Identification of Novel Protein Biomarkers and Targets to Overcome PARP Inhibitor Resistance
Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) can be used to treat ovarian cancer at nearly all phases of a patient’s cancer journey. Although the clinical impact of agents like olaparib, niraparib, and rucaparib have changed clinical practice over the last several years, there is still a need to optimize the way we use PARPis to maximize their therapeutic potential. Relying on current biomarkers to predict response to single-agent PARPi is not good enough. For instance, only about 20% of patients will have a somatic (in the tumor) or germline (in the blood) mutation in BRCA1 or BRCA2. While the benefits of a PARPi in such tumors are clear, the majority of patients will have a normal BRCA gene. For these patients, tests have also been developed to predict whether a tumor will have “BRCA-ness,” meaning it lacks a BRCA mutation but “behaves” like a tumor with a BRCA mutation. This phenomenon is reflected in a commercially available test called the homologous recombination deficiency (HRD) score. Although the HRD score can enrich for PARPi responses, it does not accurately predict which patients will respond. Importantly, the field of ovarian cancer PARPi development has moved beyond single-agent PARPi studies and is actively looking for combination partners with the greatest potential to improve the efficacy of PARPis. However, none of the aforementioned tests (BRCA mutations or HRD score) can tell doctors whether a second drug could be partnered with the PARPi to make the PARPi work more effectively. This proposal addresses two ways to improve the impact of PARPis in the clinic: (1) to discover new biomarkers to predict response and (2) to identify new combinations that work synergistically with existing PARPis. Regarding the latter, there is substantial effort to accomplish this in the laboratory and in clinical trials. Although clinical trials have investigated new PARPi combination partners (like blood vessel blockers cediranib or bevacizumab) and inhibitors of cancer cell pro-survival pathways (such as alpelisib), a comprehensive approach is needed to discover other targets that could improve the efficacy of PARPis. In particular, there is tremendous need to improve the efficacy of PARPis for patients who would otherwise be resistant to this form of therapy. Accordingly, this proposal will focus on ovarian tumors with inherent resistance to a PARPi. The ultimate impact of the proposed research for patients with ovarian cancer could be improved regression of disease while on a PARPi and/or a longer duration of response. To accomplish these goals, we have proposed specific aims that will take a comprehensive look at the protein changes that are occurring inside cancer cells to determine which proteins are most likely to be contributing to resistance. The unique approach in this proposal is to use patient tumors that have been transplanted into mice. So-call patient derived xenograft (PDX) models are thought to mimic the behavior of patient tumors more closely than traditional cell lines. Accordingly, they will be used as patient surrogates to build the foundation for all three aims of this proposal. First, the latest proteomics technology will be used to fully characterize the levels of total proteins as well as activated/inactivated proteins (e.g., phosphoproteins) in PARPi sensitive vs. resistant PDX tumors. It is noteworthy that the research team has developed the world’s largest single institution collection of ovarian cancer PDX models and a decade of experience using these models for drug development. This first aim will reveal which proteins are significantly different between sensitive and resistant tumors and will provide the initial glimpse into the differences that may drive resistance in some tumors. In addition, it is conceivable that important resistance proteins are at low basal levels and only rise as a direct result of PARPi exposure. In this case, baseline protein levels
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110405
Entities
People
- Saravut Weroha
Organizations
- Mayo Clinic
- United States Army