Discovery of First-in-Class Dual PARP and EZH2 Inhibitors for Triple-Negative Breast Cancer with Wild-Type BRCA

2021 ◽  
Author(s):  
Cheng Wang ◽  
Lailiang Qu ◽  
Shang Li ◽  
Fucheng Yin ◽  
Limei Ji ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Wild Type

scholarly journals A Phase II Single Arm Pilot Study of the CHK1 Inhibitor Prexasertib ( LY2606368 ) in BRCA Wild‐Type , Advanced Triple‐Negative Breast Cancer

2020 ◽  
Vol 25 (12) ◽  
pp. 1013
Author(s):  
Margaret E. Gatti‐Mays ◽  
Fatima H. Karzai ◽  
Sanaz N. Soltani ◽  
Alexandra Zimmer ◽  
Jeffrey E. Green ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pilot Study ◽  
Phase Ii ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Wild Type ◽  
Chk1 Inhibitor

Combined treatment using the anti-p53 drug, APR-246 and eribulin: Synergistic growth inhibition in p53-mutated breast cancer cells.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14098-e14098 ◽  
Author(s):  
Naoise C Synnott ◽  
Alyson M. Murray ◽  
Norma O'Donovan ◽  
Michael J. Duffy ◽  
John Crown
Keyword(s):  
Breast Cancer ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
P53 Protein ◽  
Combined Treatment ◽  
Cytotoxic Agents ◽  
Breast Cancer Cell Lines ◽  
Wild Type

e14098 Background: TP53 is the most frequently mutated gene in triple-negative breast cancer, being present in approximately 80% of cases. APR-246 is a novel anticancer drug that acts by reactivating the mutant p53 protein, thereby converting it to a form with wild-type properties. Previously, we showed that APR-246 had antiproliferative, anti-migratory and pro-apoptotic activities in a panel of 23 breast cancer cell lines, including triple-negative (TN) cell lines. The aim of this study was to investigate if combined treatment with APR-246 and different cytotoxic agents resulted in enhanced growth inhibition. Methods: Cell viability was determined using the MTT assay. Combination index (CI) values were calculated using Calcusyn software, based on the Chou-Talalay method. Apoptosis was detected using Annexin V-FITC Apoptosis Detection Kit followed by FACs analysis. Results: Highly synergistic cell growth inhibition was found when APR-246 was combined with eribulin (Eisai Ltd.) in 6 different p53-mutated cell lines (mean CI values range from 0.38 to 0.77). In contrast, enhanced growth inhibition was not found using this combination in the 3 p53-WT cell lines investigated (mean CI values ranged from 1.13 to 2.9). Overall, p53 mutated cell lines had a significantly lower CI values than p53 wild-type cells (p = 0.008). In all the 4 p53-mutated cell lines investigated, a significant increase in apoptosis was also seen when APR-246 was combined with eribulin. This enhanced apoptosis appeared to result from increased mRNA expression of the pro-apoptotic factors PUMA and NOXA by the drug combination compared to either compound alone. In contrast to our findings with eribulin, combined treatment with APR-246 plus docetaxel, doxorubicin, cisplatin or carboplatin was cell line-dependent. Thus, docetaxel plus APR-246 was synergistic in 1/6 cell lines, while doxorubicin, cisplatin or carboplatin plus APR-246 was synergistic in 3/6 cell lines. Conclusions: Clinical trials investigating the combination of APR-246 and eribulin should be considered in patients with a p53 mutation such as triple-negative breast cancer.

scholarly journals Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA–Wild-Type Triple-Negative Breast Cancer

2015 ◽  
Vol 14 (4) ◽  
pp. 920-930 ◽  
Author(s):  
Olga Karginova ◽  
Marni B. Siegel ◽  
Amanda E.D. Van Swearingen ◽  
Allison M. Deal ◽  
Barbara Adamo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Murine Models ◽  
Wild Type

scholarly journals Comprehensive Genomic Profiling-Guided Niraparib Treatment of Triple-Negative Breast Cancer in a Patient With Extensive Brain Metastasis: Case Report and Literature Review

2021 ◽  
Vol 4 (1) ◽  
pp. 16-20
Author(s):  
Tai-Chung Lam
Keyword(s):  
Breast Cancer ◽  
Clinical Response ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Gene Mutations ◽  
Central Nervous System Tumor ◽  
Genomic Profiling ◽  
Wild Type ◽  
Comprehensive Genomic Profiling

ABSTRACT Homologous recombination deficiency (HRD) is a common phenotypic alteration that is highly druggable with poly (ADP-ribose) polymerase inhibitors (PARPi). Although BRCA1/2 gene mutations are among the commonest genomic aberrations associated with HRD, defects in other DNA damage repair (DDR) genes also may influence clinical response to PARPi. Here, we report the case of a 51-year-old Chinese woman with extensive symptomatic brain metastases from metastatic BRCA1/2 wild-type triple-negative breast cancer (TNBC). Comprehensive genomic profiling (CGP) of resected central nervous system tumor revealed mutations in TP53 and multiple DDR pathway genes, suggesting an HRD phenotype. The patient showed a rapid and remarkable response to single-agent niraparib, and her improved condition remained stable for > 8 weeks. To the best of our knowledge, this is the first report of the use of CGP for guiding targeted therapy with PARPi in patients with TNBC, for which options have been limited. CGP may have an increasingly impactful role to predict clinical response of PARPi in patients with BRCA1/2 wild-type TNBC.

scholarly journals Lung-Derived Selectins Enhance Metastatic Behavior of Triple Negative Breast Cancer Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1580
Author(s):  
Sami U. Khan ◽  
Ying Xia ◽  
David Goodale ◽  
Gabriella Schoettle ◽  
Alison L. Allan
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Ex Vivo ◽  
Metastatic Progression ◽  
Wild Type ◽  
Potential Therapeutic Target ◽  
Metastatic Behavior

The lung is one of the deadliest sites of breast cancer metastasis, particularly for triple negative breast cancer (TNBC). We have previously shown that the lung produces several soluble factors that may enhance the metastatic behavior of TNBC, including E-, L-, and P-selectin. In this paper, we hypothesize that lung-derived selectins promote TNBC metastatic behavior and may serve as a potential therapeutic target. Lungs were isolated from mice and used to generate lung-conditioned media (CM). Lung-derived selectins were immunodepleted and TNBC migration and proliferation were assessed in response to native or selectin-depleted lung-CM. A 3D ex vivo pulmonary metastasis assay (PuMA) was used to assess the metastatic progression of TNBC in the lungs of wild-type versus triple-selectin (ELP-/-) knockout mice. We observed that individual lung-derived selectins enhance in vitro migration (p ≤ 0.05), but not the proliferation of TNBC cells, and that ex vivo metastatic progression is reduced in the lungs of ELP-/- mice compared to wild-type mice (p ≤ 0.05). Treatment with the pan-selectin inhibitor bimosiamose reduced in vitro lung-specific TNBC migration and proliferation (p ≤ 0.05). Taken together, these results suggest that lung-derived selectins may present a potential therapeutic target against TNBC metastasis. Future studies are aimed at elucidating the pro-metastatic mechanisms of lung-derived selectins and developing a lung-directed therapeutic approach.

scholarly journals HIF and COX-2 expression in triple negative breast cancer cells with hypoxia and 5-fluorouracil

2020 ◽  
Vol 2 (1) ◽  
pp. 54-63
Author(s):  
Noriko Mori ◽  
◽  
Yelena Mironchik ◽  
Flonné Wildes ◽  
Sherry Y. Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Chemotherapeutic Agents ◽  
Wild Type ◽  
Protein Levels ◽  
Cox 2 ◽  
Cox 2 Inhibitors

Our purpose was to understand the effects of normoxia or hypoxia on 5-fluorouracil (5-FU) treatment in triple negative breast cancer (TNBC) cells, and characterize the molecular changes in hypoxia inducible factors (HIFs) and cyclooxygenase-2 (COX-2) following treatment. Cell viability and protein levels of HIFs and COX-2 were determined after wild type and HIF silenced MDA-MB-231 cells, and wild type SUM-149 cells, were treated with 5-FU under normoxia or hypoxia. 5-FU reduced cell viability to the same levels irrespective of normoxia or hypoxia. HIF silenced MDA-MB-231 cells showed comparable changes in cell viability, supporting observations that hypoxia and the HIF pathways did not significantly influence cell viability reduction by 5-FU. Our data suggest that HIF-2aaccumulation may predispose cancer cells to cell death under hypoxia. SUM-149 cells that have higher COX-2 and HIF-2afollowing 24 h of hypoxia, were more sensitive to 96 h of hypoxia compared to MDA-MB-231 cells, and were more sensitive to 5-FU than MDA-MB-231 cells. COX-2 levels changed with hypoxia and with 5-FU treatment but patterns were different between the two cell lines. At 96 h, COX-2 increased in both untreated and 5-FU treated cells under hypoxia in MDA-MB-231 cells. In SUM-149 cells, only treatment with 5-FU increased COX-2 at 96 h of hypoxia. Cells that survive hypoxia and 5-FU treatment may exhibit a more aggressive phenotype. Our results support understanding interactions between HIF and COX-2 with chemotherapeutic agents under normoxia and hypoxia, and investigating the use of COX-2 inhibitors in these settings.

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