environmental and genetic traits play a major role in susceptibility. Recent research has identified 16 variant genes associated with risk for melanoma but we do not know how these gene variants contribute as co-drivers to melanoma development because normal cells from these carriers have not been studied experimentally. One major reason for the lack of data on the biological significance of melanoma risk genes is that the patients are only identified at later stages of their life when the melanocytes are very difficult to grow in tissue culture in high enough quantities for experimental studies. Our laboratories went an indirect route: we isolated normal fibroblasts from small punch biopsies of skin and reprogrammed them using four transcription factors in a technique that did not alter their genome structure. The 'induced pluripotent stem cells' acted similar to embryonic stem cells which can be turned into any of the >220 cells of the human body. Fortuitous for us, those cells readily become melanocytes when stimulated with growth factor signals. We now want to stress the cells when they are embedded in artificial skin using ultraviolet light in the B and A range to determine whether they show any abnormalities when compared to cells without the gene variants. In the second aim we will hit the melanocytes from melanoma risk individuals with driver oncogenes that cannot transform on their own but need the currently unknown co-driver(s). We expect from these studies the identification of co-drivers that cooperate with driver genes which will in the future be the targets for melanoma prevention and therapy.
Imaging and therapeutic targeting of lymphangiogenesis in melanoma
-Maria S Soengas, Ph.D., Spanish National Cancer Research Center
-Michael Detmar, M.D., Swiss Federal Institute of Technology, Zurich
-Robert Ballotti, Ph.D., National Institute of Health and Medical Research, France
-Corine Bertolotto, Ph.D., National Institute of Health and Medical Research, France
-Stefan Endres, M.D., Ludwig Maximilian University, Munich
-Collaborative Donor-MRA Young Investigator: Hector Peinado, Ph.D., Weill Cornell Medical College
Mentor: David Lyden, M.D., Ph.D., Weill Cornell Medical College
A main limitation for rational drug design in cancer, particularly in melanoma, is the lack of physiologically-relevant models and tracers to monitor metastatic cells in vivo. To overcome these complications we have assembled a team of experts in melanoma progression and drug response, tumor spectroscopy, biological chemistry, dermatology, pathology and oncology. Our main focus is neo-lymphangiogenesis. This is a process whereby cancer cells induce the formation of vessels (lymphatic capillaries) that favor tumor dissemination. We have customized new lymphatic probes, and have generated the first melanoma Lymphoreporter mouse model. A unique feature of this strategy is the possibility of imaging early events occurring before cells actually colonize distal organs. The metastatic behavior of melanoma cells can also be analyzed prior, during and after treatment. With this approach we have also found new potent blockers of lymphangiogenesis. The most effective of these compounds were nanoparticles based on dsRNA (referred to as BO-110 for simplicity). The ability of studying cells in their natural environment allowed for the identification of unexpected points of crosstalk with innate immunity programs, opening alternative avenues for therapeutic intervention. This proposal builds on this infrastructure to translate these results into the clinic. In particular, we will center on key melanoma oncogenes (including BRAF, NRAS, cMET or MITF), whose roles in lymphangiogenesis remain unknown. Further functional testing of BO-110 will be performed as single agent or in combination with therapeutic agents that are being actively pursued by the pharmaceutical industry. Results will be validated in biopsies obtained from patients at different stages of melanoma progression. The long-term goal of this proposal is to provide the melanoma community with new diagnostic and prognostic indicators, tools for pharmacological screening, and ultimately, more efficient anticancer treatments.
Studies on the mechanism(s) of resistance to RAF inhibitor-based therapies
-David Solit, M.D., Memorial Sloan-Kettering Cancer Center
-Jeffrey Gershenwald, M.D., University of Texas, M.D. Anderson Cancer Center
-Jeffrey Sosman, M.D., Vanderbilt University
-Jennifer Wargo, M.D., Massachusetts General Hospital
-Katherine Nathanson, M.D., University of Pennsylvania
-Keith Flaherty, M.D., Massachusetts General Hospital
-Stewart Rahr-MRA Young Investigator: Ryan Sullivan, M.D., Massachusetts General Hospital
Mentor: Keith Flaherty, M.D., Massachusetts General Hospital
Cancers arise as a result of mutations in genes that control normal cellular growth. By identifying and studying the biology of these mutations, we hope to develop more effective and less toxic cancer therapies. One pathway that is frequently mutated in human tumors is the RAS/RAF/MEK/ERK (“classical MAP kinase”) pathway. Activating mutations in this pathway are commonly observed in several cancer types including melanoma in which they are found in over 70% of patients. The most common mechanism is mutation of the BRAF gene. Recent clinical results with selective inhibitor of BRAF have shown that these oral drugs have unprecedented clinical activity in patients with melanoma whose tumors harbor BRAF mutations. Although effective in approximately 80% of patients, resistance to RAF inhibitors invariably develops. The addition of a selective inhibitor of MEK, a downstream effector of the RAF protein, results in more profound and durable tumor responses than RAF inhibitor treatment alone, however, the development of drug resistance eventually occurs in essentially all patients. The focus of this MRA Team Science Award will be to determine the mechanisms of drug resistance in all patients treated with RAF inhibitor based combination strategies. To accomplish the proposed aims, we have assembled a multi-institutional team of investigators who have played central roles in the design and execution of the RAF inhibitor clinical trials. We believe that this Team Science proposal has the potential to be a model for future efforts in understanding the molecular mechanisms that mediate drug resistance in patients with melanoma. Further, we believe that the data generated will serve as the basis for rational combination strategies that induce durable and complete tumor regressions in most patients with BRAF mutant melanoma.
Personalized Medicine for Patients with BRAF wild-type (BRAFwt) Cancer
Stand Up to Cancer-Melanoma Research Alliance Melanoma Dream Team Translational Cancer Research Grant
Leader: Jeffrey M. Trent, Ph.D., Translational Research Institute (TGen)
Co‐Leader: Patricia M. LoRusso, D.O., Yale Cancer Center
- Svetomir Markovic, M.D., Ph.D., Mayo Clinic
- Brian Nickoloff, M.D., Ph.D., Michigan State University College of Medicine
- Nicholas J. Schork Ph.D., The Scripps Research Institute
- Aleksandar Sekulic, M.D., Ph.D., Mayo Clinic Arizona
- Kristiina Vuori, M.D., Ph.D., Sanford‐Burnham Medical Center
-Craig Webb, Ph.D., Van Andel Research Institute
About half of the patients with metastatic melanoma (MM) have a mutation in the BRAF gene. While recently developed inhibitors have demonstrated clinical efficacy in these patients, little progress has been made in identifying therapeutic targets to treat the other half –those patients with wild‐type BRAF (BRAFwt) tumors. This latter cohort is likely to reap the benefit of genome‐based treatments (i.e., personalized medicine). The goal of the Dream Team led by Drs. Trent and LoRusso is to select patients for sensitive mutations and match them to appropriate therapies based on their individual genomic signature. The hope is that such an approach may lead to more effective and durable therapeutic interventions over an unselective standard approach, potentially sparing patients from unnecessary toxicity, expense, and time wasted on ineffective therapies; time patients do not have. Drs. Trent and LoRusso have assembled a Dream Team of colleagues with expertise in the medical management of patients with MM, drug development, genomics research, biostatistics, and bioinformatics. They propose to iteratively refine and standardize statistical and informatics methodologies for matching treatments to the patient’s tumor, based on their individual molecular profile. Armed with this knowledge, and the results of an initial ‘feasibility’ study, they will conduct a randomized clinical trial to evaluate if molecularly‐informed personalized therapy selection, based on a patient’s tumor molecular profile, improves outcomes when compared to standard of care therapy in BRAFwt MM. If successful, this individualized medicine approach to the treatment of BRAFwt MM will not only lead to therapeutic benefit for this patient population, but may also serve as a new paradigm for many other tumor and disease types.
Clinicopathologic and molecular staging & prognosis in early-stage melanoma
There is a significant need to improve our understanding and management of patients with early-stage melanoma (stage I-microscopic stage III), the most common stage at diagnosis worldwide. While these patients generally have a favorable survival, it is clear that their prognosis is heterogeneous. Although significant inroads in staging and prognosis have been made based on histologic features among patients with early-stage melanoma, it is also evident that the growing appreciation of the myriad genetic and other molecular aberrations in melanoma has not readily been incorporated into the current evaluation or management of these early-stage melanoma patients. Our central hypothesis is that combining contemporary clinical, pathological, and molecular features will enhance staging and prognostic assessment of patients with early-stage melanoma. In this regard, we have established a consortium of leading international investigators in the fields of early-stage melanoma management/staging and molecular biology/pathogenesis to establish a unique collaborative database of early-stage melanoma patients and annotated biospecimens to interrogate and integrate clinicopathologic risk factors with molecular alterations using robust platforms suitable for primary tumor evaluation to develop clinically meaningful and statistically robust prognostic and potentially predictive platforms to improve patient care. In addition to identifying improved and novel biomarkers that will facilitate outcome predictions in patients with early-stage melanoma, we will establish a unique consortium infrastructure to facilitate the evaluation of future candidate biomarkers and rapidly adopt new technology platforms to enhance discovery, and will set the stage for rational clinical trials of "high-risk" early-stage patients based on integrated models in the future.
- Jeffrey Gershenwald, M.D., University of Texas M.D. Anderson Cancer Center
- Victor Prieto, M.D., Ph. D., University of Texas M.D. Anderson Cancer Center
- Michael Davies, M.D., Ph.D., University of Texas M.D. Anderson Cancer Center
A functional approach to targeted melanoma therapy
- Gregory Hannon, Ph.D., Cold Spring Harbor Laboratory
- Christopher Hammell, Ph.D., Cold Spring Harbor Laboratory
The recent identification of a mutation in the gene BRAF as a driver of melanoma was a critical milestone in the development of targeted melanoma therapy. While BRAF-mutant tumors initially show good responses to BRAF-targeted drugs, most eventually progress to therapy-resistant disease. Understanding how resistance can be reversed or prevented is therefore of critical importance to patients. The BRAF mutation is present in only about half of melanomas. Thus, it is critical that we also develop effective targeted therapies for those patients that lack BRAF as an oncogenic driver. The goal of this proposal is to address both of these critical issues. We will use a series of cell lines that represent the recognized spectrum of melanoma as a context in which to search for novel therapeutic targets. Over the past several years, the Team has devised functional, genetic methods that enable rapid identification of tumor-selective therapeutic targets and that permit rigorous validation in preclinical models. As one example, the proposed approaches have been used by team members to identify an effective target for a therapy-resistant form of acute myeloid leukemia. This has led them to a highly selective drug that will be taken into clinical trials for leukemia patients in the next year. At the end of the two years of proposed support, we hope to have in hand validated candidate targets and paired treatment biomarkers for non-BRAF melanomas and mechanisms to prevent or reverse therapy resistance in drug-resistant, BRAF-positive tumors. This will serve as a foundation for collaborations with academic and pharmaceutical groups to bring inhibitors of those targets into the clinic in a patient-appropriate fashion. We will also begin to dig deeply into the biological systems influenced by these targets. Only in this way can we hope to improve patient outcomes by understanding how the therapies that we develop will affect diseased cells and the patient as a whole.
Combined immunotherapy of melanoma with long peptides and TLR agonists
Generously supported by the Hess Foundation
This project will test novel approaches to optimize melanoma vaccines using defined antigens, by combining a new strategy using long (30-amino acid) peptides plus each of several experimental agents that activate the immune system through toll-like receptor (TLR) signaling. The molecular and cellular effects of this combination immunotherapy will be studied by biopsies at the vaccine site and in lymph nodes.
- Craig Slingluff, M.D., The Rector and Visitors of the University of Virginia
- Patrick Hwu, M.D., M.D. Anderson Cancer Center
Role of the X chromosome in melanoma biology and prognosis
Cutaneous melanoma is a highly aggressive skin tumor with poor prognosis for survival once metastasized. Intriguingly, women with melanoma, even at a metastatic stage, have a far more favorable prognosis than men. There is no evidence that female-specific hormones contribute to this phenomenon that is also observed in prepubertal and postmenopausal women. It is likely that the strong gender effect has a genetic basis, and we hypothesized that it is related with the sexual chromosomes-related biology. Our preliminary data show that approximately 10% of women with melanoma have lost one X-chromosome in the tumor cells. The survival of these women is worse than survival of men, and indicates that the X-chromosome contains one or more important genes that strongly reduce melanoma aggressiveness. We have identified an X-chromosome gene whose high level of expression correlates with prolonged survival, and identified other genes that could be responsible for this gender effect too. The objective of our project is to understand the gender effect in melanoma survival and to identify drivers of melanoma progression, and therefore putative therapeutic targets, localized on the X chromosome. Our team will validate the previously identified genes in large collection tumor samples and perform in depth analyses of the X chromosome in melanoma. We predict that this will result in the identification of potential novel therapeutic avenues to improve melanoma survival.
- Alan Spatz, M.D., Jewish General Hospital/Lady Davis Institute for Medical Research
- Teresa Petrella, Sunnybrook Health Sciences Centre
- Joos van den Oord, Katholieke Universiteit Leuven
- Leon van Kempen, Ph.D., McGill University
- Boris Bastian, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center
Neural crest stem cell programs as targets in melanoma
- Leonard Zon, M.D., Children's Hospital Boston
- Keith Flaherty, M.D., Massachusetts General Hospital
- Richard Mark White, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center
Despite recent progress in treatment options, melanoma remains a deadly disease. Drugs have been identified that target the BRAF gene and show great promise in clinical trials, but patients invariably become resistant to these drugs, highlighting the need for new, innovative treatment approaches. We utilized an emerging cancer model, the zebrafish, to screen for drugs that target melanoma in a different way: we found one drug, called leflunomide, that blocked melanoma growth by interfering with the "identity" of the cancer cell, causing it to lose many characteristics of a melanoma. When we combined leflunomide with the BRAF inhibitor from Plexxikon, we found a remarkable effect of the two drugs together, giving hope that this combination may be better than BRAF inhibitors alone. In this proposal we seek preclinical evidence necessary for moving this work into the clinic, and will undertake a phase II clinical trial of the combination therapy.
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Development of targeted therapies for Gq/11 mutant melanomas
- Boris Bastian, M.D., University of California, San Francisco
- Richard Carvajal, M.D., Memorial Sloan-Kettering Cancer Center
- Gary Schwartz, M.D., Memorial Sloan-Kettering Cancer Center
Uveal melanoma is the most common intraocular malignancy in the United States and has a 10-year disease specific survival rate of 50%. No effective treatment options exist. We recently identified mutations in two novel cancer genes, GNAQ and GNA11, that are found in 82% of uveal melanomas. GNAQ and GNA11 mutations are found in a mutually exclusive and only occur in melanocytic tumors without BRAF, NRAS, or KIT mutations. The mutations are thought to arise early during tumor progression, as they can also be found in benign lesions. The nature of the additional genetic alterations required for full transformation is currently not known. Work to date has shown that mutations in GNAQ/GNA11 activate several signaling cascades, which are likely to harbor targets for therapy. We have assembled a team of investigators and clinicians at a major cancer center to identify predictive markers by using tumor tissue obtained from patients with uveal melanoma treated with AZD6244. This drug is a MEK inhibitor which was implicated by our cell-based studies. We will analyze patient tissues to identify genetic alterations that can help predict which patients will best respond to this drug.
Modulating anti-tumor immunity with dendritic cells
Henry Silverman – MRA Team Science Award
- Nina Bhardwaj, M.D., Ph.D., New York University
- Jedd Wolchok, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center
This research project aims to improve dendritic cell (DC) vaccines that stimulate effective immune responses against melanoma. Small clinical trials have demonstrated that DC vaccines are safe and can lead to improved immune responses; however, the two large clinical trials had mixed results. This is probably because there is not enough known about how to make the best DCs that will be most effective against cancer. A promising new strategy to help DCs is by activating specialized proteins found on DCs called Toll-like receptors (TLR). Activation of TLRs on DC leads to enhancement of the ability of DCs to stimulate effective immune responses. Our own studies showed that activation of TLRs stimulate immune responses in patients with melanoma. We believe that activating these TLRs on DCs will be an important step in generating the best DCs to stimulate immune responses against melanoma that is effective.We propose several projects with the goal of improving DC vaccines that stimulate effective immune responses against cancer. We will study the effects of activating TLRs in animal models of melanoma and will evaluate the effects of activating different types of TLRs on DCs and also use different antibodies, known to enhance DC function, to assess if immune responses can be improved. Finally, we propose a clinical trial based on this knowledge. Patients with melanoma in the clinical trial will receive a DC vaccine injection that is activated using TLRs followed by another injection of proteins that activates TLRs on DCs and other immune cells in the body. If successful, this will meet the ultimate goal of improving DC vaccines to benefit patients with melanoma.
The isolation of human anti-MICA monoclonal antibodies
- Glenn Dranoff, M.D., Dana-Farber Cancer Institute
- Kai Wucherpfennig, M.D., Ph.D., Dana-Farber Cancer Institute
This project is aimed at isolating specific antibodies from the blood of melanoma patients who have derived durable clinical benefits from experimental immunotherapies. Our studies have indicated that antibodies directed to a target expressed on melanoma cells (called MICA) may be involved in the therapeutic benefits of melanoma vaccines and blockade of CTLA-4. We have developed a novel approach to identify the blood cells that produce the antibodies to MICA. We will use this approach to isolate a panel of the anti-MICA antibodies from long-term responding melanoma patients. These antibodies will then be evaluated for functional activity in a variety of model systems. The most potent antibody could be considered for future clinical development, so as to allow testing for therapeutic benefits in patients with advanced melanoma.
Advanced immune monitoring and TCR cloning in clinical trials of T cell receptor (TCR) engineered adoptive cell transfer therapy
- Antoni Ribas, M.D., The University of California, Los Angeles
- David Baltimore, Ph.D., California Institute of Technology
- James R. Heath, Ph.D., California Institute of Technology
We propose a patient-oriented research to improve the performance of adoptive cell transfer (ACT) therapy using T cell receptor (TCR) engineered lymphocytes by incorporating new generation immune monitoring assays and molecular cloning of TCRs for future clinical use. This project proposes to accelerate the assessment of the results of genetic engineering of the human immune system tested in clinical trials leading to the development of new therapeutic reagents in order to aid in the formulation of new clinical protocols. It capitalizes on existing efforts to develop miniaturized and multiplexed diagnostic platforms for immune monitoring coupled with advanced molecular cloning to efficiently analyze immune responses to cancer and isolate the minimal components providing the cancer specificity to killer immune cells.
Studies on the mechanism(s) of de novo and acquired resistance to selective RAF inhibition
Generously supported by the Carson Family Charitable Trust and the Lawrence and Carol Saper Foundation
- David Solit, M.D., Memorial Sloan-Kettering Cancer Center
- Paul Chapman, M.D., Memorial Sloan-Kettering Cancer Center
- Michael Davies, M.D., Ph.D., University of Texas M.D. Anderson Cancer Center
- Roger Lo, M.D., Ph.D., University of California Los Angeles
- David Fisher, M.D., Ph.D., Massachusetts General Hospital
- Keith Flaherty, M.D., Massachusetts General Hospital
- Katherine Nathanson, M.D., University of Pennsylvania
- Jeffrey Sosman, M.D., Vanderbilt University
- Hensin Tsao, M.D., Ph.D., Massachusetts General Hospital
Approximately half of melanomas have an activating mutation of the BRAF gene. PLX4032 (also called RG7204) is a potent and selective inhibitor of the most common mutant form of BRAF. In a Phase I trial of PLX4032, approximately 80% of patients with melanoma whose tumors express the BRAF mutation experienced significant tumor shrinkage with minimal side effects. In contrast, none of the patients with melanomas without a BRAF mutation responded to the drug. These promising results demonstrate what can be achieved with personalized, molecularly targeted therapy for melanoma. However, the degree of tumor shrinkage varied greatly among patients and many of the patients who initially responded to PLX4032 subsequently developed resistance. The experience with targeted therapies in other diseases suggests that understanding the causes of resistance can lead to improved patient selection for treatments like PLX4032 and the development of more effective drug combinations. A number of laboratories including those directed by the investigators leading this proposal have conducted research that suggests possible mechanisms of resistance to PLX4032. However, none of these mechanisms have been definitively confirmed as clinical relevant in patients treated with PLX4032. We believe that identifying the mechanisms of resistance to PLX4032 and demonstrating their clinical significance is one of the highest priorities in the melanoma community. We will establish a consortium of the academic melanoma centers that have led the clinical trials with PLX4032 to work together to share their patient specimens and expertise to systematically evaluate possible mechanisms of resistance to PLX4032 and other highly selective BRAF inhibitors. The effort will include laboratory studies to further elucidate potential mechanisms of resistance, development of a multi-institutional database to track the acquisition and analysis of clinical specimens, standardization of molecular testing procedures, and analysis of biopsies obtained from patients who were treated with highly selective BRAF inhibitors. This project will address not only the critical challenge of overcoming resistance to selective BRAF inhibition, but it will set the stage for the efficient development and improvement of other new, promising therapies for this highly aggressive disease.
Strategies to enhance the efficacy of adoptive T cell therapy
- Cassian Yee, M.D., Fred Hutchinson Cancer Research Center
- Stan Riddell, M.D., Fred Hutchinson Cancer Research Center
- Philip Greenberg, M.D., Fred Hutchinson Cancer Research Center
A number of studies performed by our labs and others using adoptive T cell therapy have been successful in treating patients with melanoma in its advanced stages. However, only a limited number of patients respond completely to treatment; many patients respond incompletely, or relapse at a later date after an initial response. An important factor contributing to an effective and long-lasting response to adoptive T cell therapy is the capacity of the T cell to survive, persist and expand, in the body after it has been infused. We have explored different strategies to extend the persistence of T cells in patients. One of these approaches involves combining a vaccine with the T cells. A vaccine that is given after T cell infusion allows the vaccine to stimulate the infused T cells and enhance their survival by driving them to expand in the patient. To test this idea, we are proposing a clinical trial that involves two T cell infusions: first, an infusion of antigen-specific T cells given without the vaccine and then, a second infusion given with the vaccine. By comparing the survival of the T cells from the first infusion with that from the second infusion, we can determine if the vaccine was effective in expanding the infused T cells in the patient. Because we have developed tools in the lab that can track and analyze the infused T cells, even at the single cell level, we can begin to understand the requirements for effective T cell therapy. We believe that the results of this study may benefit not only adoptive T cell therapy of melanoma but other cancers and make it possible in the future to treat patients in a manner that is safe, effective and long-lasting. [^] Back to Top
The MRA awarded seven teams pursing multidisciplinary translational research.
Developing melanoma screening in primary care
-Martin A. Weinstock, M.D., Ph.D., Rhode Island Hospital and Brown University
-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
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.
Manipulating immune regulation in adoptive T-cell therapy for melanoma
- Jeffrey Weber, M.D., Ph.D., H. Lee Moffitt Cancer Center and Research Institute
- Patrick Hwu, M.D., M.D. Anderson Cancer Center
- Laszlo Radvanyi, Ph.D., MD Anderson Cancer Center
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.
Identification and Validation of Combination Therapies for Melanomas
- Michael J. Weber, Ph.D., University of Virginia
- Levi Garraway, M.D., Ph.D., Dana-Farber Cancer Institute
- Dan Gioeli, Ph.D., University of Virginia
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.
Sequencing of the Melanoma Exome, Transcriptome and Epigenome
- Ruth Halaban, Ph.D., Yale University
- Marcus Bosenberg, M.D., Ph.D., Yale University
- Michael Krauthammer, M.D., Ph.D., Yale University
- David Stern, Ph.D., Yale University
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.
Combinatorial Immunotherapy for Melanoma with B7-H1/PD-1 Checkpoint Blockade
MRA Team Science Award (Anonymous Donor)
- Team Lead: Drew Pardoll, M.D., Ph.D., Johns Hopkins University
- Lieping Chen, M.D., Ph.D., Yale University
- Suzanne Topalian, M.D., Johns Hopkins University
|Pardoll, Topalian and Chen
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.
Identification of Novel Melanoma Risk Genes Using High-throughput Genomics
- 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
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.
Defining the Importance of Immunity to NY-ESO-1 in Melanoma
(Co-funded by the Cancer Research Institute)
- 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
NY-ESO-1 is a prototypical cancer testis antigen and is expressed in up to 40% of metastatic melanoma specimens. Immunity to NY-ESO-1 occurs spontaneously during tumor progression or via active immunization strategies. A major focus of the Cancer Vaccine Collaborative has been the identification of optimal methods for vaccination against NY-ESO-1. As part of an Established Investigator project funded by MRA, we have found that treatment with the CTLA-4 blocking antibody ipilimumab results in the induction and enhancement of antibody and T cell responses to NY-ESO-1. Importantly, patients with NY-ESO-1 immunity have a higher likelihood of achieving clinical benefit with this novel immunotherapy. In this proposal we seek to develop a more comprehensive assessment of NY-ESO-1 expression and immunity, especially in the context of anti-CTLA-4 therapy. Our group has been given access to serum specimens from the planned 900 patients in the EORTC-sponsored randomized phase III trial of ipilimumab in stage 3 melanoma. We believe this is an unprecedented opportunity to analyze: 1) the prevalence of NY-ESO-1 antibodies in melanoma patients through the stage 3-4 transition and 2) the effect of ipilimumab on NY-ESO-1 immunity in stage 3 disease and its correlation with disease state in a large randomized cohort. In addition, we have also been granted access to 60 sets of serum specimens from a randomized trial of ipilimumab with or without two chemotherapy regimens. This will allow us to define the immunologic interaction between ipilimumab and chemotherapy, especially as it relates to antibodies and T cells recognizing NY-ESO-1.
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MRA awarded six team science awards of $1,000,000 over three years.
Therapeutic targeting of melanoma stem cells
- Jonathan Cebon, M.B.B.S., F.R.A.C.P., Ph.D., Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences
- Mike Bridge, BSc., Ph.D., Mulligan Institute of Medical Research, New Zealand
- Otavia Caballero, M.D., M.Sc., Ph.D., Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center
- Weisan Chen, Ph.D., Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences
- Ian Davis, MBBS, PhD, FRACP, FAChPM, Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Studies
- Winston Hide, B.Sc (Honors), M.A., Ph.D., Harvard University
This research will further characterize the melanoma stem cells (MSC) phenotypically and biologically, identify novel therapeutic targets on MSC, and validate potential targets in vitro and in vivo. Recent data suggest that melanoma tumors may contain 'stem-like' or repopulating cells that are responsible for tumor initiation and metastasis. Conventional treatments may target the majority of cells within the cancer but to be truly effective will also need to eradicate these malignant repopulating cells. This research project aims to define novel therapeutic targets on these cells and to investigate whether it is possible to target these cells using the immune system. We are developing a vaccine against a target molecule on cancer cells (NY-ESO-l) that can also be selectively present on melanoma repopulating cells. If successful, this research may yield new treatments for malignant melanoma.
MHC-associated phosphopeptides as targets for melanoma immunotherapy
- Victor H. Engelhard, Ph.D., University of Virginia
- Donald Hunt, Ph.D., University of Virginia
- Suzanne Topalian, M.D., Johns Hopkins University
Melanoma is among the most immunogenic of all human cancers. Although many melanoma antigens have been identified, few are related to the underlying changes responsible for the malignant phenotype. This research aims to identify and characterize the immunogenicity of a novel cohort of phosphopeptide antigens, and elucidate molecular pathways determining their expression in order to enhance expression and immune recognition. This step will lead to the potential for treatment strategies of vaccines in rational combinations with kinase inhibitors and/or immunomodulatory biological agents.
A genome-wide association study to identify melanoma predisposition genes
- Nicholas K. Hayward, Ph.D., Queensland Institute of Medical Research
- Graham Mann, Ph.D., Westmead Hospital, Australia
- Nicholas Martin, Ph.D., Queensland Institute of Medical Research
In the general population, melanoma susceptibility is thought to be governed by variation in a series of 'low penetrance' genes, and only one such gene (MC1R) had been found. Even though such genes confer relatively low individual risk, if they are common they can account for a large proportion of the population burden of melanoma. Thus cumulatively, it is conceivable that a small number of low risk genes could predict an individual's risk of melanoma with considerable accuracy. Using a Genome Wide Association Study approach, this team identified and validated five new melanoma risk genes - PARP1, SETDB1, ATM, MX2, and CASP8 - that confer and increase risk of melanoma of 14-22%. These findings point to new pathways in melanoma susceptibility, processes in melanoma development, and identify new genes that can lead to better individual risk prediction.
Accelerating melanoma therapy: Genomics, drug screening and informatics
Treatment of advanced melanoma is stymied by incomplete understanding of the genetic lesions that drive its growth. We propose to identify prognostically relevant molecular subtypes of stage IV metastatic melanoma and select drugs and drug combinations that target genomic alterations of these subtypes. First we will apply state-of-the-art genomic technologies to representative specimens from the John Wayne Cancer Institute’s exceptional collection of clinically-annotated melanoma paired metastatic tumor tissue, cell lines, and matched normal lymphocytes. Melanoma specimens linked to known clinical outcomes will be statistically clustered into distinct clinical/pathological subtypes characterized by tumor-related genes representing potential drug targets. In addition to providing diagnostic and prognostic utility, this subtype information can improve clinical management and streamline the selection of more effective drug combinations. To this end we will conduct high-throughput testing of metastatic subclass-specific cell lines against a panel of FDA-approved drugs alone and in two-drug combinations, as well as targeted agents which attack molecular lesions identified in the genomic analyses. This combined attack should efficiently identify drug-susceptible vulnerabilities in the melanoma subtypes.
- David Hoon, Ph.D., John Wayne Cancer Institute
- David Fisher, M.D., Ph.D., Massachusetts General Hospital
- Levi Garraway, M.D., Ph.D., Dana-Farber Cancer Institute
Surgery and immunotherapy for melanoma metastatic to distant sites
- Donald Morton, M.D., Chief, Melanoma Program at John Wayne Cancer Institute
Dr. Morton will start a randomized phase III trial asking whether initial resection improves time to progression as compared with best available nonsurgical care.
Therapeutic inhibition of mutant activated signaling pathways in melanoma
- Neal Rosen, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center
- David Solit, M.D., Memorial Sloan-Kettering Cancer Center
- James Allison, Ph.D., Memorial Sloan-Kettering Cancer Center
- Jedd Wolchok, M.D., Assistant Memorial Sloan Kettering Cancer Center
This proposal is aimed at developing new therapies for the treatment of melanoma. It is based on two premises. Recent discoveries show that the most common forms of melanoma almost always have mutations that activate growth by activating one particular pathway in the cell, the so-called ERK signaling pathway. Mutations in the N-RAS or B-RAF genes activate this pathway, and one or the other of these genes is mutated in the great majority of melanomas. Our previous work showed that drugs inhibiting this pathway effectively inhibit the growth of melanomas with these mutations. The first premise of our proposal is that activation of this pathway is required for the growth of melanomas and that drugs that inhibit the pathway will be useful for the treatment of advanced metastatic disease. As two types of ERK pathway inhibitor are already in development, we expect to test this hypothesis rapidly. Agents that cause the patients immune system to attack the tumor have also been shown to have some therapeutic benefit. One such agent, an anti-CTLA-4 antibody discovered by one of us, has been show to have antitumor activity in melanoma patients. Thus, there are two new strategies for treating metastatic melanoma: immunotherapy, and inhibition of growth pathways that drive tumor growth. The second premise of our proposal is that combining these modalities will have enhanced and potentially significant clinical benefit. We plan to determine whether this strategy is feasible, identify the best ways of combining the two therapies, and then use this work to develop rational protocols for testing this idea in patients.
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