MRA awarded three young investigators $100,000 over two years, whose work has the potential to transform melanoma diagnosis and treatment.
18F Labeled benzamides for pre-clinical PET imaging of melanoma metastases
Dr. Zhen Cheng, Stanford University
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| Cheng |
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.
Combining an MDM2 inhibitor with chemotherapy for the treatment of melanoma
Dr. Sanjev Kumar, University of Michigan
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| Kumar |
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.
The role of oncogenic signaling pathways in human melanoma immune evasion
Dr. Patrick Ott, New York University
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| Ott |
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.