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Faculty Profile

Susan B. Horwitz, Ph.D.

Dr. Susan B. Horwitz

Distinguished Professor, Department of Molecular Pharmacology

Co-Chair, Department of Molecular Pharmacology

Rose C. Falkenstein Chair in Cancer Research

 

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.

 

Selected Publications

Rao, S., He, L., Chakravarty, S., Ojima, I., Orr, G.A. and Horwitz, S.B. (1999) Characterization of the Taxol Binding Site on the Microtubule. Identification of Arg282 in b-tubulin as the Site of Photoincorporation of a 7-Benzophenone Analogue of Taxol. J. Biol. Chem. 274, 38990- 37994.

He, L., Jagtap, P.G., Kingston, D.G.I., Shen, H.-H., Orr, G.A. and Horwitz, S.B. (2000) A Common Pharmacophore for Taxol and the Epothilones based on the Biological Activity of a Taxane Molecule Lacking a C-13 Side Chain. Biochemistry 39, 3972-3978.

He, L., Yang, C.-P.H. and Horwitz, S.B. (2001) Mutations in b-tubulin Map to Domains Involved in Regulation of Microtubule Stability in Epothilone-Resistant Cell Lines. Mol. Cancer Therap. 1, 3-10.

Rao, S., Aberg, F., Nieves, E., Horwitz, S.B. and Orr, G.A. (2001) Identification by Mass Spectrometry of a New b-Tubulin Isotype Expressed in Human Breast and Lung Carcinoma Cell lines. Biochemistry 40, 2096-2103.

McDaid, H.M. and Horwitz, S.B. (2001) Selective Potentiation of Taxol-induced Cell Death by MEK Inhibition in Human Cancer Cell Lines. Molecular Pharm. 60, 290-301.

McDaid, H.M., Mani, S., Shen, H.-J., Muggia, F. Sonnichsen, D. and Horwitz, S.B. (2002) Validation of the Pharmacodynamics of BMS-247550, an Analog of Epothilone B, During a Phase I Clinical Study. Clinical Cancer Res. 8, 2035- 2043.

Martello, L.A., Verdier-Pinard, P., Shen, H.-J., He, L., Torres, K., Orr, G.A. and Horwitz, S.B. (2003) Elevated Levels of Microtubule Destabilizing Factors in a Taxol-resistant/dependent A549 Cell Line with an a-Tubulin Mutation. Cancer Research 63, 1207-1213.

Verdier-Pinard, P., Wang, F., Martello, L.A., Orr, G.A. and Horwitz, S.B. (2003) Analysis of Tubulin Isotypes and Mutations from Taxol-resistant Cells by Combined Isoelectrofocusing and Mass Spectrometry. Biochemistry 42, 5349-5357.

Verdier-Pinard, P., Wang, F., Burd, B., Angeletti, R.H., Horwitz, S.B. and Orr, G.A. (2003) Direct Analysis of Tubulin Expression in Cancer Cell Lines by Electrospray Ionization Mass Spectrometry. Biochemistry 42, 12019-12027.

Orr, G.A., Verdier-Pinard, P., McDaid, H.M. and Horwitz, S.B. (2003) Mechanisms of Taxol Resistance Related to Microtubules. Oncogene 22, 7280-7295.

Chen, J.-G., Yang, C.-P. H, Cammer, M. and Horwitz, S.B. (2003) Gene Expression and Mitotic Exit Induced by Microtubule Stabilizing Drugs. Cancer Research 63, 7900-7906.

Mani, S., McDaid, H.M., Hamilton, A., Hochster, H., Cohen, M.B., Khabelle, D., Griffin, T., Lebwohl, D.E., Liebes, L., Muggia, F. and Horwitz, S.B. (2004) Phase I Clinical and Pharmacokinetic Study of BMS-247550, a novel derivative of Epothilone B, in Solid Tumors. Clinical Cancer Res. 10, 1289-1298.

Chen, J.-G., Yang, C.-P. H, Cammer, M. and Horwitz, S.B. (2003) Gene Expression and Mitotic Exit Induced by Microtubule Stabilizing Drugs. Cancer Research 63, 7900-7906.

Mani, S., McDaid, H.M., Hamilton, A., Hochster, H., Cohen, M.B., Khabelle, D., Griffin, T., Lebwohl, D.E., Liebes, L., Muggia, F. and Horwitz, S.B.  (2004)  Phase I Clinical and Pharmacokinetic Study of BMS-247550, a novel derivative of Epothilone B, in Solid Tumors. Clinical Cancer Res. 10, 1289-1298.

Honore, S., Kamath, K., Braguer, D., Horwitz, S.B., Wilson, L., Briand, C. and Jordan, M.A. (2004) Synergistic Suppression of Microtubule Dynamics by Discodermolide and Paclitaxel in Non-Small Cell Lung Carcinoma Cells. Cancer Research 64, 4957-4964.

Klein, L.E., Freeze, B.S., Smith III, A.B. and Horwitz, S.B. (2005) The Microtubule Stabilizing Agent Discodermolide is a Potent Inducer of Accelerated Senescence. Cell Cycle 4:3, 124-130.

McDaid, H.M., Lopez-Barcons, L., Grossman, A., Lia, M., Keller, S., Perez-Solar, R. and Horwitz, S.B. (2005) Enhancement of the Therapeutic Efficacy of Taxol by the MEK Inhibitor CI-1040 in Nude Mice Bearing Xenografts. Cancer Research 65, 2854-2860.

Yang, C.-P.H., Verdier-Pinard, P., Wang, F., Lippaine-Horvath, E., He, L., Orr, G.A. and Horwitz, S.B. (2005) A Highly Epothilone B-resistant A549 Cell Line with Mutations in Tubulin that Confer Drug Dependence. Mol. Cancer Ther. 4, 987-995.

Ikui, A.E., Yang, C.-P.H., Matsumoto, T. and Horwitz, S.B. (2005) Low Concentrations of Taxol Cause Mitotic Delay Followed by Premature Dissociation of p55CDC from Mad2 and BubR1 and Abrogation of the Spindle Checkpoint, Leading to Aneuploidy. Cell Cycle 4:10, 1385-1388.

Mani, S., Huang, H., Sundarababu, S., Liu, W., Ganjam, K. Smith III, A.B., and Horwitz, S.B. (2005) Activation of the Steroid and Xenobiotic Receptor (hPXR or SXR) by Non-Taxane Microtubule Stabilizing Agents. Clinical Cancer Res. 11(17), 6359-6369. 

Verdier-Pinard, P., Shahabi, S., Wang, F., Burd, B., Goldberg, G.L., Orr, G.A. and Horwitz, S.B. (2005) Detection of Human bV-Tubulin Expression in Epithelial Cancer Cell Lines by Tubulin Proteomics. Biochemistry 44, 15858-15870.

Huang, G.S., Lopez-Barcons, L., Perez-Soler, R., Freeze, B.S., Smith III, A.B., Goldberg, G.L., Horwitz, S.B. and McDaid, H.M. (2006) Potentiation of Taxol Efficacy by Discodermolide in Ovarian Carcinoma Xenograft-bearing Mice. Clinical Cancer Res. 12, 298-304.

Xiao, H., Verdier-Pinard, P., Fernandez-Fuentes, N., Burd, B., Angeletti, R., Fiser, A., Horwitz, S.B. and Orr, G.A. (2006) Insights into the Mechanism of Microtubule Stabilization by Taxol.  Proc. Natl. Acad. Sci. 103, 10166-10173.

Xia, S., Kenesky, C.S., Rucker, P.V., Smith III, A.B., Orr, G.A. and Horwitz, S.B. (2006) A Photoaffinity Analog of Discodermolide Specifically Labels a Peptide in b-tubulin.  Biochemistry 45, 11762-11775.

 

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Contact

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Golding Building, Room 201
Bronx, NY 10461

Tel: 718.430.2163
Fax: 718.430.8922
susan.horwitz@einstein.yu.edu

 
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Media Coverage

Medscape Medical News profiles Dr. Susan Band Horwitz, who will receive the Eighth American Association for Cancer Research (AACR) Award for Lifetime Achievement in Cancer Research on April 3. (Free subscription required.)

CR magazine (a publication of the American Association for Cancer Research) profiles Dr. Susan Band Horwitz on her role in evaluating and championing the use of Taxol, the revolutionary cancer drug now widely used to treat breast and ovarian cancers.

More media coverage