PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Boussios, Stergios; Karathanasi, Afroditi; Cooke, Deirdre; Neille, Cherie; Sadauskaite, Agne; Moschetta, Michele; Zakynthinakis-Kyriakou, Nikolaos; Pavlidis, Nicholas

doi:10.3390/diagnostics9020055

Cited by 56 publications

(76 citation statements)

References 116 publications

(139 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PARP inhibitors have been combined with chemotherapy based on the fact that they block BER, and consequently may potentiate the efficacy of cytotoxins [104]. A major concern for this therapeutic strategy is the high risk of overlapping myelotoxicity; for this reason, initiation of standard chemotherapy doses has been accompanied by dose escalation of the PARP inhibitor.…”

Section: Talazoparib Combination Therapiesmentioning

confidence: 99%

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

et al. 2020

View full text Add to dashboard Cite

Genetic complexity and DNA damage repair defects are common in different cancer types and can induce tumor-specific vulnerabilities. Poly(ADP-ribose) polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality and have emerged as promising anticancer therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA ) mutations. However, the utility of PARP inhibitors could be expanded beyond germline BRCA1/2 mutated cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. US Food and Drug Administration (FDA)-approved PARP inhibitors include olaparib, rucaparib, and niraparib, while veliparib is in the late stage of clinical development. Talazoparib inhibits PARP catalytic activity, trapping PARP1/2 on damaged DNA, and it has been approved by the US FDA for the treatment of metastatic germline BRCA1/2 mutated breast cancers in October 2018. The talazoparib side effect profile more closely resembles traditional chemotherapeutics rather than other clinically approved PARP inhibitors. In this review, we discuss the scientific evidence that has emerged from both experimental and clinical studies in the development of talazoparib. Future directions will include optimizing combination therapy with chemotherapy, immunotherapies and targeted therapies, and in developing and validating biomarkers for patient selection and stratification, particularly in malignancies with 'BRCAness'. Key PointsPARP inhibitors are a family of enzymes that play a role in DNA repair.

show abstract

Section: Talazoparib Combination Therapiesmentioning

confidence: 99%

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Thus, PI3K/AKT targeting by PI3K inhibitors may be potential therapeutic implications for TNBC patients with BRCA mutations or HR deficiency. However, further molecular investigations are needed to identify the efficacy of LY294002 in DNA repair mechanisms including HR, non-homologous end-joining (NHEJ), microhomology-mediated end-joining (MMEJ), alternative NHEJ (alt-NHEJ), synthetic lethality, "BRCAness", and the Fanconi anemia signaling network (39).…”

Section: Discussionmentioning

confidence: 99%

The Interaction of PI3K Inhibition with Homologous Recombination Repair in Triple Negative Breast Cancer Cells

Eskiler

2019

J Pharm Pharm Sci

View full text Add to dashboard Cite

Purpose: Aberrant activation of the phosphatidylinositol 3'-kinase (PI3K)-Akt signaling pathway is observed in many types of human cancer including triple negative breast cancer (TNBC). Additionally, dysregulation in the homologous recombination (HR)-dependent DNA-repair is associated with TNBC phenotype due to BRCA1/2 mutations or HR deficiency. Therefore, the hypothesis of this study was to evaluate the association of PI3K inhibition with HR pathway in TNBC in terms of BRCA1 mutation status. Methods: To examine the potential therapeutic effect of LY294002, an inhibitor of PI3K, on TNBC cell lines with known BRCA1 status, WST-1, annexin V, cell cycle analysis and AO/EB staining were performed. Additionally, RT-PCR and immunofluorescence analysis was used to explore the interaction between the inhibition of PI3K and HR functionality. Results: The findings showed that LY294002 could significantly inhibited the proliferation of TNBC cells. Furthermore, the suppression of PI3K resulted in HR impairment by BRCA1 and RAD51 downregulation and apoptotic cell death by the induction of DNA damage and BAX overexpression. Therefore, LY294002 was more effective in BRCA1-deficient TNBC cells. Conclusions: Consequently, targeted therapies based on the interaction of PI3K inhibition with BRCA1 mutations or HR deficiency in TNBC may be a promising strategy for the treatment of patients with TNBC.

show abstract

“…Despite the importance of this discovery, the majority of breast cancers occur in women who lack germline mutations; increasingly, epigenetic alterations are being implicated in breast cancer initiation and progression. Study of the potential link between breast cancer and epigenetics is just beginning [20].…”

Section: Epigenetic Changes Associated With Breast Cancermentioning

confidence: 99%

“…The epigenetic inactivation of BRCA1/2: Homologous recombination deficiency can result from epigenetic processes, leading to the silencing of homologous recombination genes, including BRCA1/2 [21]. Early studies have shown significant efficacy for PARP inhibitors in patients with BRCA1/2 mutations [20]. It is not clear whether the biological effects of harboring somatic BRCA1/2 mutations are identical to their germline counterparts (BRCAness phenomenon) [21].…”

Section: Epigenetic Changes Associated With Breast Cancermentioning

confidence: 99%

Environmental Exposures during Puberty: Window of Breast Cancer Risk and Epigenetic Damage

Natarajan

Aljaber

et al. 2020

IJERPH

View full text Add to dashboard Cite

During puberty, a woman’s breasts are vulnerable to environmental damage (“window of vulnerability”). Early exposure to environmental carcinogens, endocrine disruptors, and unhealthy foods (refined sugar, processed fats, food additives) are hypothesized to promote molecular damage that increases breast cancer risk. However, prospective human studies are difficult to perform and effective interventions to prevent these early exposures are lacking. It is difficult to prevent environmental exposures during puberty. Specifically, young women are repeatedly exposed to media messaging that promotes unhealthy foods. Young women living in disadvantaged neighborhoods experience additional challenges including a lack of access to healthy food and exposure to contaminated air, water, and soil. The purpose of this review is to gather information on potential exposures during puberty. In future directions, this information will be used to help elementary/middle-school girls to identify and quantitate environmental exposures and develop cost-effective strategies to reduce exposures.

show abstract

PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Cited by 56 publications

References 116 publications

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

The Interaction of PI3K Inhibition with Homologous Recombination Repair in Triple Negative Breast Cancer Cells

Environmental Exposures during Puberty: Window of Breast Cancer Risk and Epigenetic Damage

Contact Info

Product

Resources

About