Abstract B37: Targeting the energy generation triangle to achieve synthetic lethality for treatment of hepatocellular carcinoma
In this study, we developed a synthetic lethal drug combination to treat HCC through the inhibition of the energy generation triangle. Most cancers, including HCC, increase glycolysis (the Warburg effect) to ensure sufficient supplies of energy (ATP), reducing equivalents (NADPH), and biochemical building blocks for cell growth and proliferation. Unlike most tumors, which express both hexokinase 1 (HK1) and HK2, many HCC tumors express only HK2, whereas normal hepatocytes only express HK4. We investigated the role of HK2 in HCC using a doxycycline (DOX)-inducible shRNA knockdown system. The HK4-to-HK2 isoform switch during...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Xu, S., Catapang, A., Braas, D., Stiles, L., Lee, J. T., Graeber, T. G., Damoiseaux, R., Shirihai, O., Herschman, H. R. Tags: Chemical Biology: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A37: Synthetic lethality as a tool to reveal novel vulnerabilities in NF1-associated tumorigenesis
Neurofibromatosis Type 1 (NF1) is a common (1:2500 births) genetic disorder and cancer predisposition syndrome, caused by mutations in the tumor suppressor gene NF1. One of the known functions of the protein encoded by NF1 (neurofibromin) is that of a negative regulator of Ras pathway signaling, through its Ras-GAP activity. Among other symptoms, individuals with NF1 often develop benign tumors of the peripheral nervous system (called dermal or plexiform neurofibromas), originating from the Schwann cell linage or their precursors. While these benign tumors can cause significant pain and mobility problems, some (~10%) progr...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Williams, K. B., Williams, R. L., Rathe, S. K., Hawkinson, J., Largaespada, D. A. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B36: A 1,5-diheteroarylpenta-1,4-dien-3-one inhibits TNBC cell growth by blocking AKT/mTOR/P70S6K pathway
One in 8 women will develop breast cancer during the course of her life. Recent developments in the field of drug development have provided a significant increase in progression free survival and decrease in mortality of this disease. However, one of the main problems in breast cancer remains the development of resistance to current treatments and relapse of the disease. Moreover, there is no known target for the treatment of the triple negative breast cancers (TNBC) subset, which is more aggressive than the other types of the disease. Therefore, it is imperative to develop new drugs that can block the activity of pro-surv...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Atefi, M., Patanapongpibul, M., Ma, L., Chen, Q.-H., Wang, G., Wu, Y., Vadgama, J. Tags: Chemical Biology: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A36: Genome-scale ORF screening to identify modulators of the epithelial-to-mesenchymal transition
Epithelial-mesenchymal transition (EMT) is an essential developmental program and is often reactivated during tumor initiation and progression. EMT is a reversible reprogramming of the cells. It not only promotes cell morphology alterations, but also provokes a profound cell state change in multiple regulatory circuits in global cell signaling, transcriptional and post-transcriptional modifications. Among all breast cancer subtypes, basal-like breast cancer displayed a high degree of mesenchymal and stem-like cell properties. To systematically interrogate the modulators of epithelial-to-mesenchymal transition, we performed...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Li, J., Choi, P., Chaffer, C., Labella, K., Kim, J. W., Doench, J., Dai, C., Giacomelli, A., Ly, S. H., Hwang, J., Hong, A., Ilic, N., Gjoerup, O., Meyerson, M., Brooks, A., Weinberg, R., Hahn, W. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A35: Precision targeting of Homologous Recombination-deficient cancers using microRNA synthetic lethality
Conclusions: Packaging miR223-3p in a nanoparticle can be a potential therapeutic for HR-deficient malignancies and it can confer less risk of toxicity to normal cells since this microRNA is naturally present in mammalian cells.Citation Format: Gayathri Srinivasan, Elizabeth Williamson, Robert Hromas. Precision targeting of Homologous Recombination-deficient cancers using microRNA synthetic lethality [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Sup...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Srinivasan, G., Williamson, E., Hromas, R. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A34: The identification of combinatorial therapeutic approaches with BCR inhibitors in B cell malignancies
Conclusion: We have performed gene expression analysis of primary samples obtained from patients on ibrutinib, and identified gene expression changes that are associated with adaptation of B cells and/or selection of B cell resistant to BCR inhibition. We have shown that malignant B cells are dependent on integrin-signalling and the up-regulation of Bcl2 protein, which makes them synergistically lethal targets.Supported by: The results of this research have been acquired within CEITEC 2020 (LQ1601) project with financial contribution made by the Ministry of Education, Youths and Sports of the Czech Republic within special ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Pavlasova, G., Musilova, K., Seda, V., Cerna, K., Vojackova, E., Svobodova, V., Mraz, M. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B33: Tgif inactivation defines a synthetic lethal interaction among oncogenic Kras and Twist1 in pancreatic ductal adenocarcinoma
The homeodomain protein TGIF function as a potent inhibitor of transforming growth factor beta (TGF-β) cytostatic signaling, whose inactivation is deemed instrumental to the pathogenesis and progression of pancreatic ductal adenocarcinoma (PDAC) driven by oncogenic Kras. Surprisingly, we found that deletion of Tgif in the context of mutant Kras (KrasG12D) expression culminated in the development of highly metastatic PDAC, despite leading to hyperactivation of TGF-(β/Smad) signaling. Mechanically, we found that TGIF associated with and antagonized Twist1 by a process involving Smad4, a tumor suppressor that is fre...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Parajuli, P., Singh, P., Wang, Z., Kumar, S., Li, L., Eragamreddi, S., Nguyen, T. L., Younes, S. T., Zhang, X., Xu, K., Razzaque, M., Prunier, C., Atfi, A. Tags: Other Topics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract B32: Restoration of beta cell mass as a synthetic lethal strategy to overcome oncogenic Kras-driven pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains incurable due to diagnosis at advanced stages, which renders any therapeutic intervention impracticable. The vast majority of PDAC patients develop new-onset diabetes, which often culminates in dysfunction of vital organs, leading to severe morbidity and high mortality. How PDAC development leads to diabetes is still unfolding. More than 90% of PDAC cases have an oncogenic mutation that affects the proto-oncogene Kras, mostly G12D. Using several mouse models of KrasG12D-driven PDAC, which faithfully recapitulate the human disease, we observed a massive deple...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Nguyen, T., Parajuli, P., Ahmad, A., Singh, P., Eragameddy, S., Ramakrishnan, G., Levy, L., Ferrigno, O., Mo, Y.-Y., Pochampally, R., Razzaque, M. S., Prunier, C., Atfi, A. Tags: Other Topics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract A32: Screening for synthetic lethal interactions using customized epigenetic CRISPR-Cas9 libraries
Identification of synthetic lethal (SNL) interactions provides a framework for exploring novel treatment options to cancer based on biomarker analysis. Recent research in this field has been powered up by the latest CRISPR-Cas9 gene editing technology, which allows for single gene manipulation or genome-scale knockout/activation screens. Typically, any non-essential gene can be inactivated in a cell line to generate an isogenic mutant cell line, and single-guide RNA (sgRNA) sequences against any list of genes of interest can be constructed to lentiviral Cas9 vectors to interrogate the isogenic cell lines for SNL interactio...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Zhou, W., Long, M., Li, X., Peng, Z., Ji, Q., Cang, Y. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B31: miRNAs regulated cancer metastasis in esophageal squamous cell carcinoma
MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs and negatively regulate gene expression through base pairing of 3' UTRs of the target genes. Over the past decade, much of important evidences have been obtained to clarify that miRNAs are unusual expressed in human malignancies and could act as OncomiRs or Tumor suppressive miRs.Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers of the gastrointestinal tract. Especially, metastatic recurrences after esophagectomy for ESCC bears unfortunately prognosis and little exists for treatment strategy. Clarification of molecular indicator...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Kano, M., Matsubara, H., Masahiko, T. Tags: Other Topics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract A31: Targeting APC loss using synthetic lethality in Colorectal Cancer
Conclusions: We have identified seven genes as potential therapeutic targets and a number of FDA-approved compounds, which could potentially be new selective therapies for 80% of CRC patients. Currently we are validating these findings and investigating the mechanism of synthetic lethality with APC mutation. To further validate our findings we are also exploring whether these results extend to other CRC cell lines with different mutational backgrounds, this will help us access how many patients may benefit from our novel therapeutic targets.Acknowledgments: We would like to thank Bowel and Cancer Research and The Rosetree ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Shailes, H., Bridge, G., Foxler, D., Sharp, T. V., Silver, A., Martin, S. A. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B30: Novel targets for combination therapy in EGFR mutated NSCLC
Non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR) gene generally show good responses to therapy with EGFR tyrosine kinase inhibitors (EGFR-TKIs). Unfortunately resistance emerges during treatment, driven by different mechanisms. Mutation-driven mechanisms are becoming well understood and include secondary mutations in the EGFR (T790M for 1st generation EGFR-TKIs and C797S for 3rd generation EGFR-TKIs) and activating mutations in NRAS. On the other hand, non-mutation based resistance mechanisms are less well understood but may involve activation of alternati...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Drobnitzky, N., Patel, A., Mumin, A., Cahill, F., Lourenco, L. M., Olyha, S., Corbacioglu, S., Jiang, Y., Ryan, A. J. Tags: Other Topics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract A30: Identifying microenvironment-dependent vulnerabilities in multiple myeloma using CRISPRi
This study will pave the way to better understand the crosstalk between the tumor and its microenvironment and enable rational design of combination therapies to overcome drug resistance.Citation Format: Poornima Ramkumar, Jaime Tawney, Diego Acosta-Alvear, Martin Kampmann. Identifying microenvironment-dependent vulnerabilities in multiple myeloma using CRISPRi [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A30. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Ramkumar, P., Tawney, J., Acosta-Alvear, D., Kampmann, M. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B29: Analysis of Clinical Cancer Gene Panels by Next Generation Sequencing in Tumor and Circulating Cell-Free DNA Samples in Recurrent Ovarian Cancer Patients
Conclusion: Ovarian cancer has a diverse genetic landscape and molecular profiling via NGS offers the opportunity to identify genetic alterations that can be utilized to direct therapy. Approximately 15% of patients with recurrent ovarian cancer have a mutation that can be targeted with a commercially available drug. We have been successful in providing patients with a mutation the NGS-directed therapy. Challenges still exist with the large variation in NGS technology and reporting and further research is needed to better identify actionable oncogenic drivers.Citation Format: Angelina I. Londono, Naveed Farrukh, Mary Kat S...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Londono, A. I., Farrukh, N., Smith, M. K., Tawfik, C. M., Alvarez, R. D., Huh, W. K., Bevis, K. S., Leath, C. A., Michael, S., Yang, E. S. H., Harada, S., Kim, K. H., Arend, R. C. Tags: Other Topics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract A29: Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression
Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifically killing CBP-deficient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP-deficient cancers identified the CBP paralog p300/EP300. Ablation of p300 in CBP-knockout and -deficient cancer cells induced G1/S cell-cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Ogiwara, H., Sasaki, M., Oike, T., Higuchi, S., Tominaga, Y., Kohno, T. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
