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Pharmacologic Ascorbate Influences Multiple Cellular Pathways Preferentially in Cancer Cells
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Qi Chen, Kishore Polireddy, Ping Chen, Ramesh Balusu, Tao Wang, Ruochen Dong
Thus, pharmacologic ascorbate not only damages cancer cell DNA, but it also suppresses DNA repairing machinery. This makes it mechanistically plausible to combine ascorbate not only with DNA damaging chemotherapeutics (such as platinum-based drugs), but also with PARP inhibitor—one of the most exciting new classes of oncology drugs that has transformed the management of ovarian cancer. An early phase clinical trial in ovarian cancer patients combing high-dose intravenous ascorbate (IVC) and the standard carboplatin/paclitaxel proved the safety and feasibility, achieved improved toxicity profiles in the patients, and suggested prolonged disease progression-free survival (PFS) [4]. PARP inhibitors (such as olaparib, rucaparib, and niraparib) exhibit good efficacy and clinical benefits in women carrying BRCA1/2-mutated ovarian cancers. However, the majority of women who have ovarian or breast cancer (∼80%) do not have germline or somatic BRCA1/2 mutation, to whom PARP inhibitors alone have very limited efficacy. In a mouse model, adding pharmacologic ascorbate treatment significantly sensitized a BRCA1/2 wild-type ovarian cancer to olaparib treatment [22]. The combination treatment of ascorbate and PARP inhibitor provides a novel and promising therapeutic option for patients with cancers not responding to PARP inhibition alone, and it is worth clinical investigation. Such a strategy could be applied to a variety of heterogeneous and hard-to-treat malignancies, such as breast, pancreatic, and prostate cancers, where BRCA1, BRCA2 or other HR repair proteins are instrumental in the repair of DNA DSBs, and the potential of both PARP inhibitors and ascorbate has not been fully exploited.
Overview of Therapeutic Biomarkers in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Janet E. Dancey Treatment
The drugs that target the base excision repair (BER) pathway by inhibition of poly-ADP ribose polymerase (PARP), an enzyme critical to BER, have shown clinical activity in patients with BRCA mutations (Chapter 15) [76, 77]. Both BRCA1 and BRCA2, which are involved in the process of homologous recombination (HR) that mediates the repair of double-strand DNA breaks, are not the direct targets of PARP inhibitors. The incurred killing upon PARP inhibition in cells with the BRCA dysfunctions is largely ascribed to a mechanism of synthetic lethality, a type of genetic interaction that one mutation or defect is not lethal, but two (or more) are lethal to a cell [78]. In this scenario, BRCA deficiency is considered to be a surrogate therapeutic biomarker for anti-PARP agents. Several PARP inhibitors such as olaparib, rucaparib, and niraparib have gained approval for the treatment of advanced ovarian, fallopian tube, primary peritoneal cancer and metastatic pancreatic adenocarcinoma. Olaparib and talazoparib have recently shown activity in metastatic breast cancer patients with germline BRCA mutations after chemotherapy and endocrine therapy if HR-positive as well as in metastatic prostate cancer patients with DNA-repair defects [79, 80]. In 2018, the FDA granted approval to olaparib and talazoparib for the treatment of individuals with deleterious or suspected deleterious germline BRCA-mutated HER2-negative metastatic breast cancer. More recently, niraparib was approved for advanced ovarian, fallopian tube, or primary peritoneal cancer with homologous recombination deficiency (HRD). HRD is defined by either a deleterious or suspected deleterious BRCA mutation, or genomic instability in patients with disease progression greater than six months after response to the last platinum-based chemotherapy. The FDA granted approval to rucaparib for the treatment of or men with metastatic castration-resistant prostate cancer (mCRPC) with a deleterious BRCA mutation (germline and/or somatic) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. It also approved olaparib for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone
Romiplostim for PARP inhibitor-induced thrombocytopenia in solid tumor malignancies
Published in Platelets, 2022
Abraham Z. Cheloff, Hanny Al‐Samkari
All five patients had advanced cancer that had progressed beyond initial cytotoxic-based treatment regimens and were subsequently prescribed niraparib. One patient had prior radiation treatment in the setting of bone metastasis. Prior to initiation of romiplostim, all 5 patients had experienced dose-reduction, treatment delay, and/or planned discontinuation of niraparib treatment due to persistent thrombocytopenia. Faced with this, they were treated on romiplostim on our institutional weekly romiplostim CIT treatment pathway, described previously [8]. Throughout the course of treatment, 4 out of 5 patients (80%) showed improvement in platelet counts, with 3 showing marked improvements (Table I). Platelet counts just before the first dose of romiplostim ranged from 14 × 109/L to 97 × 109/L, with a per-patient median of 41 × 109/L. By comparison, on romiplostim therapy, the range of the mean platelet count was 65 × 109/L to 190 × 109/L, with a per-patient median of 118 × 109/L.
The evolving landscape of PARP inhibitors in castration-resistant prostate cancer: a spotlight on treatment combinations
Published in Expert Review of Clinical Pharmacology, 2022
Benjamin A. Teply, Emmanuel S. Antonarakis
Niraparib is a PARP inhibitor that has been investigated as a monotherapy in mCRPC after promising results were seen in a phase I study [53]. Men who had mCRPC and prior treatment with both chemotherapy and a novel ARSI were treated with niraparib in a single-arm phase II study of niraparib called GALAHAD [54]. The trial was a biomarker-selected trial and tumors were required to have biallelic deleterious alterations in ATM, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, HDAC2, or PALB2. Niraparib was administered at a dose of 300 mg once daily. Data was reported on the outcomes for 223 patients, including 142 with BRCA1 or BRCA2 alterations and 81 with non-BRCA mutations. The primary endpoint for the study was the objective response rate in patients with measurable disease with BRCA1 or BRCA2 mutations. The study met its pre-specified endpoint for efficacy of an objective response rate of at least 32%, demonstrating 26 responses out of 76 patients (34% [95% CI 23.7%–46.0%]). Responses in the non-BRCA1 or BRCA2 cohort were seen but less commonly (10.6%). For all patients with BRCA1 or BRCA2 mutations treated with niraparib, the PSA50 response rate was 43% and the median radiographic progression-free survival was 8.1 months. In the non-BRCA1 or BRCA2 cohort, PSA50 responses were uncommon (5%) and radiographic progression-free survival was poor (3.7 months).
Risk of fatigue with PARP inhibitors in cancer patients: a systematic review and meta-analysis of 29 phase II/III randomized controlled trials
Published in Journal of Chemotherapy, 2021
The development of PARP inhibitors has opened up a new array of effective and relatively safe drugs for the treatment of patients with ovarian cancer, breast cancer, and other types of cancers. The five PARP inhibitors evaluated within our analysis are olaparib, rucaparib, niraparib, talazoparib, and veliparib. Olaparib and rucaparib were approved by FDA for treatment of patients with deleterious BRCA mutation advanced ovarian cancer who have received two or more chemotherapy regimens. Niraparib was approved by FDA in 2017 for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In 2018, talazoparib was approved by FDA for treating patients with deleterious or suspected deleterious germline BRCA-mutated, HER2‐negative locally advanced or metastatic breast cancer. However, combining PARP inhibitors with chemotherapy has been challenging because of toxic effects that result in substantial dose reductions.19 Veliparib is an oral PARP inhibitor that has shown activity as a single agent in early-phase trials and that can be combined with standard chemotherapy doses.28,38,39 A number of ongoing phase II and III studies28,32,37 are assessing the efficacy and toxicity of veliparib in solid tumors, thus veliparib was also included in our study.