Translating the role of PARP inhibitors in triple-negative breast cancer

Beniey, Michèle; Haque, Takrima; Hassan, Saima

doi:10.18632/oncoscience.474

Cited by 32 publications

(22 citation statements)

References 8 publications

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“…The inhibition of PARP1 or PARP2—the most abundant PARP enzymes—leads to the accumulation of irreparable breaks of both single-stranded and double-stranded DNA and cytotoxic PARP-DNA complexes [ 180 , 185 , 186 , 187 ]. As a result, TNBC tumors carrying BRCA mutations and/or other similar DNA repair pathway mutations are sensitive to PARP inhibitor therapy [ 179 , 188 , 189 ]. The OlympiAD trial (NCT02000622) is a phase 3 randomized study to examine the efficacy of olaparib, a PARP1 inhibitor, for patients with metastatic, germline BRCA mutated, HER2-negative breast cancer, and who had received no more than two previous lines of chemotherapy or treatments of physician’s choice [ 190 ].…”

Section: Newly Fda-approved Targeted Therapies For Tnbcmentioning

confidence: 99%

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies

Gupta

Collier

Lee

et al. 2020

Cancers

210

160

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Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERβ), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.

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Section: Newly Fda-approved Targeted Therapies For Tnbcmentioning

confidence: 99%

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies

Gupta

Collier

Lee

et al. 2020

Cancers

210

160

View full text Add to dashboard Cite

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“…Luminal A and B are both sensitive to hormone therapy, although luminal A patients have often low-grade tumors and good prognosis while luminal B is recognized as having a higher proliferation rate. HER2-enriched and basal-like types are widely considered to have poorer survival and tumors with higher grade [ 15 ]. In relation to therapeutic conduct, positive estrogen subtypes benefit from treatment by Tamoxifen and HER2-enriched patients can benefit from monoclonal antibody therapy.…”

Section: Introductionmentioning

confidence: 99%

Novel lncRNAs Co-Expression Networks Identifies LINC00504 with Oncogenic Role in Luminal A Breast Cancer Cells

Mathias

Groeneveld

Trefflich

et al. 2021

IJMS

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Long non-coding RNAs (lncRNAs) are functional transcripts with more than 200 nucleotides. These molecules exhibit great regulatory capacity and may act at different levels of gene expression regulation. Despite this regulatory versatility, the biology of these molecules is still poorly understood. Computational approaches are being increasingly used to elucidate biological mechanisms in which these lncRNAs may be involved. Co-expression networks can serve as great allies in elucidating the possible regulatory contexts in which these molecules are involved. Herein, we propose the use of the pipeline deposited in the RTN package to build lncRNAs co-expression networks using TCGA breast cancer (BC) cohort data. Worldwide, BC is the most common cancer in women and has great molecular heterogeneity. We identified an enriched co-expression network for the validation of relevant cell processes in the context of BC, including LINC00504. This lncRNA has increased expression in luminal subtype A samples, and is associated with prognosis in basal-like subtype. Silencing this lncRNA in luminal A cell lines resulted in decreased cell viability and colony formation. These results highlight the relevance of the proposed method for the identification of lncRNAs in specific biological contexts.

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“…Literature [5,[10][11][12] showed that EGFR is a promising oncological target in both human [13][14][15] and mouse [16][17][18] TNBCs. Moreover, EGFR stimulates cell proliferation signaling via phosphorylating phosphatidylinositol 3-kinase (PI3K) [19,20] and enhances the DNA replication and repair through BRCA1 [21][22][23][24]. Furthermore, monoclonal antibodies (mAbs) that target EGFR and folate receptor have been developed to treat TNBC, but the efficacy is limited as a single agent in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Anti‐EGFR antibody‐drug conjugate for triple‐negative breast cancer therapy

Guan³

et al. 2020

Engineering in Life Sciences

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Triple‐negative breast cancers (TNBCs) are highly aggressive, metastatic and recurrent. Cytotoxic chemotherapies with limited clinical benefits and severe side effects are the standard therapeutic strategies, but, to date, there is no efficacious targeted therapy. Literature and our data showed that epidermal growth factor receptor (EGFR) is overexpressed on TNBC cell surface and is a promising oncological target. The objective of this study was to develop an antibody‐drug conjugate (ADC) to target EGFR+ TNBC and deliver high‐potency drug. First, we constructed an ADC by conjugating anti‐EGFR monoclonal antibody with mertansine which inhibits microtubule assembly via linker Sulfo‐SMCC. Second, we confirmed the TNBC‐targeting specificity of anti‐EGFR ADC by evaluating its surface binding and internalization in MDA‐MB‐468 cells and targeting to TNBC xenograft in subcutaneous mouse mode. The live‐cell and live‐animal imaging with confocal laser scanning microscopy and In Vivo Imaging System (IVIS) confirmed the TNBC‐targeting. Finally, both in vitro toxicity assay and in vivo anti‐cancer efficacy study in TNBC xenograft models showed that the constructed ADC significantly inhibited TNBC growth, and the pharmacokinetics study indicated its high circulation stability. This study indicated that the anti‐EGFR ADC has a great potential to against TNBC.

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Translating the role of PARP inhibitors in triple-negative breast cancer

Cited by 32 publications

References 8 publications

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies

Novel lncRNAs Co-Expression Networks Identifies LINC00504 with Oncogenic Role in Luminal A Breast Cancer Cells

Anti‐EGFR antibody‐drug conjugate for triple‐negative breast cancer therapy

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