The focus of my research is to (1) elucidate the molecular mechanisms underlying hematological malignant transformation that occurs secondary to disruption of the Fanconi anemia pathway of proteins and (2) identify novel therapeutic targets for the treatment of these cancers.
The Fanconi anemia pathway of proteins, which includes BRCA1 and BRCA2, is critical to genomic stability and prevention of cancer. Germline biallelic loss of any of the known 22 FA genes causes the childhood cancer predisposition syndrome, Fanconi anemia (FA), which is associated with an especially high risk of acute myeloid leukemia (AML). Within the general population, somatic disruption of the FA pathway is observed in a significant subset of sporadic AMLS and may represent a targetable vulnerability.
While the role of FA proteins in DNA damage repair is well established, our group has discovered that many FA proteins also regulate the mitotic spindle assembly checkpoint, revealing an additional source of genomic instability in FA-deficient cells. A better understanding of FA protein function in mitosis will likely reveal novel therapeutic strategies for the treatment of cancers with FA pathway disruption.
Consistent with this notion, we have demonstrated that FA-deficient cells are hypersensitive to pharmacological inhibition of multiple mitotic kinases. Using the human AML cell line THP1, we found that shRNA-mediated stable knockdown of FANCA, which encodes an upstream component of the FA pathway, renders cells hypersensitive to volasertib, a clinical small molecule inhibitor of PLK1. Others have found that fibroblasts and colon cancer cells deficient in FANCG or BRCA1/2, respectively, are also more susceptible to loss of PLK1 activity. We hypothesize that FA pathway disruption may serve as a biomarker for responsiveness to PLK1 inhibition. Thus, the current focus of my research is to test this hypothesis. Primary AML samples available through the IU Simon Cancer Center Tissue Procurement and Distribution facility will be critical to our work. We will identify samples with FA pathway disruption through whole exome sequencing and use these samples to validate our findings of sensitivity to PLK1 inhibitors.
Ph.D. - Indiana University, Bloomington, IN 01/2010
