Resistance to DNA-damaging agents is a significant problem in the treatment of cancer patients. Activation of poly(ADP-ribose) polymerase (PARP) is one of the mechanisms by which tumors avoid cell death (apoptosis) caused by DNA-damaging agents. PARP activity is essential for the repair of single-stranded DNA breaks through the base excision repair (BER) system. Therefore, inhibition of PARP sensitizes rapidly-dividing tumor cells to cytotoxic agents which induce cell damage normally repaired through the BER system. However, if single strand DNA breaks are not repaired, they form double strand breaks (DSB) upon DNA replication. The latter are then repaired through a different mechanism, called homologous recombination (HR) repair. A functioning HR mechanism may, therefore, compensate for PARP inhibition. The Karmanos Cancer Institute's Phase I service has recently received approval from the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) to conduct a Phase I clinical trial of the novel PARP inhibitor ABT-888, in combination with the single strand DNA-damaging agent irinotecan in patients with advanced solid tumors. The primary aim of the Phase I clinical trial is to determine the recommended Phase II dose of the drug combination, to attempt to find the optimal biologic dose (OBD) for PARP inhibition, and to determine the safety profile of the combined therapy. The PARP inhibitor ABT-888 is a novel investigational agent that has not been extensively studied in humans, and never clinically in combination with irinotecan in humans. We hypothesize that tumors defective in HR DNA-damage repair mechanisms (e.g. breast, ovarian, colon and lung cancer), will be more sensitive to the combination therapy of ABT- 888 and irinotecan versus monotherapy irinotecan because both HR and single strand repair, proposed mechanisms of resistance to irinotecan therapy, may be prevented. The purpose of this application is to propose correlative studies in support of the Phase I trial, using pre- and post-treatment specimens to perform pharmacodynamic (PD) and pharmacogenomic (PG) analyses. To investigate the stated hypothesis, blood, fresh tumor biopsies, and archival tissue blocks will be obtained to assist in determining expression levels, mutation status, or polymorphisms of important candidate biomarker proteins involved in DSB repair. Biomarkers under evaluation include phosphorylated H2AX (3-H2AX), which is critical to recruit repair factors to DSB sites; Rad51, a recombinase essential in HR; the tumor suppressor protein BRCA2, a HR mediator; and the excision repair enzyme ERCC1. PARP expression, topoisomerase I expression, and p53 status will also be assessed. The goal of this proposal is to attempt to identify a set of biomarkers that will be examined in future studies designed to determine which genetic characteristics of patients allow for the greatest benefit from ABT-888 therapy in combination with DNA damaging agents.
Cancer is a major cause of death in the world and cancer patients are in need of more effective treatment options. The clinical trial NCI#7977 is designed to test a novel combination of a commercially-available chemotherapy and a new cancer drug in patients with advanced solid tumors; this application seeks funding for studies designed to better understand the mechanism of action of this therapy in cancer cells. If successful, the proposed experiments may point the way to assays that identify patients who are more or less likely to respond to this therapy, thereby permitting individualized therapy of patients in the future. ? ? ?
| LoRusso, Patricia M; Li, Jing; Burger, Angelika et al. (2016) Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors. Clin Cancer Res 22:3227-37 |
| Boerner, Julie L; Nechiporchik, Nicole; Mueller, Kelly L et al. (2015) Protein expression of DNA damage repair proteins dictates response to topoisomerase and PARP inhibitors in triple-negative breast cancer. PLoS One 10:e0119614 |
