RAS proto-oncogenes are mutated at high frequency in many different malignancies, and developing targeted inhibitors to reverse the underlying biochemical aberrations caused by oncogenic RAS alleles represents a central unsolved problem in cancer therapeutics. Activated Ras engages a complex network of kinase effector cascades of which the Raf/MEK/ERK and phosphoinositide-3-OH kinase (PI3K), Akt, mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathways are most implicated in cancer initiation and maintenance. Kevin Shannon, M.D. leads a research group at the University of California, San Francisco (UCSF) that focuses on using innovative in vivo mouse models of human hematologic malignancies to investigate the role of specific Ras effector pathways in leukemia initiation and maintenance, to perform preclinical trials to elucidate mechanisms of drug response and resistance, and to characterize how selective pressure imposed by different therapeutic agents modulates cancer evolution. In addition to performing bench research to address these biologic and translational questions, my responsibilities include: (1) technology development for the group; (2) oversight of the lab's infrastructure and large mouse colony; (3) insuring that all animal research is conducted in a safe and ethical manner in accordance with local and national regulatory requirements; and, (4) primary responsibility for training new lab members of the Shannon lab (including technicians, graduate students, post-doctoral scholars, and hematology/oncology fellows) as well as members of collaborating groups in research techniques and the use of specialized equipment. This application for a R50 NCI Research Specialist Award requests salary support for these ongoing activities to advance the scientific goals of the following NCI-funded research projects: Translational Investigation of Ras and NF1 in Myeloid Leukemia (R37 CA72614); Response and Resistance to Inhibitors of Ras Effectors in Blood Cancers (R01 CA180037); Selectively Targeting Oncogenic NRAS in Cancer (R01 CA193994); Developmental and Hyperactive Ras SPORE (P50 CA196519); and Research Training in Childhood Cancer (T32 CA128583).
KRAS, NRAS, and NF1 mutations are found in ~1/3rd of human cancers and lead to aberrant activation of multiple kinase effector pathways. The goals of this R50 project are to support ongoing NCI-funded research projects that utilize advanced mouse models of human hematologic cancers to elucidate the biology of transformation by RAS oncogenes, to test innovative therapeutic strategies, and to characterize mechanisms of drug response and resistance.
