Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer

Gunderson, Camille C.; Moore, Kathleen N.

doi:10.2217/fon.14.313

Cited by 69 publications

(61 citation statements)

References 37 publications

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“…In the majority of the studies, co-treatment of an HDAC inhibitor with another compound induced the inhibition of tumor growth and showed anti-proliferative effects (46,47,77,84,115,123,138,154). Also, several HDAC inhibitors are assosiated not only with autophagic cell death, but also apoptosis (44,55,70,71,84,97,153). Interestingly, many studies have found that HDAC inhibitors have the ability to convert ER-negative tumors to ER-positive tumors (111,160,161).…”

Section: Resultsmentioning

confidence: 99%

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

2017

CGP

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Section: Resultsmentioning

confidence: 99%

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

2017

CGP

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“…Therefore, targeted therapies increasing the frequency or the persistence of spontaneous DSBs or DSBs induced by treatments such as radiotherapy or chemotherapy have been extensively studied during the last two decades. The most advanced drugs in this field are the Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, with clinical trials showing significant benefits in patients with BRCA mutated ovarian cancer (2). Essentially, cells deficient in BRCA1 or 2 are 100- to 1000-fold more sensitive to PARP inhibitors than BRCA1/2 heterozygote or wild-type cell lines (3)(4).…”

Section: Introductionmentioning

confidence: 99%

Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors

Jdey

Thierry

Russo

et al. 2017

Clinical Cancer Research

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Purpose Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are Poly(ADP-Ribose) Polymerase (PARP) inhibitors (PARPi), which trigger synthetic lethality in tumors with Homologous Recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and Non Homologous End Joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy. Experimental design We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage. We analyzed the cell survival to standalone and combined treatments of 21 tumor cells, and 3 non-tumor cells. In 12 Breast Cancer (BC) cell lines, correlation with sensitivity to each drug and transcriptome were statistically analyzed to identify resistance pathways. Results Molecular analyses demonstrate that olaparib and AsiDNA respectively prevent recruitment of XRCC1 and RAD51/53BP1 repair enzymes to damage sites. Combination of both drugs increases the accumulation of unrepaired damage resulting in an increase of cell death in all tumor cells. In contrast, non-tumor cells do not show an increase of DNA damage nor lethality. Analysis of multi-level omics data from BC cells highlighted different DNA repair and cell cycle molecular profiles associated with resistance to AsiDNA or olaparib, rationalizing combined treatment. Treatment synergy was also confirmed with 6 other PARPi in development. Conclusion Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status.

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“…One of the PARP inhibitors, olaparib, was recently approved by the FDA to treat BRCA1 and BRCA2 germline-mutated OvCa patients, and other PARPi drugs are undergoing active phase I and II trials [155]. However, BRCA1 and 2 germline mutations only account for approximately 15% of the OvCa patients.…”

Section: Biomarkers Predicting Responses To Biotherapies In Ovcamentioning

confidence: 99%

Biological markers of prognosis, response to therapy and outcome in ovarian carcinoma

Szajnik

Czystowska-Kuźmicz

Elishaev

et al. 2016

Expert Review of Molecular Diagnostics

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Introduction Ovarian cancer (OvCa) is among the most common types of cancer and is the leading cause of death from gynecological malignancies in western countries. Cancer biomarkers have a potential for improving the management of OvCa patients at every point from screening and detection, diagnosis, prognosis, follow up, response to therapy and outcome. Areas covered The literature search has indicated a number of candidate biomarkers have recently emerged that could facilitate the molecular definition of OvCa, providing information about prognosis and predicting response to therapy. These potentially promising biomarkers include immune cells and their products, tumor-derived exosomes, nucleic acids and epigenetic biomarkers. Expert commentary Although most of the biomarkers available today require prospective validation, the development of noninvasive liquid biopsy-based monitoring promises to improve their utility for evaluations of prognosis, response to therapy and outcome in OvCa.

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Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer

Cited by 69 publications

References 37 publications

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors

Biological markers of prognosis, response to therapy and outcome in ovarian carcinoma

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