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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 -
JCO Precision Oncology Jun 2022Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes,...
PURPOSE
Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes, including familial pancreatic cancer. HR-DDR genes beyond , , , and may also mutate and confer the HR-DDR deficiency in pancreatic ductal adenocarcinoma (PDAC).
METHODS
We conducted a study to examine the genetic alterations using a companion diagnostic 15-gene HR-DDR panel in PDACs. HR-DDR gene mutations were identified and characterized by whole-exome sequencing and whole-genome sequencing. Different HR-DDR gene mutations are associated with variable homologous recombination deficiency (HRD) scores.
RESULTS
Eight of 50 PDACs with at least one HR-DDR gene mutation were identified. One tumor with mutations is associated with a high HRD score. However, another tumor with a mutation is associated with a zero HRD score. Notably, four of eight PDACs in this study harbor a gene mutation. All four gene mutations were germline mutations. However, currently, is not the gene panel for germline tests.
CONCLUSION
The finding in this study thus supports including in the germline test of HR-DDR pathway genes.
Topics: Carcinoma, Pancreatic Ductal; DNA-Binding Proteins; Genes, BRCA2; Germ-Line Mutation; Humans; Pancreatic Neoplasms
PubMed: 35737913
DOI: 10.1200/PO.21.00404 -
Medical Principles and Practice :... 2022In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homologous end joining (NHEJ). DNA damage is... (Review)
Review
In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homologous end joining (NHEJ). DNA damage is detected by PARP proteins that facilitate this repair, both in normal cells and in cancer cells. Cells containing BRCA1/2 mutations have an HRR-deficient repair mechanism which may result in unrepaired one-ended double-strand breaks and stalled replication forks, considered as the most lethal cell damage. Here, we review the state of the art of the role of Poly (ADP-ribose) polymerase (PARP) inhibitors as a precision-targeted anticancer drug in BRCA1/2-mutated female breast cancer. Although knowledge is incomplete, it is assumed that the main role of the archetype PARP1 in the cell nucleus is to detect and adhere to single-strand breaks. This mediates possible damage repair, after which cells may continue replication; this process is called synthetic lethality. As for PARP clinical monotherapy, progression-free survival has been observed using the FDA- and EMA-approved drugs olaparib and talazoparib. In the case of combined drug therapy, a synergy has been demonstrated between veliparib and platinum drugs. Information regarding adverse effects is limited, but hematological effects have been described. However, there is need for multicenter trials, preferably conducted without commercial guidance and funding. Some of the available trials reported resistance to PARP inhibitors. In this review, we also describe the various causes of resistance to PARP inhibitors and research indicating how resistance can be overcome.
Topics: Animals; Breast Neoplasms; Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Risk Reduction Behavior
PubMed: 35636395
DOI: 10.1159/000525281 -
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 -
Cancer Chemotherapy and Pharmacology May 2022BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are...
A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer.
PURPOSE
BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCAmut and BRCAwt ovarian and basal-like breast cancers. This phase I study determined the recommended phase II dose (RP2D) and preliminary efficacy of the PARP inhibitor, veliparib (ABT-888), in these patients.
PATIENTS AND METHODS
Patients (n = 98) were dosed with veliparib 50-500 mg twice daily (BID). The BRCAmut cohort (n = 70) contained predominantly ovarian (53%) and breast (23%) cancers; the BRCAwt cohort (n = 28) consisted primarily of breast cancer (86%). The MTD, DLT, adverse events, PK, PD, and clinical response were assessed.
RESULTS
DLTs were grade 3 nausea/vomiting at 400 mg BID in a BRCAmut carrier, grade 2 seizure at 400 mg BID in a patient with BRCAwt cancer, and grade 2 seizure at 500 mg BID in a BRCAmut carrier. Common toxicities included nausea (65%), fatigue (45%), and lymphopenia (38%). Grade 3/4 toxicities were rare (highest lymphopenia at 15%). Overall response rate (ORR) was 23% (95% CI 13-35%) in BRCAmut overall, and 37% (95% CI 21-55%) at 400 mg BID and above. In BRCAwt, ORR was 8% (95% CI 1-26%), and clinical benefit rate was 16% (95% CI 4-36%), reflecting prolonged stable disease in some patients. PK was linear with dose and was correlated with response and nausea.
CONCLUSIONS
Continuous veliparib is safe and tolerable. The RP2D was 400 mg BID. There is evidence of clinical activity of veliparib in patients with BRCAmut and BRCAwt cancers.
Topics: Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Benzimidazoles; Female; Humans; Lymphopenia; Nausea; Ovarian Neoplasms; Platinum; Poly(ADP-ribose) Polymerase Inhibitors; Seizures; Triple Negative Breast Neoplasms
PubMed: 35435472
DOI: 10.1007/s00280-022-04430-6 -
American Journal of Translational... 2022MiR-199a-3p was previously predicted to target tumor suppressor gene , which has been linked to cancer onset and therapeutic response. In this study, the effects of...
MiR-199a-3p was previously predicted to target tumor suppressor gene , which has been linked to cancer onset and therapeutic response. In this study, the effects of miR-199a-3p-mediated dysfunction on triple-negative breast cancer (TNBC) progression and chemosensitivity were assessed. The association between miR-199a-3p and expression was examined in TNBC tumors and verified with luciferase reporter and protein assays. Tumorigenic functions of miR-199a-3p in TNBC cells were investigated by cell proliferation, clonogenic and migration assays. The sensitivities to chemotherapeutic drugs were tested with cisplatin and PARP inhibitor (veliparib) treatments. Mouse xenograft model was used to examine the effects of miR-199a-3p on tumor growth and drug response . MiR-199a-3p was shown to directly target in TNBC cells, resulting its downregulation and reduced luciferase reporter activity mediated by 3'-UTR. Ectopic miR-199a-3p in TNBC cells exerted inhibitory effects on cell proliferation, migration and xenograft tumor growth. Moreover, miR-199a-3p was shown to reverse cisplatin-resistance and sensitize TNBC cells to veliparib, which might be due to repressed DNA repair ability and induced cell apoptosis. Our results demonstrated the tumor suppressive effects of miR-199a-3p on TNBC and induction on chemotherapeutic sensitivities, which were correlated with gene dysfunction. These findings may provide insights into the potential prognostic and therapeutic values of miR-199a-3p in patients with TNBC.
PubMed: 35422914
DOI: No ID Found -
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 -
Clinical Lung Cancer May 2022This open-label Phase III trial (NCT02264990) evaluated the PARP inhibitor, veliparib, combined with carboplatin/paclitaxel versus chemotherapy alone for first-line... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This open-label Phase III trial (NCT02264990) evaluated the PARP inhibitor, veliparib, combined with carboplatin/paclitaxel versus chemotherapy alone for first-line treatment of patients with advanced non-squamous non-small cell lung cancers (NSCLC). A 52-gene expression classifier (LP52) previously shown to identify patients more likely to respond to veliparib was evaluated as a planned correlative analysis.
MATERIALS AND METHODS
Adult current or former smokers with advanced non-squamous NSCLC were randomized 1:1 to veliparib (120 mg daily for 7 days/cycle) with carboplatin and paclitaxel or to investigators' choice of platinum doublet chemotherapy (up to 6, 21-day cycles), with optional pemetrexed maintenance. Prospective analysis of the LP52 signature was conducted using a clinical Qiagen/HTG assay. The primary endpoint was overall survival (OS) in LP52+ patients.
RESULTS
Overall, 595 patients received veliparib + carboplatin/paclitaxel (n = 298) or chemotherapy alone (n = 297); 13% (n = 40) in each arm were LP52+. The primary endpoint was not met; median OS was 11.2 months with veliparib + carboplatin/paclitaxel versus 9.2 months with chemotherapy alone in the LP52+ subgroup (hazard ratio [HR] 0.644, 95% confidence interval [CI]: 0.396-1.048; P = .113). In the overall population, median OS was 12.1 months in both arms (HR 0.986, 95% CI: 0.827-1.176; P = .846). No new safety signals were observed.
CONCLUSION
In patients with non-squamous NSCLC, there was no significant improvement in OS with veliparib + carboplatin/paclitaxel versus chemotherapy alone, although a trend toward improved OS in the LP52+ population suggests this subgroup may benefit from veliparib. Statistical power was limited due to the small sample size.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Paclitaxel
PubMed: 35331641
DOI: 10.1016/j.cllc.2022.01.005 -
BMC Cancer Mar 2022Management of bladder cancer (BLCA) has not changed significantly in the past few decades, with platinum agent chemotherapy being used in most cases. Chemotherapy...
BACKGROUND
Management of bladder cancer (BLCA) has not changed significantly in the past few decades, with platinum agent chemotherapy being used in most cases. Chemotherapy reduces tumor recurrence after resection, but debilitating toxicities render a large percentage of patients ineligible. Recently approved immunotherapy can improve outcomes in only a third of metastatic BLCA patients. Therefore, more options for therapy are needed. In this study, we explored the efficacy of PARP inhibitors (PARPi) as single agents or as combinations with platinum therapy.
METHODS
We treated BLCA cells with PARPi (olaparib, niraparib, rucaparib, veliparib, or talazoparib) alone or as the combination of cisplatin with PARPi. We then measured their survival, proliferation, apoptosis, as well as their ability to form colonies. BLCA xenografts in male SCID mice were treated similarly, followed by the assessment of their growth, proliferation, and apoptosis.
RESULTS
PARPi niraparib and talazoparib were effective in reducing BLCA cell survival as single agents. Combinations of Cisplatin with talazoparib and niraparib effectively reduced the survival of BLCA cells, while veliparib was not effective even at high concentrations. In vivo, the combinations of cisplatin with niraparib, rucaparib, or talazoparib reduced BLCA xenograft growth significantly.
CONCLUSIONS
We provide evidence that PARPi can be effective against BLCA as single agents or as combinatorial therapy with cisplatin.
Topics: Animals; Cell Survival; Cisplatin; Humans; Male; Mice; Mice, SCID; Neoplasm Recurrence, Local; Poly(ADP-ribose) Polymerase Inhibitors; Urinary Bladder Neoplasms
PubMed: 35321693
DOI: 10.1186/s12885-022-09376-9 -
Brain Communications 2022The accumulation of α-synuclein inclusions in vulnerable neuronal populations pathologically defines Lewy body diseases including Parkinson's disease. Recent...
The accumulation of α-synuclein inclusions in vulnerable neuronal populations pathologically defines Lewy body diseases including Parkinson's disease. Recent pre-clinical studies suggest poly(ADP-ribose) polymerase-1 activation and the subsequent generation of poly(ADP-ribose) polymer represent key steps in the formation of toxic α-synuclein aggregates and neurodegeneration. Several studies suggest that the inhibition of poly(ADP-ribose) polymerase-1 activity via the poly(ADP-ribose) polymerase-1/2 small molecule inhibitor ABT-888 (Veliparib), a drug in clinical trials for different cancers, may prevent or ameliorate α-synuclein fibril-induced aggregation, inclusion formation and dopaminergic neurodegeneration. Herein, we evaluated the effects of poly(ADP-ribose) polymer on α-synuclein fibrillization , the effects of ABT-888 on the formation of fibril-seeded α-synuclein inclusions in primary mouse cortical neurons and the effects of an in-diet ABT-888 dosage regimen with the intracranial injection of α-synuclein fibrils into the mouse dorsal striatum. We found that poly(ADP-ribose) polymer minimally but significantly increased the rate of spontaneously formed α-synuclein fibrils . Machine-learning algorithms that quantitatively assessed α-synuclein inclusion counts in neurons, both in primary cultures and in the brains of fibril-injected mice, did not reveal differences between ABT-888- and vehicle-treated groups. The in-diet administered ABT-888 molecule demonstrated outstanding brain penetration in mice; however, dopaminergic cell loss in the substantia nigra caused by α-synuclein fibril injections in the striatum was similar between ABT-888- and vehicle-treated groups. α-Synuclein fibril-induced loss of dopaminergic fibres in the dorsal striatum was also similar between ABT-888- and vehicle-treated groups. We conclude that additional pre-clinical evaluation of ABT-888 may be warranted to justify further exploration of ABT-888 for disease modification in Lewy body diseases.
PubMed: 35282165
DOI: 10.1093/braincomms/fcac042