A phase I trial of the PARP inhibitor olaparib (AZD2281) in combination with the antiangiogenic cediranib (AZD2171) in recurrent ovarian or triple-negative breast cancer.

Liu, J.; Fleming, Gini F.; Tolaney, Sara M.; Birrer, M. J.; Penson, R. T.; Berlin, Suzanne; Whalen, Christin; Tyburski, Karin; Matijevich, Karen; Kasparian, Elizabeth; Roche, Maria; Lee, H.; Winer, Eric P.; Ivy, S. Percy; Matulonis, Ursula A.

doi:10.1200/jco.2011.29.15_suppl.5028

Cited by 12 publications

(8 citation statements)

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“…A phase 1 study of ABT-888 (veliparib; Abbott Laboratories) in combination with carboplatin, paclitaxel, and bevacizumab, as first-line treatment for stage II-IVovarian cancers, is ongoing (NCT00989651). Preliminary results of a phase 1 study if olaparib in combination with the VEGF receptor inhibitor cedirinib in recurrent ovarian or triple negative breast cancer indicate that myelosuppression is dose-limiting [42]. An unconfirmed response rate of 56% in ovarian cancer patients is reported, suggesting that this strategy is worth further exploration.…”

Section: How To Optimize the Potential Of Parp Inhibitors?mentioning

confidence: 89%

PARP Inhibitors in BRCA Gene-Mutated Ovarian Cancer and Beyond

Banerjee

Kaye

2011

Curr Oncol Rep

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Poly(ADP-ribose)polymerase (PARP) inhibitors are showing considerable promise for the treatment of BRCA mutation-associated ovarian and breast cancer. This approach exploits a synthetic lethal strategy to target the specific DNA repair pathway in cancers that harbor mutations in the BRCA1 or BRCA2 genes. Accumulating evidence suggests that PARP inhibitors may have a wider application in the treatment of sporadic, high-grade serous ovarian cancers and other cancers including endometrial cancer. In this review, we discuss the clinical development of PARP inhibitors in ovarian cancer and explore challenges that need to be addressed if the full potential of these agents is to be realized.

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Section: How To Optimize the Potential Of Parp Inhibitors?mentioning

confidence: 89%

PARP Inhibitors in BRCA Gene-Mutated Ovarian Cancer and Beyond

Banerjee

Kaye

2011

Curr Oncol Rep

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“…Several combinations of olaparib with cytotoxic chemotherapy have been explored [48, 70–72]. Initial combinations have been plagued by significant myelosuppression - even at olaparib dose levels of 100 mg twice daily.…”

Section: Discussionmentioning

confidence: 99%

Role of PARP Inhibitors in Cancer Biology and Therapy

Davar¹,

Beumer²,

Hamieh³

et al. 2012

CMC

114

100

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Deeper understanding of DNA repair mechanisms and their potential value as therapeutic targets in oncology heralded the clinical development of poly (ADP-ribose) polymerase (PARP) inhibitors. Although initially developed to exploit synthetic lethality in models of cancer associated with defective DNA repair, our burgeoning knowledge of PARP biology has resulted in these agents being exploited both in cancer with select chemotherapeutic agents and in non-malignant diseases. In this review article, we briefly review the mechanisms of DNA repair and pre-clinical development of PARP inhibitors before discussing the clinical development of the various PARP inhibitors in depth.

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“…PARP inhibition also resulted in down-regulation of genes involved in angiogenesis during skin carcinogenesis in mice (55). A phase I study combining olaparib with cediranib, a multi-targeted kinase inhibitor of VEGFR-1/2/3 and c-kit, in recurrent ovarian and TNBC, showed a 56% unconfirmed response rate in the cohort of ovarian cancer patients, but with hematologic dose-limiting toxicities (56). Recent comparative analyses of rucaparib, olaparib, and veliparib in TNBC cell lines suggest target pleiotropism of the various PARP inhibitors, and implicate additional PARP-independent signaling mechanisms thought to account for differing levels of anti-tumor activity (57).…”

Section: Future Directionsmentioning

confidence: 99%

Molecular Pathways: Targeting PARP in Cancer Treatment

Chen

2013

Clinical Cancer Research

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Poly (ADP-ribose) polymerases (PARPs) are a family of nuclear protein enzymes involved in the DNA damage response. The role of PARP-1 in base excisional repair has been extensively characterized. More recent in vitro studies additionally implicate a role for PARP-1 in facilitating homologous recombination and non-homologous end-joining. The more faithful process of homologous recombination repair of double-stranded DNA breaks, involves localization of BRCA-1 and BRCA-2 to sites of DNA damage, resection of the double-stranded break, and gap-filling DNA synthesis using the homologous sister chromatid as a template. Simultaneous dysfunction of both DNA repair pathways decreases the ability of cells to compensate, and forms the basis for the concept of synthetic lethality. Treatment strategies thus far have focused on two main principals: 1) exploitation of the concept of synthetic lethality in homologous recombination deficient tumors, primarily in breast and ovarian cancer patients with BRCA mutation, and 2) as radio-sensitizers and chemo-sensitizers. BRCA deficiency accounts for only a fraction of dysfunction in homologous recombination repair. Epigenetic alterations of BRCA function and defects within the Fanconi anemia pathway also result in defective DNA repair. Rational therapeutic combinations exploiting alternate mechanisms of defective DNA repair, abrogation of cell cycle checkpoints, and additional functions of PARP-1, present novel opportunities for further clinical development of PARP inhibitors. Based on the results of clinical studies of PARP inhibitors thus far, it is imperative that future development of PARP inhibitors take a more refined approach, identifying the unique subset of patients that would most benefit from these agents, determining the optimal time for use, and identifying the optimal combination partner in any particular setting.

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A phase I trial of the PARP inhibitor olaparib (AZD2281) in combination with the antiangiogenic cediranib (AZD2171) in recurrent ovarian or triple-negative breast cancer.

Cited by 12 publications

References 0 publications

PARP Inhibitors in BRCA Gene-Mutated Ovarian Cancer and Beyond

PARP Inhibitors in BRCA Gene-Mutated Ovarian Cancer and Beyond

Role of PARP Inhibitors in Cancer Biology and Therapy

Molecular Pathways: Targeting PARP in Cancer Treatment

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