Research Overview

We used inherited predispositions to myeloid leukemia and recurring cytogenetic alterations in leukemia cells as entry points to identify mutations that cause human developmental disorders and drive malignant growth. Aberrant Ras signaling and chromosome 7 deletions (monosomy 7) emerged as long-term areas of focused research interest from these initial studies.

High throughput sequencing technologies have revolutionized our understanding of human cancer pathogenesis, and showed that cancer is extraordinarily diverse at the molecular level. Importantly, however, a few canonical genes are mutated at high frequency in many forms of cancer. RAS genes are in the latter category. The KRAS, NRAS, HRAS, and NF1 genes encode core components of the Ras/GAP GTPase complex, which is altered by somatic mutation in ~ 1/3rd of human cancers. Despite this high prevalence, the Ras/GAP molecular switch is an exceedingly difficult target for rational drug discovery and no mechanism-based therapies exist for reversing the biochemical consequences of RAS/NF1 mutations exist for cancers with RAS or NF1 mutations.

We are actively testing novel strategies for treating cancers characterized by hyperactive Ras signaling and characterizing mechanisms of response and resistance to conventional and targeted anti-cancer drugs. A cornerstone of this approach is the use of a robust system for performing preclinical trials in vivo that harnesses a novel collection of primary Kras, Nras, and Nf1 mutant murine leukemias that we generated using insertional mutagenesis. Advantages of this strategy include: (1) these cancers recapitulate the inter- and intra-tumoral genetic heterogeneity that is a hallmark of advanced human cancers; (2) primary cancers are treated in congenic immunocompetent mice; (3) insertion sites provide a molecular sequence tag for monitoring clonal dynamics and evolution; and (4) relapsed leukemia cells can be re-transplanted to verify intrinsic drug resistance and manipulated ex vivo to validate candidate resistance mechanisms. Other work in the lab focuses on generating Ras mutant “knock in” alleles for functional and biochemical studies, testing novel strategies for directly targeting oncogenic Ras proteins, and investigating rational drug combinations. We continue to collaborate extensively with investigators in academic, pharma, and biotech to execute these studies.

Monosomy 7 and loss of the long arm of this chromosome (7q) are detected in patients with a variety if myeloid malignancies with an adverse prognosis, including myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia. RAS and NF1 gene mutations are common in these patients. Despite intensive effort, the underlying 7q gene(s) are largely unknown and haploinsufficiency for multiple myeloid tumor suppressors likely explains the complex disease phenotypes seen in human patients. We have harnessed chromosome engineering technology to create large segmental deletions in the mouse corresponding to human chromosome 7q22 deletions found in human leukemia cells. Current studies include extensively characterizing the hematopoietic stem and progenitor cell compartments in these mice and introducing cooperating mutations identified in human patients to generate robust new disease models.

Recent post-doctoral trainees have launched successful careers at leading academic institutions, biotechnology companies in the San Francisco Bay Area, and in government. Interested individuals are welcome to contact current or past members of the lab directly, and are encouraged to forward a Curriculum Vitae to Dr. Shannon at: kevin.shannon@ucsf.edu.