The PARP1 Inhibitor AZD5305 Impairs Ovarian Adenocarcinoma Progression and Visceral Metastases in Patient-derived Xenografts Alone and in Combination with Carboplatin

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) have changed the management of ovarian cancer patients and their effectiveness has been demonstrated especially in homologous recombination repair-deficient tumors. These first-generation drugs target PARP1, but also PARP2 and other family members potentially responsible for adverse effects that limit their therapeutic potential and restrict their use in combination with chemotherapeutic agents. We investigated patient-derived ovarian cancer xenografts (OC-PDXs) to assess whether malignant progression could be impaired by a novel inhibitor selective for PARP1 (AZD5305) and to assess the potential of its combination with carboplatin (CPT), the standard-of-care for ovarian cancer patients. In BRCA-mutated OC-PDXs, AZD5305 achieved greater tumor regressions and longer duration of response as well as a superior impairment of visceral metastasis and improved survival benefit compared to the first-generation dual PARP1/2 inhibitors. The combination of AZD5305 plus CPT was more efficacious than single-agents. Subcutaneously growing tumors experienced regression that persisted after therapy stopped. Combination efficacy was greater against tumors that did not respond well to platinum, even at a dose at which AZD5305 monotherapy was ineffective. The combination therapy impaired metastatic dissemination and significantly prolonged the lifespan of mice bearing OC-PDXs in their abdomen. This combination benefit was evident even when CPT was used at suboptimal doses, and was superior to full dose platinum treatment. These pre-clinical studies demonstrate that the PARP1-selective inhibitor AZD5305, retains and improves the therapeutic benefit of the first-generation PARPi, providing an opportunity to maximize benefits for this class of anti-cancer agents.

NAD metabolism: Role in senescence regulation and aging

“…Besides dysregulations in cancer itself, cancer treatments can also influence NAD metabolism through the induction of DNA damage (Banerjee et al, 2022 ). Several studies have investigated the potential of targeting NAD metabolism as a strategy to enhance cancer treatment efficacy or to prevent drug toxicity (Beltrà et al, 2023 ; Chini et al, 2014 ; Dellavedova et al, 2023 ; Margier et al, 2022 ; Sauriol et al, 2023 ; Yoo et al, 2021 ).…”