The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial

Sandhu, Shahneen; Schelman, William R.; Wilding, George; Moreno, Víctor; Baird, Richard D.; Miranda, Susana; Hylands, Lucy; Riisnaes, Ruth; Förster, Martin; Omlin, Aurelius; Kreischer, N.; Thway, Khin; Gevensleben, Heidrun; Sun, Linda; Loughney, John W.; Chatterjee, Manash; Toniatti, Carlo; Carpenter, Christopher L.; Iannone, Robert; Kaye, Stan B.; Bono, Johann S. de; Wenham, Robert M.

doi:10.1016/s1470-2045(13)70240-7

Cited by 498 publications

(364 citation statements)

References 34 publications

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“…A recent clinical trial with niraparib/MK4827 was the first study to report clinical activity of a PARPi in sporadic CRPC without BRCA mutations, where 9 of 21 (43%) patients experienced disease control (49), suggesting that BRCAproficient patients with HR defects are susceptible to PARP inhibition. Our data indicate that HDAC inhibitor in combination with PARPi can additively downregulate HR proteins, especially RAD51, and induce apoptosis in prostate cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Loss of Prostate Cancer Cell Viability by Coinhibition of HDAC and PARP

Chao

Goodman

2014

Molecular Cancer Research

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Tumors with BRCA germline mutations are defective in repairing DNA double-strand breaks (DSB) through homologous recombination (HR) pathways, making them sensitive to PARP inhibitors (PARPi). However, BRCA germline mutations are rare in prostate cancer limiting the ability to therapeutically target these pathways. This study investigates whether histone deacetylase (HDAC) inhibitors (HDACi), reported to modulate DSB repair pathways in sporadic cancers, can downregulate DSB repair pathways and sensitize prostate cancer cells to PARPi. Prostate cancer cells cotreated with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) and the PARPi, olaparib, demonstrated a synergistic decrease in cell viability compared with single-agent treatment (combination index < 0.9), whereas normal prostatic cells did not. Similarly, clonogenicity was significantly decreased after cotreatment. Flow cytometric cell-cycle analysis and Annexin-V staining revealed significant apoptosis upon treatment with SAHAþolaparib. This coincided with increased DNA damage observed by immunofluorescence microscopy analysis of gH2AX foci, a marker of DSBs. In addition, immunoblot analysis showed a significant and persistent increase in nuclear gH2AX levels. Both SAHA and olaparib downregulated the expression of HR-related proteins, BRCA1 and RAD51, whereas SAHA þ olaparib had an additive effect on RAD51. Silencing RAD51 sensitized prostate cancer cells to SAHA and olaparib alone. Collectively, cotreatment with HDACi and PARPi downregulated HR-related protein expression and concomitantly increased DNA damage, resulting in prostate cancer cell death.Implications: These findings provide a strong rationale for supporting the use of combined HDAC and PARP inhibition in treating advanced prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Synergistic Loss of Prostate Cancer Cell Viability by Coinhibition of HDAC and PARP

Chao

Goodman

2014

Molecular Cancer Research

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“…PARP inhibitors, initially olaparib, have shown single agent response rates of up to 30% in recurrent ovarian cancer with the greatest activity in cancers with BRCA mutations and in platinum-sensitive disease (197)(198)(199). Other PARP inhibitors (such as niraparib, rucaparib, and veliparib) that have single agent activity in ovarian cancer, are in phase III studies of, for example, use as maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer, following a response to treatment with platinum-based chemotherapy (206,207) (Table 6); rucaparib was recently given breakthrough status (to accelerate the development and review of the drug) by the FDA based on results from the ARIEL2 trial (208). Veliparib has been added to the NACT armamentarium with carboplatin and paclitaxel for newly diagnosed advanced ovarian cancer in a phase III study, in addition to testing as a maintenance therapy (209).…”

Section: [H2] Emerging Therapiesmentioning

confidence: 99%

Ovarian cancer

Matulonis

Sood

Fallowfield

et al. 2016

Nat Rev Dis Primers

845

787

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Ovarian cancer is not a single disease and can be subdivided into at least five different 2 histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at late stage, and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents, and poly (ADP ribose) polymerase (PARP) inhibitors are used and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and is typically very responsive to platinum-based chemotherapy at diagnosis. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy.Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Significant progress has been made in identifying genes associated with high risk of ovarian cancer (such as BRCA1 and BRCA2) as well as a precursor lesion of HGSC called a serous tubal intraepithelial carcinoma, which hold promise for identifying individuals at high risk of developing the disease and for developing prevention strategies. Competing interestsU.A.M. has served as a consultant for AstraZeneca, ImmunoGen, Pfizer, Genentech, and Merck.

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“…Multiple clinical trials with PARP inhibitors, including olaparib and niraparib, have demonstrated tolerability and efficacy of these treatments in OC patients [Audeh et al., 2010; Sandhu et al., 2013]. Moreover, progression‐free survival of OC patients is further improved when olaparib is administered in combination with other treatments (e.g., paclitaxel, carboplatin, and cediranib) [Liu et al., 2014; Oza et al., 2015].…”

Section: Introductionmentioning

confidence: 99%

NovelBRCA1andBRCA2Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas

et al. 2016

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With the recent introduction of Poly(ADP‐ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin‐fixed, paraffin‐embedded (FFPE) tissue, we have developed a single‐molecule molecular inversion probe (smMIP)‐based targeted next‐generation sequencing (NGS) approach. Our smMIP‐based NGS approach provides analysis of both strands of the open reading frame of BRCA1 and BRCA2, enabling the discrimination between real variants and formalin‐induced artefacts. The single molecule tag enables compilation of unique reads leading to a high analytical sensitivity and enabling assessment of the reliability of mutation‐negative results. Multiplex ligation‐dependent probe amplification (MLPA) and Methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) were used to detect exon deletions of BRCA1 and methylation of the BRCA1 promoter, respectively. Here, we show that this combined approach allows the rapid and reliable detection of both germline and somatic aberrations affecting BRCA1 and BRCA2 in DNA derived from FFPE OCs, enabling improved hereditary cancer risk assessment and clinical treatment of ovarian cancer patients.

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The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial

Cited by 498 publications

References 34 publications

Synergistic Loss of Prostate Cancer Cell Viability by Coinhibition of HDAC and PARP

Synergistic Loss of Prostate Cancer Cell Viability by Coinhibition of HDAC and PARP

Ovarian cancer

NovelBRCA1andBRCA2Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas

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