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Abstract C25: Targeting cancer stem cells using ALDH-dependent 5-nitrofuran pro-drugs
We hypothesise that cancer stem cells with high aldehyde dehydrogenase (ALDHhigh) activity present a new therapeutic target and will be selectively sensitive to 5-nitrofuran pro-drugs.Cancers are heterogeneous and contain subpopulations of ALDHhigh cells with tumour initiating potential. ALDH enzymes metabolize toxic aldehydes, and are highly expressed in somatic and cancer stem cells (CSCs), although their function in stem cells is not fully understood. In a small molecule screen coupled with target ID, we recently discovered that clinically active 5-nitrofurans (5-NFNs) are substrates of ALDH2 (Zhou et al., 2012). 5-NFNs...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Crispin, R., Spockeli, N., Brunton, V., Carragher, N., Gourley, C., Houston, D., Unciti-Broceta, A., Patton, E. E. Tags: Cancer Stem Cells: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B50: Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation
ConclusionOur results implicate the actin cytoskeleton in the induction of YAP/TAZ-dependent resistance to vemurafenib, and inhibition of actin remodeling might be a promising synthetic lethal strategy to suppress resistance in BRAF inhibitor therapies.Citation Format: Min Hwan Kim, Joon Kim. Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B50.
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Kim, M. H., Kim, J. Tags: Drug Resistance and Modifiers: Poster Presentations - Proffered Abstracts Source Type: research

Abstract C171: Human anti-Nucleolin recombinant immunoagents as new potential tools for melanoma treatment
Immunotherapy and immune-based anti-cancer molecules represent a valid strategy to fight cancer. However, the choice of tumor-specific surface molecules for the selective targeting of cancer cells still represents a critical step in the study design for the development of new therapeutic approaches. Notably, the development of phage-display technology for the selection of fully human single chain antibody fragments (scFvs) and complete antibodies directed toward tumor-associated antigens has represented a significant advancement for immunotherapy.Nucleolin (NCL) is one of the most abundant non-ribosomal proteins in the nuc...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Braddom, A., Richmond, T., Sheetz, T., Reese, E., Tessari, A., Tober, K., Burd, C. E., De Lorenzo, C., Martin, E. W., Coppola, V., Tweedle, M. F., Oberyszyn, T., Croce, C. M., Palmieri, D. Tags: Therapeutic Agents: Biological: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A05: Identification of RASA1 as a novel melanoma tumor suppressor gene
In this study, we addressed functional roles of RASA1 in melanoma tumorigenesis. Ectopic expression of wild-type RASA1 in human melanoma cell lines SKMEL28 and WM983C (with BRAF V600E) decreased, while RASA1 Y472H mutant enhanced soft agar colony formation, tumor growth, and Ras activity. The RASA1 L481F mutant lost its tumor suppressive activity. The siRNA- or shRNA-mediated knockdown of RASA1 promoted soft agar colony formation, tumor growth, and RAS activation in human melanoma cell lines IGR1 and KML1 (with BRAFV600E). Mechanistically, RASA1 required RasGAP activity to suppress colony formation and showed higher activi...
Source: Cancer Research - July 16, 2015 Category: Cancer & Oncology Authors: Sung, H., Kanchi, K. L., Messina, J., Lee, J.-H., Ding, L., Wilson, R. K., Weber, J. S., Kim, M. Tags: Advances in Melanoma Biology Source Type: research

Abstract A26: Protein phosphatase 4 (PP4) as a potential therapeutic target gene for BRAF wild type melanoma
Protein phosphatase 4 (PP4) participates in cell cycle progression and regulation of centrosome maturation. Gene expression of PP4 is elevated in cancerous tissues of various origins and its overexpression in pancreatic cancer is of prognostic importance. Microarray analysis from primary and metastatic melanoma tissues (N=89) showed that PP4 mRNA expression was up-regulated in metastatic melanoma as compared to primary melanoma of any thickness (relative expression: 1.12 ±0.14, p intestine> skin and subcutaneous tissue. Human melanoma cell lines also demonstrate PP4 gene expression with variable levels. We hypothesized th...
Source: Cancer Research - July 16, 2015 Category: Cancer & Oncology Authors: Essner, R., Gong, K. W., Kaufman, D., Chen, H., Ginther, C., Dering, J., Euw, E. v., Chmielowski, B., Finn, R., Slamon, D. Tags: Advances in Melanoma Biology Source Type: research

Abstract B32: Responses of direct in vivo melanoma xenograft cells to targeted therapeutics
The purpose of this study was to investigate the mechanism of resistance of a melanoma cell line generated from a direct in vivo xenograft (DIVX) model. Although BRAF and MKK1/2 inhibitors have produced positive clinical responses in melanoma patients with BRAF-V600 mutations, between 25-50% of patients show intrinsic resistance. Deciphering the mechanisms of intrinsic resistance will be critical for developing future treatment strategies. MB947P cells were established from a direct in vivo xenograft of a resected metastatic melanoma and exhibited innate resistance to apoptosis induced by MKK1/2 inhibitor (AZD6244/selumeti...
Source: Cancer Research - July 16, 2015 Category: Cancer & Oncology Authors: Basken, J., Fujita, M., Ahn, N. Tags: Principles of Response and Resistance to Therapy 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 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 A62: TGF-{beta} regulates CXCL1 expression in mammary carcinoma associated fibroblasts through novel Smad2/3- and HGF/c-Met-dependent mechanisms.
CXCL1 is a chemokine secreted by macrophages, neutrophils, epithelial cells and fibroblasts, and plays a role in inflammation and wound healing. Enhanced expression of CXCL1 in tumor epithelium is associated with cell invasion, angiogenesis in melanoma, bladder, ovarian and breast cancer. However, little is known about CXCL1 expression in tumor stroma. Through analysis of gene expression data, our studies reveal that high RNA levels of CXCL1 in breast tumor stroma is associated with increased rate of recurrence and shorter relapse-free survival. We noticed decreased secretion levels of TGF-β and increased secretion of CXC...
Source: Cancer Research - January 12, 2015 Category: Cancer & Oncology Authors: Zou, A., Lambert, D., Yeh, H., Fang, W. B., Cheng, N. Tags: Translational and Therapeutic Potential of the Tumor Microenvironment Source Type: research