Developing effective combination therapy for pancreatic cancer: An overview

Abstract

Pancreatic cancer is a fatal disease. The five-year survival for patients with all stages of this tumor type is less than 10%, with a majority of patients dying from drug resistant, metastatic disease. Gemcitabine has been a standard of care for the treatment of pancreatic cancer for over 20 years, but as a single agent gemcitabine is not curative. Since the only therapeutic option for the over 80 percent of pancreatic cancer patients ineligible for surgical resection is chemotherapy with or without radiation, the last few decades have seen a significant effort to develop effective therapy for this disease. This review addresses preclinical and clinical efforts to identify agents that target molecular characteristics common to pancreatic tumors and to develop mechanism-based combination approaches to therapy. Some of the most promising combinations include agents that inhibit transcription dependent on BET proteins (BET bromodomain inhibitors) or that inhibit DNA repair mediated by PARP (PARP inhibitors).

Keywords: AZD6738 (PubChem CID: 54761306); BET bromodomain inhibitors; Bevacizumab (PubChem SID: 46504473); Cetuximab (PubChem SID: 46507042); Erlotinib (PubChem CID: 176870); Gemcitabine; Gemcitabine (PubChem CID: 60750); JQ1 (PubChem CID: 49871818); MK-8776 (PubChem CID: 46239015); Nivolumab (PubChem SID: 178103907); Olaparib (PubChem CID: 23725625); PARP inhibitors; Pancreatic cancer; Vorinostat (PubChem CID: 5311).

Figure 1.. Model depicting complementary cytotoxicity of PARP inhibitors (PARPi) and JQ1 (BET bromodomain inhibitor).

(a) Schematic DNA double strand break (DSB) repair pathways: NHEJ and HR. (b) PARP recruits base excision repair (BER) enzymes to SSB loci. PARP inhibitors reduce SSB BER. Cells with reduced SSB repair result in DSB. (c) JQ1-mediated inhibition of BET protein (BRD2/3/4) activity inhibits expression of DSB repair proteins Ku80 and RAD51. Decreased DSB DNA repair sensitizes cells to PARP inhibitors. Multiple ongoing preclinical studies focus on the hypothesis that simultaneous inhibition of the expression or activity of enzymes that contribute to NHEJ, HR, and BER have complementary anti-tumor efficacy. Black font = normal pathway. Red font = effect of JQ1. Blue font = effect of PARPi. (Abbreviations: NHEJ, nonhomologous end joining; HR, homologous recombination; DSB, double-strand break; SSB, single-strand break; ac, acetylation).