Gerald V. Denis, PhD
AB, Harvard College
MSc, University of Tokyo
PhD, University of California, Berkeley
Postdoctoral Training, University of Massachusetts Worcester
BUMC Research Profile
We are interested in the BET bromodomain proteins, a family of transcriptional co-regulators comprised of BRD2 (originally named RING3), BRD3 and BRD4 in somatic cells, which are important in chromatin control of genes that encode cytokines and chemokines, as well as genes that control cellular proliferation. These pathways are particularly important in human cancers of the immune system, breast, prostate, lung and other tissues. Our lab pioneered studies of the BET bromodomain proteins: we were the first group to report a function for a BET protein and link these co-regulators to human cancer. The BET protein field has grown from sixteen papers, when we published the first papers, to over 1,300 to date; they have since been implicated in several cancer types. Careful targeting of these proteins is critical because BRD2 and BRD4 oppose each other in several transcriptional programs, such as the epithelial-to-mesenchymal transition in breast cancer. Current small molecules that inhibit all the family members, called ‘pan-BET inhibitors’ obliterate these important differences and create confusion for mechanism.
We are now realizing that BET proteins regulate cytokine/chemokine production in the immune cells that infiltrate the microenvironment of prostate and breast cancer, which are important for chemoresistance and metastasis. The BET family also regulates the expression of immune exhaustion proteins such as PD-1 and PD-L1, which are exciting new targets for immunotherapy in a number of cancers. We are currently investigating how the BET proteins are important for breast and prostate cancer in adults with Type 2 diabetes and other metabolic abnormalities, which are also chronic inflammatory diseases. We hypothesize that the elevated PD-1 and PD-L1 expression in our cancer disparities cohorts of patients may on the one hand contribute to tumor progression and metastasis, but on the other hand render these patients well suited to new immune checkpoint therapies for cancer that take advantage of PD-1. Our discoveries should uniquely benefit the cancer patients at Boston Medical Center, where the burden of both advanced cancer and metabolic disease co-morbidity is high. These patients stand to benefit greatly from innovative clinical approaches that consider metabolic and inflammatory status.