EINSTEIN FACULTY FACULTY PROFILE

Overview of Professional Interests

The research program in this laboratory is focused on: 1) the development of drugs derived from natural products, such as Taxol, for the treatment of malignancies and 2) the problem of drug resistance. The mechanism of action of Taxol, an antimitotic agent that enhances the polymerization of tubulin by forming stable microtubules, is being pursued. The novel structure of Taxol, its unique mechanism of action that was first described in this laboratory, and the positive results that have been observed in ovarian, breast and lung carcinomas have generated extensive interest in this drug. Photoaffinity analogues of Taxol have been utilized to define the binding cavity for the drug within b-tubulin. The goal is to understand at a molecular level the interaction of Taxol with the microtubule and the mechanisms by which the drug induces growth arrest and cell death. Recent evidence indicates that Taxol alters specific intracellular signal transduction events essential for drug-induced apoptosis. Newly discovered potentially important antitumor drugs, such as the epothilones and discodermolide that are currently in clinical trials and whose mechanism of action is similar to that of Taxol, are being actively investigated. We have searched for differences between these agents that could be exploited in the clinic and have reported that discodermolide is the first microtubule stabilizing agent that includes a powerful induction of accelerated senescence in its repertoire of tumor cell growth inhibitory mechanisms. Quantitative mass spectrometric-based methods to analyze the expression of tubulin isotypes and their posttranslational modifications are being developed. This is crucially important since there is accumulating evidence in human cancer cell lines, tissues and tumors that different isotypes exhibit differential sensitivity to Taxol and may also be related to Taxol resistance. This laboratory is committed to using the knowledge gained in research for the development of therapies for the treatment of human cancer. We are presently evaluating new drug combinations such as Taxol and signal transduction inhibitors that may have improved efficacy compared to single agents alone, using the non-small cell lung cancer xenograft model and human lung heterotransplants in nude mice. Taxol-resistant cell lines derived from mammalian tumor cells growing in tissue culture have been developed as model systems for studying drug resistance. Some of these cell lines display the multidrug resistance phenotype that includes overproduction of a plasma membrane phosphoglycoprotein, P-glycoprotein, that is coded for by an amplified or transcriptionally activated gene. Other mechanisms of Taxol-resistance relate to alterations in normal tubulin isotype expression and mutations in alpha- and beta-tubulin. Methodology has been developed that utilizes high-resolution isoelectrofocusing combined with mass spectrometry to analyze tubulin mutations in cell lines and human tumors. In addition, the laboratory is examining endogenous proteins such as MAPs and stathmin that may modulate drug resistance through their interactions with microtubules.