Vitamin D – Exploring Its Role in Osteoporosis and Cancer
Sara Peleg, MD Anderson
Department of Endocrine Neoplasia and Hormonal Disorders
The laboratory of Sara Peleg, Ph.D., focuses on the nuclear receptor for vitamin D. Nuclear receptors are transcription factors that function as transmitters of signals delivered by small lipophilic molecules such as steroid hormones and retinoids. These signals regulate embryonic development, cellular differentiation and organ physiology.
The physiologic role of vitamin D is to regulate calcium homeostasis and bone remodeling. Bone remodeling effects of vitamin D include activation of osteoclasts, which cause bone resorption, as well as induction of maturation and differentiation of bone-forming osteoblasts. Therefore, significant efforts have been made to develop synthetic vitamin D analogues, or deltanoids, to treat metabolic and metastatic bone disease without inducing excessive bone resorption or hypercalcemia. To that end, Dr. Peleg and her colleagues have developed the concept of hybrid vitamin D deltanoids, which are synthetic compounds that combine two types of building blocks—one to reduce calcemia, and the other to promote cellular differentiation. Because both of these deltanoid actions are mediated through the transcriptional activities of the vitamin D receptor (VDR), Dr. Peleg and her colleagues are studying how modifications in the structure of deltanoids may change the profile of their VDR-mediated biological activities.
Biochemical studies performed by this group determined the relationship between deltanoid structures and their contact points in the VDR’s ligand-binding pocket. They showed that the mode of interaction in the ligand-binding pocket has a fundamental effect on the outer shape of the VDR, and a direct impact on its interactions with cellular proteins (transcription coregulators) that modulate the level and spectrum of VDR transcriptional activities. Importantly, the change in the mode of interaction of several hybrid deltanoids with the VDR caused a cell-selective recruitment of VDR nuclear chaperones and transcription coregulators. Furthermore, in vitro and ex vivo studies with hybrid deltanoids have revealed that they induce transcriptional activity of the VDR in a cell- and tissue-selective fashion.
Dr. Peleg’s lab is translating their in vitro findings into preclinical studies using animal models of osteoporosis and prostate cancer-induced metastatic bone disease. The results of their research provide a foundation for the design of deltanoids that will have sufficient target cell and target gene specificity to be both potent and safe drugs for treatment of human disease.