The Gutierrez Laboratory is focused on discovering molecular pathogenesis and therapeutic targets in treatment-resistant human cancer. Our understanding of mutations that induce tumorigenesis has improved markedly over the past several decades, but the molecular determinants of treatment resistance remain very poorly understood. Indeed, we often lack the ability to accurately identify the subset of patients whose tumors will be resistant to conventional chemotherapy. Moreover, the available therapeutic options we have for patients with such treatment-resistant tumors are too often woefully inadequate. The primary objective of our work is to identify mechanisms of treatment resistance and to discover novel effective therapies for patients with chemoresistant human cancer. Our approach combines functional genetics and biochemistry in the zebrafish model system and in human tumor cells.

Molecular Pathogenesis of High-Risk T-Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of T-cell progenitors that has a peak incidence in older children and young adults. Although the intensification of therapy has improved outcomes for pediatric patients, this disease remains fatal in 25% of children and in 60% of adults. Until recently, it was impossible to accurately identify at diagnosis the subset of patients with T-ALL whose disease will be resistant to standard therapy. Our work, together with that of the Campana group at St. Jude, has recently defined a very high-risk subset of T-ALL that is characterized by differentiation arrest at the earliest stages of T-cell development, defined either by absence of biallelic TCRγ deletion (ABD) or by an early T-cell progenitor (ETP) phenotype. These leukemic cells harbor a signature implicating upregulation of the PI3K-AKT pathway, often as a result of PTEN deletions. To define the functional significance of PTEN inactivation in T-ALL, we have generated a zebrafish model of high-risk T-ALL, and used it to show that high-risk PTEN-inactivated T-ALL cells are resistant to the therapeutic effects of MYC oncogene inactivation, in contrast to PTEN-wild type tumors. Current efforts in the lab are focused on the identification of novel effective therapies for high-risk T-ALL.

Therapeutic Targets in Well-Differentiated Liposarcoma

Liposarcoma is the most common sarcoma of humans, and the well-differentiated liposarcoma (WDLPS) subtype accounts for 50% of these cases. Although complete surgical resection can be curative, these tumors often arise in deep anatomical locations, where their propensity to enwrap vital structures typically makes complete resection difficult or impossible. There are no therapeutic regimens known to prolong survival for these patients, leading to very high mortality rates. Despite its frequency, the molecular pathogenesis underlying well-differentiated liposarcoma is very poorly understood, largely due to the lack of suitable experimental models. We have recently developed the first animal model of well-differentiated liposarcoma in the zebrafish model system, and used it to show that aberrant AKT pathway activation drives the growth of human tumors. Current work in the lab is focused on exploiting the zebrafish model to dissect molecular pathogenesis and discover novel therapeutic targets for this chemoresistant disease.

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