Our research efforts are directed toward discovering molecular targets that are selective for cancer, developing agents that are selectively toxic to cancer cells, and devising optimal combinations of therapeutic agents aimed at different molecular pathways for the prevention and treatment of cancer. We are currently focusing our efforts in understanding the role of PER-ARNT-SIM (PAS) homology-domain proteins in carcinogenesis and developing small molecules to treat Bcl-2 overexpressing cancers. Kolluri et al. 2008. Cancer Cell.
Nuclear Receptors as Therapeutic Targets in Cancer: Nuclear receptors are a large superfamily of ligand-modulated transcription factors comprising receptors for steroids, retinoids and thyroid hormones. Nuclear receptors regulate a wide variety of processes and play a key role in development, physiology and disease. The estrogen receptor, retinoic acid receptor, vitamin D receptor, androgen receptor and peroxisome proliferators-activated receptor are examples of ligand-activated transcription factors. Nuclear receptors have ligand binding pockets, which can be targeted by small molecules to modulate their function and therefore are suitable pharmacological targets. Many of these receptors potently regulate cell growth and differentiation. Because of this they are excellent molecular targets for developing anti-cancer therapeutics. Our research goal is to understand the mechanism of action of some of these receptors in both normal and cancer cells and to develop nuclear receptor-based therapeutics for prevention and treatment of cancer. Kolluri et al. 2005. PNAS.
Understanding Ah Receptor Signaling: Dioxins are ubiquitous environmental pollutants and are potent mammalian toxins. Ah receptor (AhR), a ligand activated transcription factor belonging to the basic-helix-loop-helix (bHLH)-Per-AhR/Arnt-Sim (PAS) protein family, mediates the toxicity of dioxins and structural analogues. We are investigating AhR-mediated actions in cancer (O’Donnell et al. 2014. Cell Death Dis.), in the immune system (Punj et al. 2014. PLoS One. in collaboration with Dr. Nancy Kerkvliet) and in zebrafish models (O’Donnell et al. 2010. PLoS One. in collaboration with Dr. Robert Tanguay).
Hypoxia-inducible Factor as a Target for Cancer Therapy: A major strategy in developing new cancer chemotherapeutics is to identify and target biological processes that differ between normal and malignant cells. Hypoxia, a reduction in the normal level of oxygen in tissue, occurs during cancer progression. Tumors become hypoxic because their new blood vessels are abnormal and they outgrow their blood supply. Cancer cells undergo genetic and adaptive changes that allow them to survive and proliferate in a hypoxic environment. These processes contribute to malignancy and aggressive tumor behavior.
Hypoxia inducible factor 1 (Hif-1) is a key protein factor induced by hypoxia and is involved in determining the levels of many protein factors in cancer cells. Vascular endothelial growth factor (VEGF), which promotes new blood vessel growth in tumors, is one of the important genes induced by Hif-1. Other genes regulated by Hif-1 activation are expressed at higher levels in cancer cells than in their normal tissue counterparts, and have roles in progression cancer. Hif-1 activity is also correlated with poor response to radiation therapy and chemotherapy. Our laboratory is interested in identifying pathways that disrupt Hif-1signaling in cancer cells in order to develop novel cancer therapeutics.
