bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-02-03: FASN inhibition as a potential treatment for therapy of endocrine resistant breast cancer
Authors: Gruslova A , Sareddy GR , Vadlamudi RK , Viswanadhapalli S , Brenner A 
Published: May 2019

Abstract
INTRODUCTION: Fatty acid synthase (FASN) is a key enzyme in tumor cell biology controlling endogenous lipid biosynthesis. It is overexpressed in a biologically aggressive subset of tumors, including breast carcinoma. We previously reported prolonged stabilization of disease with TVB-2640 in patients with advanced metastatic breast cancer, including some endocrine resistant ER+ tumors. Using in vitro and in vivo models, we assessed the role of FASN inhibition by TVB-3166 (preclinical version of TVB-2640) for treatment of endocrine resistant breast cancer. METHODS: Breast tumor cells were incubated with TVB-3166 (200nM), imaged and analyzed by automated Live-Cell analysis system (IncuCyte). For tumor growth inhibition, cells (2X106)were subcutaneously injected into SCID mice implanted with estrogen pellets. Once tumors were measurable, mice were divided into treatment groups: tamoxifen (4mg/kg), TVB-3166 (60mg/kg) and the combination. Patient tumor explants were incubated for 72h on gelatin sponges in culture medium in the absence or presence of 200nM TVB-3166. Tissue were fixed in 10% formalin and processed into paraffin blocks. Sections were stained with H&E, ERα and Ki67. RESULTS: The effectiveness of FASN inhibition on the growth of tumor cells has been confirmed in a number of breast cancer cell lines such as MCF7, ZR75, MDA-MB-231 and others. TVB-3166 leads to a marked inhibition of growth in tamoxifen resistant (TamR) cells, which 15% greater than in the parent line. IHC and Western blot showed FASN inhibition leads to significantly reduction of ERα levels. Immunofluorescent confocal microscopy showed inhibition of FASN by TVB-3166 alters subcellular localization of ERα. TVB-3166 was able to significantly inhibit tamoxifen resistant breast tumor growth in mice (p&lt;0.05). Additionally, TVB-3166 treatment of primary tumor explants decreased their proliferation (Ki67) compared to untreated controls (21% vs 38%, p&lt;0.01). CONCLUSION: Our preclinical data provide evidence that FASN inhibition by TVB-3166 presents a promising therapeutic strategy for treating of endocrine resistant breast cancer. RNA sequencing of tumor explants is being performed to evaluate FASN inhibition impact on canonical and non-canonical ERα signaling pathways.
Citation Format: Gruslova A, Sareddy GR, Vadlamudi RK, Viswanadhapalli S, Brenner A. FASN inhibition as a potential treatment for therapy of endocrine resistant breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-03.
Abstract P2-02-09: Not presented
Authors: An J , Yang J , Lee W-H , Kim JB , Kim J-k , Kim H , Paek SH , Lee JW , Woo J , Kwon H , Lim W , Paik NS , Kim Y-K , Moon B-I 
Published: May 2019

Abstract
This abstract was not presented at the conference.
Citation Format: An J, Yang J, Lee W-H, Kim JB, Kim J-k, Kim H, Paek SH, Lee JW, Woo J, Kwon H, Lim W, Paik NS, Kim Y-K, Moon B-I. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-09.
Abstract P2-02-11: Combinational treatment of biguanides and fatty acid β-oxidation inhibitor in triple-negative breast cancers
Authors: Park JH , Jung KH , Vithayathil S , Jia D , Kaipparettu BA 
Published: May 2019

Abstract
Among breast cancers (BCs), the driver pathways and therapeutic targets are still poorly understood for triple negative (TN) BCs. Advances in cancer metabolism research over the last decade have enhanced our understanding on metabolic reprogramming in cancer therapy. We have previously shown that metabolic reprogramming to fatty acid β-oxidation (FAO) is a major energy pathway in metastatic TNBC. Moreover, we reported that FAO regulates c-Src, one of the frequently upregulated oncopathways in TNBC via autophosphorylation of Src at Y419. Since FAO inhibitors alone cannot effectively control the tumor progression in TNBC, suitable combination therapies with other metabolic targets are necessary. Recently increasing evidences show that anti-diabetic biguanides have attractive anticancer effect in various cancer types including BC. However, its significance as an anticancer drug is not well established due to parallel metabolic pathways that support tumor growth.
Phenformin, a biguanide derivative similar to metformin, has a greater potency than metformin. Like metformin, phenformin also inhibits mitochondrial electron transport chain (ETC) through complex I inhibition. In addition, biguanides lead to the activation of AMPK, which plays a key role in insulin signaling and energy sensing. Importantly, AMPK is an upstream regulator of FAO pathway because it can phosphorylate ACC to activate FAO. Considering the dependency of TNBC to FAO, we evaluated the therapeutic significance of the combination of biguanides(ETC inhibitors) and FAO inhibitors in TNBC progression and metastasis. We hypothesize that blocking both 'arms' of the pathway can provide more pronounced and durable responses in TNBCs. Our different in vitro and in vivo studies using TNBC cell line and PDX models suggest that the combination of both inhibitors can provide better therapeutic significance in metastatic TNBCs. This is a rationale and cost-effective metabolic approach to manage the currently non-targetable metastatic TNBCs. Further investigation into the clinical effectiveness of this combination may provide better treatment opportunities for TNBC patients.
Citation Format: Park JH, Jung KH, Vithayathil S, Jia D, Kaipparettu BA. Combinational treatment of biguanides and fatty acid β-oxidation inhibitor in triple-negative breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-11.
Abstract P2-02-13: Computational metabolism modeling predicts risk of relapse in breast cancer patients
Authors: Zamora P , Trilla-Fuertes L , Gámez-Pozo A , Prado-Vázquez G , Zapater-Moros A , Ferrer-Gómez M , Díaz- Almirón M , López Vacas R , Espinosa E , Fresno Vara JA 
Published: May 2019

Abstract
Introduction
Breast cancer is one of the most prevalent cancers in the world. In previous works we observed differences in glucose metabolism between breast cancer subtypes, suggesting that metabolism plays an important role in this disease. Flux Balance Analysis (FBA) is widely used to study metabolic networks, allowing predicting growth rates or the rate of production of a given metabolite.
Material and methods
Proteomics data from 96 breast cancer tumors were obtained applying a high-throughput proteomics approach to routinely archive formalin-fixed, paraffin-embedded tumor tissue. Proteomics tumor data were analyzed using the human metabolic reconstruction Recon2 and FBA. The tumor growth rate for each tumor was calculated. In order to analyze fluxes from the different metabolic pathways, flux activities were calculated as the sum of the fluxes of each reaction in each pathway defined in the Recon2. Then, flux activities were used to build prognostic models.
Results and discussion
Using the results obtained from FBA in the proteomics dataset, flux activities were calculated for each pathway. Employing these flux activities, a prognostic signature was built. Flux activities of vitamin A, tetrahydrobiopterin metabolism and beta-alanine metabolism pathways split our population into a low and a high risk group (p=0.044).
Conclusion
Vitamine A, beta-alanine and tetrahydrobiopterin metabolism flux activities could be used to predict relapse risk. Flux activities is a method proposed in a previous work to study response against drugs that now also demonstrated its utility in summarizing FBA data and is associated with prognosis.
Citation Format: Zamora P, Trilla-Fuertes L, Gámez-Pozo A, Prado-Vázquez G, Zapater-Moros A, Ferrer-Gómez M, Díaz- Almirón M, López Vacas R, Espinosa E, Fresno Vara JA. Computational metabolism modeling predicts risk of relapse in breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-13.
Abstract P2-03-04: A novel druggable target upstream of Notch: MEK5/ERK5 signaling regulates Jagged-1 and Notch1 expression in triple negative breast cancer stem cells
Authors: Ucar DA , Matossian MD , Hoang-Barnes VT , Hossain FM , Gupta M , Burks HE , Wright TD , Cavanaugh J , Flaherty P , Burow ME , Miele L 
Published: May 2019

Abstract
Triple negative breast cancer (TNBC) is a molecularly heterogeneous, clinically aggressive disease group that is highly prevalent among African-Americans and younger patients. Standard chemo/radio therapy often produces clinical responses, but recurrence and metastasis are unfortunately common. Metastatic disease is generally incurable. Chemo/radiotherapy has been shown to induce EMT and enrich a chemo-resistant cancer stem-like cell (CSC) population in TNBC. CSCs are thought to drive disease recurrence. Notch signaling is critical for maintenance of TNBC CSC. Expression of Notch1 and its ligand Jagged1 are correlated with poor prognosis. Efforts to pharmacologically target Notch with Gamma Secretase Inhibitors (GSIs) have been impaired by the systemic toxicity of the GSIs, and by the fact that Notch1 also plays a key role in anti-tumor adaptive immunity. Therapeutic agents that indirectly and selectively target Notch signaling in breast cancer cells would be a potentially attractive strategy. However, no such agents have been identified to date. We have found that the MAPK5-ERK5 kinase pathway, which contains at least two druggable targets, functions as a master regulator of Notch signaling in TNBC cells. ERK5 knockout TNBC cells have dramatically decreased expression of Notch receptors, ligands and transcriptional targets. In vivo, these cells form barely detectable tumors that do not metastasize and express lower levels of Notch1 and its ligand Jagged1. Using in silico screening, we identified a class of compounds that selectively target MAP2K5 (MEK5) and decrease the phosphorylation of MAPK7 (ERK5). We selected compound SC-181 for further study. Consistent with ERK5KO cells, pharmacological suppression of ERK5 phosphorylation with SC-181 decreased Notch1 and Jagged1 mRNAs and proteins. SC-181 reversed EMT and reduced the CD44hi/CD24lo CSC population in TNBC cells, but had no effect on T-cell proliferation. SC-181 decreased the number and size of mammospheres in a concentration-dependent manner. Overexpression of the Notch1 intracellular domain (N1IC) in ERK5KO cells rescues their phenotype, dramatically increasing the CSC fraction and promoting EMT. Our results suggest that targeting the MEK5-ERK5 pathway is a promising new strategy to selectively modulate Notch signaling in TNBC CSC without compromising tumor immunity.
Citation Format: Ucar DA, Matossian MD, Hoang-Barnes VT, Hossain FM, Gupta M, Burks HE, Wright TD, Cavanaugh J, Flaherty P, Burow ME, Miele L. A novel druggable target upstream of Notch: MEK5/ERK5 signaling regulates Jagged-1 and Notch1 expression in triple negative breast cancer stem cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-03-04.
Abstract P2-03-08: Preclinical evaluation of the PI3Kα/δ inhibitor, copanlisib in HER2+ breast cancer: A proof of concept study
Authors: De P , Carlson JH , Dey N , Leyland-Jones B 
Published: May 2019

Abstract
Purpose: The PI3K-AKT-mTORC1/C2 pathway is frequently activated in HER2+ breast cancer and upregulation of this pathway is a key mechanism of trastuzumab resistance. However, attempts to indirectly target this pathway by using the allosteric mTOR inhibitor everolimus have had limited clinical success. Here, we present the results of a preclinical study of the PI3K α/δ (dominant) inhibitor copanlisib alone and in combination with T-DM1, in HER2 amplified cell lines including a model with acquired resistance to trastuzumab.
Method: Anti-proliferative, apoptotic, cell cycle, and intracellular signaling effects of copanlisib alone and in combination with T-DM1 were evaluated in a panel of HER2 amplified (ER+ or ER-), and HER2 amplified/PIK3CA mutated cell lines, as well as trastuzumab-resistant breast cancer cell lines.
Results: 1) Copanlisib inhibited PI3K, mTOR and their downstream signaling molecules in HER2 amplified/PIK3CA WT or PIK3CA mutated as well as in trastuzumab-resistant cell lines, 2) interestingly, copanlisib also inhibited RAS-MAPK signaling in the earlier time points, 3) copanlisib caused a strong differential growth inhibition in HER2 amplified BC cell lines by 3D-ON-TOP clonogenic assay and real-time monitoring in an IncuCyte Zoom. Inhibition was greater when copanlisib was combined with T-DM1, 4) administration of copanlisib induced cell cycle G0/G1 arrest and resulted in increased apoptosis in a dose-dependent manner, 5) unlike everolimus copanlisib blocked HIF1α accumulation in hypoxic condition and this blocking effect was reversed by prior treatment with the proteasome inhibitor, carfilzomib and 6) copanlisib also attenuated HER2 amplified cell migration, an important phenotypic feature for metastasis.
Conclusions: Copanlisib is highly effective (blocks proliferation, induces apoptosis, and inhibits PI3K and its downstream signaling targets) in HER2 amplified breast cancer cell lines including trastuzumab-resistant and PIK3CA mutated cell lines. The addition of copanlisib to T-DM1 might represent an improved treatment strategy for patients with refractory metastatic HER2+ breast cancer.
Citation Format: De P, Carlson JH, Dey N, Leyland-Jones B. Preclinical evaluation of the PI3Kα/δ inhibitor, copanlisib in HER2+ breast cancer: A proof of concept study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-03-08.
Abstract P2-03-10: Not presented
Authors: Mallinger A , Dalenc F , Poirot M , Silvente-Poirot S 
Published: May 2019

Abstract
This abstract was not presented at the conference.
Citation Format: Mallinger A, Dalenc F, Poirot M, Silvente-Poirot S. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-03-10.
Abstract P2-05-04: The WNT pathway gene, LBH, is critically required for breast carcinogenesis by promoting tumor initiation and survival
Authors: Garikapati K , Chen P , Ashad-Bishop K , Briegel K 
Published: May 2019

Abstract
Background: Cancer stem cells (CSCs) are a small subset of tumor cells with stem cell properties that drive tumor initiation, treatment resistance, and metastasis, thereby leading to rapid disease relapse. However, no cancer stem cell specific treatments are currently available in the clinic. Thus, there is a need to identify novel cancer stem cell-specific molecular targets.
LBH (Limb-Bud and Heart), is a poorly characterized transcription co-factor in the WNT pathway, a signaling network that is key to normal stem cell control and cancer stem cell transformation. We previously identified LBH as a basal mammary stem cell specific marker critically required for stem cell self-renewal and maintenance during normal mammary gland development. Significantly, LBH is also abnormally over-expressed specifically in worst prognosis basal-like breast cancers, a treatment-resistant breast cancer subtype that is enriched in cancer stem cells. Moreover, high inter-tumor LBH expression levels correlate with reduced metastasis-free patient survival and increased chemo-resistance. However, the role of LBH in breast carcinogenesis is not known.
Results: To identify the potential role of LBH in breast carcinogenesis, we abrogated LBH expression in breast cancer cell lines with high CSC populations (HCC1395, MDA-MB-231) using shRNA and CRISPR/Cas technologies. Conversely, we stably introduced LBH into more differentiated breast cancer cell lines with low CSC populations (MCF7, BT549). We found that LBH depletion significantly reduced, while LBH overexpression increased in vitro tumor sphere formation and clonogenic ability, suggesting LBH promotes a CSC phenotype. Modulation of LBH expression did not change proliferation rates, indicating the CSC promoting effects of LBH were not due to increased cell proliferation. However, LBH reduced apoptosis rates and increased tumor cell survival. Importantly, loss of LBH markedly decreased in vivo tumor initiation and metastatic potential of triple negative breast cancer cells, which are important functions of CSC. The underlying mechanisms will be discussed.
Conclusions: Collectively our results suggest that LBH is required for breast CSC self-renewal and maintenance. Thus, LBH inhibition may have value for future CSC-targeted anti-cancer therapy.
Citation Format: Garikapati K, Chen P, Ashad-Bishop K, Briegel K. The WNT pathway gene, LBH, is critically required for breast carcinogenesis by promoting tumor initiation and survival [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-05-04.
Abstract P2-05-08: An assessment of the potential role of intracellular Ca2+ store regulators in breast cancer cells
Authors: Bong AH , Roberts-Thomson SJ , Milevskiy MJ , Monteith GR 
Published: May 2019

Abstract
Background: Calcium (Ca2+) regulates many crucial cellular processes including cell survival, proliferation and death. Endoplasmic reticulum (ER) Ca2+ store levels are critical in the death-inducing effects of some anti-cancer agents. Modulators of ER Ca2+ signalling, such as neuronal calcium sensor-1 (NCS-1) may therefore represent new therapeutic opportunities to enhance the effect of some anti-cancer agents. NCS-1 is associated with poorer survival in breast cancer patients. However, the expression of NCS-1 in specific breast cancer molecular subtypes and its potential role in intracellular Ca2+ signalling in breast cancer cells has not been fully explored.
Aim: To assess expression of NCS-1 in breast cancer molecular subtypes and assess the effect of silencing NCS-1 on intracellular Ca2+ homeostasis and on sensitivity to doxorubicin treatment in MDA-MB-231 breast cancer cells.
Methods: NCS-1 levels were assessed in breast cancer molecular subtypes based on PAM50 subtyping using the TCGA public breast cancer database. Intracellular Ca2+ changes as a consequence of siRNA-mediated silencing of NCS-1 were evaluated using a Fluorescence Imaging Plate Reader (FLIPR) in MDA-MB-231 cells expressing the genetically-encoded Ca2+ indicator GCaMP6m. The effect of NCS-1 silencing on MDA-MB-231 cells treated with doxorubicin (0.03 and 1 μM, 24 h) was evaluated by cell nuclear enumeration (Hoechst 33342 staining) and the percentage of dead cells (propidium iodide staining). Images were acquired using an automated epifluorescence microscope (ImageXpress Micro).
Results: Levels of NCS-1 were higher in the basal molecular subtype compared to other molecular subtypes. NCS-1 silencing promoted cell death induced by 1 μM doxorubicin. NCS-1 silencing had no major effect on cytosolic free Ca2+ levels as a result of either IP3-mediated Ca2+ store release with the purinergic receptor activator ATP or the protease activated receptor activator trypsin. However, NCS-1 silencing suppressed constitutive Ca2+ influx in MDA-MB-231 breast cancer cells. The expression of NCS-1 was positively correlated with the Ca2+ entry channel Orai1 in breast cancers on the TCGA database. Orai1 is associated with increased migration and invasiveness in some breast cancers.
Discussion: These studies suggest that elevation in NCS-1 is a feature of breast cancers of the basal molecular subtype and that NCS-1 is a regulator of the cytotoxic effects of doxorubicin. Further studies are required to determine if this effect is related to changes in constitutive Ca2+ influx that may be mediated via Orai1.
Citation Format: Bong AH, Roberts-Thomson SJ, Milevskiy MJ, Monteith GR. An assessment of the potential role of intracellular Ca2+ store regulators in breast cancer cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-05-08.
Abstract P2-05-09: Withdrawn
Authors: Connelly L , Tsang Mui Chung S 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Citation Format: Connelly L, Tsang Mui Chung S. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-05-09.
Abstract P2-06-10: Withdrawn
Authors: Sood AK , Mukhopadhyay A , Wang J 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Citation Format: Sood AK, Mukhopadhyay A, Wang J. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-10.
Abstract P2-06-13: A novel small molecule JMX0293 inhibits the growth of triple-negative breast cancer via suppressing STAT3 and inducing apoptosis
Authors: Dong J , Xu J , Kim H , Zhou J , Shen Q 
Published: May 2019

Abstract
Approximately 30-40% of breast cancer cases are estrogen receptor negative (ENBC), including the most aggressive triple-negative subtype (TNBC) which spread early and recur frequently with a poor prognosis. ENBCs do not respond to selective ER modulators such as tamoxifen or aromatase inhibitors, and therefore, there is an urgent need of non-ER-based therapies for ENBC and TNBC. We recently developed a novel small molecule JMX0293 based on our lead drug candidate HJC0152. Both HJC0152 and JMX0293 were able to suppress cell proliferation of both ER+ (MCF-7, T-47D) and ER- (MDA-MB-231 and MDA-MB-468) breast cancer cell lines in a dose-dependent manner, with significantly lower toxicity against normal mammary epithelial cells (MCF-10A) in vitro. JMX0293 exhibited moderately improved anti-proliferative effects against highly invasive TNBC cell line MDA-MB-231 and ER+ breast cancer cell line MCF-7 with IC50 values of 0.92 and 2.24 μM, respectively. JMX0293 was also demonstrated to induce apoptosis of MDA-MB-231 cells dose-dependently. Mechanistically, JMX0293 inhibited STAT3 phosphorylation at Tyr705 residue, leading to the down-regulation of Bcl-2 and upregulation of apoptotic proteins including Bax, cleaved-caspase 3 and cleaved-PARP. In addition, JMX0293 reduced the ratio of Bcl-2 to Bax. In vivo, JMX0293 treatment for 2 weeks at a dose of 10 mg/kg significantly suppressed the growth of TNBC xenograft tumors in mice with minimal impact on general health and body weight. Our results suggest that JMX0293 induces TNBC cell apoptosis and contributes to its anti-proliferative effect through inhibiting transcription factor STAT3, and JMX0293 could be further characterized and optimized for developing a promising therapeutic for treating ENBC and TNBC. This work was supported by grant (R01 CA231150) from the NIH/NCI.
Citation Format: Dong J, Xu J, Kim H, Zhou J, Shen Q. A novel small molecule JMX0293 inhibits the growth of triple-negative breast cancer via suppressing STAT3 and inducing apoptosis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-13.