Sucharita Mistry

Research

Microtubules are dynamic protein polymers that are essential for a myriad of cellular functions, including mitosis, intracellular transport, polarity, and motility. During cell division, the mitotic spindle, which is composed of microtubule polymers of alpha/beta tubulin heterodimers, plays the primary role in the segregation of chromosomes to the two daughter cells. The movement of chromosomes toward the spindle poles is made possible by the dynamic instability of microtubules that switches between phases of elongation and shortening. The dynamics of microtubule during the different phases of the cell cycle is regulated by two major classes of proteins, microtubule-stabilizing proteins and microtubule destabilizing proteins. Stathmin is the founding member of a family of microtubule-destabilizing proteins that regulate the polymerization and depolymerization of microtubules. It plays a critically important role in the assembly and disassembly of the mitotic spindle. Thus, stathmin is one of the key regulators of the microtubule cytoskeleton and the mitotic spindle.  In addition to its well-documented role in cell proliferation, stathmin also plays an important role in cell motility and cancer metastasis.  Interestingly, stathmin is expressed at high levels in nearly all types of human cancers and its overexpression is directly linked to disease progression. Hence, stathmin provides an attractive molecule to target in cancer therapies that aim to disrupt the mitotic apparatus of proliferating cancer cells.

A major focus of my research program is geared towards developing novel cancer therapies by using stathmin as a potential therapeutic target, mainly in solid tumor malignancies including breast and prostate cancer. We are developing two different approaches for targeting stathmin function in cancer cells.  As a first step, we designed ribozymes that target stathmin mRNA for degradation in cancer cells. We had previously cloned the genes that encode these ribozymes in adenoviral gene transfer vectors. We are currently testing the utility of these recombinant adenoviruses in in vitro and in vivo models of breast cancer. These studies may lead to the development of stathmin based gene therapy strategies for the treatment of localized early stage breast cancer.  A second strategy is aimed towards developing systemic pharmacological approaches that target stathmin function by interfering with its interaction with tubulin in widespread tumor cells. Towards this end, we are testing stathmin-like peptide drugs in in vitro and in vivo models of breast cancer. We are also developing an assay to screen chemical libraries in a high throughput setting to identify small molecule inhibitors that interfere with stathmin-tubulin interaction. The future development of such candidates into effective drugs may offer hope to a large number of patients who die from this dreadful malignancy.