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Expert Opinion on Investigational Drugs Jun 2022Poly (ADP-ribose) polymerase inhibitors (PARPis) are an exciting class of agents that have shown efficacy, particularly for BRCA-mutant triple-negative breast cancer... (Review)
Review
PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers.
INTRODUCTION
Poly (ADP-ribose) polymerase inhibitors (PARPis) are an exciting class of agents that have shown efficacy, particularly for BRCA-mutant triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC). However, most patients who receive PARPi as their standard of care therapy inevitably develop resistance and this underscores the need to identify additional targets that can circumvent such resistance. Combination treatment strategies have been developed in preclinical and clinical studies to address the challenges of efficacy and resistance.
AREAS COVERED
This review examines completed or ongoing clinical trials of PARPi mono- and combination therapies. PARPi monotherapy in HER2 negative breast (HR+ and TNBC subtypes) and ovarian cancer is a focal point. The authors propose potential strategies that might overcome resistance to PARPi and discuss key questions and future directions.
EXPERT OPINION
While the advent of PARPis has significantly improved the treatment of tumors with defects in DNA damage and repair pathways, careful patient selection will be essential to enhance these treatments. The identification of molecular biomarkers to predict disease response and progression is an endeavor.
Topics: Carcinoma, Ovarian Epithelial; DNA Damage; Female; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms
PubMed: 35435784
DOI: 10.1080/13543784.2022.2067527 -
Expert Opinion on Therapeutic Targets 2023Sensitization of mismatch repair (MMR)-deficient colorectal cancer (CRC) cells by 5-Fluorouracil (5-FU) is well-documented. But not much is known about the treatment of...
Veliparib (ABT-888), a PARP inhibitor potentiates the cytotoxic activity of 5-fluorouracil by inhibiting MMR pathway through deregulation of MSH6 in colorectal cancer stem cells.
OBJECTIVE
Sensitization of mismatch repair (MMR)-deficient colorectal cancer (CRC) cells by 5-Fluorouracil (5-FU) is well-documented. But not much is known about the treatment of MMR-proficient CRC cancer stem cells (CRC-CSCs). Here, we investigated whether a PARP inhibitor (ABT-888) can enhance the 5-FU-mediated apoptosis in CRC-CSCs through MMR pathway inhibition.
METHODS
The anti-cancer action of 5-FU+ABT-888 combination in CRC-CSCs has been studied by using in vitro, ex vivo, and in vivo preclinical model systems.
RESULTS
5-FU caused DNA damage in CRC-CSCs, and ABT-888 enhanced the accumulation of DNA mismatches by downregulating the MMR pathway, triggering S-phase arrest, and finally apoptosis and cell death in 5-FU-pre-treated MMR-proficient-CRC-CSCs at much lower concentrations than their individual treatments. After 5-FU treatment, PARylated-PARP1 activated MMR pathway by interacting with MSH6. But, upon ABT-888 treatment in 5-FU-pre-exposed CSCs, PARylation was inhibited, as a result of which PARP1 could not interact with MSH6, and other MMR proteins were downregulated. The role of MSH6 in PARP1-mediated MMR activation, was confirmed by silencing MSH6 gene, which resulted in MMR pathway shutdown. Similar results were obtained in ex vivo and in vivo model systems.
CONCLUSIONS
5-FU+ABT-888 combination enhanced CRC-CSCs death by increasing DNA damage accumulation and simultaneously inhibiting the MMR pathway in MMR-proficient cells. But this study does not discuss whether the combination treatment will increase the sensitivity of MMR-deficient CSCs, for which further research will be performed in the future.
Topics: Humans; Fluorouracil; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents; Colorectal Neoplasms; DNA-Binding Proteins; Neoplastic Stem Cells
PubMed: 37787493
DOI: 10.1080/14728222.2023.2266572 -
Oncogene Sep 2022DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi)...
DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. However, therapy resistance is a major clinical challenge and genes contributing to PARPi resistance are poorly understood. Using a genome-wide CRISPR-Cas9 knockout screen, this study aimed at identifying genes involved in PARPi resistance in CRPC. Based on the screen, we identified PARP1, and six novel candidates associated with olaparib resistance upon knockout. For validation, we generated multiple knockout populations/clones per gene in C4 and/or LNCaP CRPC cells, which confirmed that loss of PARP1, ARH3, YWHAE, or UBR5 caused olaparib resistance. PARP1 or ARH3 knockout caused cross-resistance to other PARPis (veliparib and niraparib). Furthermore, PARP1 or ARH3 knockout led to reduced autophagy, while pharmacological induction of autophagy partially reverted their PARPi resistant phenotype. Tumor RNA sequencing of 126 prostate cancer patients identified low ARH3 expression as an independent predictor of recurrence. Our results advance the understanding of PARPi response by identifying four novel genes that contribute to PARPi sensitivity in CRPC and suggest a new model of PARPi resistance through decreased autophagy.
Topics: Antineoplastic Agents; CRISPR-Cas Systems; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Male; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant
PubMed: 35933519
DOI: 10.1038/s41388-022-02427-2 -
The Oncologist May 2023Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors,...
BACKGROUND
Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors, but such combinations have proven too toxic in clinical trials. Liposomal irinotecan (nal-IRI) achieved similar intratumoral exposure with better antitumor activity than the conventional TOP1 inhibitor irinotecan in preclinical models. Tumor targeted delivery of TOP1 inhibitor using nal-IRI and an intermittent schedule of administration of PARP inhibitor may provide a tolerable combination.
METHODS
A phase I study was performed to evaluate the safety and tolerability of escalating doses of nal-IRI and the PARP inhibitor veliparib in patients with solid tumors resistant to standard treatments. Nal-IRI was administered on days 1 and 15 and veliparib on days 5-12 and 19-25 in 28-day cycles.
RESULTS
Eighteen patients were enrolled across 3 dose levels. Five patients encountered dose-limiting toxicities, including grade 3 diarrhea lasting more than 72 h in 3 patients and 1 patient each with grade 4 diarrhea and grade 3 hyponatremia. The most common grade 3 or 4 toxicities included diarrhea (50% of patients), nausea (16.6%), anorexia, and vomiting (11.1% each) (Table 1). There was no difference in frequencies of adverse events based on UGT1A1*28 status or prior opioid use (Table 1).
CONCLUSION
The clinical trial was terminated due to high frequency of unacceptable gastrointestinal toxicities, which precluded dose escalation of veliparib in combination with nal-IRI (ClinicalTrials.gov Identifier: NCT02631733).
Topics: Humans; Irinotecan; Poly(ADP-ribose) Polymerase Inhibitors; Neoplasms; Antineoplastic Agents; Topoisomerase I Inhibitors; Poly(ADP-ribose) Polymerases; Diarrhea; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37010988
DOI: 10.1093/oncolo/oyad023 -
Journal of Clinical Oncology : Official... Jan 2023In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival...
PURPOSE
In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival (PFS) compared with carboplatin-paclitaxel alone in patients with high-grade ovarian carcinomas. We explored the prognostic value of the modeled cancer antigen (CA)-125 elimination rate constant K (KELIM), which is known to be an indicator of the intrinsic tumor chemosensitivity (the faster the rate of CA-125 decline, the higher the KELIM and the higher the chemosensitivity), and its association with benefit from veliparib.
PATIENTS AND METHODS
Individual KELIM values were estimated from longitudinal CA-125 kinetics. Patients were categorized as having favorable (≥ median) or unfavorable (< median) KELIM. The prognostic value of KELIM for veliparib-related PFS benefit was explored in cohorts treated with primary or interval debulking surgery, according to the surgery completeness, the disease progression risk group, and the homologous recombination (HR) status ( mutation, HR deficiency [HRD], or HR proficiency [HRP]).
RESULTS
The data from 854 of 1,140 enrolled patients were analyzed (primary debulking surgery, n = 700; interval debulking surgery, n = 154). Increasing KELIM values were associated with higher benefit from veliparib in HRD cancer, as were decreasing KELIM values in HRP cancer. The highest PFS benefit from veliparib was observed in patients with both favorable KELIM and mutation (hazard ratio, 0.28; 95% CI, 0.13 to 0.61) or wild-type HRD cancer (hazard ratio, 0.43; 95% CI, 0.26 to 0.70), consistent with the association between poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy and platinum sensitivity. In contrast, seventy-four percent of patients with a mutation and unfavorable KELIM progressed within 18 months while on veliparib. The patients with HRP cancer and unfavorable KELIM might have benefited from the veliparib chemosensitizing effect.
CONCLUSION
In addition to HRD/ status, the tumor primary chemosensitivity observed during the first-line chemotherapy might be another complementary determinant of poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy.
Topics: Female; Humans; Carboplatin; Ribose; Antineoplastic Combined Chemotherapy Protocols; Ovarian Neoplasms; Paclitaxel; Adenosine Diphosphate
PubMed: 35867965
DOI: 10.1200/JCO.22.00430 -
Journal of Clinical Laboratory Analysis May 2022Our study aimed to investigate the potential clinical utility of a poly(ADP-ribose) polymerase (PARP) inhibitor, veliparib (ABT-888), as a radiosensitizer in the...
OBJECTIVE
Our study aimed to investigate the potential clinical utility of a poly(ADP-ribose) polymerase (PARP) inhibitor, veliparib (ABT-888), as a radiosensitizer in the medication of endometrial carcinoma (EC).
METHODS
Human Ishikawa endometrial adenocarcinoma cells were treated with veliparib, radiotherapy (RT), or combination treatment. The viabilities, radiosensitivity enhancement ratio (sensitizer enhancement ratio (SER), and apoptosis of Ishikawa cells were, respectively, evaluated by Cell Counting Kit-8 (CCK-8), colony formation experiment, and flow cytometry. The tumor growth was assessed by xenograft mice models. Western blot assay investigated the expression of DNA damage and apoptosis-related proteins in vivo and in vitro.
RESULTS
Cell Counting Kit-8 revealed that the 10% inhibition concentration (IC ) and 50% inhibition concentration (IC ) values of veliparib-treated Ishikawa cells were 1.7 and 133.5 µM, respectively. The SER of veliparib combined with RT was 1.229 in vitro. Flow cytometry analysis results indicated that the apoptosis rate of the veliparib + RT group was markedly higher than that of the RT group in vitro (p < 0.05). Furthermore, in vivo data revealed that veliparib + RT treatment significantly decreased tumor growth compared with single treatments of veliparib or RT and with the control group (p < 0.05). Then western blot confirmed the levels of anti-phospho-histone (γH2AX), caspase-3, and B-cell lymphoma 2 (Bcl-2) associated protein X (Bax) were significantly higher in the veliparib + RT group, while the level of Bcl-2 was lower compared with that of the RT group (p < 0.05), both in vivo and in vitro.
CONCLUSION
Our results indicate that veliparib in combination with RT markedly improved the therapeutic efficiency in human endometrial carcinoma.
Topics: Animals; Benzimidazoles; Cell Line, Tumor; Endometrial Neoplasms; Female; Humans; Mice; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Radiation Tolerance
PubMed: 35421273
DOI: 10.1002/jcla.24435 -
Gynecologic Oncology Feb 2022
Topics: Benzimidazoles; Homologous Recombination; Humans; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 35086648
DOI: 10.1016/j.ygyno.2022.01.018 -
Journal of Labelled Compounds &... Jul 2021Veliparib, a potent PARP inhibitor used against multiple cancerous cells such as metastatic melanoma, breast, non-small cell lung cancer (NSCLC) and prostatic cancer, is...
Veliparib, a potent PARP inhibitor used against multiple cancerous cells such as metastatic melanoma, breast, non-small cell lung cancer (NSCLC) and prostatic cancer, is required for absorption, distribution, metabolism and excretion (ADME) and environmental toxicology assessments studies. Tritium-labeled Veliparib was prepared via the tritiodebromination using tritium gas (T ) in two steps. [ C]Veliparib was achieved through an asymmetric synthetic route in seven radioactive steps starting from [ C] (S)-benzyl 2-aminopropanoate.
Topics: Carcinoma, Non-Small-Cell Lung
PubMed: 34050966
DOI: 10.1002/jlcr.3928 -
Seminars in Oncology 2024PARP inhibitors have emerged as a promising class of anticancer agents approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. These inhibitors... (Review)
Review
PARP inhibitors have emerged as a promising class of anticancer agents approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. These inhibitors target PARP enzymes involved in DNA repair pathways and exhibit remarkable efficacy in cancers with genetic deficiencies in the homologous recombination pathway responsible for mending DNA double-strand breaks. While all PARP inhibitors demonstrate potent and selective inhibition of PARP1 and PARP2, the key enzymes involved in DNA repair, each agent within the class possesses unique pharmacological profiles distinguishing them from one another. This review aims to comprehensively examine the properties of the entire PARP inhibitor class while emphasizing individual pharmacologic and pharmacokinetic distinctions that inform clinical recommendations. Currently, four agents, namely olaparib, rucaparib, niraparib, and talazoparib, have obtained approval in the United States and Europe. Olaparib, the first approved PARP inhibitor, has been extensively studied and is indicated for a wider range of cancer types. Niraparib and talazoparib, the more recent additions to the PARP inhibitor class, possess the longest half-lives and are formulated for convenient once-daily dosing, alleviating the pill burden for patients when compared to older agents. Moreover, talazoparib undergoes minimal hepatic metabolism, reducing the potential for drug-drug interactions. Notably, niraparib is the sole PARP inhibitor recommended for dose reduction in hepatically impaired populations, whereas talazoparib and olaparib should be dose reduced in renally impaired populations. The mechanisms underlying these dose adjustment recommendations are further explored in this review. Additionally, this review briefly covers veliparib, a PARP inhibitor under development, and two recently approved PARP inhibitors in China, fuzuloparib and pamiparib. Although significant progress has been made in understanding PARP inhibitors, there are several unanswered questions that remain, necessitating further research across a broader spectrum of cancer types within this evolving class of anticancer agents.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Pharmacogenetics; Antineoplastic Agents; Neoplasms; Ovarian Neoplasms
PubMed: 37880048
DOI: 10.1053/j.seminoncol.2023.09.005 -
PloS One 2023As a poly-ADP ribose polymerase (PARP) inhibitor, veliparib has been identified as a potential therapeutic agent for lung cancer. The present study aimed to conduct a...
BACKGROUND
As a poly-ADP ribose polymerase (PARP) inhibitor, veliparib has been identified as a potential therapeutic agent for lung cancer. The present study aimed to conduct a systematic review of clinical trials investigating the efficacy and safety of veliparib for treating lung cancer.
METHODS
PubMed, Scopus, the Web of Science, and Google Scholar were systematically searched up to October 30, 2022. Only randomized controlled trials (RCTs) evaluating the efficacy or safety of veliparib in the treatment of lung cancer patients were included. Studies were excluded if they were not RCTs, enrolled healthy participants or patients with conditions other than lung cancer, or investigated therapeutic approaches other than veliparib. The Cochrane risk-of-bias tool was used for quality assessment.
RESULTS
The seven RCTs (n = 2188) showed that patients treated with a combination of veliparib and chemotherapy had a significantly higher risk of adverse events, when compared to the control arm. There was no statistically significant difference in overall survival (OS) between those treated with veliparib plus chemotherapy and those receiving the standard therapies. Only two trials demonstrated an improvement in progression-free survival (PFS), and only one study found an increase in objective response rate (ORR). Furthermore, adding veliparib to standard chemotherapy showed no benefit in extending the duration of response (DoR) in any of the studies.
CONCLUSIONS
Only a small number of studies have found veliparib to be effective, in terms of improved OS, PFS, and ORR, while the majority of studies found no benefit for veliparib over standard treatment.
Topics: Humans; Benzimidazoles; Lung Neoplasms; Healthy Volunteers; Poly(ADP-ribose) Polymerases; Randomized Controlled Trials as Topic
PubMed: 37682974
DOI: 10.1371/journal.pone.0291044