The goal of Dr. Ali Jazirehi’s laboratory is to focus on determination of the major signaling pathways and apoptosis-associated gene products responsible for apoptosis-resistance that can be regulated by sensitizing agents, thus averting the resistant phenotype of drug-refractory tumors. To this end, the functional complementation (sensitization) model is proposed, whereby treatment of tumor cells with a nontoxic sensitizing agent alters the expression profile of apoptosis-associated gene products (signal I), removes the inhibitory block in the apoptotic pathway and by lowering the apoptosis threshold sensitizes the tumor cells to the killing effects of the second agent (signal II) (e.g., cytotoxic ligands, biological response modifiers and/or chemo-therapeutic drugs).

The functional complementation model further attests to the contention that therapeutic compounds, in addition to the ability to directly induce apoptosis, are capable of altering the gene expression profile and decreasing the apoptosis threshold of drug-resistant tumor cells, thus overcoming the acquired or intrinsic apoptosis-resistance. Delineation of signaling pathways modulated by specific agents will reveal intracellular targets for therapeutic intervention in the treatment of refractory melanomas. Further, based on the genetic profile of tumors and identification of the targets that control response to treatment, it is possible to identify cancer patients suitable for alternative therapeutic intervention to circumvent the resistant phenotype (molecular signatures).