The RAS Initiative facilitates connections between and among researchers, bringing new ideas and technologies to bear on RAS. A guiding principle for these collaborations is close coordination with the activities at the Frederick National Laboratory for Cancer Research (FNLCR) Hub, so that new efforts can have a maximum amount of leverage on each other.
Calvin Kuo, Stanford University, and Kevan Shokat, University of California, San Francisco, for “Modeling KRAS-Dependent Synthetic Lethality in Human Colon Organoids.” Drs. Kuo and Shokat and their team will use surgical samples to establish human normal colon and colorectal cancer patient-derived organoids with different KRAS mutations. By maintaining three-dimensional colonic tissue architecture, the team proposes to identify synthetic lethalities through a combination of activity-based proteomic screens to map signaling pathways affected by KRAS and high-throughput FDA-drug approved small molecule screens. Hits will be validated using both genomic shRNA and CRISPRi approaches.
Channing Der and Adrienne Cox, University of North Carolina at Chapel Hill, for "Identification of Synthetic Lethal Interactors in Pancreatic Cancer." Drs. Der and Cox and their team will use low-passage cell lines derived from patient-derived xenografts to discover synthetic lethalities in pancreatic cancer. In one aspect they will combine known inhibitors of KRAS effectors with a library of 500 clinical candidate and approved cancer drugs to find cytotoxic combinations that are specific for cells expressing mutant KRAS. Drug combinations will be tested in organoids and mouse models.
Kevin Haigis, Beth Israel Deaconess Medical Center, and Stephen Elledge, Harvard Medical School, for "A Multi-Faceted Approach to Identifying KRAS Synthetic Lethal Relationships." Drs. Haigis and Elledge and their team will use cell lines and mouse models to discover synthetic lethalities in colorectal cancers containing mutant KRAS genes. They will study changes in signaling networks and radiation sensitivity when mutant KRAS is reverted to wild type in colorectal cancer cells, and both loss and gain of function high-throughput screens for synthetic lethalities. Hits will be tested in mouse models of cancer.
Peter Jackson, Michael C. Bassik, and Alejandro Sweet-Cordero, Stanford University School of Medicine, for "Using Protein Interaction Networks and Combinatorial Screens to Target KRAS-driven Cancer." Drs. Jackson, Bassik, and Sweet-Cordero and their team will look for synthetic lethalities in non-small cell lung cancers expressing mutant KRAS. Proteomics and CRISPR-CAS9 screens will discover vulnerabilities that will be tested in mouse models and patient-derived xenografts.
Charles Rudin, Memorial Sloan Kettering Cancer Center, for "Identification and Validation of Synthetic Lethality in KRAS Mutant Lung Adenocarcinoma Patient Derived Xenografts." Dr. Rudin and his team will modify patient-derived xenografts of human lung cancers harboring the most common mutant KRAS alleles to express Cas9, after which they will be selected and transduced with sgRNAs in vivo. DNAs from resulting tumors will be sequenced to determine which sgRNAs are underrepresented and thus indicate target genes that are essential for KRAS-dependent tumor formation.
William Hahn, Broad Institute, for "Systematic Identification of Oncogenic KRAS Synthetic Lethal Interactions." Dr. Hahn and his team will perform genome scale CRISPR mediated loss of function experiments to identify KRAS co-dependencies in both in vitro and in vivo model systems and identify genes and pathways that when inhibited synergize with known KRAS effector pathways to induce tumor regression in KRAS driven cancers. Targets identified by these approaches will form the basis of translational studies to develop novel therapeutic approaches.
2016 KRAS Postdoctoral Fellowships
In cooperation with the Frederick National Laboratory for Cancer Research (FNLCR), The Pancreatic Cancer Action Network (PanCan) has established fellowships and scholarships to support talented post-doctoral researchers engaged in KRAS research. PanCan recently announced two outstanding postdoctoral fellowship awardees: Marco Biancucci, Ph.D. who works in the laboratory of Karla Satchell at Northwestern University in Chicago; and Perry Kennedy, Ph.D., who is under the mentorship of Said Sebti at the Moffitt Cancer Center, Tampa.
PanCan also awarded travel scholarships to Bjoern Papke, Ph.D., in the laboratory of Channing Der at the University of North Carolina, Chapel Hill and Kamini Singh, Ph.D., in the laboratory of Hans-Guido Wendel at the Memorial Sloan Kettering Cancer Center, New York. Both the fellowship and travel awardees will receive training and mentorship at the FNLCR with the RAS team and with Dr. Frank McCormick, who is coordinating the RAS effort there. They will also be involved in PanCAN’s Community for Progress which affords them opportunities to participate in scientific meetings, establish research collaborations, and engage with the broader pancreatic cancer community.
2015 KRAS Postdoctoral Fellowships
The 2015 PanCan KRAS Postdoctoral Fellowship awardees are John Hunter, Ph.D. who works in the laboratory of Kenneth Westover at the University of Texas Southwestern Medical Center; and Lynn McGregor, Ph.D., who is under the mentorship of Kevan Shokat at the University of California, San Francisco.
Contract Awardees for RAS Pathway Assays
The NCI Clinical Proteomic Tumor Analysis Consortium has awarded contracts to the Fred Hutchinson Cancer Research Center (Dr. Amanda Paulovich), the Moffitt Cancer Center (Dr. John Koomen), and the Broad Institute (Dr. Steven Carr). They will develop quantitative immuno-multiple reaction monitoring (MRM) assays to measure important peptides and phospho-peptides in the RAS pathway. Data from these assays will provide a valuable link between phenotypes and genotypes in cancers. For more details please see the blog post in RAS Central.