Abstract B28: Overcoming drug resistance to Trk inhibition by rational combination of entrectinib and trametinib: from bench to bedside
In conclusion, we have identified a mitigation strategy, utilizing an approved agent combined with a well-characterized clinical stage agent, to overcome acquired Trk-inhibitor resistance, presumably by overcoming solvent front mutation-driven MAPK activation. The successful translation of a preclinical observation made at the bench to clinical practice at the bedside has greatly extended the duration of tumor regression and provided continued care to a Trk-fusion positive patient even after the emergence of resistance. This clinical observation will be further explored in a dedicated Phase 1/1b combination study.Citation ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Wei, G., Maneval, E. C., Esquibel, V., Berger, M. F., Haque, S., Patel, R., Walsh, C., Hornby, Z., Multani, P., Li, G. Tags: Other Topics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract A28: Casein kinase 1{epsilon} (CSNK1{epsilon}) is a synthetic lethal target in MYC-driven ovarian cancer
In this study, 45 genes were selected for further study based on druggability, involvement in cancer pathways, and differential toxicity. We focused on 23 genes based on their expression pattern in ovarian cancers, of which 9 genes were identified to exhibit strong synthetic lethality in ovarian cancer cells with cMYC overexpression. Casein kinase 1 (CSNK1) was one of the top candidates and was therefore selected for subsequent validation and further analysis. Knock-down of CSNK1 had minimal toxicity in human fibroblasts, suggesting the possibility of a good therapeutic window.Using qPCR and immunohistochemistry analysis o...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Lui, G. Y. L., Schaub, F., Agrawal, S., Kitatani, K., Kemp, C. J., Toyoshima, M., Grandori, C. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B27: Identifying therapeutic combinations with EGFR-targeted therapy through the generation of genome-wide CRISPR-Cas9 knockout libraries in oral cancer cell lines
Oral squamous cell carcinoma (OSCC) remains a disease with poor survival. With recent characterization of the mutational landscape of OSCCs, there is great potential for personalized targeted therapies. However, to date utilization of targeted therapies in OSCC have had limited success with anti-EGFR therapy. Combinations of targeted therapies, which may have greater efficacy by inhibiting compensatory pathways, have not been well studied. To identify synergistic combinations with EGFR-targeted therapy, we introduced Genome-scale CRISPR-Cas9 Knock-Out (GeCKO) libraries into OSCC cell lines. CRISPR-Cas9 generates individual...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Ludwig, M., Birkeland, A., Nimmagadda, S., Foltin, S., Jiang, H., Carey, T., Brenner, J. C. Tags: Resistance Against Drug Combinations: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A27: Identification of novel KRAS-synthetic lethal targets for treatment of KRAS-dependent Non-Small Cell Lung Cancer
Lung cancer is the number one cause of cancer-related deaths worldwide. The most prevalent type of lung cancer is Non-Small Cell Lung Cancer (NSCLC). A significant number of patients with NSCLC carry oncogenic KRAS mutations. However, the efforts to target KRAS directly have thus far proven unsuccessful and tumors harboring mutations in this gene remain the most difficult to treat, highlighting the need for alternative approaches. One promising avenue to treat these cancers is to exploit the concept of synthetic lethality.To identify novel KRAS synthetic lethal interactions we performed shRNA gene knock-down screens in 3D ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Kostyrko, K., Simpson, D., Broyde, J., Kelly, M., Califano, A., Honig, B., Jackson, P., Sweet-Cordero, A. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A26: Prediction of synergistic anticancer drug combinations by integrating chemical and genetic screens
Identification of effective drug combinations inhibiting multiple target genes that are essential for cancer cell survival is seen as an effective strategy to overcome drug resistance. Cellular pathways are often redundant, and network rewiring in the face of an assault promotes the emergence of resistant cells that contribute to clinical relapse. However, the number of possible drug-target combinations to investigate by conducting experiments is exponentially large and impractical, therefore warranting the need for systematic approaches to prioritize the most effective drug combinations. Here, we aimed to integrate large-...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Jaiswal, A., Gautam, P., Tang, J., Wennerberg, K., Aittokallio, T. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A25: Synthetic lethal CRISPR-Cas9 screen imply an oncogenic role for FBXW7 mutations in colon cancer
Mutations in tumour suppressors and un-druggable oncogenes dominate the landscape of cancer driver genes. Only a minority of colon cancers have mutations in druggable cancer drivers, such as PIK3CA. Conversely, mutations in tumour suppressors such as APC and TP53 are frequent, as are mutations in the notoriously difficult to drug KRAS target. There is an urgent need for new therapeutics to target tumours driven by these mutations: immune checkpoint approaches are likely to only prove effective in the fraction of patients whose tumours bear high mutation loads, which is colon cancer may be restricted to the minority of mism...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Moore, J. D., Hudson, C., Russell, P., Tiwana, G., Walter, D., Wiggins, C. M., Yarker, J. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA24: PRMT5 as a therapeutic target in MTAP-deleted cancers
An understanding of driver genetic events in tumorigenesis has led to the development of targeted therapies with clinical benefit for subsets of patients with melanoma, non-small cell lung cancer, and other malignancies. The identification of new cancer vulnerabilities may provide additional therapeutic opportunities for malignancies refractory to standard treatments and may expand the use of targeted therapies to a broader patient population.To identify new cancer vulnerabilities and associated genetic features, we have integrated insights about recurrent genetic alterations (from the Cancer Cell Line Encyclopedia) with c...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Wilson, F. H. Tags: Resistance against Drug Combinations: Oral Presentations - Invited Abstracts Source Type: research
Abstract IA23: Overcoming drug resistance and tumor heterogeneity in gastrointestinal cancers
Personalized cancer medicine approaches, inhibiting kinases in tumors driven by defined genomic alterations, have demonstrated striking efficacy in many cancer types. However, the development of drug resistance is a major limitation to the efficacy of targeted therapies in oncology. Identifying and understanding the molecular mechanisms driving resistance may foster opportunities to develop therapeutic strategies to overcome resistance. For example, in the ~10% of colorectal cancer patients whose tumors harbor BRAF V600 mutations, we have found that feedback reactivation of MAPK signaling, often mediated by EGFR, underlies...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Corcoran, R. B. Tags: Resistance against Drug Combinations: Oral Presentations - Invited Abstracts Source Type: research
Abstract A23: Multi-parametric genetic interactions map dynamic genetic network rewiring upon anti-proliferative treatment
Signaling pathways are often characterized as rather static networks whose outcome is the result of state changes of pathway components, e.g. by protein phosphorylation or other post-translational modifications. These state changes along signaling networks have been systematically studied using, for example proteomics methods. However it remained unknown how networks rewire under the influence of external stimuli, such as anti-cancer drug treatment. To analyze dynamic rewiring of a signaling network, we performed an arrayed high-throughput co-RNAi screen in a Drosophila melanogaster cell line (Dmel-2). Therin, we assessed ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Heigwer, F., Scheeder, C., Miersch, T., Blass, C., Boutros, M. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA22: Exploiting the heterogeneity of mutant Kras lung tumors to improve therapy
Lung cancer is currently the most lethal cancer worldwide with non-small cell lung carcinoma (NSCLC) accounting for ~85% of all cases. The vast majority of lung cancer patients present with locally advanced, inoperable or metastatic disease and median survival at this stage remains low. Targeted therapies are already improving treatment outcomes, but frequent mutations such as those affecting KRAS (present in ~30% of lung adenocarcinomas, a common subtype of NSCLC) still remain untargetable. Our lab aims to define new vulnerabilities associated with these aggressive and largely therapy-resistant tumors. To achieve this, we...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Martins, C. Tags: Chemical Biology: Oral Presentations - Invited Abstracts Source Type: research
Abstract B22: Mdig gene-environment interaction in human cancers
Mineral dust-induced gene, mdig has recently been identified and is known to be over expressed in a majority of human cancers and holds predictive power in the poor prognosis of the disease. Mdig is an environmentally expressed gene that is involved in cell proliferation, neoplastic transformation and immune regulation. With the advancement in deciphering the prognostic role of mdig in human cancers, our understanding on how mdig renders a normal cell to undergo malignant transformation is still very limited. This work displays the current knowledge of the mdig gene in context to human neoplasias and its relation to the cl...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Thakur, C., Chen, F. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A22: Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency
In human somatic cells, telomeres shorten every cell division due to the end replication problem. Once reaching a critically short length, the cells will undergo permanent cell cycle arrest and become senescent. Cancer cells acquire unlimited proliferation ability by activation of a telomere maintenance mechanism, either the enzyme telomerase or the homologous recombination-based mechanism Alternative Lengthening of Telomeres (ALT). Cancers that utilize the ALT mechanism commonly are deficient for ATRX protein expression, are difficult to treat, and have a poor prognosis. We discovered that ICP0-null herpes simplex virus t...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Han, M., Napier, C. E., Frölich, S., Everett, R. D., Cesare, A. J., Reddel, R. R. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA21: Systematic, network-based elucidation of synthetic lethal proteins and synergistic compounds
Given the complex nature of cancer and the cell's ability to effectively compensate for individual perturbation through evolutionarily honed adaptive mechanisms, there is strong expectation that combination therapy approaches may be required to address the limitations that have emerged from single agent therapy. Synthetic lethality provides strong biological rationale supporting this observation, although mechanisms of compound synergy and sensitization are in general more complex than individual gene-pair interactions. Synthetic lethal genes have been elucidated mainly via large-scale screens in model organisms, or by poo...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Califano, A. Tags: Chemical Biology: Oral Presentations - Invited Abstracts Source Type: research
Abstract B21: CRISPR screens provide a comprehensive assessment of cancer vulnerabilities but generate false-positive hits for highly amplified genomic regions
In this study, we compare the performance of CRISPR to RNAi-based loss-of-function screens for the identification of cancer dependencies by performing parallel deep-coverage shRNA and CRISPR screens targeting 2722 genes across several cancer cell lines. CRISPR-based dropout screens identified more lethal genes compared to RNAi in all five cancer models, indicating that the identification of many cellular dependencies may require full gene inactivation, as induced by CRISPR but not RNAi. However, in two aneuploid cancer models we found that all genes within highly amplified regions, including non-expressed genes, scored as ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Munoz, D., Stegmeier, F. P., Schlabach, M. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA20: Chemical-genetic interaction maps for precision therapies in breast and ovarian cancers
There is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic-lethal genetic interactions or emergent dependencies that cancer cells acquire in the presence of specific mutations. Using breast epithelial cells as a base we have developed methodologies to connect tumor mutations with drug sensitivity using quantitative functional genomic screens to create chemical-genetic interaction maps. The focus of the lab is to use these maps to uncover new synthetic-lethal relationships and identify new biomarkers for ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Bandyopadhyay, S. Tags: Chemical Biology: Oral Presentations - Invited Abstracts Source Type: research
