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Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review).

ABSTRACT: With the development of precision medicine, targeted therapy has attracted extensive attention. Poly(ADP‑ribose) polymerase inhibitors (PARPi) are critical clinical drugs designed to induce cell death and are major antitumor targeted agents. However, preclinical and clinical data have revealed the limitations of PARPi monotherapy. Therefore, their combination with other targeted drugs has become a research hotspot in tumor treatment. Recent studies have demonstrated the critical role of small molecular inhibitors in multiple haematological cancers and solid tumors via cellular signalling modulation, exhibiting potential as a combined pharmacotherapy. In the present review, studies focused on small molecular inhibitors targeting the homologous recombination pathway were summarized and clinical trials evaluating the safety and efficacy of combined treatment were discussed.

SUBMITTER: Jin N

PROVIDER: S-EPMC9851129 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review).

Jin Ning N Xia Yu Y Gao Qinglei Q

International journal of oncology 20230105 2

With the development of precision medicine, targeted therapy has attracted extensive attention. Poly(ADP‑ribose) polymerase inhibitors (PARPi) are critical clinical drugs designed to induce cell death and are major antitumor targeted agents. However, preclinical and clinical data have revealed the limitations of PARPi monotherapy. Therefore, their combination with other targeted drugs has become a research hotspot in tumor treatment. Recent studies have demonstrated the critical role of small mo ...[more]

PMID: 36601757

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Project description:Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.

Project description:Ovarian cancer is a leading cause of mortality among women with gynecological malignancies, largely due to its asymptomatic nature in early stages and frequent late diagnosis. Targeted therapies, such as angiogenesis inhibitors and poly(ADP-ribose) polymerase inhibitors (PARPi), have emerged as promising treatments by disrupting tumor vasculature and impairing DNA repair mechanisms, particularly in patients with BRCA mutations. The objective of the present study was to comprehensively evaluate the combined use of different angiogenesis inhibitors and PARPi in ovarian cancer treatment by meta-analysis. This included assessing their impact on objective response rate (ORR) and progression-free survival (PFS), understanding the role of BRCA mutation status, and comparing the effects of various angiogenesis inhibitors when used in combination with PARPi. The PubMed, Embase and Cochrane databases were searched from inception to February 2024. Only studies on the combined treatment of ovarian cancer with angiogenesis inhibitors and PARPi were included. Duplicate studies, studies with incomplete data, animal studies, literature reviews and systematic studies were excluded. The results underscored a noteworthy improvement in the ORR and median PFS (mPFS) among patients receiving combination therapy compared with those on monotherapy. Specifically, the pooled ORR for combination therapy was significantly higher than that of monotherapy, indicating a substantial benefit in terms of tumor response. Furthermore, combination therapy was found to significantly prolong PFS, offering patients a longer duration without disease progression. Subgroup analyses of patients treated with angiogenesis inhibitors combined with PARPi provided deeper insights, revealing that patients with BRCA mutations exhibited an ORR of 90% compared with 61% in those without BRCA mutations. Additionally, when different angiogenesis inhibitors were compared, patients treated with anti-VEGF agents combined with PARPi showed a longer mPFS (15.53 months) than those treated with TKIs combined with PARPi (7.49 months). In conclusion, the present study demonstrates that combinations of angiogenesis inhibitors and PARPi show great potential for improving treatment outcomes in ovarian cancer, particularly in patients with BRCA mutations. The observed differences in efficacy between various angiogenesis inhibitors highlight the importance of personalized treatment approaches. Further research is warranted to explore the long-term benefits of these combination strategies and refine them to obtain optimal patient outcomes.

Dataset Information

Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review).

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Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review).

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