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Direct Pharmacological Inhibition of {beta}-Catenin by RNA Interference in Tumors of Diverse Origin
In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Signif...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Ganesh, S., Koser, M. L., Cyr, W. A., Chopda, G. R., Tao, J., Shui, X., Ying, B., Chen, D., Pandya, P., Chipumuro, E., Siddiquee, Z., Craig, K., Lai, C., Dudek, H., Monga, S. P., Wang, W., Brown, B. D., Abrams, M. T. Tags: Large Molecule Therapeutics Source Type: research

{beta}-Catenin Targeting DsiRNAs
In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Signif...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Ganesh, S., Koser, M. L., Cyr, W. A., Chopda, G. R., Tao, J., Shui, X., Ying, B., Chen, D., Pandya, P., Chipumuro, E., Siddiquee, Z., Craig, K., Lai, C., Dudek, H., Monga, S. P., Wang, W., Brown, B. D., Abrams, M. T. Tags: Large Molecule Therapeutics Source Type: research

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

MEK/Aurora Kinase Inhibition in Melanoma
Resistance to BRAF inhibitors is a major clinical problem. Here, we evaluate BI-847325, an ATP-competitive inhibitor of MEK and Aurora kinases, in treatment-naïve and drug-resistant BRAF-mutant melanoma models. BI-847325 potently inhibited growth and survival of melanoma cell lines that were both BRAF inhibitor naïve and resistant in 2D culture, 3D cell culture conditions, and in colony formation assays. Western blot studies showed BI-847325 to reduce expression of phospho-ERK and phospho-histone 3 in multiple models of vemurafenib resistance. Mechanistically, BI-847325 decreased the expression of MEK and Mcl-1 w...
Source: Molecular Cancer Therapeutics - June 4, 2015 Category: Cancer & Oncology Authors: Phadke, M. S., Sini, P., Smalley, K. S. M. Tags: Cancer Biology and Signal Transduction Source Type: research