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Source: Cancer Research
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Total 807 results found since Jan 2013.
Abstract 2679: Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma
Melanoma harboring BRAF mutations frequently develop resistance to BRAF inhibitors, limiting the impact of treatment. The most prevalent mechanisms of acquired resistance appear to reactivate MAPK pathway. Furthermore, relatively little is known about the determinants of de novo resistance. Here, we establish such a mechanism of resistance and subsequently identified a suitable drug combination to overcome the resistance. Single treatment of BRAF mutant melanoma cell lines with vemurafenib or dabrafenib (BRAF inhibitors) alone or in combination with trametinib (MEK1/2 inhibitor) resulted in overexpression of Mcl-1. Overexp...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Fofaria, N. M., Frederick, D. T., Sullivan, R. J., Flaherty, K. T., Srivastava, S. K. Tags: Experimental and Molecular Therapeutics Source Type: research
Abstract 2431: Co-targeting ROS and CLU-mediated stress response using SMIP004 (a novel inducer of ROS and cancer cell selective apoptosis) and OGX-011 in MDV3100-resistant, castrate-resistant prostate cancer
Prostate cancer is the most common male carcinoma in North America and the second leading cause of cancer related death in men. While new drugs targeting Androgen Receptor (AR), like abiraterone and MDV3100, significantly increase survival of patients with castration resistant prostate cancer (CRPC), many patients still die of metastatic resistant disease. Continued therapeutic improvements towards prolonging the chronicity of CRPC will require characterization of innate and stress-activated survival responses, and rational combinatorial co-targeting strategies designed to abrogate them. OGX-011 is a second generation anti...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Nappi, L., Beraldi, E., Zhang, F., Wolf, D., Gleave, M. Tags: Clinical Research (Excluding Clinical Trials) Source Type: research
Abstract 2435: FGFR1 is associated with resistance to interaction with estrogen receptor (ER) {alpha} endocrine therapy in ER+/FGFR1-amplified breast cancer
Conclusions: These data suggest FGFR1 binds ER and regulates ligand-independent ER transcriptional activity. This role depends on the FGFR1 kinase activity and may involve its association with cyclin D1. These interactions may explain the endocrine resistance reported in ER+/FGFR1 amplified breast cancers and suggest these tumors should be treated with a combination of antiestrogen and FGFR inhibitors.Citation Format: Luigi Formisano, Christian D. Young, Neil Bhola, Jennifer M. Giltnane, Monica V. Estrada, Carlos L. Arteaga. FGFR1 is associated with resistance to interaction with estrogen receptor (ER) α endocrine therapy...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Formisano, L., Young, C. D., Bhola, N., Giltnane, J. M., Estrada, M. V., Arteaga, C. L. Tags: Clinical Research (Excluding Clinical Trials) Source Type: research
Abstract 2716: Epstein-Barr virus-encoded BARF1 downregulates SMAD4 and increases miR-146a in gastric carcinoma cells
In conclusion, EBV-encoded BARF1 could promote proliferation of gastric carcinoma cells, thereby contributing to EBV-induced cancer progression, in which SMAD4 downregulation, probably through miR-146a increase, may be entailed.Citation Format: Dong Ha Kim, Chan Jin Yoon, Jin, Kyung Rho, Jaap M. Middeldorp, Jun Hee Woo, Mee Soo Chang. Epstein-Barr virus-encoded BARF1 downregulates SMAD4 and increases miR-146a in gastric carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Sup...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Kim, D. H., Yoon, C. J., Rho, J. K., Middeldorp, J. M., Woo, J. H., Chang, M. S. Tags: Carcinogenesis Source Type: research
Abstract 2732: The role of protein P in hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third leading cause of cancer-related death worldwide. Although treatment options have improved in the past 30 years, 5-year survival rate remains below 20%. To improve the therapeutics of HCC, great efforts are needed in understanding the mechanisms underlying HCC. Protein P, plays an important role in the development of cancer. To clarify the role of P in the development of HCC, we investigated the expression level of P in HCC tissue chips. The results showed that P level is much higher in carcinoma than adjacent tissue, and the overall 5-year surv...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Fu, H., Guo, L., HUANG, L. Tags: Carcinogenesis Source Type: research
Abstract 2558: The mechanistic study on the effect of platinum-based chemotherapy efficacy imposed by EGFR-TKI regulated ERCC1 in non-small cell lung cancer (NSCLC)
Platinum-based chemotherapy is conventionally the first line treatment for EGFR wild type patients while EGFR-TKI is the standard for patients with mutation. Subgroup biomarker studies conducted in FASTACT-2 (Wu et al Lancet Oncology 2013) indicated that patients with positive ERCC1 attained longer overall survival and progression free survival under intercalated chemotherapy and EGFR-TKI, in comparison with solely chemotherapy. EGFR-TKI is postulated to down-regulate ERCC1 expression in EGFR wild type NSCLC cells, hence enhancing the Chemo efficacy. The study aims to investigate the missing link between EGFR and ERCC1 in ...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Cheong, H. T., Hui, C. W. C., Xu, F., Mok, T. S. K., Wong, C. H. Tags: Experimental and Molecular Therapeutics Source Type: research
Abstract 2561: Contextual combination of PARP inhibitors with p110beta inhibitors: Functional logistics to tame PTEN null tumors
Background: Hyper-activation of the PI3K pathway due to a functional loss of PTEN is a characteristic feature of many tumors including TNBC and GBM. Although p110b rarely undergoes activating mutations in these cancers, loss of PTEN function makes these tumor cells dependent specifically on p110b. In a mechanism-based study we have recently established an integral role of the PI3K pathway in DNA damage repair (DDR)-mediated anti-tumor efficacy of PARP inhibitor wherein we have demonstrated that PTEN-nullness confers in vivo sensitivity to the combination as compared to tumors carrying PTEN WT (De et al., Neoplasia, 2014). ...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Carlson, J. H., Sun, Y., Lin, X., De, P., Leyland-Jones, B., Dey, N. Tags: Experimental and Molecular Therapeutics Source Type: research
Abstract 2577: Aurora kinase inhibitors require PUMA to induce apoptosis and preferentially kill KRAS-mutant colon cancer cells
In this study, we found that inhibition of aurora kinases by siRNA or small-molecule inhibitors led to induction of p53-upregulated modulator of apoptosis (PUMA), a BH3-only BCL-2 family protein, in colorectal cancer cells irrespective of p53 status. Deficiency in PUMA increased polyploidy and abrogated mitochondria-mediated apoptosis induced by aurora kinase inhibitors. In response to aurora kinase inhibition, PUMA was directly activated by p65 through the canonical NF-kB pathway following AKT inhibition. Interestingly, aurora kinase inhibitors were found to preferentially kill KRAS-mutant colon cancer cells, which is ass...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Sun, J., Knickelbein, K., He, K., Chen, D., Yu, J., Zhang, L. Tags: Experimental and Molecular Therapeutics Source Type: research
Abstract 2579: Combination therapy with MEK inhibition is efficacious in intracranial triple negative breast cancer models
In this study, we evaluated the efficacy of BBB-permeable, clinically-available inhibitors of MEK and identified rational co-target pathways in preclinical models of intracranial (IC) TNBC.Methods: In vitro IC50s, synergy, and siRNA screens (700 kinase genes) were conducted in 4 human-derived TNBC lines (SUM149, MDA-MB-468, MDA-MB-436, MDA-MB-231Br). We evaluated the efficacy of the MEK1/2 inhibitor AZD6244 (AZD), the pan-PI3K inhibitor BKM120 (BKM), and the PDGFR inhibitor Pazopanib (Pazo) in IC TNBC mouse models. Tumor burden was monitored via bioluminescence, and IC tumors were frozen for gene expression analyses using ...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Van Swearingen, A. E. D., Siegel, M. B., Sambade, M. J., Sud, S., Miller, S. M., Silva, G., Bash, R. E., Santos, C. M., Darr, D. B., Golitz, B., Parker, J. S., Miller, C. R., Johnson, G. L., Anders, C. K. Tags: Experimental and Molecular Therapeutics Source Type: research
Abstract 2583: Refinement of inhibitors of the KRAS-signaling naocluster protein, CNKSR1, that block oncogenic KRAS signaling and growth
Conclusion: Potent and specific inhibitors of CNK1 PH-domain with improved pharmacokinetics have been identified. These novel PH-domain inhibitors now provide a therapeutic potential for patients with oncogenic KRAS for which there is currently no effective therapy.Citation Format: D. Lynn Kirkpatrick, Martin Indarte, Mike Scott, Assael Madrigal, Geoffrey Grandjean, Garth Powis. Refinement of inhibitors of the KRAS-signaling naocluster protein, CNKSR1, that block oncogenic KRAS signaling and growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Phil...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Kirkpatrick, D. L., Indarte, M., Scott, M., Madrigal, A., Grandjean, G., Powis, G. Tags: Experimental and Molecular Therapeutics Source Type: research
Abstract 2622: Fluorocyclopentenylcytosine (RX-3117) is activated by uridine-cytidine kinase 2, a potential biomarker
Fluorocyclopentenylcytosine (RX-3117) is an orally bioavailable novel cytidine analog, currently being tested in a Phase I clinical trial. RX-3117 shows promising antitumor activity in various human tumor xenografts including patient derived xenografts resistant to gemcitabine. Initial characterization of RX-3117 indicates that this compound is incorporated into both RNA and DNA, and downregulates DNA methyltransferase I (DNMT1). RX-3117 is not deaminated by cytidine deaminase, an enzyme that limits the efficacy of most cytidine analogs due to extensive deamination. Our studies also demonstrate that RX-3117 is taken up by ...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Peters, G. J., Julsing, J. R., Smid, K., De Klerk, D., Sarkisjan, D., Yang, M. Y., Lee, Y. B., Kim, D. J. Tags: Experimental and Molecular Therapeutics Source Type: research
Abstract 2640: Small molecule compound NCI-8 induces ERK2-dependent mutant-p53 protein degradation
The tumor suppressor p53 is mutated in over 50% of human cancers leading not only to loss of wild-type p53 function, but also to gain-of-function (GOF) mutant p53 which acts as an oncogene. Mutant p53 is expressed at very high levels and can inhibit residual wild-type p53 activity as well as the function of p53 family member proteins such as p73 or p63. Therefore, targeting mutant p53 by either restoring the p53 pathway or depleting its GOF is an attractive strategy for cancer therapy. NCI-8 is a small molecule compound with dual abilities to induce p53 signal pathway and destabilize mutant p53 protein (deplete GOF) in mut...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Zhang, S., Zhou, L., Dicker, D. T., EL-Deiry, W. S. Tags: Experimental and Molecular Therapeutics Source Type: research
Abstract 2642: EF2-kinase (EF2K): A novel molecular target in ovarian and pancreatic cancers
Ovarian cancer (OC) and Pancreatic ductal adenocarcinoma (PDAC) are the most aggressive and deadliest cancers and is currently incurable disease with the poorest prognosis and survival rates (4% and 30% 5-year survival rates, respectively). The poor prognosis is attributed to the extensive local tumor invasion and the resistance to existing cancer therapeutics, which are the major characteristics of both cancers and the impediment to effective cure this lethal diseases. Although both cancers have a well-defined spectrum of highly recurrent oncogenic lesions, including p53, c-myc, K-ras, CDKN2A /p16, TP53 and SMAD4/DPC4 eff...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Ashour, A., Erdogan, A., Alpay, S. N., Kahraman, N., Yuka, E., Lopez-Berestein, G., Ozpolat, B. Tags: Experimental and Molecular Therapeutics Source Type: research
Abstract 2389: Eps8: a negative regulator of myofibroblast differentiation and function
In this study we investigate the mechanisms regulating myofibroblast differentiation and function, and identify the adapter protein Epidermal growth factor receptor kinase substrate 8 (Eps8) as a negative regulator of the cancer-associated myofibroblast phenotype.Cancer-associated fibroblasts (CAFs) are a heterogenous, poorly defined cell population. Most commonly CAFs are identified by de novo expression of α-smooth muscle actin (αSMA) incorporated into stress fibres generating enhanced contractility, which is associated with an enhanced secretory profile. Myofibroblasts promote a number of the hallmarks of malignancy, ...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Frampton, S. J., Jenei, V., Mellone, M., Hanley, C. J., Rucka, M. M., Tod, J., Moutasim, K. A., King, E. V., Thomas, G. Tags: Tumor Biology Source Type: research
Abstract 2646: Targeting cancer stem cell pathways with cell-permeable peptide inhibitors
Direct targeting of several important cancer pathways has so far proved challenging, owing to the lack of pathway-specific targets that can be accessed by conventional small molecule drugs or therapeutic antibodies. Nexigen develops and advances peptide-based cancer therapeutics, a new class of drugs that functionally modulate currently undruggable pathways by targeting intracellular protein-protein-interactions.One of these undruggable pathways, the Wnt signaling cascade, has been identified as a key pathway in cancer stem cells maintenance. Targeting oncongenic Wnt signaling therefore holds great promise for tackling not...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Arndt, V., Friebe, A., Meuser, E., Ross, K., Agerer, F., Schulten-Schulz, C., Waak, J., Friedrich, D., Hennemann, H., Vollmer, J. Tags: Experimental and Molecular Therapeutics Source Type: research
