MRA awarded six team science awards of $1,000,000 over three years.
Therapeutic targeting of melanoma stem cells
Principal Investigators:
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Jonathan Cebon M.B.B.S., F.R.A.C.P., Ph.D., Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences |
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Mike Berridge, B.Sc., Ph.D., Malaghan Institute of Medical Research, New Zealand |
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Otavio Caballero, M.D., Ms.C., Ph.D., Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center |
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Weisan Chen, Ph.D., Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences |
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Ian Davis, MBBS, PhD, FRACP, FAChPM, Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Studies |
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Winston Hide, B.Sc (Honors), M.A., Ph.D., Harvard University |
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| Jonathan Cebon |
This research will further characterize the melanoma stem cells (MSC) phenotypically and biologically, identify novel therapeutic targets on MSC, and validate potential targets in vitro and in vivo. Recent data suggest that melanoma tumors may contain 'stem-like' or repopulating cells that are responsible for tumor initiation and metastasis. Conventional treatments may target the majority of cells within the cancer but to be truly effective will also need to eradicate these malignant repopulating cells. This research project aims to define novel therapeutic targets on these cells and to investigate whether it is possible to target these cells using the immune system. We are developing a vaccine against a target molecule on cancer cells (NY-ESO-l) that can also be selectively present on melanoma repopulating cells. If successful, this research may yield new treatments for malignant melanoma.
MHC-associated phosphopeptides as targets for melanoma immunotherapy
Principal Investigators:
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Victor H. Engelhard, Ph.D., University of Virginia |
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Donald Hunt, Ph.D., University of Virginia |
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Suzanne Topalian, M.D., Johns Hopkins University |
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Melanoma is among the most immunogenic of all human cancers. Although many melanoma antigens have been identified, few are related to the underlying changes responsible for the malignant phenotype. This research aims to identify and characterize the immunogenicity of a novel cohort of phosphopeptide antigens, and elucidate molecular pathways determining their expression in order to enhance expression and immune recognition. This step will lead to the potential for treatment strategies of vaccines in rational combinations with kinase inhibitors and/or immunomodulatory biological agents.
A genome-wide association study to identify melanoma predisposition genes
Principal Investigators:
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Nicholas K. Hayward, Ph.D., Queensland Institute of Medical Research |
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Graham Mann, Ph.D., Westmead Hospital, Australia |
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Nicholas Martin, Ph.D., Queensland Institute of Medical Research |
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Family and twin studies indicate that melanoma susceptibility has a strong genetic component. Very rarely melanoma runs in families in which there is an inherited mutation in a single ‘high penetrance’ gene. In the general population, melanoma susceptibility is thought to be governed by variation in a series of ‘low penetrance’ genes. To date, one such gene (MC1R) has been found. Even though such genes confer relatively low individual risk, if they are common they can account for a large proportion of the population burden of melanoma. Thus cumulatively, it is conceivable that a small number of low risk genes could predict an individual’s risk of melanoma with considerable accuracy. In this proposal, the team aims to find new low penetrance melanoma genes via a genome-wide association study on samples from 2500 melanoma patients and 2500 controls already collected in Brisbane and Sydney. Upon finding new candidate genes, validation of the top associations in replication case-control samples will be performed. For a number of the most robustly replicated genes, more extensive genetic analyses will be carried out to identify the precise causal variants.
Accelerating melanoma therapy: Genomics, drug screening and informatics
Principal Investigators:
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David Hoon, Ph.D., John Wayne Cancer Institute |
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David Fisher, M.D., Ph.D., Massachusetts General Hospital |
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Levi Garraway, M.D., Ph.D., Dana-Farber Cancer Institute |
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Treatment of advanced melanoma is stymied by incomplete understanding of the genetic lesions that drive its growth. We propose to identify prognostically relevant molecular subtypes of stage IV metastatic melanoma and select drugs and drug combinations that target genomic alterations of these subtypes. First we will apply state-of-the-art genomic technologies to representative specimens from the John Wayne Cancer Institute’s exceptional collection of clinically-annotated melanoma paired metastatic tumor tissue, cell lines, and matched normal lymphocytes. Melanoma specimens linked to known clinical outcomes will be statistically clustered into distinct clinical/pathological subtypes characterized by tumor-related genes representing potential drug targets. In addition to providing diagnostic and prognostic utility, this subtype information can improve clinical management and streamline the selection of more effective drug combinations. To this end we will conduct high-throughput testing of metastatic subclass-specific cell lines against a panel of FDA-approved drugs alone and in two-drug combinations, as well as targeted agents which attack molecular lesions identified in the genomic analyses. This combined attack should efficiently identify drug-susceptible vulnerabilities in the melanoma subtypes.
Surgery and immunotherapy for melanoma metastatic to distant sites
Principle Investigator:
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Donald Morton, M.D., Chief, Melanoma Program at John Wayne Cancer Institute |
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| Donald Morton |
Dr. Morton will start a randomized phase III trial asking whether initial resection improves time to progression as compared with best available nonsurgical care.
Therapeutic inhibition of mutant activated signaling pathways in melanoma
Principal Investigators:
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Neal Rosen, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center |
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David Solit, M.D., Memorial Sloan-Kettering Cancer Center |
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James Allison, Ph.D., Memorial Sloan-Kettering Cancer Center |
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Jedd Wolchok, M.D., Assistant Memorial Sloan Kettering Cancer Center |
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This proposal is aimed at developing new therapies for the treatment of melanoma. It is based on two premises. Recent discoveries show that the most common forms of melanoma almost always have mutations that activate growth by activating one particular pathway in the cell, the so-called ERK signaling pathway. Mutations in the N-RAS or B-RAF genes activate this pathway, and one or the other of these genes is mutated in the great majority of melanomas. Our previous work showed that drugs inhibiting this pathway effectively inhibit the growth of melanomas with these mutations. The first premise of our proposal is that activation of this pathway is required for the growth of melanomas and that drugs that inhibit the pathway will be useful for the treatment of advanced metastatic disease. As two types of ERK pathway inhibitor are already in development, we expect to test this hypothesis rapidly. Agents that cause the patients immune system to attack the tumor have also been shown to have some therapeutic benefit. One such agent, an anti-CTLA-4 antibody discovered by one of us, has been show to have antitumor activity in melanoma patients. Thus, there are two new strategies for treating metastatic melanoma: immunotherapy, and inhibition of growth pathways that drive tumor growth. The second premise of our proposal is that combining these modalities will have enhanced and potentially significant clinical benefit. We plan to determine whether this strategy is feasible, identify the best ways of combining the two therapies, and then use this work to develop rational protocols for testing this idea in patients.
