Update on PARP inhibitor therapy for solid tumors

Abstract

Abbreviations: SSB, single-strand break; HR, homologous recombination; NHEJ, non-homologous end joining; PARPi, PARP inhibitors; PFS, progression-free survival; CT, care chemotherapy; CI, confidence interval; TNBC, triple-negative breast cancer; FDA, food and drug administration; G-CSF, granulocyte colony stimulating factors (SSB), mismatch repair (MMR), and double-strand break (DSB). 1 Polyadenosine diphosphate [ADP] ribose polymerase-1 (PARP1) and -2 (PARP2) enzymes 2 are responsible for repair of most of the SSB. After they detect the defective site, they bind to the DNA damage site and recruit a set proteins to repair the break. 3,4 When those proteins are recruited to the damaged site, the PARP-DNA interaction becomes unstable so that DNA repair can proceed. 5 If the SSB are not repaired, they are converted to DSB. 6 In that situation, another repair mechanism called homologous recombination (HR) will play a role. This mechanism is well represented in PARP1 knockout mice that SSB could not be repaired, but HR repair and non-homologous end joining (NHEJ) pathways were able to repair the formed DSB ( Figure 1). HR is slower than NHEJ, but it is more accurate. 7 J Cancer Prev Curr Res. 2019;10(4):98-107. 98 AbstractPoly (ADP-ribose) polymerases (PARPs) play an important role in DNA damage repair. They are primarily involved in base excision repair in single strand breaks. So far, the clinical trial results are very promising in breast and ovarian cancer with deleterious germline BRCA1 and BRCA2 mutations, and their use is expanding to include other solid tumors with homologous recombination (HR) repair defect. Studies suggest a correlation between tumor sensitivity to platinums and response to PARP inhibitors (PARPi) in women with ovarian cancer. The hypothesis is that by interfering with DNA repair, PARPi sensitize cells to DNA-damaging chemotherapies and radiation therapy. This article provides an overview of clinical trial results obtained with PARPi in the treatment of breast, ovarian, prostate, gastric, pancreatic, and lung cancers. In addition, we review resistance mechanisms to PARPi, toxicities of PARPi, and potential treatment combinations with PARPi.

Renal insufficiency in patients on PARP inhibitors: Case-based review of possible mechanisms and management

“…Poly ADP ribose polymerase (PARP) inhibitors are a new class of drugs that are extensively used today in ovarian cancer, as well as several other solid tumors, like breast cancer, prostate cancer, and pancreatic cancer. 1,2 They have demonstrated efficacy in all these cancers and are currently being evaluated in clinical trials for other types of cancers. 2…”

“…1,2 They have demonstrated efficacy in all these cancers and are currently being evaluated in clinical trials for other types of cancers. 2…”

“…1,2 They have demonstrated efficacy in all these cancers and are currently being evaluated in clinical trials for other types of cancers. 2 Newly diagnosed advance ovarian cancer is usually treated with palliative intent cytoreductive surgery and platinum-based chemotherapy given in the neoadjuvant or adjuvant settings. 3 The vast majority of patients with advanced disease, however relapse within 10-18 months after the primary treatment.…”