Metabolic Vulnerabilities of MDSCs in the Melanoma Tumor Microenvironment
Abstract
I have made important contributions to understanding the metabolic regulation in melanoma and its therapeutic implications since the beginning of my independent scientific career. For example, our work has led to a phase 1 clinical trial evaluating phenformin, an old drug for diabetes, with the dabrafenib BRAF inhibitor and trametinib MEK inhibitor combination in patients with BRAF 600E/K-mutated melanoma (NCT03026517). With our recent work on the metabolism of myeloid-derived suppressor cells (MDSCs), a group of immune suppressive cells found in tumors, as well as the unpublished preliminary findings described in this proposal, I have expanded my research interests to melanoma cancer immunology. I will collaborate with leaders in cancer immunology in this project to accomplish its goal. Successful completion of this proposal will further strengthen my contributions to melanoma research and increase my potential to become a leader in the melanoma field in the near future. Our proposal addresses the following fiscal year 2002 (FY22) Melanoma Research Program (MRP) Focus Area: identify how the tumor microenvironment (e.g., stromal, immune, microbiome) impacts tumor initiation, response to therapy, progression, recurrence, and/or dormancy. Our proposal is responsive to the FY22 MRP Challenge Statement by characterizing a metabolic enzyme as a novel drug target in MDSCs in the melanoma tumor microenvironment. Biologic drugs that target the immune checkpoint proteins have shown significant clinical benefits in melanoma but only produce durable responses in a fraction of patients. Therefore, improving the response rates of these therapies represents a major challenge in melanoma treatment. MDSCs are a group of immune suppressive cells that play important roles in melanoma formation and progression. In addition, high number of MDSCs in melanoma patient blood samples have been found be associated with poor response to immune checkpoint blockade therapies. Hence, targeting MDSCs in melanoma tumors represents a promising new strategy to improve the current immune therapies in melanoma. In addition, our proposed studies may also lead to the development of novel interventional strategies for preventing melanoma progression and metastases. We recently discovered that the metabolism of MDSCs has different characteristics than other cells. This feature may provide an opportunity to selectively remove this group of tumor-promoting immune cells for the treatment of melanoma. In particular, we found that MDSCs are very sensitive to the inhibition of the pyrimidine synthesis metabolic pathway, which is important for the synthesis of DNA and RNA among others. Based on these discoveries, we propose that MDSCs would be vulnerable to drugs that inhibit a key enzyme in the pyrimidine synthesis pathway and that these drugs can be combined with immune checkpoint blockade therapies to increase their efficacy in melanoma patients. In this proposal, we will test this idea in preclinical mouse models and investigate how this group of drugs would work to enhance anti-tumor immunity. Such kind of drugs are currently being tested in clinical trials for other hematological malignancies as a single agent. If successful, our proposed studies will provide the basis to evaluate this novel idea of combining this group of drugs that inhibit pyrimidine synthesis pathway and immune checkpoint blockade, such as anti-PD-1 antibody, in melanoma patients, and clinical trials can be quickly implemented in the near future. Our proposed studies have the potential to contribute to improving melanoma therapy response and survivorship in melanoma patients within the U.S. military and Veterans, and beyond.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310889
Entities
People
- Bin Zheng
Organizations
- Cedars-Sinai Medical Center
- United States Army