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Understanding the Genetic Basis of Cancer

Research projects in the Cowell Laboratory are aimed at improving our understanding of the molecular genetic basis of cancer. A broad range of cell and molecular biology, proteomics, genomics, protein chemistry and animal modeling techniques are used to dissect the genetic contribution to various aspects of cancer predisposition, development and progression in a variety of tissue types. Current specific areas are outlined below.

Wave3 Gene

We discovered the WAVE3 gene some years ago and have demonstrated that it plays a central role in the promotion of invasion and metastasis through regulation of the actin cytoskeleton reorganization required for invasion in a wide variety of different cancer cell types. Suppression of the WASF3 protein leads to loss of invasion in vitro and loss of metastasis in vivo using model cell systems. WASF3 requires phosphoactivation by a variety of kinases, which is promoted by growth factor receptors and cytokines. Transcription is controlled by STAT3, and WASF3 activation promotes NFkB through down-regulation of KISS1 and E-cadherin and up-regulation of ZEB1. Inactivation of WASF3 function, therefore, by whatever means, leads to loss of invasion regardless of the genetic background of the cells involved, making its suppression of broad potential application to suppressing metastasis. WASF3 is an auto-inhibited protein that is maintained through a regulatory protein complex involving NCKAP1 and CYFIP1. Genetic knockdown of these two proteins leads to destabilization of WASF3 and loss of function. We have developed highly stable, stapled peptides that target protein interactions between WASF3 and NCKAP1/CYFIP1. In vitro, these peptides lead to loss of WASF3 function and suppression of invasion. In vivo, the same peptides lead to suppression of metastasis using breast cancer cells as the model. Ongoing studies are designed not only to further understand the function of this gene using molecular and genomic approaches, but also to optimize the stapled peptides through medicinal chemistry approaches to improve their effectiveness and stability and to develop formulations for effective delivery in vivo.

Syngeneic mouse models

One hallmark of leukemias is the presence of powerful, chimeric, fusion kinases that result from chromosome translocations that lead to the ligand-independent, constitutive activation of kinases. We defined the chimeric FGFR1 kinase associated with a myeloproliferative disorder that progresses to AML in 80% of patients and is frequently accompanied by T- and B-cell lymphomas, depending on the specific fusion partner that provides the dimerization domain to constitutively activate the kinase domain. To facilitate these studies, we have developed syngeneic mouse models of this disease using transduction and transplantation of bone marrow cells in mice where the various fusion kinases lead to diseases identical to that seen in the comparable human diseases. Further, using CD34+ hemato-progenitor cells from cord blood, we have developed human cell models of FGFR1-driven AML in immunocompromised mice. These models have been used to investigate the use of FGFR1 inhibitor drugs as a means of treating this disease. Using genomics approaches, we have demonstrated that the genetic changes seen in the syngeneic, CD34+ cells and human primary disease share commonalities that support the idea of targeting different genetic abnormalities in the treatment of FGFR1 disease. Currently we are investigating the possibility that targeting FGRF1 in sporadic AML that shows up-regulation of FGFR1 may be a means of treating this subset of AML and determining the mechanisms of resistance to FGFR1 inhibitors in cell lines developed in vitro and in vivo overexpressing FGFR1.