Abstract A05: Derivation of chemotherapeutic combination against gastric cancer cells via synthetic lethal targeting of conserved drug-resistance network in fission yeast surrogate
Cancer is a global health problem and there is a critical need for new advancements in its management and treatment if we are to meet the projected increase in new cases. One important challenge facing clinicians is how to determine the most appropriate treatment strategy for patients. Thus far, chemotherapy has remained the mainstay for cancer management. Contemporary chemotherapeutic treatments incorporate the use of typically three to four agents in combination. The determination of the most suitable drug combination profoundly affects chemotherapeutic success. However, selecting the most appropriate drugs for such ther...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Chen, E.-., Seah, K.-., Nguyen, T.-. Tags: Model Organisms to Identify Synthetic Lethal Interactions: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR04: A CRISPR-based genetic interaction map identifies synergistic drug combinations for cancer
Identification of effective combination therapies is critical to address the emergence of drug-resistant cancers. Although millions of drug combinations might be created by repurposing existing drugs, direct screening of these combinations is infeasible. Here, we designed a scalable CRISPR-based double knockout (CDKO) system to generate a mammalian genetic interaction (GI) map at unprecedented scale, comprised of 490,000 double-sgRNAs directed against 21,321 pairs of drug targets. We first developed an efficient strategy for cloning and sequencing the libraries, as well as a robust statistical scoring method for calculatin...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Han, K., Jeng, E., Hess, G., Morgens, D., Li, A., Bassik, M. Tags: New Technology and Bioinformatics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract B04: RAD51 expression as a biomarker of homologous recombination deficiency in ovarian cancer
RAD51 is a critical component of the homologous recombination pathway, forming a nucleoprotein filament that enables strand exchange and templated error-free DNA repair. The tumor suppressors BRCA1 and BRCA2 interact with RAD51 to control its activity on DNA. Defects in homologous recombination in tumors are clinically relevant, with evidence of synthetic lethality of such cancers to poly ADP ribose polymerase (PARP) inhibitors.Mutations in RAD51 are uncommon in cancer, but aberrant over-expression of RAD51 has been reported as a mechanism to overcome a recombination defect in in-vitro models. However there are no large sc...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Hoppe, M. M., Tan, D. S., Lim, D. G., Karnezis, A., Huntsman, D., Steel, J., Liu, X., Paul, J., Lewsley, L.-A., Siddiqui, N., Brown, R., Jeyasekharan, A. D. Tags: New Technology and Bioinformatics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A04: Cross-species analysis identifies MUS81, a structure-specific endonuclease, as a novel synthetic lethal interaction with PARP
Recently, the inhibition of poly ADP-ribose polymerase, or PARP, in BRCA-mutated cells has been exploited as a therapeutic strategy for cancer due to the strong PARP/BRCA synthetic lethal relationship. Evidence suggests this lethality is likely due to DNA repair defects; however, details of this mechanism remain unclear. To this end, we sought to identify a larger spectrum of genes whose mutation renders cells sensitive to PARP inhibition. Using the model organism Caenorhabditis elegans, we developed an in vivo variomics approach to screen mutated C. elegans strains for sensitivity to the PARP inhibitor olaparib. Multiple ...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Bailey, M. L., O'Neil, N. J., Hieter, P. Tags: Model Organisms to Identify Synthetic Lethal Interactions: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR03: Linking AP/MS-driven protein-protein interaction networks and combination CRISPR/sgRNA screens defines new Kras effectors and target candidates for non-small cell lung cancer
The Kras pathway is a central driver in prevalent and deadly cancers including pancreas, colon and lung. Despite decades of work studying the Raf and PI3 kinase pathways downstream of Kras, therapies targeted to these pathways have shown varied responses in tumorsTo better understand whether important Kras dependences have been overlooked, we used tandem affinity purification of Kras, Hras, and Nras interactors and a set of baits representing ~50 interacting pathway regulators, and have compared these interactions in Kras transformed A549 NSCLC lines versus an isogenic shRNA Kras knockdown line, to identify key protein-pro...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Kelly, M. R., Kyuho, H., Jeng, E. E., Morgans, D., Kostyrko, K., Simpson, D., Gwinn, D., Sweet-Cordero, A., Bassik, M. C., Jackson, P. K. Tags: New Technology and Bioinformatics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract B03: Functional Stratification of Cancer Variants via Network Perturbations
In the past decade, genome and exome sequencing projects have identified thousands of genetic variants in patients across a large number of cancer types. However, the explosion of genomic information has left many fundamental questions regarding genotype-phenotype relationships unresolved. One critical challenge is to distinguish causal disease mutations from non-pathogenic polymorphisms. Even when causal mutations are identified, the functional consequence of such mutations is often elusive. Classical one gene, one function, one disease models can not reconcile with the complexity that different mutations of the same gene...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Sahni, N., Yi, S. Tags: New Technology and Bioinformatics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A03: Several rational combination kinase inhibitor treatments identified by synthetic lethality screens are efficacious in intracranial triple negative breast cancer models
Conclusions: Synthetic lethality screens identified multiple rational combination therapies based on PI3K and/or MEK inhibition in TNBC cells, particularly PI3K+MEK, MEK+PDGFR, and PI3K+AURKA. Combined use of brain-penetrant, clinically available inhibitors against these targets showed promising efficacy in intracranial TNBC mouse models. Rational combinations of brain-penetrant kinase inhibitors are promising strategies for a patient population with few options. In vivo studies assessing the efficacy of other identified combinations, as well as more extensive characterization of potential resistance mechanisms, in intracr...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Swearingen, A. E. D. V., Sambade, M. J., Siegel, M. B., Sud, S., Bevill, S. M., Golitz, B. T., Bash, R. E., Santos, C. M., Darr, D. B., Parker, J. S., Miller, C. R., Johnson, G. L., Anders, C. K. Tags: Model Organisms to Identify Synthetic Lethal Interactions: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR02: Synthetic lethality screen identifies novel druggable targets in the MYC pathway
The MYC oncogene is frequently overexpressed in human cancers. However, targeting MYC directly has proven to be extremely difficult and MYC itself is currently considered undruggable. We sought to identify alternative genetic vulnerabilities of MYC-driven cancer by using CRISPR-based genome-wide synthetic lethality screens. The library screens were performed in a MYC-driven cancer cell line derived from our transgenic mouse model of hepatocellular carcinoma. In this cancer cell line, the level of MYC is regulated by the Tet-Off transgenic system. Using lentiviral infection, the Cas9 nuclease was delivered into the cells, f...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Li, Y., Deutzmann, A., Bell, J., Ji, H., Felsher, D. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Oral Presentations - Proffered Abstracts Source Type: research
Abstract A02: Expanding tumor chemical-genetic interaction map using next-generation cancer models
The development of new cancer therapeutics requires sufficient genetic and phenotypic diversity of cancer models. Current collections of human cancer cell lines are limited and for many rare cancer types, zero models exist that are broadly available. Here, we report results from the pilot phase of the Cancer Cell Line Factory (CCLF) project that aims to overcome this obstacle by systematically creating next-generation in vitro cancer models from adult and pediatric cancer patients' specimens and making these models broadly available.We first developed a workflow of laboratory, genomics and informatics tools that make it po...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Tseng, Y.-Y., Hong, A., Gill, S., Keskula, P., Raghavan, S., Cheah, J., Tsherniak, A., Vazquez, F., Alkhairy, S., Peng, A., Sayeed, A., Deasy, R., Ronning, P., Kantoff, P., Garraway, L., Rubin, M., Kuo, C., Puram, S., Gazdar, A., Wagle, N., Bass, A., Ligo Tags: Model Organisms to Identify Synthetic Lethal Interactions: Poster Presentations - Proffered Abstracts Source Type: research
Abstract PR01: A functional variomic chemi-genetic screen in C. elegans identifies new synthetic lethal interactions with PARP inhibition that are conserved from worm to human
Poly ADP-ribose polymerase (PARP) inhibitors are anti-cancer therapeutics that are synthetic lethal (SL) with mutations affecting the homologous recombination genes BRCA1 or BRCA2. Previous work from our lab found that cohesin mutations, which are common in a range of tumour types, also confer sensitivity to PARP inhibition. We want to extend the SL profile of PARP inhibitors to identify the full spectrum of genetic variants that result in sensitivity to PARP inhibitors alone or in combination with DNA damaging agents.To this end, we are using the model organism Caenorhabditis elegans to screen for new SL interactions with...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: O'Neil, N. J., Bailey, M. L., Hieter, P. Tags: Model Organisms to Identify Synthetic Lethal Interactions: Oral Presentations - Proffered Abstracts Source Type: research
Metformin Inhibits Cellular Proliferation and Bioenergetics in Colorectal Cancer Patient-Derived Xenografts
There is increasing preclinical evidence suggesting that metformin, an antidiabetic drug, has anticancer properties against various malignancies, including colorectal cancer. However, the majority of evidence, which was derived from cancer cell lines and xenografts, was likely to overestimate the benefit of metformin because these models are inadequate and require supraphysiologic levels of metformin. Here, we generated patient-derived xenograft (PDX) lines from 2 colorectal cancer patients to assess the properties of metformin and 5-fluorouracil (5-FU), the first-line drug treatment for colorectal cancer. Metformin (150 m...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Mohamed Suhaimi, N.-A., Phyo, W. M., Yap, H. Y., Choy, S. H. Y., Wei, X., Choudhury, Y., Tan, W. J., Tan, L. A. P. Y., Foo, R. S. Y., Tan, S. H. S., Tiang, Z., Wong, C. F., Koh, P. K., Tan, M.-H. Tags: Models and Technologies Source Type: research
Modeling Therapy Resistance in BRCA1/2-Mutant Cancers
Although PARP inhibitors target BRCA1- or BRCA2-mutant tumor cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2. Whether secondary mutant tumor cells are selected for in a Darwinian fashion by treatment is unclear. Furthermore, how PARP inhibitor resistance might be therapeutically targeted is also poorly understood. Using CRISPR mutagenesis, we generated isogenic tumor cell models with secondary BRCA1 or BRCA2 mutations. Using these in heterogeneous in vitro culture or in vivo xenograft experiments in which the cl...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Drean, A., Williamson, C. T., Brough, R., Brandsma, I., Menon, M., Konde, A., Garcia-Murillas, I., Pemberton, H. N., Frankum, J., Rafiq, R., Badham, N., Campbell, J., Gulati, A., Turner, N. C., Pettitt, S. J., Ashworth, A., Lord, C. J. Tags: Models and Technologies Source Type: research
Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation
Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared with single agents. In addition, a breast cancer patient–derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared with single agents. Mice bearing plasma cel...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Simmons, J. K., Michalowski, A. M., Gamache, B. J., DuBois, W., Patel, J., Zhang, K., Gary, J., Zhang, S., Gaikwad, S., Connors, D., Watson, N., Leon, E., Chen, J.-Q., Kuehl, W. M., Lee, M. P., Zingone, A., Landgren, O., Ordentlich, P., Huang, J., Mock, B Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
Optimization of RAS/BRAF Mutational Analysis Confirms Improvement in Patient Selection for Clinical Benefit to Anti-EGFR Treatment in Metastatic Colorectal Cancer
In metastatic colorectal cancer (mCRC), recent studies have shown the importance to accurately quantify low-abundance mutations of the RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of an extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti–EGFR- (n = 255) or bevacizumab- (n = 328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas, therascreen, ...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Santos, C., Azuara, D., Garcia-Carbonero, R., Alfonso, P. G., Carrato, A., Elez, M. E., Gomez, A., Losa, F., Montagut, C., Massuti, B., Navarro, V., Varela, M., Lopez-Doriga, A., Moreno, V., Valladares, M., Manzano, J. L., Vieitez, J. M., Aranda, E., Sanj Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-{delta}
In patients undergoing irradiation (IR) therapy, injury to nontumor tissues can result in debilitating, and sometimes permanent, side effects. We have defined protein kinase C- (PKC) as a regulator of DNA damage–induced apoptosis and have shown that phosphorylation of PKC by c-Abl and c-Src activates its proapoptotic function. Here, we have explored the use of tyrosine kinase inhibitors (TKI) of c-Src and c-Abl to block activation of PKC for radioprotection of the salivary gland. Dasatinib, imatinib, and bosutinib all suppressed tyrosine phosphorylation of PKC and inhibited IR-induced apoptosis in vitro. To determine...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Wie, S. M., Wellberg, E., Karam, S. D., Reyland, M. E. Tags: Cancer Biology and Signal Transduction Source Type: research
