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Total 20 results found since Jan 2013.
Abstract B21: The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma
Glioblastoma (GBM) represents one of the most aggressive cancer types with the vast majority of patients succumbing to disease within the first five years. This dire prognosis reflects the limited efficacy of our frontline therapies which include radiation therapy and temozolomide (TMZ) chemotherapy. The cellular response to these therapies is critically mediated by DNA damage response signaling networks that are regulated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia And Rad3-Related Protein (ATR). Preliminary studies from our laboratory suggest the ATR inhibitor VX-970 has single agent efficacy in both...
Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Burgenske, D., Mladek, A., Sarkaria, J. Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research
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 B45: Silencing ss3 integrin by targeted ECO/siRNA nanoparticles inhibits EMT and metastasis of triple-negative breast cancer
Metastatic breast cancer is the second leading cause of cancer-related deaths among women. Triple-negative breast cancer (TNBC) is a highly aggressive subcategory of breast cancer and currently lacks well-defined molecular targets for effective targeted therapies. Disease relapse, metastasis, and drug resistance render standard chemotherapy ineffective in the treatment of TNBC. Because previous studies coupled β3 integrin (ITGB3) to epithelial-mesenchymal transition (EMT) and metastasis, we exploited β3 integrin as a therapeutic target to treat TNBC by delivering β3 integrin siRNA via lipid ECO-based nanoparticles (ECO/...
Source: Cancer Research - January 15, 2017 Category: Cancer & Oncology Authors: Jenny G. Parvani, Maneesh D. Gujrati, Margaret A. Mack, William P. Schiemann, Zheng-Rong Lu Tags: Drug Delivery and Nanomedicine Source Type: research
Abstract B08: ER chaperone GRP78 increases chemoresistance in pancreatic ductal adenocarcinoma
Conclusions: Collectively, our data show that GRP78 expression promotes chemoresistance in PDAC and therapeutic strategies blocking the activity of GRP78 increase the efficacy of currently available therapies.Citation Format: Jenifer B. Gifford, Wei Huang, Ann E. Zeleniak, Antreas Hindoyan, Hong Wu, Timothy R. Donahue, Reginald Hill.{Authors}. ER chaperone GRP78 increases chemoresistance in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B08.
Source: Cancer Research - December 13, 2016 Category: Cancer & Oncology Authors: Jenifer B. Gifford, Wei Huang, Ann E. Zeleniak, Antreas Hindoyan, Hong Wu, Timothy R. Donahue, Reginald Hill Tags: Molecular Drivers of Pancreatic Cancer Biology and Metastasis Source Type: research
Abstract A35: SOX9 induces chemo-resistance in pancreatic cancer cells and its high expression predicts poor prognosis
Conclusions: These data indicate that Sox9 plays an important role in chemo-resistance by the induction of stemness in pancreatic cancer cells.Citation Format: Shingo Kagawa, Taku Higasihara, Hideyuki Yoshitomi, Shigetsugu Takano, Hiroaki Shimizu, Masayuki Ohtsuka, Atsushi Kato, Katsunori Furukawa, Masaru Miyazaki.{Authors}. SOX9 induces chemo-resistance in pancreatic cancer cells and its high expression predicts poor prognosis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 S...
Source: Cancer Research - December 13, 2016 Category: Cancer & Oncology Authors: Shingo Kagawa, Taku Higasihara, Hideyuki Yoshitomi, Shigetsugu Takano, Hiroaki Shimizu, Masayuki Ohtsuka, Atsushi Kato, Katsunori Furukawa, Masaru Miyazaki Tags: Early Detection Source Type: research
Abstract B21: Exostosin 1 regulates cancer cell stemness in breast cancer cells
Cancer stem cells (CSCs), a group of cancer cells, are associated with resistance to radiation and chemotherapy and are implicated in recurrent of cancer. Exostosin 1 (EXT1) gene is widely reported as tumor suppressor and its indispensable role in elongation of heparan sulfate (HS) can speculate probable role as tumor promotor. In recent years, a number of tumors are reported to over express EXT1. Here, we investigated the role of EXT1 in the maintenance of cancer cell stemness. MCF7/ADR cells developed by exposing MCF7, breast cancer cells, to doxorubicin for several months in culture, showed high resistance to doxorubici...
Source: Cancer Research - July 27, 2016 Category: Cancer & Oncology Authors: Manandhar, S., Kim, C.-g., Oh, S. Y., Lee, S.-H., Seok, J., Jung, Y.-D., Lee, H.-E., Choi, Y.-S., Lee, Y. M. Tags: Therapeutic Targeting Tumor Microenvironment Source Type: research
Abstract PR10: The chromatin remodeler CHD4 as a potential specific target for alveolar rhabdomyosarcoma therapy
Fusion-positive alveolar rhabdomyosarcoma (FP-RMS) is a paediatric tumour driven by an oncogenic fusion transcription factor, PAX3-FOXO1. Conventional chemotherapy is only effective for low risk patients which carry no metastasis, achieving a 5-year overall survival of 65%. The unique presence of this fusion protein in FP-RMS as well as the tumour cell survival dependency on PAX3-FOXO1 make this transcription factor a promising target for therapy. However, due to the difficulties associated with drug development targeting transcription factors, we performed a combined proteomic and genetic screen to identify new druggable ...
Source: Cancer Research - April 3, 2016 Category: Cancer & Oncology Authors: Marques, J., Boehm, M., Wachtel, M., Schaefer, B. Tags: Epigenetics Source Type: research
Abstract B31: Combined siRNA and small molecule screening identifies Aurora B kinase as an effective target in MYCN-driven neuroblastoma
Despite advances in multimodal treatment, neuroblastoma (NB) is often fatal for children with high-risk disease and many survivors need to cope with long-term side effects from high-dose chemotherapy and radiation. To identify new therapeutic targets, we performed a siRNA screen of the druggable genome combined with a small molecule screen of 465 compounds targeting 39 different mechanisms of actions in four NB cell lines. We identified 58 genes as targets, including AURKB, in at least one cell line. In the drug screen, aurora kinase inhibitors (nine molecules) and in particular the AURKB-selective compound, barasertib, we...
Source: Cancer Research - April 3, 2016 Category: Cancer & Oncology Authors: Bogen, D., Wei, J. S., Azorsa, D. O., Ormanoglu, P., Buehler, E., Guha, R., Keller, J. M., Griner, L. A. M., Ferrer, M., Song, Y. K., Liao, H., Mendoza, A., Gryder, B. E., Sindri, S., He, J., Wen, X., , Zhang, S., Shern, J. F., Yohe, M. E., Taschner-Mandl Tags: Targeted Therapeutics and Resistance Source Type: research
Abstract C68: SLCO1B3 influences taxane-response in prostate cancer
Conclusion: Prostate cancer cells that overexpress SLCO1B3 are more sensitive to docetaxel and cabazitaxel treatment, which could be linked to increased uptake of both taxanes. Further studies are needed to clarify the role of SLCO1B3 in the uptake of cabazitaxel into the cell. Moreover, SLCO1B3 expression affects hormonal status of prostate cancer cells as reflected by PSA production. Research is ongoing to further elucidate the role of SLCO1B3 in prostate cancer and its impact on taxane efficacy and response.Citation Format: Ellen S. de Morree, Rene Bottcher, Robert J. van Soest, Ashraf Aghai, Corrina M. de Ridder, Alice...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: de Morree, E. S., Bottcher, R., van Soest, R. J., Aghai, A., de Ridder, C. M., Gibson, A. A., Mathijssen, R. H., Burger, H., Wiemer, E. A., Sparreboom, A., van Weerden, W. M., de Wit, R. Tags: Drug Resistance and Modifiers: Poster Presentations - Proffered Abstracts Source Type: research
Abstract C5: FLIP protein-protein interaction inhibitors enhance sensitivity of colorectal cancer cells to chemotherapy and TRAIL
ConclusionWe have developed inhibitors of FLIP that decrease its recruitment to the TRAIL-R2 DISC and increase TRAIL-induced caspase activation and apoptosis. Moreover, these inhibitors synergise with 5-Fluorouracil, oxaliplatin and SN38, suggesting that this novel class of agents has therapeutic potential in CRC when used in conjunction with standard-of-care chemotherapeutic agents.AcknowledgementsThis work was supported by a Seeding Drug Discovery award from the Wellcome Trust (reference: 099470).Citation Format: Jennifer P. Fox, Joanna Majkut, Catherine Higgins, Zsuzsanna Nemeth, Adnan Malik, Christopher J. Scott, Peter...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Fox, J. P., Majkut, J., Higgins, C., Nemeth, Z., Malik, A., Scott, C. J., Blurton, P., Boffey, R. J., Perrior, T. R., Harrison, T., Longley, D. B. Tags: Apoptosis, Necrosis, and Autophagy: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A103: Cell-autonomous activation of the interferon/STAT1 pathway in response to genotoxic treatment
In conclusion, this study supports that cell-autonomous activation of the IFN/STAT1 pathway is a surrogate biomarker of initial tumor shrinkage in response to genotoxics, and suggests that it may play a role in tumor resistance to treatment.Citation Format: Julie Gaston, Laura Cheradame, Marie-Emmanuelle Legrier, Olivier Déas, Myriam Lassalle, Enora Le Ven, Jean-Gabriel Judde, Vincent Goffin, Stefano Cairo. Cell-autonomous activation of the interferon/STAT1 pathway in response to genotoxic treatment. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Gaston, J., Cheradame, L., Legrier, M.-E., Deas, O., Lassalle, M., Le Ven, E., Judde, J.-G., Goffin, V., Cairo, S. Tags: In Vitro and in Vivo Models for Targets: Poster Presentations - Proffered Abstracts Source Type: research
Abstract C195: A Wee1 inhibitor analog of AZD1775 demonstrates synergy with cisplatin with reduced single-agent toxicity in medulloblastoma
Medulloblastoma is the most common primary brain tumor in children. Current treatment for medulloblastoma includes surgical resection, radiation and cytotoxic chemotherapy. Although this approach has improved survival rates, the high doses of chemotherapy required to circumvent drug resistance mechanisms and result in clinical efficacy often give rise to lasting neurocognitive defects, stunted growth, deafness, and even secondary tumors. Therefore, synergistic drug combinations that maintain clinical efficacy, but allow dose reductions of cytotoxic agents limiting their adverse effects would be an attractive approach for p...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Matheson, C. J., Venkataraman, S., Amani, V., Harris, P., Backos, D. S., Foreman, N. K., Vibhakar, R., Reigan, P. Tags: Therapeutic Agents: Small Molecule Kinase Inhibitors: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A2-18: The challenges of using large-scale genomics data to identify novel drivers of lung cancer
Lung cancer is one of the major causes of cancer deaths worldwide and only 30% of patients survive the disease for at least one year after diagnosis. Patients are often too frail to receive systemic chemotherapy and there is an urgent need for less toxic, efficacious, targeted therapies. Despite recent efforts with large-scale genomics data we still lack knowledge about driver mutations for the majority of lung cancers.Increasingly, cancer researchers are using online cancer genomic databases to identify novel targets to investigate. A comparison of two prominent databases from different institutes (CCLE and COSMIC) reveal...
Source: Cancer Research - November 15, 2015 Category: Cancer & Oncology Authors: Hudson, A. M., Yates, T., Wirth, C., Li, Y., Trotter, W., Fawdar, S., Miller, C., Brognard, J. Tags: Genomics and Target Discovery Source Type: research
Abstract PR09: MYCN and is a therapeutic target in neuroblastoma
Neuroblastoma is a childhood cancer of the sympathetic nervous system. Approximately 20% of patients present with an aggressive metastatic disease characterized by amplification of the MYCN locus. However, an additional 30% of patients suffer from an equally aggressive disease, yet there are no unified genetic markers available.To identify potential biomarkers of poor prognosis in neuroblastoma, we conducted unsupervised hierarchical clustering on 649 primary neuroblastoma tumors based on a 51 gene MYC core target signature. This demonstrated strong activation within the MYCN amplified cohort as expected, but surprisingly ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Carter, D. R., Murray, J., Cheung, B. B., Kalla, H., Gamble, L., Tsang, J., Sutton, S., Koach, J., Syed, S., Gifford, A., Issaeva, N., Biktasova, A., Atmadibrata, B., Sun, Y., Sokolowski, N., Ling, D., Kim, P. Y., Webber, H., Clark, A., Ruhle, M., Liu, B. Tags: Targeting Myc-Driven Cancers: Oral Presentations - Proffered Abstracts Source Type: research
Abstract A36: Combined inhibition of PI3K isoforms and mTOR kinase is critical for cancer stem cell inhibition by VS-5584
We report here that VS-5584 is up to 30-fold more potent at inhibiting the proliferation and survival of CSCs than non-CSCs in breast cancer cell lines using multiple orthogonal CSC assays. Moreover, VS-5584 preferentially induced apoptosis in Aldefluor-positive CSCs relative to Aldefluor-negative non-CSCs as measured by Annexin V and Caspase 3/7 assays. In contrast, paclitaxel induced more apoptosis in non-CSCs than CSCs cells. VS-5584 also preferentially diminished CSCs in human breast and small cell lung cancer xenograft models in vivo, as evidenced by marked reduction of tumor-initiating capacity in an in vivo limiting...
Source: Molecular Cancer Therapeutics - July 6, 2015 Category: Cancer & Oncology Authors: Kolev, V. N., Wright, Q. G., Weaver, D. T., Padval, M. V., Pachter, J. A., Xu, Q. Tags: Preclinical and Clinical Studies in Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research
