Background: The cytoskeleton of eukaryotic cells participates in various cellular functions such as motility, secretion, signaling and proliferation. Microtubules (MTs) are an integral part of the cytoskeleton. Among anti-cancer agents, drugs targeting tubulin or MTs are among the most, if not the most, effective class of agents. The list of compounds that bind to tubulin or the MTs is large and continues to expand. The overwhelming majority are natural products, and their chemical structures are remarkably diverse. The vinca alkaloids were introduced in the 1950's, and although they were useful in a wide range of malignancies, interest in developing new agents targeting MTs gradually declined, until the introduction of Taxol. Arguably the most effective agent since cisplatin, the remarkable activity of Taxol stimulated interest in tubulin and MTs as targets for chemotherapy. The clinical success of Taxol has led to a wealth of new scientific knowledge, reinforced the importance of the tubulin/MT system as a target for cancer chemotherapy and spurred efforts to identify novel tubulin-active agents. In keeping with the research focus of the laboratory on the problem of drug resistance, we initially began studies aimed at identifying non-Pgp mechanisms of paclitaxel resistance. Selections performed with paclitaxel in the presence of verapamil succeeded in isolating cell lines with acquired resistance to paclitaxel that did not over-express MDR 1. Characterization of these cells led to the identification of mutations in the predominant tubulin isotype, M40. Similar studies performed using two additional tubulin stabilizing agents, epothilone A and epothilone B, led to the isolation of drug resistant cells which were also shown to harbor mutations in beta tubulin. In the field of MT targeting agents (MTAs), our current research goals are to (1) to increase our understanding of how MTAs interact with tubulin and lead to cell death; (2) understand the mechanisms of resistance to MTAs; and (3) develop assays to monitor the pharmacodynamics of MTAs in patients. In the clinic, we continue to conduct trials examining MTAs. Project Description and Plans: Given our success in identifying mutations in paclitaxel- and epothilone-resistant cells, and encouraged by the information accumulated and the lessons learned, we began selections with HTI-286 a synthetic hemiasterlin in development by Wyeth-Ayerst. The hemiasterlins are sponge-derived tripeptides that depolymerize existing MTs and inhibit MT assembly. Since hemiasterlins are poor Pgp substrates, they have been considered attractive candidates for cancer therapy. We were interested in the hemiasterlins for several reasons: (1) We had worked with paclitaxel and the epothilones, two agents that promote MT polymerization, and we were interested in investigating a depolymerizing agent; and (2) Unlike paclitaxel and the epothilones, the binding site of the hemiasterlins is less well defined, and it offered us the opportunity of contributing to its elucidation by identifying crucial residues as we had done with paclitaxel and the epothilones. The basis of resistance to HTI-286 was examined in cell populations derived from A2780/1A9 cells selected in HTI-286. A2780/1A9-HTI-resistant cells (1A9-HTIR series) were 57- to 89-fold resistant to HTI-286. Cross-resistance (3 to 186 fold) was observed to other MT depolymerizing drugs, with collateral sensitivity (2 to 14 fold) to tubulin polymerizing agents. Evaluation of the percentage of polymerized and soluble tubulin in 1A9 parental and 1A9-HTIR cells corroborated the HTI-286 cytotoxicity data. Specifically, we were able to demonstrate the presence of more stable MTs in the resistant cell populations by several criteria.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010625-02
Application #
7292914
Study Section
(MOB)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Widemann, Brigitte C; Goodspeed, Wendy; Goodwin, Anne et al. (2009) Phase I trial and pharmacokinetic study of ixabepilone administered daily for 5 days in children and adolescents with refractory solid tumors. J Clin Oncol 27:550-6
Edgerly, Maureen; Fojo, Tito (2008) Is there room for improvement in adverse event reporting in the era of targeted therapies? J Natl Cancer Inst 100:240-2
Trostel, Shana Y; Sackett, Dan L; Fojo, Tito (2006) Oligomerization of p53 precedes its association with dynein and nuclear accumulation. Cell Cycle 5:2253-9
Niederhuber, John E; Fojo, Tito (2006) Treatment of metastatic disease in patients with neuroendocrine tumors. Surg Oncol Clin N Am 15:511-33, viii
Demidenko, Zoya N; Fojo, Tito; Blagosklonny, Mikhail V (2005) Complementation of two mutant p53: implications for loss of heterozygosity in cancer. FEBS Lett 579:2231-5
Zhuang, Sen H; Agrawal, Manish; Edgerly, Maureen et al. (2005) A Phase I clinical trial of ixabepilone (BMS-247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days. Cancer 103:1932-8
Fojo, Antonio Tito; Menefee, Michael (2005) Microtubule targeting agents: basic mechanisms of multidrug resistance (MDR). Semin Oncol 32:S3-8
Low, Jennifer A; Wedam, Suparna B; Lee, James J et al. (2005) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 23:2726-34
Rao, V Koneti; Knutsen, Turid; Ried, Thomas et al. (2005) The extent of chromosomal aberrations induced by chemotherapy in non-human primates depends on the schedule of administration. Mutat Res 583:105-19
Agrawal, Manish; Edgerly, Maureen; Fojo, Tito et al. (2003) Treatment of recurrent cervical adenocarcinoma with BMS-247550, an epothilone B analog. Gynecol Oncol 90:96-9

Showing the most recent 10 out of 11 publications