Advances in the use of PARP inhibitor therapy for breast cancer

McCann, Kelly; Hurvitz, Sara A.

doi:10.7573/dic.212540

Cited by 110 publications

(89 citation statements)

References 76 publications

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“…The PARP inhibitors olaparib and talazoparib were recently FDA approved for use as monotherapy in patients with metastatic germline BRCA1/2 -mutated breast cancer based on significant improvement in progression free survival compared to chemotherapy (42). However, the utility of PARP inhibitors in BLBC is limited as clinical trials did not show an improvement in overall survival, and partial and complete responses were infrequent.…”

Section: Discussionmentioning

confidence: 99%

Cyclin E1 protein is stabilized inBRCA1mutated breast cancers leading to synergy between CDK2 and PARP inhibitors

Aziz

Portman

et al. 2020

Preprint

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26Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly 27 to targeted therapies and chemotherapies. In order to define therapeutically 28 targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. 29 In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, 30 and define therapeutic subsets. We tested the same hypothesis for BLBC. 31Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between 32 BRCA1 loss and high cyclin E1 expression, in contrast to HGSOC in which CCNE1 33 amplification drives increased cyclin E1 gene expression. Instead, BRCA1 loss 34 stabilized cyclin E1 during the cell cycle. Using siRNA we showed that BRCA1 loss 35 leads to stabilization of cyclin E1 by reducing phospho-cyclin E1-T62, and 36 conversely the overexpression of BRCA1 increased phospho-T62. Mutation of cyclin 37 E1-T62 to alanine increased cyclin E1 stability. We showed that tumors with high 38 cyclin E1/BRCA1 mutation in the BLBC cohort had decreased phospho-T62, 39 supporting this hypothesis. 40Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in 41 BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these 42 cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized 43 with PARP inhibitors to reduce cell viability in BRCA1 mutated cell lines. Treatment 44 of BLBC patient-derived xenograft models with combination PARP and CDK2 45 inhibition led to tumor regression and increased survival. We conclude that BRCA1 46 status and high cyclin E1 have potential as predictive biomarkers to dictate the 47 therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC. 48 3 instability in cancer cells, and is frequently elevated in BLBC (9). Perplexingly, in 65 high grade serous ovarian cancer (HGSOC) cyclin E1 amplification and BRCA1/2 66 mutation are mutually exclusive, presumably because both aberrations drive 67 genomic instability and together they precipitate lethal genomic damage (10-12). 68We recently described two subsets of HGSOC, one where cyclin E1 gene 69 amplification and BRCA1 mutation were mutually exclusive, and another where high 70 cyclin E1 protein expression was due to post-transcriptional deregulation rather than 71 4 gene amplification, and was often concurrent with BRCA1/2 mutation (12). Cyclin E1 72 protein stability is regulated by a multi-step process of specific phosphorylation and 73 ubiquitination, leading to its cyclic expression and turnover (13). Key regulators in the 74 turnover of cyclin E1, such as the ubiquitin ligase component FBXW7 and the 75 deubiquitinase USP28, are frequently dysregulated in cancer (13-15) leading to 76 altered stability of the cyclin E1 protein. 77In this study, we examined whether BRCA1 loss and cyclin E1 gain occurred 78 concurrently or independently in breast cancer. We also explored the mechanisms 79 underpinning high cyclin E1 expression in BRCA1 mutated breast cancer including 80 gene amplification and p...

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Section: Discussionmentioning

confidence: 99%

Cyclin E1 protein is stabilized inBRCA1mutated breast cancers leading to synergy between CDK2 and PARP inhibitors

Aziz

Portman

et al. 2020

Preprint

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“…Similar beneficial outcomes have been observed in ovarian cancer mouse models [93][94][95]. PARP inhibitors have additionally been used in multiple clinical trials (reviewed in [96]). PARP inhibitors have been found to induce IFN-α anti-tumour responses and promote tumour infiltrating cells which was enhanced by the checkpoint inhibitors [94].…”

Section: Emerging Combination Therapies For Cancermentioning

confidence: 57%

Natural Compounds with Potential to Modulate Cancer Therapies and Self-Reactive Immune Cells

Moody

Wilson

Jaworowski

et al. 2020

Cancers

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Cancer-related deaths are approaching 10 million each year. Survival statistics for some cancers, such as ovarian cancer, have remained unchanged for decades, with women diagnosed at stage III or IV having over 80% chance of a lethal cancer recurrence after standard first-line treatment (reductive surgery and chemotherapy). New treatments and adjunct therapies are needed. In ovarian cancer, as in other cancers, the immune response, particularly cytotoxic (CD8+) T cells are correlated with a decreased risk of recurrence. As well as completely new antigen targets resulting from DNA mutations (neo-antigens), these T cells recognize cancer-associated overexpressed, re-expressed or modified self-proteins. However, there is concern that activation of self-reactive responses may also promote off-target pathology. This review considers the complex interplay between cancer-reactive and self-reactive immune cells and discusses the potential uses for various leading immunomodulatory compounds, derived from plant-based sources, as a cancer therapy option or to modulate potential autoimmune pathology. Along with reviewing well-studied compounds such as curcumin (from turmeric), epigallocatechin gallate (EGCG, from green tea) and resveratrol (from grapes and certain berries), it is proposed that compounds from novel sources, for example, native Australian plants, will provide a useful source for the fine modulation of cancer immunity in patients.

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“…TNBC patients harboring germline mutations in BRCA were recently shown to benefit from improved sensitivity to the FDA-approved poly-ADP-ribose polymerase (PARP) inhibitor Olaparib, by rendering DNA repair mechanisms dysfunctional during therapy. 59,60 Furthermore, biomarkers predictive of response to epidermal growth factor receptor (EGFR) targeted therapy are under investigation for the treatment of TNBC. EGFR methylation is being evaluated as a biomarker indicative of resistance to anti-EGFR monoclonal antibody therapeutics for TNBC patients.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated STAT3 (Tyr705) as a biomarker of response to pimozide treatment in triple-negative breast cancer

Dees

Pontiggia

Jasmin

et al. 2020

Cancer Biology & Therapy

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Triple-negative breast cancer (TNBC) displays an aggressive clinical course, heightened metastatic potential, and is linked to poor survival rates. Through its lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), this subtype remains unresponsive to traditional targeted therapies. Undesirable and sometimes life-threatening side effects associated with current chemotherapeutic agents warrant the development of more targeted treatment options. Targeting signal transducer and activator of transcription 3 (STAT3), a transcription factor implicated in breast cancer (BCa) progression, has proven to be an efficient approach to halt cancer growth in vitro and in vivo. Currently, there are no FDA-approved STAT3 inhibitors for TNBC. Although pimozide, a FDA-approved antipsychotic drug, has been attributed a role as a STAT3 inhibitor in several cancers, its role on this pathway remains unexplored in TNBC. As a "one size fits all" approach cannot be applied to TNBC therapies due to the heterogeneous nature of this aggressive cancer, we hypothesized that STAT3 could be a novel biomarker of response to guide pimozide therapy. Using human cell lines representative of four TNBC subtypes (basal-like 1, basal-like 2, mesenchymal-like, mesenchymal stem-like), our current report demonstrates that pimozide significantly reduced their invasion and migration, an effect that was predicted by STAT3 phosphorylation on tyrosine residue 705 (Tyr705). Mechanistically, phosphorylated STAT3 (Tyr705) inhibition resulting from pimozide treatment caused a downregulation of downstream transcriptional targets such as matrix metalloproteinase-9 (MMP-9) and vimentin, both implicated in invasion and migration. The identification of biomarkers of response to TNBC treatments is an active area of research in the field of precision medicine and our results propose phosphorylated STAT3 (Tyr705) as a novel biomarker to guide pimozide treatment as an inhibitor of invasion and migration.

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Advances in the use of PARP inhibitor therapy for breast cancer

Cited by 110 publications

References 76 publications

Cyclin E1 protein is stabilized inBRCA1mutated breast cancers leading to synergy between CDK2 and PARP inhibitors

Cyclin E1 protein is stabilized inBRCA1mutated breast cancers leading to synergy between CDK2 and PARP inhibitors

Natural Compounds with Potential to Modulate Cancer Therapies and Self-Reactive Immune Cells

Phosphorylated STAT3 (Tyr705) as a biomarker of response to pimozide treatment in triple-negative breast cancer

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