MRA Research Awards »
The Established Investigator Award program supports senior investigators with an established record of scientific productivity and accomplishment and who are past the initial four years of their first academic faculty appointment.
Kinetics and effects of vemurafenib on intratumoral immunity
Michael Atkins, M.D., Georgetown University
Approximately 40-50% of malignant melanomas contain a mutation in B-Raf called (BRAFV600E). This results in activation of a critical intracellular pathway leading to unrestrained tumor growth. Recently, highly selective inhibitors of BRAFV600E have shown significant antitumor activity in patients with BRAFV600E mutant melanoma and one agent, vemurafenib, received FDA approval in August 2011. Despite this major treatment breakthrough, few patients experience complete regression of tumor and all patients will eventually develop disease progression. Thus, achievement of more meaningful clinical results will require identification of ways to extend or enhance the efficacy of drugs like vemurafenib. Immunotherapy (eg interleukin 2, ipilimumab, and PD1 antibody) represents an alternative treatment strategy for patients with melanoma that can induce durable tumor regressions in a small subset of patients. Preliminary evidence suggests that blocking BRAF enhances immune recognition of melanoma. These results have stimulated interest in combining BRAF inhibitors with immunotherapy as a means to sustain their efficacy. However, critical information about the timing and nature of the immune effects of BRAF inhibition is needed to be able to rationally design such combination protocols. The present proposal will study the effects of vemurafenib on tumor immunity (mechanisms and timing of immune cell infiltration, specificity and function of these cells, and the effect of therapy on immune regulatory pathways, particularly those associated with treatment response); thereby laying the groundwork for such combination studies.
Development of effective melanoma combination therapies
Marcus Bosenberg, M.D., Ph.D., Yale University
In 2010 for the first time, two different treatments were shown to make more than half of treated melanoma patients live longer. One of the therapies is anti-CTLA4 (also known as Ipilimumab or Yervoy), which works by helping the immune system fight melanoma. The second therapy is vemurafenib (also known as PLX4032), which blocks the BRAF protein that is altered in about half of melanomas. Despite these two very important advances, neither of these therapies cure the vast majority of advanced melanoma patients. It is possible that combining these two therapies will result in higher response rates in melanoma patients. Clinical trials for melanoma patients of some combinations involving these two agents are currently being planned and will likely begin soon. In order to better understand how the combinations work, we propose to comprehensively test combinations of these promising therapies in our melanoma models. We hope to understand why some patients respond better than others and why some combinations are more effective than others. This will help to design more effective future clinical trials that result in more frequent and longer responses and to better predict which patients are likely to benefit most from combination therapies.
Targeting inducible invasive cells in melanoma
Jonathan Cebon, Ph.D., FRACP, Ludwig Institute for Cancer Research,
Although newly emerging therapies have shown early successes in melanoma, treatment failure is common. Many recent reports have identified mechanisms of resistance and the development of new gene mutations can explain some cases. Commonly, however, resistance often develops without mutation. Here we demonstrate that treatment-resistant cells can be identified among melanoma cells growing in the laboratory. The features of these cells have been studied in detail and it appears that they are more likely to invade and therefore perhaps form secondary tumors. We have identified the role of molecules that are able to switch these cells on, and propose that blocking the emergence of these invasive resistant cells may prevent treatment failure. The aims of this project are therefore to: (1) further investigate the mechanisms which switch these cells on, (2) study the mechanisms that make them resistant to drug treatments and immune therapies, (3) block the principal switching mechanisms thereby identifying potentially new treatment options and (4) to test these approaches in melanoma-bearing mice to establish proof-of-principle before proceeding to clinical trials.
Targeting N-RAS as a therapeutic approach for melanoma
Douglas V. Faller, M.D., Ph.D., Boston University, B U Medical Campus
Current therapies for melanoma are inadequate. Activating mutations of a protein called N-RAS, or RAS-related pathways, are found more than 90% of melanomas. A novel therapeutic modality selectively targeting melanomas with activation of N-RAS signaling would make a significant impact on the way melanoma cancer is treated. Mutated, activated N-RAS is an attractive target for therapy of melanoma, but approaches aimed directly at RAS or its critical signaling pathways (which are required for the viability of normal cells) have had very limited success. Our "synthetic lethality" approach, however, exploits an Achilles' heel of melanoma cells containing a mutated, activated N-RAS - i.e., their absolute requirement for a survival pathway mediated by PKC-delta. In contrast, normal cells and tissues do not require PKC-delta for growth and development. This novel approach therefore "hijacks" the RAS signaling pathway, which normally promotes melanoma growth and progression, and redirects it to promote tumor cell death. Furthermore, it is likely that this targeted approach would also show activity in melanoma cells with oncogenic activation of a RAS downstream signaling pathway (BRAF), and in melanoma cells that have become resistant to the new BRAF inhibitors, thereby further broadening its potential application in melanoma.
The development of rational therapeutic regimens for NRAS-mutant melanoma
Levi A. Garraway, M.D., Ph.D., Dana-Farber Cancer Institute
Treatment options are still very limited for the >50% of metastatic melanoma patients whose tumors lack BRAF gene mutations. A large proportion of those tumors contain mutations in a different gene, called NRAS. Cancer-associated NRAS mutations bring about biological effects that are somewhat similar to BRAF mutations; however, the new melanoma drug vemurafenib is completely ineffective against tumors with NRAS mutations. The goal of this project is to identify new drug combinations capable of suppressing the growth of NRAS-mutant tumors. Leveraging the integration of "bleeding edge" experimental approaches, we will identify biological processes that can be effectively targeted in NRAS-mutant melanomas using existing and emerging medicines. Since some of the tumor-promoting effects of BRAF and NRAS mutations are similar, we will focus our discovery efforts around an exciting new class of drugs-called MEK and ERK inhibitors-which are capable of intercepting those effects. However, we will utilize both global and focused experimental approaches to discover new drug targets and candidate drugs that might form the basis of highly effective drug combinations. Finally, we will leverage in-depth genetic and molecular studies of clinical specimens to evaluate the validity of top-tier candidate drug targets and combinations. Upon completion of this research, we expect to identify new drug combinations that could move rapidly into clinical trials of patients with NRAS-mutant melanoma, thereby directly supporting the development of more effective treatment options for many melanoma patients. Publications: Highly Recurrent TERT Promoter Mutations in Human Melanoma
Delineating BRAF inhibitor resistance mechanisms using proteomic profiling
Thomas G. Graeber, Ph.D., University of California, Los Angeles
An exciting advance in cancer therapies has been the development of drugs that specifically target the function of mutated genes. Regression of tumors targeted by these drugs has been remarkable. Drugs targeted at inhibiting the BRAF mutation in certain melanomas have led recent news headline reports due to spectacular tumor regression. Because of the specificity of these 'molecularly targeted' drugs, they have fewer clinical side effects. Unfortunately, most patients develop drug resistance in less than a year, and this traumatic aspect has also led news headlines. Cancer is a complex mix of interconnected events gone awry through mutations. We know much about the individual events, but we need a better understanding of how they function together, as a system, to cause malignancy. The future of molecular therapies relies on targeting multiple events, thus making it exponentially more difficult for tumor cells to gain the multiple mutations required to escape this coincident drug assault. This is somewhat analogous to anti-HIV drug cocktail therapies. In our work, we use technologies that concurrently measure thousands of events within cancer cells. In particular, we use mass spectrometry-based 'proteomics' to measure the activity of signaling proteins that drive aberrant tumor cell growth and survival. We then analyze the data using computational algorithms to identify points of susceptibility in the system. We are applying this approach to build a 'systems biology' perspective of how melanoma cells become resistant to BRAF inhibitors. These studies have broader implications since the BRAF V600E mutation occurs in 7% of all cancers.
Mechanisms of Cooperation between BRAF & PI3'-kinase Signaling in Melanoma
The Safeway Foundation is providing partial support for this project
Martin McMahon, Ph.D., University of California, San Francisco
In the past year, two new drugs have been approved for treatment of patients with advanced, metastatic melanoma: Vemurafenib and IpiIimumab. Although this represents a sterling success in treatment of patients with advanced disease, the holy grail of melanoma therapy would be an adjuvant regimen, administered after surgery, that eradicates residual melanoma cells thereby preventing metastatic disease from occurring. The current adjuvant regimen, high dose interferon, has marginal efficacy and severe side effects in many patients. Although we are starting to understand the inner workings of the melanoma cell, it remains unclear how best to eradicate melanoma cells after surgical removal of the primary tumor. Moreover, although there are many potential new melanoma drugs being developed, it is unknown which will work best as single agents and how such drugs might best be combined for maximum patient benefit. We have acquired access to a portfolio of promising new drugs to treat melanoma. Using bona fide human melanoma cells we will evaluate the role of various signal transduction proteins in the aberrant behavior of melanoma cells. In addition, using genetically engineered mice, we have invented a mouse model of melanoma, which will be used to test the ability of drugs administered in the adjuvant setting to prevent recurrence of metastatic melanoma. Studies proposed here offer the long-term prospect of evidence-based, effective and comparatively less toxic adjuvant chemotherapy for melanoma patients based on a molecular understanding of how signal transduction pathways contribute to the aberrant biology and biochemistry of the melanoma cell.
Enhancing immunotherapeutic activity of agonistic anti-CD40 antibodies
Jeffrey Ravetch, M.D., Ph.D., The Rockefeller University
Immunotherapy of melanoma has emerged as an area of great promise in the treatment of this disease. Activation of the patient's own immune response against his tumor is hampered by the ability of the tumor to suppress normal immune activation. To overcome this barrier approaches have been developed to induce immune cell activation by bypassing the normal controls that prevent T cells from becoming activated and eliminating the tumor cell. We have discovered that an important immune modulating molecule called CD40 can be triggered to induce killer T cells to eliminate melanoma through a pathway that involves co-engagement of an inhibitory molecule. This novel pathway results in considerable enhancement of tumor killing. We propose to investigate how this pathway operates and how to exploit this pathway to develop novel immunotherapeutics to treat melanoma
Combinatorial approaches to treating mutant BRAF melanomas
Neal Rosen, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center
In approximately 60% of melanomas, a gene called BRAF is mutated. The mutant BRAF protein is activated and responsible for the unregulated abnormal growth of these tumors. New drugs that inhibit the mutant BRAF protein have had remarkable therapeutic effects. They arrest the growth of the metastases and cause them to get smaller in almost all patients with mutant BRAF melanomas, an unprecedented result in this disease. However, only rare tumors are eradicated and the therapeutic effects are temporary; most tumors eventually recur. This proposal is aimed at devising new combination therapies for mutant BRAF melanoma that cause the tumor to regress more completely and for a longer time and that are effective after resistance to the RAF inhibitor develops. Our recent results suggest strategies to accomplish these goals. We have shown that treatment of tumors with RAF inhibitors causes other compensatory pathways to become activated, which attenuate the antitumor activity of the drugs. Our data suggest that more complete inhibition of RAF in combination with drugs that inhibit these compensatory pathways will be much more effective than either therapy alone. We have also recently attained a better understanding of how tumors become resistant to RAF inhibition, which suggests logical means of attacking the resistant cells. We now propose to use these strategies to attempt to get more complete, long-lasting control of mutant BRAF tumors and to develop treatments that are active in patients with resistant disease. The overarching goal is to radically change the natural history of melanoma.
Network models of signaling pathways and combinatorial therapy in melanoma
Chris Sander, Ph.D., Memorial Sloan-Kettering Cancer Center
Melanoma treatment has experienced recent breakthroughs in targeted therapy with the introduction of specific RAF inhibitors. The specific inhibition of mutant forms of BRAF in melanomas have generated particular excitement, only to be tempered as resistance evolved to these new therapies. This motivates us to pursue the design of combinatorial therapies to target melanomas that are insensitive to RAF inhibitor treatment. For this purpose, we have developed a novel network pharmacology approach. Our strategy combines systematic drug perturbation experiments, high-throughput protein array technologies and advanced computational algorithms to model cell type specific regulatory mechanisms leading to cancer formation. Using our theoretical cellular models, we are predicting novel combinatorial therapies tailored to achieve desired therapeutic responses in melanoma. In addition, we are carrying out comprehensive analysis of genome-wide molecular data from different stages and subtypes of melanoma in order to select a representative panel of cell lines from hundreds of established human melanoma cell lines at MSKCC to be used in our drug perturbation and modeling studies. Our analysis will be a resource for the research community by elucidating molecular signatures of melanoma stages/subtypes. By applying the computational biology methods we have adapted from statistical physics, we can construct pathway diagrams of the protein networks in selected melanoma cell lines. These pathway models can then be analyzed to nominate new drug combinations to test experimentally. Drug combinations that we discover can be rapidly translated to the clinic through our clinical collaborators.
Targeting XIAP for the treatment of melanoma
Hermann Steller, The Rockefeller University
All human cells have the ability to self-destruct by activating an intrinsic cell suicide program when they are damaged or no longer needed. The execution of this cell death program leads to a distinct form of cell death termed apoptosis. Apoptosis provides a crucial natural defense against cancer, and most cancer therapeutics activate this cell suicide program. Unfortunately, tumor cells find ways to escape apoptosis and continue to grow. A common mechanism by which tumor cells block apoptosis is through expressing high levels of anti-apoptotic proteins. Anti-apoptotic proteins normally act as safeguards to prevent unwanted cell loss, but cancer cells can exploit this mechanism to acquire resistance towards apoptosis. In particular, high levels of X-linked Inhibitor of Apoptosis Protein (XIAP), a potent anti-apoptotic protein, have been found in both primary and metastatic melanoma and are thought to play an important role in therapeutic resistance. The goal of this proposal is to develop small-molecule inhibitors of XIAP and test their suitability for the selective killing of melanoma cells. For this purpose, we will take two distinct approaches. First, we will exploit our extensive knowledge of how natural IAP-antagonists function to rationally design novel compounds that target XIAP with high specificity. Second, we will identify compounds that can inactivate XIAP by systematically screening small-molecule libraries. We will initially test and optimize our compounds in cell-based models to identify leads that are suitable for subsequent clinical development. This project has the potential to radically transform the treatment of malignant melanoma.
Synergistic Targeting of Inhibitory T cell Pathways in Melanoma
Kai W. Wucherpfennig, M.D., Ph.D., Dana-Farber Cancer Institute
T cells, an important population of immune cells, can kill melanoma cells. Unfortunately, the activity of T cells is frequently blocked by the tumor microenvironment. Recent exciting work has shown that blockade of an inhibitory receptor on T cells - CTLA-4 - with the antibody ipililumab enhances the activity of T cells against melanomas and thereby induces regression of metastatic disease in a subset of patients. These results raise an important question: how can the activity of this antibody be enhanced so that a larger fraction of patients with metastatic melanoma can benefit? We have developed a novel approach to identify targets for immunotherapy of melanoma. One of the most important recent discoveries in biomedical research is the RNAi pathway, which is used by cells to regulate the activity of many genes. The principles of RNAi have opened many new possibilities for the identification of therapeutic targets. We developed a novel approach to identify new therapeutic targets for melanoma using an in vivo RNAi screen. The goal of this project is to determine which of the new molecules identified in the RNAi screen show synergistic benefit with an antibody to CTLA-4, an approved treatment for melanoma. We will examine which combination therapies induce optimal expansion of T cells in tumors and are most effective in eradicating established melanomas.
Targeting the Bap1 tumor suppressor gene in a mouse model of melanoma
MRA-Melanoma Research Foundation Established Investigator Award
J. William Harbour, M.D., University of Miami
Metastasis, the spread of cancer cells to distant parts of the body, is the most common cause of death in patients with melanoma and most other cancers. Yet, our understanding of how cancer cells acquire the ability to metastasize remains very limited, making it difficult to tailor therapies that are specific to metastatic tumors. Uveal melanoma (UM) is the most common primary cancer of the eye and the second most common form of melanoma. UMs are notoriously metastatic, resistant to conventional chemotherapy and often fatal. UMs that metastasize can be distinguished from those that do not by their distinct patterns of gene expression, and are classified into "class 1" tumors, which have a low risk of spreading outside of the eye, and "class 2" tumors, which have a very high risk of spreading. Using state-of-the-art genome sequencing techniques, we have identified the gene BAP1 that is located at chromosome 3p21 and that is mutated in almost all class 2 tumors but not in class 1 tumors. BAP1 meets several of the major criteria expected for a metastasis suppressor gene, but very little is known about the role of BAP1 in the spread of melanoma to distant sites. Thus, one objective of this research proposal is to study the effects of BAP1 mutation in melanoma cells using animal models. We expect to find that disabling BAP1 in UM cells increases their ability to metastasize. More importantly, we will use this animal model to identify potential therapeutic agents that block the spread of melanoma cells that have lost BAP1. Overall, the project is expected to lead to innovative new strategies for treating metastatic melanoma.
Optimal T cell receptor affinity for adoptive T cell therapy of melanoma
MRA Established Investigator Award (Anonymous Donor)
David Kranz, Ph.D., University of Illinois at Urbana-Champaign
T cells are white blood cells that are capable of killing cancer cells without harming nearby normal cells. The T cells recognize and respond to the cancer cells using a molecule on their surface that binds to a specific antigen on the tumor cells. The molecule is called a T cell antigen receptor, or T cell receptor (TCR). There has been recent progress in using our knowledge of TCRs in a therapeutic strategy called adoptive T cell therapy. In this approach, T cells are isolated from the peripheral blood of an individual with cancer, and the T cells are expanded in the lab and infused with a TCR that recognizes the cancer. These T cells are then reintroduced into the patient in an effort to have the tumor specifically destroyed by the T cells, without the side effects associated with many cancer treatments. This approach could be improved if information were available about what properties of the TCRs will work most effectively. The goal of our project is to use a mouse model for melanoma, in which we are able to test various TCRs that we have engineered in the lab against a specific model cancer antigen. The mouse model involves both subcutaneous tumors and brain tumors in order to simulate the situation in humans in which melanoma often metastasizes to the brain. The results of the study will provide a guide for the use of TCRs in human therapies.
Combined inhibition of NF-kappaB and AKT for melanoma treatment
Genentech, Inc. is providing funding for this project
Ze'ev Ronai, Ph.D., Sanford-Burnham Medical Research Institute
The recent advances in understanding mechanisms underlying melanoma biology have promoted the development of several drugs that offer, for the first time, effective and specific therapy with limited side effects. Despite this major advance, we recognize the limitations of these current approaches, given the development of resistance in patients that initially respond to mono-specific B-Raf inhibitors. It is now recognized that mono-therapy in melanoma will not be sufficient and combination therapy is warranted. Here we offer to test a novel compound, which exhibits promising results in initial preclinical assessment. Notably, this inhibitor, namely BI-69-A11, targets two of the most prominent pathways that are activated in melanoma and which contribute to the notorious resistance of this tumor to therapy. While initial data suggest that treatment with this newly discovered inhibitor suffices for inhibition of melanoma, we anticipate that it would perform even better when combined with specific existing inhibitors. Our proposed studies will allow comprehensive assessment of this inhibitor, alone and in combination with B-Raf/MEK inhibitors in three complementary experimental systems. Our studies will also gauge possible emergence of tumors that are resistant to such treatment(s) and determine their underlying mechanism. Successful completion of the proposed studies is expected to result in further evaluation of this compound in clinical trials of melanoma.
Defining tumor-host interactions in regional advanced melanoma
Douglas Tyler, M.D., Duke University
Melanoma is currently increasing in incidence faster than other cancers in the United States. For advanced stages of melanoma, there are few effective treatment strategies. This proposal aims to understand more clearly the interactions of treatment on tumor characteristics and the immune system so that patients can be treated with therapies on a more rational, scientific basis. One model of advanced melanoma is in-transit disease, when a patient develops multiple tumor deposits (often >5) in the extremity. Regional chemotherapy (RC) delivers chemotherapy to an isolated extremity (with use of a tourniquet) such that the systemic circulation is NOT exposed to the chemotherapy. While L-phenylalanine mustard (LPAM) is currently utilized for this treatment, preclinical data suggests that temozolomide (TMZ) may be more effective. In this proposal, we will collect tumor, lymph node, and blood samples from 20 patients (10 treated with TMZ and 10 treated with LPAM). Several novel technologies will then be used to characterize the genomic and immunologic makeup of the specimens. Traditional methods like tumor pathology and drug analysis will also be performed. Insight from treating patients regionally will have application to not only systemic therapeutic strategies for melanoma patients but also help identify patients in whom additional targeted approaches may be applied. Because the studies are performed in patients and analysis does not require any long-term follow-up, the projected time from the application of concepts learned from this work to having the potential to impact patient-related outcomes could be fewer than five years.
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Multipeptide vaccination with or without IL - 12 and Daclizumab
Thomas Gajewski, M.D., Ph.D., The University of Chicago
Melanoma vaccines offer an opportunity for instructing the immune system to selectively kill melanoma cancer cells in patients, thus comprising a treatment with minimal side effects. Vaccines developed to date frequently induce activated T cells against tumor antigens, yet only a minority of melanoma patients have tumor regressions. Metastatic melanoma tumors often contain CD4+CD25+ FoxP3+ regulatory T cells (Tregs), which have been shown to suppress the immune response that is induced. We propose that depleting such Tregs from patients will relieve this suppression and thus improve efficacy of melanoma vaccines in patients. The overall goal of this proposal is to test two strategies for vaccination, then deplete Tregs using a monoclonal antibody called Daclizumab. This study also will probe the tumor microenvironment in search for molecular details of the tumor that predict clinical benefit with this treatment.
Entrapment and deletion of melanoma-specific T cells at vaccination sites
Willem W. Overwijk, Ph.D., University of Texas M.D. Anderson Cancer Center
While cancer vaccines can stimulate the body's defenses to fight cancer, this stimulation often isn't strong enough to cause complete cure. Recently, vaccination with a mineral oil-based vaccine increased the lifespan of patients with metastatic melanoma undergoing standard therapy. Much room for improvement remains, and we here show results that suggest inherent limitations to mineral oil-based melanoma vaccines. Specifically, we find that melanoma-specific killer cells travel to the vaccine injection site and not to the melanoma where they are needed to destroy tumor cells. In addition, the killer cells die at these vaccine injection sites. In this proposal we will investigate what causes killer cells to travel to vaccine injection sites rather than to melanoma tumors, and what causes them to die there. We will also develop new, water-based vaccines that we predict will not cause killer cells to traffic to vaccine sites and die. The findings from this proposal will directly result in new therapeutic anti-melanoma vaccines with superior anti-melanoma activity for the treatment of melanoma patients.
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Development of intra-tumoral prognostic biomarkers for primary melanoma
Dr. Lynda Chin, Dana Farber Cancer Institute, Harvard University
Chin identified six "proinvasion oncogenes" that are significantly overexpressed in metastatic lesions in preclinical models. The protein expression level of one of them, called APC5, was correlated with shorter survival of melanoma patients and, thus, may be a prognostic biomarker in human melanomas. This work is being clinically developed by a company to build prognostic tests based on the molecular characteristics of early stage melanoma. If successful, this will transform the way patients with early stage disease are treated and managed.
A phase I trial of bevacizumab plus ipilimumab in melanoma patients
Dr. F. Stephen Hodi, Dana-Farber Cancer Institute, Harvard University
Hodi conducted a Phase I trial investigating ipilimumab with bevacizumab in stage IV melanoma patients and worked to define the mechanism of action for this drug combination. Based on this work, he secured a NIH R21 grant to continue the trial. In this small group of patients, some have experienced durable clinical benefits and side effects have been manageable.
Targeted strategy for treatment of melanoma
Dr. Roya Khosravi-Far, Beth Israel Deaconess Medical Center
Disseminated melanoma is one of the most treatment-resistant and deadly cancers. Increasing incidence of melanoma worldwide in the absence of effective treatments makes a search for therapeutic strategies of vital importance. Dr. Khosravi-Far has discovered a novel biologic that potently induces death (apoptosis) of tumor cells in multiple cancer cell lines and in tumor models by targeting the anti-apoptotic factor c-FLIP. She hypothesizes that this peptide can be used either as a sensitizer or a stand-alone therapeutic agent for treatment of melanoma. Given this success, apoptosis-activating peptides could become a new class of agents for treatment of malignant melanoma.
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Targeting the IGF1R pathway in melanoma
Dr. Alexander Levitzki, Hebrew University of Jerusalem
Melanoma is one of the most aggressive cancers in humans and remains one of the leading causes of cancer death in developed countries. At present there are no clinical protocols to treat metastatic melanomas, although progress has been made in the development of signal transduction inhibitors as well as immune therapy. Preliminary results suggest that Dr. Levitzki has discovered a new family of molecules that target at the same time the IGF1R signaling pathway as well as Stat3, which in combination may hold great promise for the treatment of metastatic melanoma.
Targeting signaling pathways for therapy in a new mouse model of melanoma
Dr. Martin McMahon, University of California, San Francisco
In melanoma, the earliest and most frequently altered oncogene is BRAF. However, since mutation of BRAF is insufficient to promote melanoma on its own, it is likely that BRAF cooperates with mutations in tumor suppressor genes such as INK4A/ARF or PTEN to promote malignant melanoma. Using a mouse model of melanoma based on expression of oncogenic BRAF V600E combined with silencing of the tumor suppressor PTEN, Dr. McMahon explored the essential role of PI3-kinase and AKT in melanoma initiation and maintenance. Although experiments are ongoing, the data generated to date highlight an essential role for PI3-kinase but are ambivalent regarding the role of AKT in melanomagenesis. These data have potential implications for melanoma therapy with agents that target the PI3-kinase AKT signaling pathway.
Treatment of melanoma combining cancer gene therapy and immunotherapy
Dr. TC Wu, Johns Hopkins University
Melanomas are a highly deadly disease and malignant melanoma accounts for 75 percent of all deaths associated with skin cancer. There is an urgent need for innovative therapies for the control of melanomas. Suicidal DNA vectors have emerged as an important strategy for cancer gene therapy since they express high levels of the encoded protein for a prolonged period and cause the transfected cells to undergo apoptic cell death, making them potentially suitable for inducing cancer cell death. Suicidal DNA vectors can be used to encode an immune-stimulatory protein capable of triggering potent immune responses against tumors. Heat shock proteins (HSP) represent ideal proteins for enhancing immunity against tumors and can be encoded by suicidal DNA vectors for cancer immunotherapy. HSP70 has been shown to activate dendritic cells and prime tumor antigen-specific T cells, eliciting strong antitumor responses, representing a potentially ideal protein to be encoded by suicidal DNA vector for cancer gene therapy. One major limitation of this strategy is the limited transfection efficiency in vivo, which may limit the potency of suicidal DNA. Low-energy laser beam treatment represents a novel approach to increase the efficiency of the delivery of DNA to the tumor. In the current proposal, Dr. Wu plans to test whether intratumoral injection of naked suicidal DNA encoding a secreted form of heat shock protein 70 (sHSP70) followed by laser treatment will lead to wide-spread tumor cell death and potent tumor-specific immunity, leading to the control of melanomas in animal models.
The novel melanoma oncogene GNAQ provides new opportunities for therapeutic intervention
Boris Bastian, M.D.
University of California, San Francisco
Dr. Bastian discovered that a vast majority (83 percent) of uveal (ocular) melanomas have mutations in two genes - GNAQ and GNA11. Functional studies showed that mutations induce spontaneously metastasizing tumors in a mouse model and activate the MAP kinase pathway. The functional similarities between these two genes form the basis to develop mechanism-based therapies for most uveal melanomas, and Dr. Bastian will continue this work in a 2010 MRA Team Science Award.
Systemic MFG-E8 blockade as melanoma therapy
Glenn Dranoff, M.D.
Dana Farber Cancer Institute
Dr. Dranoff showed that the protein MFG-E8 is expressed at high levels when melanomas advance to the stage at which they acquire the capacity for invasion and metastasis. In addition to its direct action on melanoma cells, MFG-E8 aids in tumor angiogenesis and inhibits anti-melanoma immunity. His lab found that a combination of antibodies to MFG-E8 and chemotherapy killed tumors in mice and that blocking MFG-E8 enhanced the function of human T cells in vitro. Next steps include translating these findings into phase 1 clinical testing.
Targeted strategies for melanoma treatment and prevention
David Fisher, M.D., Ph.D.
Massachusetts General Hospital
Dr. Fisher studied the mechanism of action of imatinib (Gleevec) on a cell line model for Kit mutated cancer (some melanomas harbor activating mutations in the c-Kit receptor tyrosine kinase) and found that the programmed cell death protein BIM plays an important role. These insights will be important for developing strategies to address resistance to c-KIT targeted therapies. Dr. Fisher has also identified several candidate drugs for topical use to prevent melanoma in fair skinned individuals. This work will continue with funding from the NIH.
Synthetic lethality to MAP kinase pathway inhibition in BRAF-mutant melanoma
Levi Garraway, M.D., Ph.D.
Dana Farber Cancer Institute
In recent years, genetic studies have revealed that most cutaneous melanomas contain activating point mutations in the BRAF or NRAS oncogenes, indicating a profound reliance on the MAP kinase pathway for carcinogenesis. However, results from clinical trials of single agents targeting the MAP kinase pathway have had limited success. Dr. Garraway's research aims to identify a candidate set of melanoma genes that may provide rationale for combining therapeutics targeting the MAP kinase pathway. Dr. Garraway is continuing this work under a 2009 MRA Team Science Award
with Michael Weber.
Genetics of melanoma metastasis
Daniel Pinkel, Ph.D.
University of California, San Francisco
A better understanding of the metastatic potential (prognosis) of a newly diagnosed (primary) tumor is important for treatment recommendations. Dr. Pinkel's study will analyze primary melanomas and their associated metastases to detect genetic factors within the tumors that are associated with metastasis, assess their function, and test their utility for prognostication.
Platform for MHC-exchange based T cell therapy for melanoma
Ton Schumacher, Ph.D.
The Netherlands Cancer Institute
Dr. Schumacher is developing and applying technology to better understand melanoma T cell reactivity and to selectively isolate these cells for improved adoptive T cell therapy. This research led to the development of a method that allows the generation of large collections of protein complexes that can be used to detect melanoma-specific T cell populations in small amounts of patient material. A clinical grade reagent was developed in order to purify melanoma-reactive T cells that recognize an epitope of interest. In addition, this is in use to monitor T cell reactivity during other immunotherapeutic treatments, in particular
A pathway to rational combination therapies for melanoma: Synthetic lethal screening with small molecule inhibitors, guided by phosphoproteome analysis
Michael Weber, Ph.D.
University of Virginia Cancer Center
Dr. Weber will clarify how the MAP kinase pathway is networked to other cell regulatory systems. He will use an assembled library of over 100 small molecule inhibitors to search for "super-additive" inhibition of growth when used in combination. Reverse Phase Protein Arrays (RPPAs) before and after treatment will profile the phosphorylation-driven cell signaling networks of the cell lines, xenografts and patient materials. A subset of promising drugs and drug combinations that are identified will be tested in xenograft and ex vivo patient samples to assess promise as therapy. Dr. Weber is continuing this work under a 2009 MRA Team Science Award
Immunologic signatures of response to ipilimumab
Jedd Wolchok, M.D., Ph.D.
Wolchok's research goal is to extend the preliminary observations regarding changes in immune parameters occurring after CTLA-4 blockade to a larger set of melanoma patients. More detailed knowledge of the T cell phenotype and antigen recognition found in patients who experience clinical response or immune related adverse events will improve treatment results in patients with melanoma. Wolchok is continuing this work under a 2009 MRA Team Science Award
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