2009

MRA awarded three young investigators $100,000 over two years, whose work has the potential to transform melanoma diagnosis and treatment.

• Dr. Zhen Cheng, Stanford University
  Proposal Title: 18F Labeled benzamides for pre-clinical PET imaging of melanoma metastases
  

  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.



• Dr. Sanjev Kumar, University of Michigan
  Proposal Title: Combining an MDM2 inhibitor with chemotherapy for the treatment of melanoma
  

  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.



• Dr. Patrick Ott, New York University
  Proposal Title: The role of oncogenic signaling pathways in human melanoma immune evasion
  

  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.

 

MRA awarded three outstanding young investigators $100,000 over two years whose work shows great promise in the field of melanoma research.

• Proposal Title: Targeting CD4+ T cells for melanoma immunotherapy
  
  Timothy Bullock, Ph.D.
  Assistant Professor, Department of Pathology, University of Virginia
  
  Dr. Bullock's work will methods to expand the tumor antigen-specific CD4+T cell population with the ultimate goal of assessing whether the presence of such immune cells can enhance immunologic control of tumor.
  
  
  
  Regulation of T cellchemokine receptor expression during vaccination: Tumor-targetedimmunotherapy
  
  David Mullins, Ph.D.
  Assistant Professor, Department of Microbiology and Human Immune Therapy, University of Virginia
  
  Dr. Mullins will study optimal vaccination strategies in mouse models with the goal of enhancing vaccine-induced T cell expression and infiltration into melanoma lesions. This could form the basis for exploratory clinical immunotherapy vaccination trials in humans.
  
  
  
  Defining the role of inducible co-stimulator (ICOS)-expressing T cells against melanoma
  
  Dr. Padmanee Sharma, M.D., Ph.D.
  Assistant Professor, University of Texas, M.D. Anderson Cancer Center
  
  
  Anti-CTLA-4 antibody is a novel agent that enhances T cell function and induces tumor regression in approximately 10-20 percent of patients; however, it is not known how to predict who will respond. An increase in ICOS-expressing CD4 T cells has recently been found in patients treated with anti-CTLA-4 antibody. Dr. Sharma aims to correlate changes in immunologic markers with clinical outcome in patients with metastatic melanoma undergoing treatment with anti-CTLA-4 therapy, and to investigate the role of ICOS-expressing T cells in anti-tumor responses against B16 melanoma in the ICOS-knockout and ICOS-ligand-knockout mouse models.