Targeting USP14 to Promote Sensitization to PARP Inhibition and Enhance Antitumor Immunity in NSCLC
Abstract
Scientific Objective and Rationale: Lung cancer is the leading cause of cancer deaths among men and women, with non-small cell lung cancer (NSCLC) comprising ~85% of lung cancer cases in the United States. Platinum-based regimens are still the treatment choice for the majority of patients with advanced NSCLC, which produce heterogeneous response and multiple undesirable side effects. Therefore, there is an unmet critical need for novel combination regimens. PARP inhibitors (PARPis) represent a promising therapeutic tool that shows synthetic lethality in patients with a specific DNA damage response (DDR) deficiency, i.e., deficiency in the homologous recombination (HR) pathway. PARPis have shown efficacy in platinum-sensitive populations, are much better tolerated, and are being tested in multiple clinical trials in NSCLC. Thus, drug combinations that will induce HR deficiency in cancer cells have the potential to increase the effectiveness of PARPi treatment outcome in NSCLC. Moreover, immune checkpoint inhibitors (ICis) that cause cancer cell killing by the patient immune cells have been remarkably successful in NSCLC. However, they are effective in < 20% of patients. So research has focused on how to improve ICi-mediated immunity against cancer cells in NSCLC patients. This project focuses on the deubiquitinase USP14 and its novel role in controlling HR pathway and increasing cancer cell immunity. Our hypothesis is that co-inhibition of USP14 (by an inhibitor in clinical development, VLX1570) and PARP (by clinical grade inhibitor, rucaparib) in NSCLC will kill tumor cells not only by damaging their DNA, but also by attracting immune cells to attack them. Pembrolizumab, an ICi, will further increase immunogenic cell death by targeting immune cell inhibitory signaling. LCRP Area(s) of Emphasis: Identify innovative strategies for the treatment of NSCLC. Ultimate Applicability of the Research: These studies lay the foundation for establishing the combinatorial use of USP14 inhibition with PARPi +/- ICi in NSCLC as a strategy to induce malfunctioning of the DDR and/or activation of anti-tumor immune response in cancer cells to cause cell death. What Types of Patients Will It Help, and How Will It Help Them? Successful completion of the proposed studies will lead to an entirely novel treatment approach to improve and save lives of NSCLC patients. What Are the Potential Clinical Applications, Benefits, and Risks? Targeting USP14 would cause DNA repair deficiency as well as activate cancer cell immune-mediated cancer cell death in NSCLC. Thus, USP14 inhibition will induce sensitization to PARPi and/or ICi, representing a promising strategy to treat NSCLC in patients expressing high levels of USP14. Notably, USP14 mRNA is overexpressed in >10% of NSCLC patients. VLX1570 is in clinical development and there has been significant progress in the development of specific USP14 inhibitors. ICis are already Food and Drug Administration (FDA)-approved, and PARPis, either alone or in combination with ICis, are being tested in multiple clinical trials in NSCLC. Thus, our findings will have a direct impact on improving clinical outcome in NSCLC patients and will also help to stratify patients as this approach may not work in patients with low USP14 expression. What Is the Projected Time It May Take to Achieve a Clinically Relevant Outcome? Upon successful completion of the studies proposed, our findings will be validated in patient-derived NSCLC xenograft mouse models, followed by pharmacological studies. These results could pave the way for clinical trials and FDA approval. Thus, full clinical transition of our findings will take several years. What Are the Likely Contributions of This Study to Advancing the Field of Lung Cancer Research? This project identifies a new therapeutic strategy to improve clinical benefits of PARPi and ICi in NSCLC. In addition, these studies will improve our understa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010462
Entities
People
- Arishya Sharma
Organizations
- Cleveland Clinic
- United States Army