The research program in this laboratory is focused on: 1) the development of drugs derived from natural products, such as Taxol^® and 2) the problem of drug resistance. The mechanism of action of Taxol^®, a molecule 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. Our laboratory has used photoaffinity analogues of Taxol^® to define the binding cavity for the drug within β-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 in human tumors. 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 are related to Taxol^® resistance. A recent study from our laboratory indicated that compared with other β-tubulin isotypes, βIII-tubulin binds the least amount of Taxol^®. Of particular interest is the fact that in several cancers, overexpression of βIII-tubulin is associated with drug resistance. Our laboratory noted that one region of βIII-tubulin contains a unique residue compared with other isotypes. Molecular dynamic simulations indicated that the frequency of Taxol^® accommodating conformations decreased in the βIII-tubulin isotype compared with other tubulin isotypes.

This laboratory is committed to using the knowledge gained in research for the development of therapies for the treatment of human cancer.

O’Rourke, B., Yang, C-P., H., Sharp, D., Horwitz, S.B. (2014) Eribulin Disrupts EB1-Microtubule Plus Tip Complex Formation. Cell Cycle., 13(20):3218-3221. PMID:  25485501

Seagle, B-L., Yang, C-P., Eng, K.H., Dandapani, M., Odunsi-Akanji, O., Goldberg, G.L., Odunsi, K., Horwitz, S.B., Shahabi, S., (2015) TP53 Hot Spot Mutations in Ovarian Cancer: Selective Resistance to Microtubule Stabilizers In Vitro and Differential Survival Outcomes from The Cancer Genome Atlas., Gynecologic Oncology, 138:159-164. PMID:  25958320

Frimer, M., Levano, K.S., Rodriguez-Gabin, A., Wang, Y., Goldberg, G.L., Horwitz, S.B., Hou, J.Y. (2016) Germline Mutations of the DNA Repair Pathways in Uterine Serous Carcinoma. Gynecologic Oncology, 141:101-107. PMID:  27016235

Doodhi, H., Prota, A.E., Rodriguez-Garcia, R., Xiao, H., Custar, D.W., Bargsten, K., Katrukha, E.A, Hilbert, M., Hua, S., Grigoriev, I., Yang, C-P., Cox, D., Horwitz, S.B., Kapitein, L.C., Akhmanova, A., Steinmetz, M.O. (2016) Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes. Current Biology, 26, 1713–1721.  PMID:  27321995

Yang CP, Yap EH, Xiao H, Fiser A, Horwitz, S.B. 2-(m-Azidobenzoyl) Taxol Binds Differentially to Distinct β-tubulin Isotypes. (2016) Proceedings of the National Academy of Sciences 4;113 (40): 11294-11299. PMID:  27651486

Prota, A.E, , Bargsten, K., Redondo, M., Smith III, A.S., Yang, C-P, H., McDaid, H.M., Paterson. I., Horwitz, S.B., Fernando Díaz, J., and Steinmetz, M.O. (2017) Structural Basis of Microtubule Stabilization by Discodermolide.  Chem BioChem Communications,18, 1-6.  PMID:  28207984

Yang CP, Horwitz, S.B. (2017) Taxol®: The First Microtubule Stabilizing Agent.  International Journal of Molecular Sciences, 18,1733. PMID: 28792473

Matthew, D., Wang, Y., VanArsdale, A., Horwitz, S.B. and McDaid, H.M. (2017) Expression of βV-tubulin in Secretory Cells of the Fallopian Tube Epithelium as a Biomarker for Cellular Atypia.  International Journal of  Gynecological Cancer.  28, 363-370. PMID: 29298171

Yang CP, Wang, C., Ojima I., Horwitz, S.B.  (2018) Taxol® Analogues Exhibit Differential Effects on Photoaffinity Labeling of β-Tubulin and the Multidrug Resistance Associated P-Glycoprotein.  Journal of Natual Products.  81, 600-606. PMID: 29517223 Horwitz, S.B. (2019) Reflections on My Life with Taxol. Cell. 177, 1-4.