1. Deregulated epigenetic mechanisms involving histone acetylation and methylation, which govern the loss of differentiation and enhanced proliferation and survival of human cancer cells. 2. The role of molecular chaperones, e.g., heat shock proteins, in preserving the active conformation of the cancer associated onco-protein kinases and transcription factors and controlling cancer cell apoptosis or autophagy. 3. Preclinical testing and clinical trials of novel combinations of epigenetics and molecular chaperone-targeted agents with inhibitors of oncoprotein kinases and transcription factors in leukemia/lymphoma and cancers.

Through our basic research, we hope to further elucidate the perturbations in epigenetic mechanisms causing cancer and probe the dependence of aberrant cancer cell signaling on molecular chaperones -- attributes critical for cancer transformation and survival. This knowledge will illuminate novel cancer targeted treatment strategies for pre-clinical testing and subsequent implementation in therapeutic trials in the clinic. The hope is to fulfill this vision by creating the Georgia Bench-to-Clinic Programs of Cancer Epigenetics and Chaperone Biology at the Medical College of Georgia Cancer Center.

The research in my laboratory is focused on determining how pan-histone deacetylase (HDAC) inhibitors (HDIs), by inducing histone acetylation and demethylation, selectively causes growth arrest, differentiation and cell death of human leukemia and cancer cells. We recently discovered that, by inhibiting the enzyme HDAC6, HDI treatment also induces acetylation of heat shock proteins 90 and 70, which undermines their function as molecular chaperones. How this outcome compromises the proper folding and functions of the cancer causing cell surface receptors and internal protein kinases and transcription factors is under further study. The accumulation of unfolded and dysfunctional proteins leads to an initially protective but ultimately lethal effect on cancer cells. My laboratory is evaluating how inhibition of HDAC6, hsp90 and hsp70 function can be transformed into therapeutic strategies that exploit the lethal effects of the toxic unfolded and dysfunctional proteins to eradicate cancers endowed with multiple mechanisms to evade cell death.

Unique and enabling support provided by the Georgia Research Alliance and MCG.