lmayer@celatorpharma.com

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Research Interests:

Research in my laboratory is centered around two major programs; 1) characterization and therapeutic modulation of multidrug resistance (MDR) and 2) development and characterization of liposomal drug delivery systems.

Nearly half of all human cancers currently treated with chemotherapy will develop resistance to a wide variety of unrelated anticancer drugs. This resistance has been shown to be associated with altered drug transport properties in tumor cells of certain types whereas in others the genetic machinery that dictates whether tumor cells undergo apoptosis and die in response to chemotherapy is changed such that resistance occurs. We are investigating the relative roles of these mechanisms, particularly for P-glycoprotein and Bcl-2 in determining the overall level of drug resistance in cells obtained from clinical tumor specimens and cultured tumor cell lines. A key feature of this evaluation is to establish cause and effect relationships between various phenotypic markers of MDR and actual resistance to chemotherapeutic agents. We therefore focus on functional measurements of MDR and the ability of compounds known to block the mediators of the resistance mechanisms to sensitize the tumor cells to anticancer drugs. We then apply these concepts to in vivo models of MDR where we optimize the pharmacological characteristics of the MDR modulation strategies and assess their ability to improve the therapy of MDR tumors.

Liposomes have proven useful as drug delivery systems for tumor therapy due to their ability to selectively accumulate in many sites of tumor growth. This feature, which is often manifested by a decrease in the toxicity and/or increase in therapeutic potency of encapsulated agents, appears related to the more leaky vasculature of tumors where small (100 nm) liposomes extravasate and remain associated with the tumor for extended periods of time. In this research program, we are evaluating the therapeutic potential of liposome encapsulated conventional anticancer drugs (of which we have taken our liposomal vincristine formulation into clinical trials). In addition, we are developing novel systems to target the endothelium of tumor associated vasculature for improved delivery and site specific release of small molecules as well as biologicals such as antisense oligonucleotides. Investigations in this program range from formulation studies to characterization of the molecular response of therapeutic targets in animal models.

An additional facet of my research laboratory is its involvement in the Investigational Drug Program at the BC Cancer Agency which develops promising new therapeutic agents from the lab bench to the clinic. Formulation, analytical and preclinical activities are performed according to GMP and GLP guidelines in order to obtain Health Board permission to test these agents in Phase I and II clinical trials.