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Source: Cancer Research
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Total 807 results found since Jan 2013.
Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer
In this study, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a key modifier of ribociclib sensitivity in estrogen receptor–positive MCF-7 breast cancer cells. Pharmacologic inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferation and increased apoptosis in a panel of ER-positive breast cancer cell lines. Ribociclib-resistant breast cancer cells selected by chr...
Source: Cancer Research - April 30, 2017 Category: Cancer & Oncology Authors: Valerie M. Jansen, Neil E. Bhola, Joshua A. Bauer, Luigi Formisano, Kyung–Min Lee, Katherine E. Hutchinson, Agnieszka K. Witkiewicz, Preston D. Moore, Monica Valeria Estrada, Violeta Sanchez, Paula G. Ericsson, Melinda E. Sanders, Paula R. Pohlmann, Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
SDHD Promoter Mutations Ablate GABP Transcription Factor Binding in Melanoma
SDHD encodes subunit D of the succinate dehydrogenase complex, an integral membrane protein. Across cancer types, recurrent SDHD promoter mutations were reported to occur exclusively in melanomas, at a frequency of 4% to 5%. These mutations are predicted to disrupt consensus ETS transcription factor–binding sites and are correlated with both reduced SDHD gene expression and poor prognosis. However, the consequence of these mutations on SDHD expression in melanoma is still unclear. Here, we found that expression of SDHD in melanoma correlated with the expression of multiple ETS transcription factors, particularly in SDHD ...
Source: Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Tongwu Zhang, Mai Xu, Matthew M. Makowski, Christine Lee, Michael Kovacs, Jun Fang, Esther Willems, Jeffrey M. Trent, Nicholas K. Hayward, Michiel Vermeulen, Kevin M. Brown Tags: Molecular and Cellular Pathobiology Source Type: research
Abstract B22: Increased phosphorylation of eIF4E induces resistance to treatment with mTOR inhibitors together with AR antagonists in advanced prostate cancer
The anti-androgen bicalutamide is widely used in the treatment of advanced prostate cancer (CaP) in many countries, but its effect on castration resistant CaP (CRPC) is limited. We previously showed that resistance to bicalutamide results from increased activation of the mechanistic target of rapamycin (mTOR); indicating a role for mTOR inhibitors in CaP treatment. Interestingly, a clinical trial testing combinations of the mTOR inhibitor RAD001 with bicalutamide were initially effective (PSA decline>50%) in 62.5% CRPC patients, but many initial responders later developed resistance. Here we investigate causes for their di...
Source: Cancer Research - March 13, 2017 Category: Cancer & Oncology Authors: Leandro S. D'Abronzo, Michael Crapuchettes, Ryan Beggs, Ruth Vinall, Clifford Tepper, Salma Siddiqui, Maria Mudryj, Frank Melgoza, Blythe Durbin-Johnson, Ralph deVere White, Paramita Ghosh Tags: Small Molecule Drugs Selectively Targeting Translation Specialized for the Cancer Cell Source Type: research
Abstract IA05: Regulation of Ras proteins and their effectors
Ras proteins regulate multiple phenotypes, including proliferation, contact inhibition, cell motility, metabolism, and genome integrity. This range of phenotypes may relate to the number of different effector pathways that Ras activates. The best validated of these is the Raf/MAPK pathway. Ras proteins can activate PI 3-kinase pathways directly, though this seems to vary between tissue types. Ras proteins bind and activate RalGDS, but this pathway is less well understood. In addition to these three major pathways, Ras proteins in their GTP state interact directly with several other potential effectors.Analysis of the contr...
Source: Cancer Research - March 13, 2017 Category: Cancer & Oncology Authors: Tina Yuan, Frank McCormick Tags: Oncogenic Signals Translate the Cancer Genome Source Type: research
Abstract P6-11-10: Preclinical efficacy of the novel PIM2 kinase inhibitor, JP11646 in triple negative breast cancer models
Conclusions: PIM2 upregulation in TNBC cell line resulted in more aggressive phenotype. JP11646, through novel mechanism of action resulting in degradation of PIM2, showed robust activity in TNBC cell lines both in vitro and in vivo. Further correlative studies in tumors harvested from in vivo experiments are ongoing. These results encourage further exploration of use of JP11646 as a targeted agent in treatment of TNBC.Citation Format: Mehta R, Kothai Guruswamy Sangameswaran D, Bezbatchenko K, Moore J, Gil M, Khoury T, Baldino C, Caserta J, Fetterly, Jr. G, Lee K, Adjei A, Opyrchal M. Preclinical efficacy of the novel PIM2...
Source: Cancer Research - February 28, 2017 Category: Cancer & Oncology Authors: R Mehta, D Kothai Guruswamy Sangameswaran, K Bezbatchenko, J Moore, M Gil, T Khoury, C Baldino, J Caserta, G Fetterly, Jr., K Lee, A Adjei, M Opyrchal Tags: Poster Session Abstracts Source Type: research
Abstract P3-04-12: Both spliced and unspliced XBP1 regulates breast cancer cell fate response to antiestrogen via NFkappaB signaling
Unfolded protein response (UPR), a stress-induced survival mechanism, may be used by cancer cells to avoid cell death. Antiestrogen therapy, widely applied in the treatment of estrogen receptor-positive (ER+) breast cancer, induces endoplasmic reticulum stress (EnR stress) that leads to activation of each of the three arms of the UPR. One critical prosurvival activator that is regulated by two arms of the UPR is the transcription factor X-box binding protein 1 (XBP1). XBP1 exists in two isoforms, the transcriptionally inactive unspliced XBP1(U) and the spliced, active XBP1(S). Overexpression of XBP1(S) confers estrogen ind...
Source: Cancer Research - February 28, 2017 Category: Cancer & Oncology Authors: R Clarke, R Hu, A Warri, L Jin, A Zwart, R Riggins, H-b Fang Tags: Poster Session Abstracts Source Type: research
Abstract P3-10-04: Disparities in human epidermal growth factor receptor 2 testing completion: A population-based retrospective cohort study, 2010-2013
Unfolded protein response (UPR), a stress-induced survival mechanism, may be used by cancer cells to avoid cell death. Antiestrogen therapy, widely applied in the treatment of estrogen receptor-positive (ER+) breast cancer, induces endoplasmic reticulum stress (EnR stress) that leads to activation of each of the three arms of the UPR. One critical prosurvival activator that is regulated by two arms of the UPR is the transcription factor X-box binding protein 1 (XBP1). XBP1 exists in two isoforms, the transcriptionally inactive unspliced XBP1(U) and the spliced, active XBP1(S). Overexpression of XBP1(S) confers estrogen ind...
Source: Cancer Research - February 13, 2017 Category: Cancer & Oncology Authors: MC Schroeder, JM Neuner, C Xia, A Thomas Tags: Poster Session Abstracts Source Type: research
Abstract P3-13-28: Lipofilling of the axilla to reduce secondary lymphedema after axillary lymph node dissection
Conclusions: PIM2 upregulation in TNBC cell line resulted in more aggressive phenotype. JP11646, through novel mechanism of action resulting in degradation of PIM2, showed robust activity in TNBC cell lines both in vitro and in vivo. Further correlative studies in tumors harvested from in vivo experiments are ongoing. These results encourage further exploration of use of JP11646 as a targeted agent in treatment of TNBC.Citation Format: Vandermeeren L, Belgrado J-P, Vankerckhove S, Valsamis J-B, Feipel V, Rooze M, Moraine J-J, Hertens D, Carly B, Liebens F. Lipofilling of the axilla to reduce secondary lymphedema after axil...
Source: Cancer Research - February 13, 2017 Category: Cancer & Oncology Authors: L Vandermeeren, J-P Belgrado, S Vankerckhove, J-B Valsamis, V Feipel, M Rooze, J-J Moraine, D Hertens, B Carly, F Liebens Tags: Poster Session Abstracts Source Type: research
Abstract P3-14-11: Risk factors affecting post-operative complication after immediate reconstruction with implant for operable breast cancer patients
Conclusion: Together, these data demonstrate that ONC201 can kill breast cancer cells by a novel mechanism involving inhibition of mitochondrial respiration.Citation Format: Park SJ, Choi JH, Lee MH, Jung S-Y, Lee ES. Risk factors affecting post-operative complication after immediate reconstruction with implant for operable breast cancer patients [abstract]. In: Proceedings of the Thirty-Ninth Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-14-11.
Source: Cancer Research - February 13, 2017 Category: Cancer & Oncology Authors: SJ Park, JH Choi, MH Lee, S-Y Jung, ES Lee Tags: Poster Session Abstracts Source Type: research
Abstract P2-06-06: A clinical model for assessment of the individual breast cancer risk
Conclusions: Our data demonstrate that estrogen and ERβ-specific agonists cause cell cycle arrest in ERβ positive TNBC. These effects are due to ERβ-mediated suppression of multiple genes involved in cell cycle progression including CDK1 and Cyclin B. Following knockdown of CDK1, estrogen or ERβ-specific agonist treatment displayed minimal impact on cell proliferation. Therefore, ERβ's effects on proliferation may primarily be mediated by blockade of CDK1 and Cyclin B. Regardless of ERβ, our data suggest that inhibition of CDK1 activity may have therapeutic benefit in a subset of TNBC patients, an area of study that ...
Source: Cancer Research - February 13, 2017 Category: Cancer & Oncology Authors: M Eriksson, K Czene, Y Pawitan, K Leifland, H Darabi, P Hall Tags: Poster Session Abstracts Source Type: research
Abstract P2-11-02: A longitudinal look at toxicity management within a platform trial: Lessons from the I-SPY 2 TRIAL
In this study, we performed siRNA-mediated knockdown to determine the importance of SHC1 and NCOA3 in the cell proliferation and death of TNBC. The effect of siSHC1 or siNCOA3 on the invasion and chemoresistance was also assayed in vitro. We found that although SHC1 and NCOA3 knockdown slightly inhibited the tumor growth of TNBC cells (MDA-MB-231, BT549, and HS578T), siSHC1 + paclitaxel and siNCOA3 + paclitaxel significantly decreased cell proliferation and increased caspase-3/7 activity in vitro, compared to drug alone. In vivo studies using MDA-MB-231 xenografts and a TNBC PDX model also showed that siSHC1 and siNCOA3 si...
Source: Cancer Research - February 13, 2017 Category: Cancer & Oncology Authors: M Paoloni, J Lyandres, MB Buxton, DA Berry, LJ Esserman, A DeMichele, D Yee Tags: Poster Session Abstracts Source Type: research
Abstract P1-08-03: Identification and characterization of a novel endoxifen substrate, PKC{beta}1, and its interaction with the estrogen receptor
Conclusions: Our findings demonstrated that endoxifen binds and inhibits PKCβ1 at relevant concentrations achieved in the endoxifen clinical trial studies. PKCβ1 interacts with cytoplasmic ERα and PKCβ1 knockdown inhibits cell proliferation and enhances ERα turnover. However, in PKCβ1 overexpressing cells, PKCβ1 may exhibit tumor suppressive effects. These data suggest a complex interaction between PKCβ1 and ERα and that endoxifen's effects on PKCβ1 may alter drug response of endocrine therapy. Further studies are ongoing to characterize the role of PKCβ1 and its role in ER biology and response to endoxifen.Cita...
Source: Cancer Research - February 13, 2017 Category: Cancer & Oncology Authors: C Guo, MJ Kuffel, RA Kudgus, Z Huang, AM Bode, J Cheng, VJ Suman, JM Reid, ES Bruinsma, M Subramaniam, MM Ames, JR Hawse, MP Goetz Tags: Poster Session Abstracts Source Type: research
Abstract P1-08-04: SOX9 is a critical regulator of triple-negative breast cancer cell growth and invasion
Background: SRY (Sex Determining Region Y)-related HMG-box (SOX) genes belong to a super-family of genes, which is characterized by a homologous sequence called the HMG-box residing on the Y-chromosome. There are 20 SOX genes present in humans and mice. We performed a siRNA screen of SOX transcription factors, and found that SOX9 was essential for breast cancer cell growth. The SOX9 protein recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins and has been shown to be required for development, differentiation and lineage commitment. Moreover, SOX9 is expressed in adenocarcinomas...
Source: Cancer Research - February 13, 2017 Category: Cancer & Oncology Authors: Y Ma, J Shepherd, A Mazumdar, D Zhao, L Bollu, J Hill, Y Zhang, P Brown Tags: Poster Session Abstracts Source Type: research
Abstract P2-11-09: A p53-based strategy for protecting normal breast tissue from chemotherapy-induced damage in breast conserving therapy
Conclusions:Together our data show that the MAPK pathway is hyperactivated in TNBC; inhibiting this pathway impairs tumor growth, but enhances GPNMB, which facilitates mammary tumor growth and metastasis in the setting of Mek-i. These data provide rationale for combined targeting of GPNMB and the MAPK pathway in TNBC.Citation Format: Long M, Huang Y, Liu R, Liu R, Su H. A p53-based strategy for protecting normal breast tissue from chemotherapy-induced damage in breast conserving therapy [abstract]. In: Proceedings of the Thirty-Ninth Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Phil...
Source: Cancer Research - February 13, 2017 Category: Cancer & Oncology Authors: M Long, Y Huang, R Liu, , H Su Tags: Poster Session Abstracts Source Type: research
Abstract P2-12-03: Prospective study of acupuncture in the rehabilitation of women undergoing surgical treatment of breast cancer in relation to the strength and quality of life
Conclusion: DAPK1 is a novel, promising target for the treatment of triple-negative p53-mutant breast cancer. Our studies demonstrate that DAPK1 inhibition sensitizes TNBCs to the cytotoxic effects of cisplatin or the PARP inhibitor. We are now conducting studies to determine whether DAPK1 inhibition will sensitize TNBC tumors and patient-derived TNBC xenografts to the effects of cisplatin and PARP inhibition. These studies suggest that the combination of DAPK1 inhibition with drugs that interfere with DNA repair will be useful for the treatment of the most aggressive form of breast cancer, triple-negative breast cancer.Fu...
Source: Cancer Research - February 13, 2017 Category: Cancer & Oncology Authors: PS Giron, CA Haddad, SL Rizzi, TL Pinheiro, RP Luz, AP Nazario, G Facina Tags: Poster Session Abstracts Source Type: research
