2009 MRA Individual Awardee Information
In May 2009, the MRA awarded nearly two million dollars in grants to 13 individual scientists pursuing innovative melanoma research proposals. This second round of MRA grants is focused on research that addresses the gap in translational science. These proposals were reviewed and scored by a convened Grant Review Committee co-chaired by Dr. Suzanne Topalian of Johns Hopkins University and Dr. David Fisher of the Dana Farber Cancer Institute.
Read the Press Release.
Young Investigator Awards
The MRA has awarded $100,000 over two years to three young investigators whose work has the potential to transform melanoma treatment.
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Dr. Zhen Cheng, Stanford University
Proposal Title: 18F Labeled benzamides for pre-clinical PET imaging of melanoma metastases
Early diagnosis and accurate staging of cutaneous malignant melanoma is crucial for improvement in survival of melanoma patients. Positron emission tomography (PET) is a promising technology for non-invasively imaging tumor micrometastases. Currently, there is a strong need to develop PET imaging probes for detection of small melanoma metastases and accurate staging of melanomas.
In malignant melanoma, melanin formation is highly increased because tyrosinase activity is significantly elevated. Many attempts have been made to pursue imaging agents that either are involved in the melanin biosynthesis pathway or have affinities with melanin. Benzamide analogs have been demonstrated to possess affinities with melanin. This research program will develop an 18F labeled benzamide analog for melanin targeted PET imaging of melanoma metastases, and its tumor metastases imaging ability will also be compared with that of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). The probe developed in this research is expected to have great potential to translate into clinical application for PET imaging of melanoma metastases. -
Dr. Sanjev Kumar, University of Michigan
Proposal Title: Combining an MDM2 inhibitor with chemotherapy for the treatment of melanoma
The unmet need of effective treatments for malignant melanoma cannot be overstated. Advances made in melanoma biology have provided the opportunities to design innovative therapeutic strategies. One such therapeutic strategy is the reactivation of tumor suppressor p53, which plays a key role in preventing cancer development. The p53 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, including the metastatic disease. 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. MI-219, an orally available potent small-molecule inhibitor of the MDM2-p53 interaction, has been designed to test reactivation of p53 as a cancer therapeutic strategy. MI-219, however, does not target MDMX or Bcl-2/Bcl-xL proteins, suggesting that these proteins will prevent MI-219 from fully activating the p53 function. The goal of this study is to design combination strategies that fully reactivate p53 function and enhance the anti-tumor activity of MI-219. Dr. Kumar will investigate the therapeutic potential and mechanism of action of MI-219 in combination with chemotherapy drugs, which induce robust MDMX degradation, using cell line and animal models of melanoma. He will also test the combination of MI-219 with small-molecule inhibitors of Bcl-2/Bcl-xL. Since MI-219 or its analogue will soon enter clinical trials, the outcome of this study will have tremendous clinical impact on identification of effective treatment strategies for malignant melanoma. -
Dr. Patrick Ott, New York University
Proposal Title: The role of oncogenic signaling pathways in human melanoma immune evasion
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.
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Established Investigator Awards
Six investigators who have committed their research careers to oncology and are pursuing novel ideas in melanoma research have each received $225,000 in MRA grants over the course of two years.
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Dr. Martin McMahon, University of California, San Francisco
Proposal Title: Targeting signaling pathways for therapy in a new mouse model of melanoma
Melanoma, a cancer most frequently arising from pigment producing cells of the skin, is the fastest growing form of cancer among the North American population. When detected early, melanoma is often cured by surgical resection. However, melanoma has a striking ability to metastasize to distant sites such as in the kidney, lung or brain. Melanoma also has a remarkable capacity to lie dormant, only to re-emerge in a form that is highly resistant to cancer therapy. Consequently, treatment options and survival prospects for metastatic melanoma patients are extremely poor. These facts underscore the urgent need for new research to develop a better understanding of the biology and biochemistry of malignant melanoma. Armed with a better understanding of melanoma, it should then be possible to develop new treatments to combat this disease.
Most cancers arise due to alterations in the expression or activity of tumor suppressors and oncogenes. 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. Dr. McMahon has recently developed and published in Nature Genetics a mouse model of metastatic melanoma in which the most important genetic events that occur in human melanoma can be controlled. He has also conducted proof-of-concept experiments that demonstrate the utility of these mice in evaluating new therapies to prevent or treat melanoma in humans. In this proposal, Dr. McMahon seeks to take these experiments to the next level by using our mouse model of melanoma to evaluate new therapeutics that target two of the key signal transduction pathways in melanoma either alone, in combination with one another, and in combination with conventional chemotherapy. These experiments have direct relevance to the design and evaluation of new therapies to treat humans with melanoma and will speed the translation of basic science explorations in this disease into improved patient care. -
Dr. Lynda Chin, Dana Farber Cancer Institute, Harvard University
Proposal Title: Development of intra-tumoral prognostic biomarkers for primary melanoma
A major effort in cancer research is focused on identifying new cancer indicators, or biomarkers, that allow clinicians to differentiate early stage tumors into benign versus aggressive subtypes. Current melanoma diagnostic methods are inadequate in genome-wide comparisons of numerous mouse and human melanomas with a function-based genetic screen for pro-metastasis genes that led us to identify 20 "metastasis determinants" that actively promote tumor formation and cell invasion, an early step in metastasis. Expression of the metastasis determinants also correlates with advanced tumor grade in other non-melanoma tumor types that include breast adenocarcinoma, where determinant expression levels can separate breast cancer patients into two subgroups with significant differences in overall and metastasis-free survival. Therefore, Dr. Chin believes that these determinants are ideal biomarker candidates for a multi-gene prognostic test to predict metastatic risk in early stage melanoma patients. In this study, using these metastasis determinants as a starting point, she will develop and validate multi-gene prognostic tests in patient outcome-annotated clinical melanoma samples. Additionally, through examination of their mechanism of action, she plans to glean insight that can guide optimal and rational therapeutic choices in an adjuvant setting for these early stage melanoma patients. -
Dr. TC Wu, Johns Hopkins University
Proposal Title: Treatment of melanoma combining cancer gene therapy and immunotherapy
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. -
Dr. F. Stephen Hodi, Dana-Farber Cancer Institute, Harvard University
Proposal Title: A phase I trial of bevacizumab plus ipilimumab in melanoma patients
Improved understanding of mechanisms of immune function has recently provided new means to take the brakes off the immune system to treat cancer. One way to accomplish this has been to block the molecule Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4, a natural inhibitory signal to the immune system). Experience with blocking CTLA-4 in patients has shown that this can be accomplished to effectively treat melanoma. Part of the anti-tumor response involves an immune attack of the blood vessels feeding the tumors. The major factor known to be involved in the formation of blood vessels that feed tumors, vascular endothelial growth factor (VEGF), has also been found to suppress the immune system. An antibody that blocks VEGF has been shown to be highly effective when combined with other treatments such as chemotherapy against many types of cancer. Dr. Hodi proposes to combine an antibody that blocks CTLA-4 to take the brakes off the immune system with an antibody that blocks VEGF to block blood vessel formation to tumors. He aims to understand synergies in combining these two drugs that together could target the blood vessels feeding melanoma deposits. -
Dr. Alexander Levitzki, Hebrew University of Jerusalem
Proposal Title: Targeting the IGF1R pathway in melanoma
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. -
Dr. Roya Khosravi-Far, Beth Israel Deaconess Medical Center
Proposal Title: Targeted strategy for treatment of melanoma
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.
Pilot Awards
MRA granted three researchers with pilot awards, $100,000 over two years, for pursuing first-of-its-kind melanoma treatment approaches.
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Dr. Sancy Leachman, University of Utah
Proposal Title: Sulforaphane, a melanoma prevention agent for high-risk MC1R genotypes
It is now known that the cancer prevention agent sulforaphane has the potential to compensate for the defective response to ultraviolet light that underlies the increased risk for melanoma suffered by individuals with fair skin and red hair. Dr. Leachman will use this discovery to design and carry out a clinical study with human tissues that will provide information needed in order to decide if this agent merits advancement to a clinical trial for prevention of melanoma in this high-risk population. -
Dr. Maria Wei, North California Institute for Research and Education, University of California San Francisco
Proposal Title: Mechanisms of melanoma treatment resistance
Melanoma is an aggressive cancer of the skin and eyes that has a high tendency towards metastatic behavior. The incidence of this malignancy is rising, in marked contrast to the declining incidence of other, more common cancers. There has been no breakthrough development in melanoma therapeutics for more than 25 years, and currently there is no effective treatment for metastatic disease. Recent studies from this laboratory have demonstrated that melanoma sensitivity to chemotherapy treatment is influenced by a pathway that regulates the formation of a compartment found in melanomas, called melanosomes. Normally, the pigment melanin (which gives rise to the color found in the skin, eyes and hair) is synthesized and stored within melanosomes and then (in the skin) is secreted, and taken up by neighboring cells called keratinocytes. Dr. Wei found that mutations in genes resulting in aberrant melanosome formation also cause increased melanoma sensitivity to a variety of chemotherapy agents, suggesting that melanosomes may play a fundamental role in melanoma chemosensitivity. In these proposed studies, Dr. Wei will investigate what role these genes, known to regulate melanosomes, play in chemotherapy resistance and how they could be targeted for the development of novel melanoma therapies. -
Dr. Xue-Zhong Yu, Moffitt Cancer Center
Proposal Title: Treatment of established melanoma by tumor-specific Th17 cells
Tumor-specific CD8+ cytotoxic T lymphocytes have been the focus for the lymphocyte-based cancer immunotherapy; however the complete tumor regression has been achieved in only a minority of melanoma patients. Recent evidence indicates that CD4 T cells may be a determining factor in promoting or inhibiting anti-tumor responses through T helper cells or regulatory T cells, respectively. Dr. Yu's laboratory as well as others discovered that Th17 cells, a newly defined T helper subset, are highly effective in eradicating tumors once they are directed to tumor associated antigens. Dr. Yu will further study the potential of Th17 cells in cancer immunotherapy in the combination of myeloabliative bone marrow transplantation. The proposed strategy utilizes the advantages of host lymphocyte depletion, hematopoietic stem cells, and redirection of T cell specificity to endogenous melanoma-associated antigen. The proposed study is expected to establish a novel strategy to treat established melanoma in preclinical models that may be readily applicable in clinic.
Development Award
The MRA provided a development award, $50,000 for one year, to a researcher whose work shows great promise for advancing the understanding and treatment of melanoma.
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Nallasivam Palanisamy, University of Michigan
Proposal Title: Transcriptome sequencing to detect gene fusions in melanoma
Recurrent chromosomal aberrations are the hallmark of hematological malignancies and soft tissue sarcomas and identification of such aberrations in solid tumors are difficult due to limitations in the conventional approaches. Dr. Palanisamy will apply the newly developed next generation sequencing technology (RNAseq) and high density oligo nucleotide comparative genomic hybridization (oligo array CGH) for the comprehensive assessment of melanoma cancer genome and transcriptome to identify the disease causing genetic aberrations.