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Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers.

ABSTRACT: Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours (n = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.

SUBMITTER: Alhusaini A

PROVIDER: S-EPMC8392860 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Poly (ADP-ribose) polymerases (PARPs) are an important family of nucleoproteins highly implicated in DNA damage repair. Among the PARP families, the most studied are PARP1, PARP2 and PARP 3. PARP1 is found to be the most abundant nuclear enzyme under the PARP series. These enzymes are primarily involved in base excision repair as one of the major single strand break (SSB) repair mechanisms. Being double stranded, DNA engages itself in reparation of a sub-lethal SSB with the aid of PARP. Moreover, by having a sister chromatid, DNA can also repair double strand breaks with either error-free homologous recombination or error-prone non-homologous end-joining. For effective homologous recombination repair, DNA requires functional heterozygous breast cancer genes (BRCA) which encode BRCA1/2. Currently, the development of PARP inhibitors has been one of the promising breakthroughs for cancer chemotherapy. In March 2017, the United States Food and Drug Administration (FDA) approved niraparib for maintenance therapy of recurrent gynecologic cancers (epithelial ovarian, primary peritoneal and fallopian tube carcinomas) which are sensitive to previous platinum based chemotherapy irrespective of BRCA mutation and homologous recombination deficiency status. It is the third drug in this class to receive FDA approval, following olaparib and rucaparib and is the first global approval for maintenance therapy of the aforementioned cancers. Niraparib preferentially blocks both PARP1 and PARP2 enzymes. The daily tolerated dose of niraparib is 300 mg, above which dose limiting grade 3 and 4 toxicities were observed. In combination with humanized antibody, pembrolizumab, it is also under investigation for those patients who have triple negative breast cancer. By and large, there are several clinical trials that are underway investigating clinical efficacy and safety, as well as other pharmacokinetic and pharmacodynamic profiles of this drug for various malignancies.

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Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers.

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