This program aims to attract early career scientists with novel ideas into melanoma research, thereby recruiting and supporting the next generation of melanoma researchers. Young Investigators are scientists within four years of their first academic faculty appointment. A mentorship commitment from a senior investigator is required.
Inhibiting the TGF-ß Signaling Axis in the Melanoma Microenvironment
Duke-MRA Young Investigator Award in Honor of Frank Courtney
Brent A. Hanks, M.D., Ph.D, Duke University Medical Center Mentor: Gerard Blobe, Professor of Medicine
Despite recent advancements, there are limited treatment options available for patients with metastatic melanoma. Even for patients eligible for treatment with targeted biological therapy, these strategies have proven to provide relatively short-term benefit. Although immunotherapy has demonstrated the ability to significantly prolong survival, these effects are observed in only a small subset of patients undergoing treatment with these agents. Therefore, there is a significant need to improve the treatment options for patients with advanced melanoma. While current immunotherapies have focused on enhancing the immune response to cancers, they have ignored the ability of tumors to actively interfere with this process. One method that tumors use to suppress the generation of immunity is the production of an immune suppressive factor known as transforming growth factor-ß (TGF-ß). This factor has been shown to inhibit the function of a local antigen presenting cell population known as the dendritic cell, which plays a critical role in directing the generation of tumor-specific immunity. We are proposing to study the combination of a TGF-ß inhibitor with the currently approved immunotherapy agent, anti-CTLA-4 monoclonal antibody (ipilimumab), in a melanoma mouse model that closely resembles the biology of human melanoma. These studies would serve as an important foundation for future clinical trials investigating this treatment combination in patients with metastatic melanoma.
Delineating the Heterogeneity of Response to BRAF Inhibition in Melanoma
The Danny Fund-MRA Young Investigator Award
Michael Berger, Ph.D., Memorial Sloan-Kettering Cancer Center Mentor: David Solit, Assistant Member, Human Oncology and Pathogenesis Program
The emergence of targeted therapies has profoundly altered the treatment of melanoma patients. Most notably, the BRAF inhibitor vemurafenib has led to significant improvements in survival and quality of life for patients with mutations in the gene BRAF. Nevertheless, complete sustained response to vemurafenib is rare, and heterogeneity of clinical outcomes remains a major challenge. Studies have shown that this variability in response can be at least partly explained by mutations in other genes that co-occur with mutations in BRAF. We have developed a targeted deep sequencing assay enabling us to catalog all mutations and copy number alterations involving all key cancer-associated genes in clinical tumor specimens. Using this platform, we will profile advanced melanomas treated with vemurafenib in order to more comprehensively characterize the spectrum of genomic alterations that co-occur with BRAF mutations and that correlate with drug response. By comparing pre-treatment and disease progression tumors, we will identify alterations that mediate resistance to vemurafenib that may emerge through clonal selection. Finally, in cases where our targeted sequencing assay is unrevealing, we will perform whole genome sequencing and RNA sequencing to discover novel genomic determinants of drug response. Through these efforts, we will provide valuable predictive information for clinicians and patients and lay the foundation for rational BRAF inhibitor-based combination strategies for the treatment of patients with BRAF-mutant melanoma.
A Translational Approach for Developing Combination Therapy in Melanoma
Suzette and Steven Kolitch-MRA Young Investigator Award
Tara C Gangadhar, M.D., The Trustees of the University of Pennsylvania Mentor: Lynn Schuchter, Division Chief, Hematology-Oncology
Metastatic melanoma has a poor prognosis with an average survival of about one year. Recent advances have lead to the development of targeted therapies that inhibit BRAF, a gene that is abnormally activated in approximately one half of melanomas. Unfortunately, patients quickly develop resistance to BRAF targeted therapies and are still dying of melanoma. Developing new combinations of targeted therapies is essential for improving outcomes in metastatic melanoma. Furthermore, identifying biomarkers that can predict which patients are more likely to respond to a new combination therapy may ultimately guide more individualized treatment in patients with melanoma. Activation of the PI3K gene pathway is one mechanism of resistance to BRAF targeted therapies. Combination therapy inhibiting both PI3K and BRAF may improve outcomes in melanoma; identifying biomarkers that predict response will allow for more personalized individualization of combination therapy. The aims of this project are 1) to conduct a clinical trial of combined PI3K and BRAF targeted therapies in patients with advanced melanoma and 2) to learn about biomarkers that may predict which patients are most likely to respond to combined PI3K and BRAF targeted therapy in order to better personalize care to maximize results in individuals.
Blockade of a Novel CTLA-4 Pathway as a New Approach in Melanoma Therapy
Stewart Rahr-MRA Young Investigator Award
Kok-Fai Kong, Ph.D., La Jolla Institute for Allergy & Immunology Mentor: Amnon Altman, Director, Scientific Affairs
Immunologic targeting of melanoma by CTLA-4 blockade is an effective therapeutic approach. Ipilimumab, a CTLA-4 monoclonal antibody, is FDA approved for treatment of human melanomas. However, combinatorial regimens show promising effectiveness in advanced and metastatic melanomas. I propose to test the preclinical utility of blocking a novel pathway that I discovered between CTLA-4 and an enzyme protein kinase, which is essential for the proper function of regulatory T (Treg) cells, a subset of immune system T cells with the power to suppress immune responses, including against growing tumors. My studies will test whether the absence of the protein kinase can boost anti-tumor immunity and, therefore, restrain tumor growth, by attenuating the function of Treg cells. In addition, I found that genetic deletion of the protein kinase enhances the function of Th9 cells, a different T cell subset with the power to inhibit tumor growth. Therefore, I will also test the hypothesis the lack of the protein kinase can promote the generation and anti-tumor function of Th9 cells. Finally, I will utilize a preclinical animal model of melanoma to determine whether disrupting the ability of CTLA-4 to bind to the protein kinase can result in a beneficial synergistic effect of simultaneously attenuating tumor-promoting Treg function and enhancing tumor-inhibiting Th9 responses. The results that I will generate may provide a preclinical basis for developing novel, clinically useful and selective kinase inhibitory drugs, which, when included in combinatorial regimens with Ipilimumab or other therapies, could greatly improve treatment for patients with advanced melanomas.
Mechanisms of resistance for constitutively-active NRAS Melanoma
Ellis Family-MRA Young Investigator Award in Memory of Hal Ellis
Susana Ortiz-Urda, M.D., Ph.D., The Regents of the University of California, San Francisco Mentor: Pui-Yan Kwok, Professor, Dermatology
Melanomas are classified based on their genetic alterations. Oncogenic mutations of the RAS family of proteins such as BRAF or NRAS occur in approximately 2/3 of all melanomas.The development in 2010 of Plexxicon a BRAF inhibitor that elicited striking tumor regressions in clinical trials was a milestone event in our understanding of the genetics of this disease. However, the duration of the response was limited due to primary and acquired drug resistance. Recent studies in BRAF inhibitor melanoma patients have shown that there are multiple mechanisms of primary or acquired drug resistance. There are currently not therapies available for NRAS melanomas, however recent studies performed in our and other labs have shown that in order to produce regression on NRAS melanoma tumors several proteins need to be inhibit with specific drugs. Clinical trials combining these drugs are now in progress. We propose to study the possible mechanisms of resistance for NRAS melanoma studying genetic alterations and other cell elements (transcripts) that are being actively expressed at any given time and vary with external environmental conditions.
Augmenting anti-tumor immunity by modulating IL-2/IL-15 receptor binding.
Stewart Rahr-MRA Young Investigator Award
Mark Rubinstein, Ph.D., Medical University of South Carolina Mentor: David Cole, Chairman, Professor of Surgery
The goal of our research is to develop improved immunotherapeutic strategies involving the transfer of tumor-reactive white blood cells (T cells) into patients with metastatic melanoma. This technique is known as adoptive cellular therapy (ACT). ACT is the only therapy that can reliably induce long-term cures in significant frequencies of patients with metastatic melanoma. Despite its promise, there are significant limitations, including life threatening toxicities associated with the treatment, and the majority of patients are not cured. We hypothesize that one of the limitations to ACT being able to work in more patients is a failure of the transferred white blood cells to survive and persist in the cancer patient. To overcome this problem, we propose to evaluate a panel of new growth factors that can be administered to patients after ACT to selectively enhance the survival and function of adoptively transferred white blood cells. Based on our preliminary data, our approach may be significantly less toxic and clinically more efficacious against tumor, as we were able to cure mice with established melanoma tumors with radiation or chemotherapy. As our previous findings (still requiring the use of chemotherapy) are partly the basis for an ACT clinical trial for metastatic melanoma patients being initiated at our institute, funding of this proposal would put my laboratory in a strong position to have a continued impact on the development of future ACT trials both at our institute and elsewhere.
Quantitative single-cell biomarkers of melanoma immunotherapy
Stewart Rahr-MRA Young Investigator Award
Navin Varadarajan, Ph.D., University of Houston Mentor: Richard Wilson, Professor, Chemical and Biomedical Engineering, and Laszlo Radvanyi, Professor, Melanoma Medical Oncology-Research, University of Texas M.D. Anderson Cancer Center
Melanoma is one of the leading causes of cancer related deaths within the United States. Immunotherapy that aims to harness the impressive capabilities of the human immune system has emerged as one of the frontline therapies for metastatic melanoma. With the recent FDA approval of Ipilimumab, a blocking antibody against the T-cell negative stimulator, CTLA-4, against melanoma, T-cell immunotherapy is now an established cancer therapy. Adoptive cell therapy (ACT) that works directly to harness the cancer-eliminating properties of patient T-cells has shown considerable promise with clinical response rates of ~50% even in stage IV melanoma refractory to all other treatment methods. Essentially, ACT has become the last hope for survival of patients with melanoma that is refractory to conventional therapies. The objective of the current proposal is to perform extensive functional single-cell characterization of the cells used for the combined treatment employing ACT and checkpoint regulation through antibodies, to identify functional attributes of these cells that predict patient outcomes. Identifying single-cell biomarkers will serve to not only predict outcomes but ultimately guide ACT expansion and treatment towards better patient outcomes, a fundamental goal of all cancer treatment.
Targeting melanocyte precursor pathways for melanoma therapy SkinCeuticals - MRA Young Investigator Award Barbara Bedogni, Ph.D., Case Western Reserve University - School of Medicine Mentor: Ernest Borden, Deputy Director, Taussig Cancer Institute, Cleveland Clinic
New therapies against mutated BRAF have shown some promise, however they are applicable to half of the patient population and resistance inevitably sets in within few months of treatment. We propose a novel treatment approach that targets Notch and ERBB signaling cascades and that has the potential to treat patients independently of the dominant mutations that drive the disease. Notch and ERBB, are essential for the well-being of melanocytes and their precursors. Melanomas re-activate them and use them to their advantage to promote growth and survival. While inhibiting either Notch or ERBB alone only marginally affects survival, simultaneous inhibition of both pathways results in over 90% of cell death, with equal efficacy in either mutated or wild type BRAF cells. Our goal is to understand the mechanisms by which Notch and ERBB signaling regulate melanoma cell growth and survival and most importantly, to provide experimental evidence that the pharmacological targeting of these two pathways can effectively halt melanoma growth and metastasis in a majority of melanoma patients. To this end, we will use powerful transgenic mouse melanoma models that very closely recapitulate the biology of human melanoma and are particularly suitable for drug testing. We believe the evidence obtained in this study will be instrumental in supporting the use of Notch and ERBB inhibitors in melanoma therapy. Such compounds already exist and are used for the treatment of other cancers. The applicability to melanoma is therefore a concrete possibility in the short term.
Combining targeted therapy and immunotherapy to treat melanoma
MRA Collaborative Donor Young Investigator Award Fan Pan, M.D., Ph.D., Johns Hopkins University Mentor: Drew Pardoll, Professor and Co-Director of Immunology
Metastatic melanoma cases in the United States and the death rate of this disease are increasing at a disturbing rate prompting efforts to develop more effective treatments. A strategy called 'immunotherapy' involves stimulating a patient's own immune system to kill tumors. Unfortunately obstacles to effective immunotherapy arise from both tumor cells themselves and certain cells of the immune system. Through a number of poorly understood processes, tumors promote their own growth while suppressing the immune system's tumor-killing capacity. Regulatory T cells ('Tregs') that normally prevent the body from excessive or self-directed immune responses restrain the activation of other immune cells. Another T cell type called 'TH17 cells' initiate processes that aid tumors including tumor spreading (metastasis) and generating new blood vessels to the growing tumor mass (angiogenesis). Previously we found a molecule named 'HIF-1', which is commonly found in tumors, is necessary for generating TH17 cells suggesting that conditions in tumors can generate T cells capable of aiding further tumor development. We propose a strategy in which the generation of both tumor-promoting cells, TH17 and Treg cells are simultaneously abolished. We will test the effectiveness of this approach using known HIF-1 inhibitors (Digoxin, acriflavine) and Treg depleting drugs (cyclophosphamide) in a mouse model for melanoma that closely resembles the human disease. We expect that these drugs by themselves or in combination with a specialized melanoma targeting therapy (Vemurafenib) will have potent anti-tumor effects. In the process of testing this approach, we will shed light on the enigmatic tumor-immune system interaction.
Therapeutic targeting of novel metastatic microRNAs in human melanoma Amanda and Jonathan Eilian - MRA Young Investigator Award Sohail Tavazoie, M.D., Ph.D., The Rockefeller University Mentor: Barry Coller, Professor, Physician-in-Chief, VP of Medical Affairs
The major fear that most patients diagnosed with melanoma have is that their cancer will spread or metastasize throughout the body. Currently, our most effective treatment option for stage 1, 2 or 3 melanoma is surgical resection. As such, there are no effective medical therapies for the prevention of melanoma metastasis. I believe that the only way we can combat melanoma metastasis is through enhanced understanding of the underlying biology that drives metastasis. As such, we have invested heavily in the past few years in the development of an in vivo metastasis model of human melanoma metastasis. By using this system, we have discovered two small RNAs (microRNAs) that are present at high levels in highly metastatic melanoma cells. Blocking the activity of these microRNAs strongly blocks melanoma metastasis by both pigmented and non-pigmented melanoma cells. Patients whose melanoma cancers express high levels of these novel small RNAs have much higher rates of melanoma metastasis. We wish to determine how these small RNAs promote metastasis and to identify the genes that they block in order to achieve their aims. We wish to therapeutically block these small RNAs with a novel DNA-like molecule in live mice to determine if this could effectively block melanoma metastasis in human patients. We believe that the identification of the genes that these miRNAs regulate could reveal novel proteins that may possess metastasis suppressive activities in melanoma. This innovative approach has the potential to significantly impact metastatic relapse rates in human melanoma.
Transcriptional elongation in BRAFV600E sensitive and resistant melanoma Maria and Bill Bell - MRA Young Investigator Award The 2012 AACR-Conquer Cancer Foundation of ASCO Young Investigator Translational Cancer Research Award is providing partial support for this project Richard Mark White, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center Mentors: Joan Massague, Alfred P. Sloan Chair, Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center and Leonard Zon, Grousbeck Professor of Pediatrics, Children's Hospital Boston
Recent advances in the treatment of melanoma have seen unprecedented responses in this notoriously difficult disease. The discovery of a key genetic mutation in melanoma, called BRAFV600E, led to the search for specific inhibitors of this gene. The first approved BRAFV600E inhibitor, vemurafenib, produces tumor shrinkage in over 70% of patients and prolongs survival. However, almost all patients become resistant to this drug. Although finding key mutations in melanoma is of great importance, it is abundantly clear that these mutations only produce cancer when in the right context. In melanoma, this "context" is a cell type called a neural crest cell. My laboratory is interesting in discovering whether simultaneously targeting the mutation along with that neural crest context would be a new way of treating cancer. I utilize an unusual model organism for doing these studies: the zebrafish. Unexpectedly, the zebrafish develops very aggressive melanomas that are genetically identical to the human disease. Using this fish, we have been able to discover a number of chemicals which alter this neural crest cellular context. When we combined the BRAF inhibitor with our neural crest inhibitor, we saw the tumors completely regress. We now want to understand if this strategy can be used to prevent resistance to BRAF inhibitors, or be used to treat patients who have already developed such resistance. This would represent a striking example of how studying cancer across species leads to meaningful therapies for human patients.
Targeting NRAS Palmitoylation in Melanoma
Stuart Rahr-MRA Young Investigator
Xu Wu, Ph.D., Massachusetts General Hospital Mentor: David Fisher, Chairman, Department of Dermatology
Melanoma is a highly malignant form of skin cancer that arises from melanocytes. When diagnosed early, more than eighty percent of cases can be successfully treated through surgical resection. However, metastatic melanoma is resistant to currently available treatments and carries a very poor prognosis with a less than ten percent five-year survival rate. Despite efforts to improve skin cancer prevention, the incidence of melanoma has increased significantly over the past decades. MAPK (Ras/Raf) and PI3K/Akt signaling pathways have been implicated in melanoma development. NRAS mutations are found in ~20% of melanoma, and melanoma with NRAS mutation usually has poor prognosis. NRAS mutations have also been linked to the resistance of target-based therapy for melanoma currently in clinic trials. Therefore, it is important to develop new therapeutics that target NRAS. As NRAS protein requires a lipid modification (16-carbon palmitoylation) for its function, blocking this modification can efficiently block NRAS activity in cancer cells. Protein palmitoylation is catalyzed by DHHC (Asp-His-His-Cys)-family protein palmitoyl acyltransferases (PATs). We are developing chemical tools to study NRAS palmitoylation and small molecule inhibitors of NRAS palmitoylation. Such approach could potentially provide new therapeutics for NRAS dependent melanoma.
Development of combined molecular/immunotherapy regimens for human melanoma Christie's - MRA Young Investigator Award Christian Blank, M.D., Ph.D., The Netherlands Cancer Institute Mentor: Ton Schumacher, Senior Member, Division of Immunology
The treatment of human melanoma has progressed markedly in recent years. First, recent advances in the genetic characterization of melanoma now allow the specific targeting of the signaling pathway alterations that underlie this disease. As the most prominent example, the targeting of the BRAFV600E mutation with PLX4032 has led to very high response rates, although the duration of these responses is often relatively short. Second, building on the observation that immune recognition is a frequent event in melanoma, a series of antibodies that target inhibitory receptors on T cells has been evaluated in clinical trials. Intriguingly, while the response rate upon blockade of CTLA-4 or PD-1 is lower than that achieved with the targeted drugs, the effect on survival in the subgroup of responding patients is prominent. Based on these recent advances, a key next step will be to develop combination therapies, in which targeted drugs are used to drive cancer regression, and in which antibody administration is utilized to then drive immune reactivity against the liberated antigens. However, our knowledge on how to best combine targeted therapy and immunotherapy is at present highly limited. To address this issue, we have developed a spontaneous mouse melanoma model in which we will determine how combination therapy can best be achieved, using both tumor regression and immunological parameters as readouts. The results obtained in this project should provide the conceptual basis for the design of clinical studies that evaluate the value of combination immunotherapy - targeted therapy for melanoma patients.
Targeting the Pten/PI3K signaling cascade in BRaf600E-induced malignant melanoma The Canadian Cancer Society is contributing partial funding to this project David Dankort, Ph.D., McGill University Mentor: William Muller, Chair in Molecular Oncology
The prognosis for those with malignant melanoma today is as poor as it was 25 years ago. Conventional chemotherapies have failed, yet there is hope. Recent genetic and biochemical data have identified genes that are future targeted drugs candidates. Our lab uses state-of-the-art genetically modified mouse models to determine which genes are pivotal in melanoma development, progression, and metastasis. Melanoma represents a failure of built-in mechanisms to control rogue melanocytes that have acquired two types of mutation: i) Oncogene activation, which functions like a gas pedal (increasing tumor cell survival, growth, and migration) and ii) Mutational loss of tumor suppressor genes (TSGs), the tumor developmental "brake pedals." While BRaf is the most frequently mutated oncogene in melanoma, our lab has shown that for mutant BRaf to cause melanomas the TSG Pten must be lost. Unfortunately Pten cannot be restored in tumor cells and has been deemed non-druggable. This is why we seek to determine which gene product(s) biochemically up - and down-stream of Pten are important in melanoma. This is not a blind search; we know that the genes responsible lie within a specific pathway and that most of these are kinases, attractive to pharmaceutical companies. Knowing which are important in melanoma is crucial to developing specific drugs for this disease. Thus we will systematically identify these genes first in cultured cells and then our mouse models. The successful completion of this work will identify key 'druggable' targets that can be translated to the clinic where it matters.
Myeloid derived suppressor cells and immunotherapy outcomes in melanoma Ellen and Gary Davis Foundation - MRA Young Investigator Award Alexander Lesokhin, M.D., Memorial Sloan-Kettering Cancer Center Mentor: Jedd D. Wolchok, Director, Immunotherapy Clinical Trials
Ipilimumab, an antibody that stimulates the immune system, has emerged as a promising treatment option for some patients with advanced melanoma. However, the majority of patients develop toxicity from excess immune stimulation without attaining clinical benefit. These results define the need for: 1) identifying biomarkers of response to Ipilimumab treatment that will enable early identification of patients likely to achieve clinical benefit and 2) studying mechanisms of Ipilimumab failure with the goal of developing additional therapeutic options that enhance outcomes. We have found that myeloid derived suppressor cells (MDSC) increase in quantity after Ipilimumab treatment in patients who do not achieve clinical benefit. Our preclinical work and the work of others support the notion that MDSC limit the effectiveness of T cell mediated tumor immunity. This leads to the hypothesis that MDSC expansion following Ipilimumab is a mechanism of treatment failure. The current proposal aims to: 1) evaluate which MDSC surface genes are amenable to therapeutic targeting; 2) assess which MDSC subsets are increasing in patients that do not benefit from Ipilimumab therapy; and 3) evaluate if antibodies targeting genes overexpressed by MDSC can rescue T cell function. This work will define the role of MDSC in the response to Ipilimumab and potentially identify novel therapeutic targets with potential for improving the outcome of immunotherapy for melanoma and other cancers.
Epigenetic control of PDGFRbeta expression in PLX4032 acquired resistance Todd Boehly Roger Lo, M.D., Ph.D., University of California, Los Angeles Mentor: Antoni Ribas, Associate Professor of Medicine and Surgery
Recently we have witnessed a major breakthrough in the targeted therapy of melanoma. A drug PLX4032 that targets a common melanoma mutation, BRAF(V600E/K), can result in significant tumor shrinkage in about 80 percent of patients treated. One significant barrier to the ultimate success of this approach (i.e., survival benefit) lies in the problem of acquired resistance. This common scenario occurs when tumors initially respond to the drug but then become resistant. Understanding how melanoma tumors escape from PLX4032 following initial response is arguably among the highest priority scientific issues to tackle in melanoma research. We have previously discovered two mechanisms of acquired resistance to PLX4032. One involves a known cancer gene that becomes mutated and activated, bypassing or short-circuiting the effect of the drug PLX4032. The other involves the over-production of a receptor protein that turns on survival pathway(s) that cannot be controlled by PLX4032. In this proposal, we focus on understanding the mechanism of this receptor over-production and hypothesize that it occurs through a non-genetic or so-called epigenetic mechanism. In this scenario, a small population of the melanoma tumor, with more or less the same cancer genome as the tumor bulk, can reversibly adopt an altered but stable state of gene expression, resulting in the re-wiring of survival pathway(s) and the ability to survive and grow in the presence of PLX4032. Resolving a mechanism of this receptor over-production in the course of melanoma escape from PLX4032 should present additional therapeutic opportunities.
Markers and mechanisms of melanoma resistance to combination chemotherapy Stewart Rahr - MRA Young Investigator Award Aaron Mackey, Ph.D., University of Virginia Mentor: Michael Weber, Director, Cancer Center
Chemotherapies that target a single cancer-causing oncogene are generally unable to provide complete and enduring clearance of the tumor; after an initial wave of tumor cell death, the remaining chemotherapy-resistant tumor cells survive. Using both a small primary panel of current anti-cancer drugs and a larger secondary panel of FDA-approved compounds (including both cancer-related and other drugs), we have identified highly potent pairings of primary cancer drugs with secondary drugs that together kill substantially more tumor cells than either of them kill alone. Study of these synergistic drug pairings reveals how some tumors attempt to evade the killing effects of primary drugs, suggesting that secondary drugs may block such evasion responses. However, these promising results are not universal to all melanoma tumors; only some tumors will respond well to a particular combination of drugs, because either the tumor is resistant to the primary drug or the tumor's evasion of the primary drug effect is not blocked by the secondary drug. These differences in response may be due to one or more DNA mutations among involved genes. Thus, we aim to 1) identify melanoma tumor mutations in a large number of melanomas, 2) assess whether particular genes have been silenced by epigenetic mechanisms, and 3) study each tumor's drug response in light of its individual mutational/epigenetic status, to reveal the mechanism(s) by which sensitivity or resistance is achieved. With this knowledge, we can further develop and prescribe more effective chemotherapies on an individual patient basis.
Novel strategies targeting Treg cell suppression for melanoma immunotherapy Stewart Rahr - MRA Young Investigator Award Guangyong Peng, M.D., Ph.D., Saint Louis University Mentor: Daniel F. Hoft, Professor and Director, Division of Immunobiology
Melanoma is the leading cause of cancer-related death in the United States. Increasing evidence suggests that immunotherapy is a promising approach for treating patients with invasive and metastatic melanoma, but the clinical effectiveness is still discouraging so far. Several hypotheses can be postulated to explain the low clinical effectiveness, but it has become clear that regulatory T cells (Treg) exist and induce a suppressive tumor microenvironment to hamper the antitumor immune responses. Thus, the success of immunotherapy against melanoma ultimately depends on how well we understand the suppressive mechanisms mediated by Treg cells in the tumor microenvironment and how to manipulate the immune system to augment antitumor immune responses. We recently discovered a novel suppressive mechanism whereby human Treg cells induce senescence in naive/effector T cells that then exhibit potent suppressive activity. The central hypothesis of this proposal is that human Treg cells not only can directly suppress naive and effector T cells, but also can convert these T cells into senescent cells that possess potent suppressive activity and amplify the immune suppression in the melanoma suppressive microenvironment. To test this hypothesis, we will dissect the mechanisms involved in the differential induction of T-cell senescence, identify unique molecular signaling pathway(s) controlling Treg-induced senescence, and investigate enhancement of antitumor immunity through functional regulations of Treg cells and Treg-induced senescent T cells via TLR8 signaling in melanoma animal models. These studies should lead to novel strategies for manipulation of Treg-induced suppression for the treatment of human melanoma and other cancer as well.
Feedback adaptation of RAF-MEK-ERK signaling in BRAF mutant melanomas PricewaterhouseCoopers - MRA Young Investigator Award Christine Pratilas, M.D., Memorial Sloan-Kettering Cancer Center Mentor: Neal Rosen, Enid A. Haupt Chair in Medical Oncology
For the majority of patients with advanced melanoma whose tumors have a mutation in BRAF, novel therapies directed against mutant RAF are effective and represent a great advance in treatment of this disease. However, most responses are incomplete and the majority of patients' tumors will stop responding after about seven months. Many investigators are trying to determine why tumors become resistant to RAF inhibitor therapy. We however are trying to understand why responses to RAF inhibitor therapy are incomplete or suboptimal, and have observed that inhibition of the signaling pathway in these cells is associated with a subtle reinduction of other pathway elements in a negative feedback loop. Our work shows how this occurs and why the addition of a second inhibitor of the pathway results in enhanced and more prolonged response of the tumor. The studies outlined in the proposal are designed to 1) achieve a better understanding of the feedback circuits that limit the response to RAF inhibitors alone, 2) determine the impact of the reactivation on other important elements of the pathway, and 3) test whether combinations of drugs that limit the feedback reactivation result in better responses in models of BRAF mutant melanoma. The translational impact of these studies is the design of novel combination therapies for patients, which enhance the initial response to RAF inhibitor treatment.
Targeting the LKB1-AMPK signaling pathway in malignant melanoma Elizabeth and Oliver Stanton - MRA Young Investigator Award Bin Zheng, Ph.D., Columbia University Medical Center Mentor: Ricardo Dalla-Favera, Uris Professor of Pathology and Director, Herbert Irving Comprehensive Cancer Institute
BRAF kinase is a major oncogenic driver and therapeutic target in malignant melanoma. Recently, the BRAF kinase inhibitor PLX4032 (also known as RG7204) has shown remarkable anti-tumor activity in melanoma clinical trials. However, around 30 percent of patients developed keratoacanthomas-type squamous cell carcinomas (SCC). In addition, most of the patients developed drug resistance during the course of treatment. We have recently discovered a novel bi-directional crosstalk between BRAF and the tumor suppressor LKB1-AMPK pathway, an important signaling pathway involved in the regulation of cancer cell growth and proliferation. Based on our findings, we hypothesize that combinatorial targeting both pathways is a more effective approach to treat malignant melanoma and holds the potential to overcome current limitations associated with BRAF inhibitors. Preclinical studies have suggested that activating the LKB1-AMPK pathway is a promising strategy for cancer therapeutics. Metformin, an activator of the LKB1-AMPK pathway, is currently being used for treating type II diabetes and potentially can be adapted for cancer treatment. The goal of this proposal is to assess the therapeutic benefit of using AMPK activators (such as metformin and its analog phenformin), in combination with the BRAF inhibitors in melanoma treatment. We will evaluate the combinatory effect of AMPK activators and BRAF inhibitors on inhibiting tumor growth in preclinical mouse models. Moreover, we will investigate the potential of AMPK activators on preventing the development of BRAF inhibitor-induced SCC and the emergence of resistance to BRAF inhibitors. Our studies will provide important rational basis to develop better targeted therapy of malignant melanoma.
Circulating microRNAs as diagnosis and staging biomarkers for melanoma Latham & Watkins - MRA Young Investigator Award Li Zhou, M.D., Henry Ford Health System Co-Mentors: Qing Sheng Mi, Director, Immunology Program, and Henry Lim, Chair, Department of Dermatology
Malignant melanoma (MM) is the most aggressive form of skin cancer. Development of minimally invasive tests for the detection and monitoring of MM could revolutionize present clinical management. Although conventional strategies for blood-based biomarker discovery have shown promise in other cancers, the development of clinically validated detection markers for MM remains an unmet challenge. New approaches that can complement and improve current strategies for early diagnosis and prediction of MM are urgently needed. MicroRNAs (miRNAs) are small RNA molecules that modulate gene functions and play important roles in a wide range of physiologic and pathologic processes, including cancer. Recent data from our laboratory and others indicated that miRNA expression is dysregulated in melanoma cells and tumors, and serum miRNA expression profiles are altered during MM development, raising the possibility that the circulating miRNAs may serve as MM specific biomarkers. In this proposal, we will test if miRNAs could be an ideal novel class of serum biomarkers for the early diagnosis and assessment of MM progression. We will first use miRAN global gene expression profile to further identify potential serum miRNA biomarkers, which may change during MM progression, then develop serum miRNA assays suitable for large cohort analyses to validate it. Finally, we will test if serum miRNAs could serve as predictive biomarkers for the risk of MM progression and assess treatment outcome. The results from the proposed studies may revolutionize present clinical management, including early diagnosis of progressive MM, confirmation of stage, estimating prognosis, and predicting therapeutic efficacy. [^] Back to Top
Counteracting metastatic spread and outgrowth by MCSP-targeted therapy SkinCeuticals - MRA Young Investigator Award Edwin Bremer, Ph.D., University Medical Center Groningen Mentor: Wijnand Helfrich, Head Surgical Research Laboratories
Life expectancy of melanoma patients diagnosed with metastases is very limited, because metastasized melanoma is largely resistant to current treatment regimens. Therefore, new approaches that block the spread and outgrowth of metastasizing melanoma cells are urgently needed. Here, we aim to develop such novel approaches using two proteins normally involved in the fight against cancer in the human body. These proteins are called TRAIL and Galectin-9. TRAIL specifically induces cell death in melanoma cells, but not in normal cells, whereas Galectin-9 specifically blocks the ability of melanoma cells to metastasize. Unfortunately, these potentially promising proteins are not ideally equipped to hunt down melanoma cells by themselves. To overcome this hurdle, we fused TRAIL and Galectin-9 to a so-called antibody fragment that is uniquely suited to hunt down melanoma cells. This antibody fragment recognizes and strongly binds to a protein called MCSP, which is highly expressed on melanoma cells. Of note, MCSP also promotes metastasis formation, but this pro-metastatic activity is inhibited by the antibody fragment. Therefore the two fusion proteins we designed will: 1. selectively hunt down and bind to melanoma cells; 2. inhibit pro-metastatic signaling by MCSP; and 3. simultaneously attack tumor cells by TRAIL or Galectin-9. The current project aims to preclinically evaluate the approach outlined above and is expected to yield a candidate drug that will be particularly suited for the prevention/inhibition of melanoma metastases.
Identifying therapeutic targets for melanoma brain metastases PricewaterhouseCoopers - MRA Young Investigator Award Michael Davies, M.D., Ph.D., University of Texas M.D. Anderson Cancer Center Mentor: Gordon B. Mills, Chair, Department of Systems Biology
One of the most common and devastating complications of advanced melanoma is the development of brain metastases. Unfortunately, there are no effective treatments for this complication, and patients with brain metastases survival less than 4 months on average. In preliminary studies, we have demonstrated that melanoma brain metastases have significant molecular differences when compared to metastases from other sites in the body. We propose to study a set of patients for whom we have tissue samples from both their brain metastases and metastases from other sites to determine what factors and pathways contribute to the aggressive nature of these tumors. These studies should improve our understanding of brain metastases, and set the stage for rational clinical trials for these patients.
Epigenomic analysis of melanoma metastatic behavior Cartier - MRA Young Investigator Award Remco van Doorn, M.D., Ph.D., Leiden University Medical Centre Mentor: Rein Willemze, Professor and Chair of Dermatology
Most patients currently diagnosed with melanoma present at an early stage of the disease, when the prognosis after surgical removal of the primary tumor is favorable. However, a subset of patients with early melanoma lesions will develop metastatic disease. Metastasis, the spread of tumor cells from a primary tumor to distant sites, currently poses the biggest problem to melanoma treatment and is the main cause of death. Our means of identifying those patients at increased risk of metastasis, who might benefit from additional treatment are limited. This is partly due the fact that it is not well known what actually drives melanoma tumor cells to invade and spread to foreign tissues. Recent findings suggest that the capacity to metastasize is engrained and detectable in tumor cells of the primary melanoma. This study is aimed at identifying alterations in DNA methylation, a chemical modification of the molecules that carry genetic information, in metastatic melanoma. Tumor cells often harbor many DNA methylation alterations, which deregulate gene activity. We will examine whether the pattern of DNA methylation in melanomas that metastasize is different from the pattern observed in melanomas that do not metastasize. We expect to find specific molecular markers that can predict whether a primary melanoma will show metastatic spread. In addition, we will examine if and how these DNA alterations promote the metastatic behavior of melanoma tumor cells. In doing so, we hope to find new approaches to treatment by specifically targeting molecules that contribute to metastatic behavior of melanoma cells.
miRNA down-regulation in melanoma - Diagnostic and therapeutic implications Stewart Rahr - MRA Young Investigator Award Raya Leibowitz-Amit, M.D., Ph.D., Sheba Medical Center Mentor: Shai Izraeli, Head, Leukemia and Childhood Malignancies Section
Metastatic melanoma is a devastating disease with currently limited treatment options. miRNAs are small RNA species within cells that regulate gene expression. Aberrant expression of miRNAs leads to cancerous transformation, but their role in melanoma is still unknown. We have observed that many miRNAs are not expressed in malignant melanocytes in comparison to normal melanocyets. Interestingly, many of the genes encoding these miRNAs are found in very close proximity in a chromosomal region known to be implicated in differentiation and development. Indeed, some of these miRNAs were shown to suppress the growth of several cancer types but not of melanoma so far. Our preliminary results demonstrate that in some melanoma cell lines, these miRNAs are silenced because of a chromosomal deletion. Conversely, in other cell lines these miRNAs are most likely silenced by a mechanism that merely alters the chromosomal material without deleting it (termed 'epigenetic modification'), because treatment of the cells with epigenetic modifiers restores their expression.
We plan to further investigate the mechanism and timing of miRNA silencing during melanocyte transformation. We also plan to molecularly characterize the sub-group of melanoma patients with the potential to undergo tumor suppression in response to epigenetic modifiers. Eventually, we plan to design a clinical trial evaluating the use of such agents (already approved for hematological malignancies) in this specific patient sub-group. Our translational research will hopefully yield a new treatment approach along with a novel molecular assay that predicts response, thus enlarging our therapeutic arsenal in this yet incurable disease. [^] Back to Top
18F Labeled benzamides for pre-clinical PET imaging of melanoma metastases Zhen Cheng, Ph.D., Stanford University Mentor: Sanjiv Sam Gambhir, Director, Molecular Imaging Program
Cheng synthesized two novel PET scanning probes that bind with melanoma associated melanin. [18F]FDG is the most widely used PET probe for imaging metastatic melanoma in the clinic, but there is a need for additional probes that can be more specific and detect smaller metastases. In malignant melanoma, melanin formation is highly increased because tyrosinase activity is significantly elevated. In preclinical models, these new probes targeted primary and pulmonary melanotic metastatic lesions with excellent imaging quality and had the advantage of low accumulation in healthy organs.
Combining an MDM2 inhibitor with chemotherapy for the treatment of melanoma Sanjev Kumar, PhD, University of Michigan Mentor: Shaomeng Wang, Professor and Co-director, Molecular Therapeutics Program
The p53 tumor suppressor gene is mutated in half of human cancers; however, the wild-type status of p53 is retained, but remains inactive, in a high percentage (~85%) of human melanomas. The key mechanisms for the functional inactivation of wild-type p53 include the direct interactions of p53 with MDM2 or MDMX proteins, and overexpression of Bcl-2/Bcl-xL proteins, which inhibit p53-induced cell death. Dr. Kumar found that concurrent targeting of Bcl-2/Bcl-xL proteins and the p53 pathways with small molecules induced rapid and robust apoptosis in preclinical models. This research resulted in two candidate drugs that reactivate p53 that have been licensed by a company to initiate phase I clinical testing.
The role of oncogenic signaling pathways in human melanoma immune evasion Patrick Ott, M.D., New York University Mentor: Nina Bhardwaj, Professor and Director of Tumor Vaccine Program
Dendritic cells are promising as a vaccine platform because they are able to induce strong T cell responses that can lead to melanoma destruction. This study aims to investigate whether the melanoma microenvironment, possibly driven by cell signaling pathways that are upregulated in melanoma cells (such as the MAPK pathway), negatively impacts dendritic cell function. This study will also explore whether signaling pathway blockade in melanoma cells can possibly reverse a negative effect on dendritic cells and other immune cells. I expect that these investigations will lead to a more detailed understanding of the interface between melanoma biology and the melanoma-specific immune response and allow the rational integration of oncogenic pathway inhibition into dendritic cell vaccination protocols in melanoma.
Targeting CD4+ T cells for melanoma immunotherapy Timothy Bullock, Ph.D. University of Virginia
Dr. Bullock has been working to optimize a vaccination strategy that elicits the highest magnitude helper T cell response to specific targets expressed by melanoma cells. Dr. Bullock also identified targets on "corrupted" T cells (helper T cells that have been converted to regulatory T cells that suppress immune response to the tumor) in order to disrupt their function or prevent the conversion from occurring. A combination approach that suppresses and bypasses regulatory mechanisms and supports survival of cells is necessary for eliciting large populations of CD4 cells. They have also found that the presence of these cells enhances the trafficking of cytotoxic T cells to the tumor.
Regulation of T cellchemokine receptor expression during vaccination: Tumor-targetedimmunotherapy David Mullins, Ph.D. University of Virginia
Dr. Mullins confirmed that CXCR3 (a chemokine receptor previously found to be expressed on a subset of melanoma patients' CD8 T cells) serves to assist these T cells in migrating into melanomas, and vaccination with melanoma-derived peptides and adjuvant can induce CXCR3-positive T cells in greater that 95 percent of patients. His lab discovered that cells can produce these chemical beacons following local administration of IFN-gamma. In part with funding by the NIH, Dr. Mullins will initiate a Phase I trial to assess the effects of dual administration of vaccination and IFN-gamma treatment of the tumor to optimize CD8 T cell tumor infiltration.
Defining the role of inducible co-stimulator (ICOS)-expressing T cells against melanoma Padmanee Sharma, M.D., Ph.D. University of Texas, M.D. Anderson Cancer Center
Research indicates that patients who have improved survival after ipilimumab (anti-CTLA-4) treatment have sustained elevations of numbers of ICOS-expressing T cells. ICOS is a stimulatory co-regulator of T cell anti-tumor immune responses. To understand the role of these T cells in the anti-tumor response, studies conducted in mouse models showed that the ICOS pathway is necessary for optimal anti-tumor immune response.