Targeting Deubiquitinase USP10 to Potentiate Immunotherapy in Lung Cancer
Abstract
Recent advances in immunotherapy have revolutionized the treatment of metastatic lung cancer. Patients who are resistant to the standard of care (i.e., chemotherapy and radiotherapy) now have the option of using immune checkpoint blockade-based immunotherapy, which could lead to effective and durable outcomes in certain patients. However, the overall response rate in lung cancer is lower than 27%. To overcome this limitation, in our proposed research, we intend to improve the immunotherapy response rate by addressing three Areas of Emphasis for the FY21 LCRP: (1) Identify innovative strategies for the treatment of lung cancer; (2) Understand mechanisms of resistance to treatment (primary and secondary); and (3) Develop or optimize prognostic or predictive markers to assist with therapeutic decision-making. Our preliminary studies have shown that a protein-modifying enzyme called USP10 is able to increase tumor growth, confer chemoresistance, inhibit T cell activation, and upregulate the co-inhibitory molecule PD-L1 in a subset of lung cancer with null/mutant TP53. We have also found that USP10 up-regulates oncogenic STAT3 signaling. Based on our findings, we hypothesize that USP10 suppresses anti-tumor immune response and makes tumors cold to immunotherapy. We propose that USP10 inhibitors down-regulate the oncogenic STAT3 signaling and alter the immune suppressive tumor microenvironment, turning cold tumors into hot tumors. Therefore, targeting USP10 in a subset of lung cancer with mutant TP53 will enhance the efficacy of anti PD-1/L1 therapy. Our preliminary data have also shown USP10 is positively correlated with the immune checkpoint inhibitor PD-L1 in lung cancer patient samples. Thus, high-USP10 correlates with high-PD-L1, in general, predicting that this subset of lung cancer is suitable for immunotherapy. However, our findings indicate that USP10’s immune suppressive function make this subset of patients resistant to immune checkpoint inhibitors, and the patients should seek other treatment options. Therefore, our short-term goal is establishing USP10 as a biomarker for predicting the outcomes of immunotherapy in a subset of mutant TP53 lung cancer patients. Our long-term goal is to develop USP10 inhibitors and use them in combination with immune checkpoint inhibitors. We have already identified a lead compound of USP10 inhibitor, GL-320, and we plan to work with medicinal chemists and physicians to conduct phase 1 clinical trials at our cancer center, where such trials have been conducted for over two decades with an impeccable track record. We expect to develop the inhibitors and implement them in the clinic in 5 to 10 years. Because the incident rate of lung cancer in military Service Members, Veterans, and their families is higher and the overall survival is lower than that of civilians, our proposed research to increase the overall survival of lung cancer patients has high military relevance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210369
Entities
People
- Xiaohong Zhang
Organizations
- United States Army
- Wayne State University