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Total 151 results found since Jan 2013.
Abstract A112: Eradication of cancer stem-like cells in PDAC
Conclusion: These data indicate that p21 maintains chemotherapy induced CSLCs quiescence and drug resistance such that targeting p21 in combination with cytotoxic therapies is beneficial in eradicating both basal and Gem transformed CSLCs.Note: This abstract was not presented at the conference.Citation Format: Thiruvengadam Arumugam, Vijaya Ramachandran, Craig Logsdon. Eradication of cancer stem-like cells in PDAC. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A112.
Source: Cancer Research - June 30, 2015 Category: Cancer & Oncology Authors: Arumugam, T., Ramachandran, V., Logsdon, C. Tags: New Therapies Source Type: research
Abstract B114: c-Rel is a critical mediator of NF-{kappa}B dependent TRAIL resistance of pancreatic cancer cells
In conclusion, we were able to delineate a novel c-Rel, NFATc2 and COX-2 dependent anti-apoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies.Citation Format: Claudia Geismann, Frauke Grohmann, Robert Häsler, Philip Rosenstiel, Günter Schneider, Sebastian Zeissig, Stefan Schreiber, Heiner Schäfer, Alexander Arlt. c-Rel is a critical mediator of NF-κB dependent TRAIL resistance of pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Phila...
Source: Cancer Research - June 30, 2015 Category: Cancer & Oncology Authors: Geismann, C., Grohmann, F., Hasler, R., Rosenstiel, P., Schneider, G., Zeissig, S., Schreiber, S., Schafer, H., Arlt, A. Tags: Other Topics Source Type: research
Abstract A49: Carcinoma-associated fibroblasts in the tumor microenvironment affect growth, invasiveness, and drug response of human pancreatic cancer cells
Pancreatic cancer is one of the most aggressive malignancies, with a 5-year overall survival of less than 5%. Tumor drug resistance to conventional chemotherapy, such as gemcitabine, is often a significant contributor to poor overall survival. One of the common mechanisms of gemcitabine resistance is activation of cell signaling via increased phosphorylation of Mitogen-Activated kinase (MAP) kinases, leading to increased tumor survival and reduced sensitivity to chemotherapeutic agents. A growing body of evidence suggests that the CXCL12/CXCR4 signal transduction axis in the tumor microenvironment is an important mediator ...
Source: Cancer Research - June 30, 2015 Category: Cancer & Oncology Authors: Sanani, A. A., Patel, B., Duarte, A., Bansal, N., Bhagat, T., Rattigan, Y., Maitra, A., Verma, A., Banerjee, D. Tags: Inflammation/Stroma Source Type: research
Abstract A71: Post-transcriptional regulation of the proto-oncogene PIM1 by the mRNA stability factor HuR: implications for pancreatic cancer therapeutic response and cell survival
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by its insidious development and resistance to conventional and targeted therapies. As a result of selective pressures imposed by cytotoxic agents and the tumor microenvironment, PDA cells orchestrate a potent and elusive chemoresistant mechanism. Recently, the serine-threonine kinase PIM1 has emerged as a key regulator of PDA cell survival under cancer-associated stress (e.g: cytotoxic DNA-damaging agents, hypoxia). However, the molecular mechanism behind PIM1 overexpression in PDAs is unknown. Here, we demonstrate that cis-acting AU-rich ele...
Source: Cancer Research - June 30, 2015 Category: Cancer & Oncology Authors: Blanco, F. F., Meisner-Kober, N., Londin, E., Rigoutsos, I., Winter, J., Yeo, C., Brody, J. Tags: Heterogeneity in Tumor Progression Source Type: research
Abstract PR06: Impact of RAL signal transduction on genetic program and growth control in KRAS- and BRAF-mutated colorectal cells and prognostic potential of pathway-responsive genes in cancer patients
In conclusion, the RALA pathway impinges on the transcription of a distinct subset of target genes in colorectal cancer cells independent of the KRAS and BRAF mutational status. RALA pathway-responsive genes were unaffected by RAF/MAPK and PI3K signaling. These findings support the concept of a pathway-sensitive modular organization of the transcriptome. In view of the correlation of RAL pathway-responsive genes and patient survival, further investigations of the diagnostic impact in prospective trials and exploitation of therapeutic approaches are warranted.This abstract is also presented as Poster B32.Citation Format: Ba...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Gyorffy, B., Stelniec-Klotz, I., Sigler, C., Szijarto, A., Qian, Y., Schafer, R. Tags: RAS Biology - Systems Approaches: Oral Presentations - Proffered Abstracts Source Type: research
Abstract A07: Novel effectors of K-Ras-mediated and KSR1 dependent colon tumorigenesis
Conclusion: These results demonstrate the importance of AMPK and its downstream signaling effectors PGC1β and ERRα in maintaining colon tumor cell survival driven by oncogenic Ras and demonstrate the value of using KSR1 as a reference standard to detect genes essential to colon tumor survival.Citation Format: Binita Das, Kurt Fisher, Hyunseok Kim, Deanna J. Volle, Deandra R. Smith, Robert S. Livergood, John MacMillan, Michael White, Robert Lewis. Novel effectors of K-Ras-mediated and KSR1 dependent colon tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to T...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Das, B., Fisher, K., Kim, H., Volle, D. J., Smith, D. R., Livergood, R. S., MacMillan, J., White, M., Lewis, R. Tags: RAS Effectors - Basic Biology: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA15: Membrane targeting of Ras
Ras proteins are targeted to membranes by virtue of post-translational modifications of their C-terminal hypervariable regions (HVRs). Because Ras proteins signal only when associated with cellular membranes, the Ras trafficking pathway is considered an attractive area for anti-cancer drug discovery. The three mammalian Ras genes, hras, nras and kras, give rise to four Ras proteins because the transcript of the kras locus is alternatively spliced to encode K-Ras4A and K-Ras4B. The kras locus is most often mutated in human cancer and when mutated gives rise to oncogenic forms of both K-Ras4A and K-Ras4B. The four Ras protei...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Tsai, F., Fehernbacher, N., Sung, P., Court, H., Philips, M. R. Tags: RAS Regulation: Oral Presentations - Invited Abstracts Source Type: research
Abstract B36: Targeting oncogenic RAS with small molecule PKC-delta inhibitors
We report here that PKC-delta inhibition is cytotoxic in melanomas with primary NRAS mutations. Novel small-molecule inhibitors of PKC-delta were designed as chimeric hybrids of two naturally-occurring PKC-delta inhibitors, staurosporine and rottlerin. The specific hypothesis we have interrogated and validated is the concept that combining two domains of two naturally-occurring PKC-delta inhibitors into a chimeric or hybrid structure retains biochemical and biological activity, and improves selectivity for the specific PKC-delta isozyme. We have devised a potentially general synthetic protocol to make these chimeric specie...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Takashima, A., Chen, Z., English, B., Williams, R. M., Faller, D. V. Tags: RAS Targeting: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A40: Targeting TBK1 promotes apoptosis in MEK-inhibitor resistant mutant NRAS melanoma cells
Melanoma is a devastating form of skin cancer. Fifteen to twenty percent of melanoma patients have an activating mutation in the GTPase, NRAS. Despite advances in the targeted inhibitor treatment for mutant BRAF melanoma patients, the options for mutant NRAS patients remain poor. TANK-binding kinase 1 (TBK1) is an atypical IB kinase family member that acts downstream of the RAS effector RalGEF but the role of TBK1 in melanoma is not known. We found that NRAS overexpression in wild-type NRAS melanoma cells increased TBK1 phosphorylation. In a panel of NRAS mutant melanoma cells, we characterized sensitivity to MEK inhibitio...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Vu, H. L., Aplin, A. E. Tags: RAS Effectors - Therapeutics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B47: Therapeutic KRAS silencing in lung and colon cancer models
This study highlights the potential translational impact of therapeutic RNA interference, which may have broad applications in oncology, especially for traditional "undruggable" targets.Citation Format: Chad Pecot, Sherry Wu, Seth Bellister, Rajat Bhattacharya, Anshumaan Maharaj, Cristian Rodriguez-Aguayo, Vianey Gonzalez-Villasana, Rajesha Rupaimoole, Gabriel Lopez-Berestein, Lee M. Ellis, Anil Sood. Therapeutic KRAS silencing in lung and colon cancer models. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR;...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Pecot, C., Wu, S., Bellister, S., Bhattacharya, R., Maharaj, A., Rodriguez-Aguayo, C., Gonzalez-Villasana, V., Rupaimoole, R., Lopez-Berestein, G., Ellis, L. M., Sood, A. Tags: RAS Targeting: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B48: Regulation of mutant KRAS protein stability via SMURF2:UBCH5 complex mediated degradation of beta-TrCP1
Attempts to target mutant KRAS have been unsuccessful. Most of the current therapeutic approaches are indirect, mainly via inhibiting KRAS down-stream signaling, which have been marginally successful. Here we report the identification of Smad ubiquitination regulatory factor 2 (SMURF2), a HECT-type ubiquitin ligase (E3) as a critical regulator of mutant KRAS protein stability. We show that the loss of SMURF2 either by si-/sh-RNA mediated gene silencing or by overexpression of a catalytically inactive SMURF2 Cys716Ala (CA) mutant, can cause lysosome-mediated KRAS degradation; whereas, overexpression of wild type SMURF2 enha...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Shukla, S., Allam, U. S., Ahsan, A., Chen, G., Beer, D. G., Lawrence, T. S., Nyati, M. K., Ray, D. Tags: RAS Targeting: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B50: MEK inhibitors mount a two-pronged attack to kill estrogen receptor positive (ER+) breast cancer cells undergoing hormonal therapy: Attenuated autophagy and induction of apoptosis
In this study, we hypothesized that the requirement of MEK1/MAPK1/2 for pro-survival autophagy is due, in part, to its role in blocking the intracellular accumulation of dephosphorylated BimEL. To test this hypothesis, we modulated the expression of dephosphorylated BimEL with either a BimEL cDNA expression vector, siRNA targeting of BimEL, or MEK1 blockade with the small molecule inhibitor U0126 and determined the levels of the autophagic flux in ER+ breast cancer cells undergoing antiestrogen treatment. The determination of autophagic flux was made by comparing the levels of two proteins involved in autophagy -the LC3 /A...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Takhar, S., Manning, M., Eason, A., Dix, M., Periyasamy-Thandavan, S., Padi, R., Bieberich, E., Hill, W., Browning, D., Ganapathy, V., Thangaraju, M., Schoenlein, P. V. Tags: RAS Targeting: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B52: Therapeutic targeting of human KRAS in pancreatic cancer using a novel method of gene-silencing: U1 adaptors
Conclusion: We have demonstrated that the U1 Adaptor method of gene silencing can be successfully applied to target human KRAS both in vitro and in vivo. These results support the continued investigation of U1 Adaptor technology as a strategy for therapeutic targeting of RAS oncogenes.Citation Format: Ashley T. Tsang, Xin Yu, Rafal Goraczniak, Mark Brenneman, Samuel Gunderson, Darren R. Carpizo. Therapeutic targeting of human KRAS in pancreatic cancer using a novel method of gene-silencing: U1 adaptors. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; La...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Tsang, A. T., Yu, X., Goraczniak, R., Brenneman, M., Gunderson, S., Carpizo, D. R. Tags: RAS Targeting: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A55: KRAS gene amplification is a distinct molecular subgroup of gastroesophageal adenocarcinoma that may benefit from combined RAS/RAF/MEK/ERK and PI3K/PTEN/AKT/mTOR pathway inhibition
Conclusions: In this series, we observed KRAS wild type gene amp+ to be present in a subset (16%) of GEC patients at diagnosis, correlating with very high protein expression. KRAS amp+ was present after treatment with trastuzumab in HER2+ patients, and also after anti-MET therapy. These data suggest that KRAS amp+ represents a molecular subset with advanced disease at diagnosis. The observation of acquired KRAS amp+ after targeted therapies may be a resistance mechanism to anti-HER and anti-MET inhibitors. Inhibition using combined MEK/AKT pathway inhibitors, and proof-of-principle siRNA, warrants further investigation for...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Henderson, L., Xu, P., Rambo, B., Liao, W.-L., Hembrough, T., Catenacci, D. Tags: Role of WT RAS and RAS Isoforms: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A06: The role of the epidermal growth factor receptor (EGFR) in primary tumor cell escape and development of an intravasation-sustaining vasculature
In this study, we investigated the specific roles of EGFR in the early steps of tumor metastasis such as escape of cancer cells from the primary tumor and development of angiogenic vasculature, the two critical events required for tumor cell intravasation. For this purpose we employed the EGFR-overexpressing highly disseminating variant of human fibrosarcoma HT-1080 cell line, HT-hi/diss, in several independent in vivo CAM models. In the spontaneous metastasis model, siRNA silencing of EGFR significantly reduced the levels of HT-hi/diss intravasation, suggesting a role of EGFR overexpression in tumor cell escape and/or dev...
Source: Cancer Research - January 12, 2015 Category: Cancer & Oncology Authors: Minder, P., Deryugina, E. I., Quigley, J. P. Tags: Tumor-Associated Blood Vessels and Lymphatics Source Type: research
