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).
Selected Cancer-Related Publications:
Jazirehi AR, Economou JS. Proteasome inhibition blocks NF-kappaB and ERK1/2 pathways, restores antigen expression, and sensitizes resistant human melanoma to TCR-engineered CTLs. Mol Cancer Ther. 2012 Jun;11(6):1332-41. Epub 2012 Apr 24
Jazirehi AR, Wenn PB, Damavand M. Therapeutic implications of targeting the PI3Kinase/AKT/mTOR signaling module in melanoma therapy. Am J Cancer Res. 2012 Feb 15;2(2):178-91.
Masood A, Shahshahan MA, Jazirehi AR. Novel approaches to modulate apoptosis resistance: basic and clinical implications in the treatment of chronic lymphocytic leukemia (CLL). Curr Drug Deliv. 2012 Jan;9(1):30-40.
Jazirehi AR, Baritaki S, Koya RC, Bonavida B, Economou JS. Molecular mechanism of MART-1+/A0201+ human melanoma resistance to specific CTL-killing despite functional tumor-CTL interaction. Cancer Res. 2011 Feb 15;71(4):1406-17. Epub 2010 Dec 15
Jazirehi AR. Regulation of apoptosis-associated genes by histone deacetylase inhibitors: implications in cancer therapy. Anticancer Drugs. 2010 Oct;21(9):805-13.