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Abstract B16: Activation of NRF2 and adaptive resistance to chemotherapy
Nuclear factor-erythroid-2-related factor 2 (NRF2), a member of the cap ‘n’ collar family of bZIP transcription factors, confers protection against oxidative and electrophilic stress. NRF2 is of great interest in cancer research, due to its role in response to chemotherapy, including the class of drugs targeting thymidylate synthase (TYMS). It has long been known that inhibition of TYMS leads to depletion of thymidine levels and the onset of programmed cell death, deriving from the enzyme's function as the sole de novo source of thymidine for DNA replication and repair. Exposing cells to TYMS inhibitors such as fluorop...
Source: Cancer Research - January 30, 2017 Category: Cancer & Oncology Authors: Sarah A. Clinton, Karen W. Barbour, Franklin G. Berger Tags: New Therapeutic Approaches to Colorectal Cancer Source Type: research

Abstract PR03: P53 inhibits the expression of the pyrimidine catabolic gene Dihydropyrimidine dehydrogenase (DPYD)
Fluorouracil (5-FU) a widely used chemotherapeutic drug whose unpredictable pharmacokinetics is controlled by the pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD), that has recently also been shown to be a gatekeeper of the epithelial-to-mesenchymal transition (EMT) in breast cancer. Relatively little is known about the transcriptional control of DPYD and here we show for the first time an interaction between p53 and DPYD (involved in catabolism of pyrimidines as well as 5-FU) where p53 represses both the base-line expression of DPYD and that following 5-FU administration in vitro and in vivo. This mechanis...
Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Gokare, P. R., Finnberg, N., Dai, J., El-Deiry, W. Tags: Cancer Metabolic Pathways: Oral Presentations - Proffered Abstracts Source Type: research

Abstract C26: Development of selective MELK kinase inhibitors for breast cancer treatment
In this study, we are reporting development of a series of selective MELK kinase inhibitors. Synthesized compounds exert excellent selectivity and potency in MELK inhibition in a low nanomolar range. Therapeutic effect of the compounds was investigated in the panel of breast cancer cell lines with different genetic background as well as with different MELK kinase levels; it was shown that for some cell lines compounds induced cell death with nanomolar ED50 values. The compound's effect on the proliferation and in the colony formation assay was also investigated. Taken altogether, the presented data supports our rationale o...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Kowalczyk, P., Węgrzyn, P., Prokopowicz, M., Knop, M., Mazur, K., Dziedzic, K., Gluza, K., Knop, M., Dziedzic, K., Mazur, K., Radzimierski, A., Commandeur, C., Zawadzka, M., Bloudoff, K., Vaillancourt, F., Larsen, N., Wang, J., Reynolds, D., Ito, D Tags: Cancer Stem Cells: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B68: Screening for the compound that induces cell death selectively in {beta}-catenin mutant tumor cells
The Wnt signal transduction pathway plays a central role for the cell proliferation, differentiation and apoptosis. β-catenin, a component of Wnt pathway, translocates to nucleus and forms an active complex with TCF4, leading to activate cell growth signaling, and this activity is tightly regulated by the "destruction complex" consisting of Axin, APC, GSK3β and CK1α. However, when β-catenin is actively mutated, this cell growth signaling would be hyperactive and drive oncogenesis. As β-catenin is mutated in up to 10% of all sporadic colon carcinomas resulting from point mutations or in-frame delet...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Shikata, Y., Kiga, M., Tashiro, E., Imoto, M. Tags: Drug Screening: Poster 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 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 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 A61: Targeting the c-Met signaling pathway by humanized anti-HGF antibody inhibits irinotecan resistance in colorectal cancer.
Conclusion: We identified HGF as an important determinant of irinotecan resistance and metastasis of CRC. Anti-HGF monoclonal antibody treatment confirmed the importance of this growth factor for chemo-resistance in CRC. These results present new options toward the early diagnosis of chemoresistance and suggest novel combinations of chemotherapy and anti-HGF agents to prevent or significantly delay the onset of therapy resistance. These observations open new avenues toward the diagnosis of chemoresistant tumors and therapies targeting HGF overexpressing cancers. Citation Format: Jong Kyu Woo, Yeong-Su Jang, Ju-Hee Kang, Hw...
Source: Cancer Research - January 12, 2015 Category: Cancer & Oncology Authors: Woo, J. K., Jang, Y.-S., Kang, J.-H., Kim, H. M., Oh, S.-H. Tags: Translational and Therapeutic Potential of the Tumor Microenvironment Source Type: research