Tubulin Interactive Agents in Cancer Therapy
Along with Dr. Susan Horwitz, Dr. Mani has recently received approval to conduct an NCI-approved and funded phase I study to be started at Albert Einstein College of Medicine in November 1999 with anticipated completion of accrual by late 2000. The title of the study is, A Phase I Scientific Exploratory Study of Epothilone B Analog (BMS-247550) in Patients with Solid Tumors and Gynecologic Malignancies.
The Horwitz laboratory has demonstrated that taxol and related compounds achieve their pharmacologic activity by preferentially binding to microtubules rather than tubulin dimers. This results in stabilization of microtubules with inhibition of the dynamic reorganization of microtubules, which is essential to mitotic function and cell division. Disruption of mitotic function in cancer cells eventually results in apoptosis (programmed cell death).
Taxol®, a prototypical tubulin interactive agent, was approved by the US FDA for use in the treatment of ovarian cancer in 1992 and its effectiveness in treating other cancers (e.g., breast and lung) has been established. However, the majority of patients either do not respond to such treatment or relapse after treatment. The mechanisms of tumor cell resistance are complex and include mutations in $-tubulin, overexpression of MDR1 and other drug transporters, specific changes in various components of the signal transduction pathways (e.g., Her-2 overexpression), dysfunction apoptosis-regulating genes, and alterations in levels of endogenous regulators of microtubule dynamics, such as stathmin. These factors have motivated a search for novel antimitotic agents, which share the same mechanism of action as taxol but differ in their susceptibility to drug resistance mechanisms.
One such class of compounds is the epothilones, a novel non-taxane microtubule-binding agent obtained from the fermentation of the myxobacteria Sporangium cellulosum. Epothilones A and B have chemical structures distinct from taxol, are 30 times more water soluble than taxol, and competitively inhibit binding of [3H] taxol to the microtubule, implying that they share the same or overlapping binding sites on the microtubule. Like taxol, epothilone action is attributed to hyperstabilization of microtubules leading to mitotic arrest and apoptosis. Moreover, the epothilones are more potent than taxol in same cell lines and retain their activity in cell lines resistant to taxol due is overexpression of p-glycoprotein. A cell line with acquired $-tubulin mutations, resistant to taxol, is not cross-resistant to epothilone.
BMS-247550 is a semi-synthetic analog of epothilone B (BMS-205535), designed by Bristol Myers Squibb to overcome the metabolic instability of the natural product. Like taxol, BMS-247550 blocks cells in the mitotic phase of the cell division cycle and is a highly potent cytotoxic agent with IC50’s in the low nanomolar concentrations. BMS-247550 has demonstrated impressive anti-tumor activity in a number of pre-clinical human tumor models, including those that have intrinsic or acquired resistance, the latter associated with mutations in $-tubulin. These data suggest that BMS-247550 has the potential to be more efficacious than the current taxanes.
Since 1999, we have established an on-going phase I study – A Phase I Scientific Exploratory Study of Epothilone B Analog (BMS-247550) in Patients with Solid Tumors and Gynecologic Malignancies - and have presently established an active phase II for the compound. We are enrolling patients without a wait period at the phase II dose. Our phase I data confirm unequivocally that patients with traditional Taxane-refractory disease objective respond with better quality of life while on BMS-247550. In collating results from other studies to-date with BMS-247550, objective responses have been observed in chemotherapy-refractory melanoma, breast, lung, ovarian, and colorectal cancer. We have shown that the mechanisms of action of the drug in vitro are replicated in vivo (i.e., in patient’s tumor) and that this drug is NOT a substrate for MDR. Based on these encouraging results, we have moved forward in to phase II studies with BMS-247550 in breast, colorectal, gastric and melanoma. In addition to the epothilone analog, we have studied another novel microtubule interactive agent -T900607, (Tularik Inc., South San Francisco)(ASCO 2001, 2002-publish abstract after it comes out in print). Our future plans are to continue to build a portfolio of these novel agents at Montefiore Medical Center and the Albert Einstein College of Medicine.
