Professor, Department of Medicine (Oncology)
Professor, Department of Genetics
Miriam Mandel Faculty Scholar in Cancer Research
Orphan nuclear receptors (those that lack a well defined physiologic ligand) control nearly every major physiologic and biochemical process in eukaryotes - cell metabolism (e.g., cholesterol, energy, bile acids), xenobiotic detoxification, cell differentiation (e.g., gastrulation, retinal development), circadian rhythm, and cancer cell growth and apoptosis (e.g., NURR77). Alterations in the receptor are directly linked to human disease (e.g., NOR1 and extraskeletal myxoid chondrosarcomas). Of these receptors, the steroid and xenobiotic receptor (SXR) is a key regulator of genes encoding drug metabolizing and transport proteins. In addition, SXR has been implicated in cancer drug resistance, carcinogenesis and pathophysiologic states like osteomalacia. Our laboratory focuses on defining the role of SXR and other orphans by using novel and dynamic models of human pathophysiology in (i) xenobiotic metabolism and pharmacology and (ii) carcinogenesis, organogenesis and anticancer drug resistance.
1. Huang H, Wang H, Ganjam K, Staudinger J, Redinbo M, Mani S. (2007) Inhibiting the transcriptional control of drug metabolism. Oncogene. 26(2):258-68.
2. Wang H, Huang H, Li H, Teotico DG, Sinz M, Baker SD, Staudinger J, Kalpana G, Redinbo MR, Mani S. (2007) Activated Pregnenolone X- Receptor Is a Target for Ketoconazole and Its Analogs. Clin Cancer Res. 13:2488-2495
3. Wang H, Li H, Moore LB, Maglich JM, Goodwin B, Price R, Itoop ORR, Jones SA, Wisely B, Creech K, Parks DJ, Collins JL, Willson TM, Kalpana G, Xie W, Redinbo M, Moore JT, Mani S. (2007) The Phytoestrogen Coumestrol is a Naturally Occuring Antagon ist of the Pregnane X Receptor (PXR). Mol Endocrinol. 22:838-57
4. Ekins S*, Chang C*, Mani S*, Krasowski MD, Reschly EJ, Iyer M, Kholodovych V, Ai N, Welsh WJ, Sinz M, Swaan PW, Patel R, Bachmann K. (2007) Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Mol Pharmacol. 72:592-603 (*equal contribution)
5. Gupta D, Venkatesh M, Wang H, Kim S, Sinz M, Goldberg GL, Whitnet K, Mani S. Expanding the roles for PXR in Cancer: Proliferation and Drug Resistance in Ovarian Cancer. (2008) Clin Cancer Res 14(17):5332-40.
6. Mani S. (2008) Orphan Nuclear Receptors, Encyclopedia of Cancer (2nd ed.) Editor: Manfred Schwab., Springer Verlag GmbH, Heidelberg
7. Das B, Madhukumar AV, Kim S, Sinz M, Zvyaga TA, Power EC, Ganellin CR, Mani S. (2008) Synthesis of novel ketoconazole derivatives as antagonists of the human Pregnane X Receptor (PXR; NR1I2l also termed SXR, PAR). Bioorg Med Chem Lett. 18(14):3974-7
8. Ekins S, Kholodovych V, Ai N, Sinz M, Gal J, Gera L, Welsh WJ, Bachmann K, Mani S. (2008) COMPUTATIONAL DISCOVERY OF NOVEL LOW MICROMOLAR HUMAN PREGNANE X RECEPTOR ANTAGONISTS. Mol Pharmacol. 74(3):662-72
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Albert Einstein College of Medicine
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