LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

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DDIS-31. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

Neuro-Oncology ◽

10.1093/neuonc/noz175.282 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi70-vi70

Author(s):

Jiaojiao Deng ◽

Sophia Chernikova ◽

Wolf-Nicolas Fischer ◽

Kerry Koller ◽

Bernd Jandeleit ◽

...

Keyword(s):

Breast Cancer ◽

Chemotherapeutic Agent ◽

Treatment Options ◽

Leptomeningeal Metastasis ◽

Current Treatment ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Tnbc Cell Line

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106photons/sec, mice were dosed i.v. (8 mg/kg once a week for nine weeks) or i.p. (4 or 8 mg/kg twice a week for nine weeks). Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals in the i.p. group. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

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Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

10.21203/rs.3.rs-117384/v1 ◽

2020 ◽

Author(s):

Chengheng Liao ◽

Cherise Ryan Glodowski ◽

Cheng Fan ◽

Juan Liu ◽

Kevin Raynard Mott ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Lines ◽

Metabolic Profiling ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Arginine Biosynthesis ◽

Metabolic Dysregulation

Abstract Metabolic dysregulation is one of the distinctive features in breast cancer. However, examining the metabolic features in various subtypes of breast cancer in their relationship to gene expression features in a physiologically relevant setting remains understudied. By performing metabolic profiling on triple-negative breast cancer (TNBC) and ER+ breast cancers from patients, TNBC patient-derived xenografts (PDXs), and representative breast cancer cell lines grown as tumors in vivo, we identify two distinctive groups defined by metabolites; a “Nucleotide-Enriched” group that shows high levels of pyrimidine pathway metabolites and biosynthetic enzymes, and a “Arginine Biosynthesis-Enriched” group that shows high levels of arginine biosynthesis intermediates. We reveal different metabolic enrichment profiles between cell lines grown in vitro versus in vivo, where cell lines grown in vivo more faithfually recapitulate patient tumors metabolic profiles. In addition, with integrated metabolic and gene expression profiling we identify a subset of genes that strongly correlates with the Nucleotide-Enriched metabolic profile, and which strongly predicts patient prognosis. As a proof-of-principle, when we target Nucleotide-Enriched metabolic dysregulation with a pyrimidine biosynthesis inhibitor (Brequinar), and/or a glutaminase inhibitor (CB-839), we observe therapeutic efficacy and decreased tumor growth in representative TNBC cell lines and an in vivo PDX upon combinatorial drug treatment. Our study reveals new therapeutic opportunities in breast cancer guided by a genomic biomarker, which could prove highly impactful for rapidly proliferating breast cancers specifically.

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Alpelisib Inhibits PIK3CA-Mutant Breast Cancer Growth Through AKT-Dependent Bim Induction and Mcl-1 Degradation

10.21203/rs.3.rs-38718/v1 ◽

2020 ◽

Author(s):

Xiao Tan ◽

Zhongqiang Zhang ◽

Ping Liu ◽

Hongliang Yao ◽

jingshan tong

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Acquired Resistance ◽

Proteasome Inhibitors ◽

Resistant Cell ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Akt Inhibitor

Abstract Background: PIK3CA mutations are common genomic alterations in estrogen receptor (ER)-positive breast cancers, currently, the development of selective PI3Kα (phosphatidylinositol 3-kinase α) inhibitors is ongoing. The mechanisms contributing to the anticancer activity of alpelisib in PIK3CA-mutant breast cancer cells and the mechanism of acquired resistance to alpelisib remain elusive. Methods: Drug-sensitive cell lines were exposed to alpelisib to establish alpelisib-resistant cell lines. Western blotting was used to assess changes in protein expression. Apoptosis was evaluated by ﬂow cytometry. In vivo with mouse xenograft models and in vitro colony formation and MTS and assay were carried out to determine the growth inhibitory effects of the tested drugs. Protein half-lives were examined and proteasome inhibitors were used to estimate protein degradation. Gene knockdown was carried out using shRNA or siRNA. Results: In the present study, we report the potent induction of apoptosis by alpelisib in PIK3CA-mutant breast cancer cell lines. AKT phosphorylation suppression, AKT/Foxo3a-dependent Bim induction, and AKT/GSK-3β-dependent Mcl-1 degradation were observed. Apoptosis induced by alpelisib was attenuated by Mcl-1 (4A) overexpression or Bim suppression. Furthermore, alpelisib could not modulate Mcl-1 or Bim levels in cell lines that were resistant to alpelisib. AKT inhibitor and alpelisib combination restored the sensitivity of alpelisib-resistant cells to growth inhibition and apoptosis in vitro and in vivo. Conclusions: Therefore, modulation of Mcl-1 degradation and AKT-dependent Bim induction are crucial for mediating the resistance and sensitivity of PIK3CA-mutant breast tumor cells to alpelisib, thus making it a productive strategy for overcoming acquired resistance to alpelisib.

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New generation breast cancer cell lines developed from patient-derived xenografts

Breast Cancer Research ◽

10.1186/s13058-020-01300-y ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Jessica Finlay-Schultz ◽

Britta M. Jacobsen ◽

Duncan Riley ◽

Kiran V. Paul ◽

Scott Turner ◽

...

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Luminal A ◽

New Generation

Abstract Background Breast cancer is a highly heterogeneous disease characterized by multiple histologic and molecular subtypes. While a myriad of breast cancer cell lines have been developed over the past 60 years, estrogen receptor alpha (ER)+ disease and some mutations associated with this subtype remain underrepresented. Here we describe six breast cancer cell lines derived from patient-derived xenografts (PDX) and their general characteristics. Methods Established breast cancer PDX were processed into cell suspensions and placed into standard 2D cell culture; six emerged into long-term passageable cell lines. Cell lines were assessed for protein expression of common luminal, basal, and mesenchymal markers, growth assessed in response to estrogens and endocrine therapies, and RNA-seq and oncogenomics testing performed to compare relative transcript levels and identify putative oncogenic drivers. Results Three cell lines express ER and two are also progesterone receptor (PR) positive; PAM50 subtyping identified one line as luminal A. One of the ER+PR+ lines harbors a D538G mutation in the gene for ER (ESR1), providing a natural model that contains this endocrine-resistant genotype. The third ER+PR−/low cell line has mucinous features, a rare histologic type of breast cancer. The three other lines are ER− and represent two basal-like and a mixed ductal/lobular breast cancer. The cell lines show varied responses to tamoxifen and fulvestrant, and three were demonstrated to regrow tumors in vivo. RNA sequencing confirms all cell lines are human and epithelial. Targeted oncogenomics testing confirmed the noted ESR1 mutation in addition to other mutations (i.e., PIK3CA, BRCA2, CCND1, NF1, TP53, MYC) and amplifications (i.e., FGFR1, FGFR3) frequently found in breast cancers. Conclusions These new generation breast cancer cell lines add to the existing repository of breast cancer models, increase the number of ER+ lines, and provide a resource that can be genetically modified for studying several important clinical breast cancer features.

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The Effect of Leucine Restriction on Akt/mTOR Signaling in Breast Cancer Cell Lines In Vitro and In Vivo

Nutrition and Cancer ◽

10.1080/01635581.2011.523504 ◽

2011 ◽

Vol 63 (2) ◽

pp. 264-271 ◽

Cited By ~ 10

Author(s):

Gopal Singh ◽

Argun Akcakanat ◽

Chandeshwar Sharma ◽

David Luyimbazi ◽

Katherine Naff ◽

...

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Lines ◽

Mtor Signaling ◽

Breast Cancer Cell Lines

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Computational, Pharmacological and Toxicological Approach of Repurposed Lamotrigine Schiff Base Derivatives for Reduction of Hormone-Positive Breast Tumor

10.21203/rs.3.rs-1026443/v1 ◽

2021 ◽

Author(s):

Saima Najm ◽

Humaira Naureen ◽

Fareeha Anwar ◽

Muhammad Mubbashir Khan ◽

Rabia Ali

Keyword(s):

Breast Cancer ◽

Schiff Base ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Mcf 7

Abstract Background and objectives: Breast cancer presents high morbidity among women with various treatment challenges. This study aims to evaluate the repurposed lamotrigine schiff base metal (LTG-SB-M) coordinates against in-vitro MCF-7 breast cancer cell lines and in-vivo N-methylnitrosourea (NMU)-persuaded toxicity of rats’ mammary gland. Method: In-silico computational analysis and in vitro cytotoxic studies on MCF-7 breast cancer cell lines was executed to build up the assumptions. In-vivo NMU-induced anticancer potential was assessed in forty Wistar rats; assigned into five groups of 8 rats each. Group I served as normal control and received normal saline, Group II received NMU (50 mg/kg), Group III received tamoxifen, whereas; Group IV and V received LTG-SB-M derivative (LAC3, LBC3) at dose of 100 mg/kg body weight, for 15 consecutive days. Intraperitoneal injection of NMU (single dose) was given at the age of 5, 9 and 13 weeks to the rats with the three week interval. For all experimental animals; biochemical markers were assessed. DNA strand breakage alongside the hormonal profile of estrogen and progesterone was also estimated. Results: All tested compounds present significant activity against MCF-7 cell lines in vitro and NMU-induced mammary tumor in vivo. The in vivo results of tested compounds present a significant decrease in weight of organ; with reinstated renal and hepatic enzymes. Histological analysis revealed strong countenance of proteins, estrogen, and progesterone in NMU-treated rats. Conclusion: These results suggest that LTG-SB-M complex can be used as better anticancer agent against breast cancer.

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