Richard Ho, M.D., M.S.C.I.
Associate Professor of Pediatrics (Pediatric Hematology and Oncology)
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2220 Pierce Avenue
Nashville, TN 37232
Monroe Carell Jr. Children's Hospital at Vanderbilt
2200 Children's Way
Nashville, TN 37232
Vanderbilt University Medical Center
2220 Pierce Avenue
397 Preston Research Building
Nashville, TN 37232-6310
Dr. Ho is a pediatric hematologist/oncologist and physician scientist whose research focuses on the molecular mechanisms by which drug transporters contribute to overall chemotherapy disposition and interindividual response to drug therapy in pediatric oncology. Drug transport proteins have important roles in regulating the absorption, distribution, and excretion of many medications as well as endogenous substances.
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Dr. Ho is a pediatric hematologist/oncologist and physician scientist whose research focuses on the molecular mechanisms by which drug transporters contribute to overall chemotherapy disposition and interindividual response to drug therapy in pediatric oncology. Drug transport proteins have important roles in regulating the absorption, distribution, and excretion of many medications as well as endogenous substances. To this extent, a major focus in his lab centers on the contribution of uptake transporters, in particular the organic anion transporting polypeptide (OATP) family and bile acid uptake transporters, to the disposition of pediatric chemotherapeutic agents. In addition, another area of major focus is cancer pharmacogenetics, the study of the role of inheritance in the individual variation in chemotherapy response. Projects are primarily laboratory based with translational promise and rely on background knowledge in the fields of molecular biology and clinical pharmacology. His research has been continuously funded by grants (K08, R01) from the National Institute of General Medical Sciences (NIGMS/NIH) since 2007. Dr. Ho is also a co-investigator on a NIH-funded multicenter clinical trial evaluating the pharmacogenetics of vincristine neuropathy in children with acute lymphoblastic leukemia. Dr. Ho's clinical interests are focused on pediatric stem cell transplantation.
- M.D.-Vanderbilt University, Nashville, TN, 1997
- Pediatric Resident-Vanderbilt University Medical Center
- Research Fellow-Pediatric Hematology-Oncology and Clinical Pharmacology; Vanderbilt University
- Clinical Fellow-Pediatric Hematology-Oncology, Vanderbilt University
Drug Uptake Transporters and Chemotherapy Disposition
Our research program focuses on the molecular mechanisms by which drug transporters contribute to overall chemotherapy disposition and interindividual response to drug therapy in cancer therapy. Drug transport proteins have important roles in modulating the absorption, distribution, and excretion of many drugs and drug metabolites as well as endogenous substances. They tend to be highly expressed in tissues of importance to drug disposition, including the liver, intestine, kidney and at the blood:brain barrier. To this extent, a major focus in my lab centers on the contribution of specific drug uptake transporters, in particular the organic anion transporting polypeptide (OATP) family and bile acid uptake transporters, to the disposition of pediatric chemotherapeutic agents. In addition, another area of major focus is cancer pharmacogenetics, the study of the role of inheritance in the individual variation in chemotherapy response. Projects are primarily laboratory based with translational promise and rely on background knowledge in the fields of molecular biology and clinical pharmacology. We utilize a number of in vitro techniques to study these transporter proteins, including vaccinia-based expression systems for functional transport studies, drug screening, and drug inhibition studies, protein expression studies utilizing western analysis, immunohistochemistry and immunofluorescent confocal microscopy, and generation of polarized stable cell lines for directional transport studies and comprehensive kinetic analysis. We have also integrated animal models utilizing recently generated knockout mice for various transporter genes into our research program for in vitro:in vivo correlative data in our drug disposition studies.
Moreover, our research has important implications for drug discovery and experimental therapeutics. ADME (absorption, distribution, metabolism and excretion) deficiency is one of the major causes of failure during drug development. In vitro ADME screening of potential lead compounds and drug candidates in the early discovery phase has been employed as a more cost-effective approach to identify compounds that have unfavorable drug-like characteristics. Many compounds with promising pharmacological characteristics never become drugs because they have poor solubility, quickly degrade in biological fluids and tissues or rapidly metabolized in the liver. Utilizing our in vitro screening transport and detailed studies of kinetic analysis, we are able to identify potential drug compounds as substrates for a complement of drug uptake and efflux transporters, which may have important implications not only for drug disposition in vivo, but also for drug toxicity, efficacy and tissue targeting. Furthermore, as many of the transporters we study are known to be polymorphic, we have the ability to assess transporter polymorphisms for differential transport of drugs and/or drug metabolites, which may have significant consequences for determining the interindividual response to anticancer agents.
Drug disposition and toxicity
Pharmacogenetics and pharmacokinetics
- Frangoul, H, Min, E, Wang, W, Chandrasekhar, R, Calder, C, Evans, M, Manes, B, Bruce, K, Brown, V, Ho, R, Domm, J Incidence and risk factors for hypogammaglobulinemia in pediatric patients following allo-SCT. Bone Marrow Transplant, 48(11), 1456-9, 2013.
- Lavoie Smith, EM, Li, L, Hutchinson, RJ, Ho, R, Burnette, WB, Wells, E, Bridges, C, Renbarger, J Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia. Cancer Nurs, 36(5), E49-60, 2013.
- Vear, SI, Stein, CM, Ho, RH Warfarin pharmacogenomics in children. Pediatr Blood Cancer, 60(9), 1402-7, 2013.
- Minson, KA, Prasad, P, Vear, S, Borinstein, S, Ho, R, Domm, J, Frangoul, H t(17;19) in Children with Acute Lymphocytic Leukemia: A Report of 3 Cases and a Review of the Literature. Case Rep Hematol, 2013563291, 2013.
- McManus, MP, Wang, L, Calder, C, Manes, B, Evans, M, Bruce, K, Ho, RH, Domm, J, Frangoul, H Comparison of pre-cryopreserved and post-thaw-and-wash-nucleated cell count on major outcomes following unrelated cord blood transplant in children. Pediatr Transplant, 2012.
- Korhonen, K, Lovvorn, HN, Koyama, T, Koehler, E, Calder, C, Manes, B, Evans, M, Bruce, K, Ho, RH, Domm, J, Frangoul, H Incidence, risk factors, and outcome of pneumatosis intestinalis in pediatric stem cell transplant recipients. Pediatr Blood Cancer, 58(4), 616-20, 2012.
- Degorter, MK, Ho, RH, Leake, BF, Tirona, RG, Kim, RB Interaction of Three Regiospecific Amino Acid Residues Is Required for OATP1B1 Gain of OATP1B3 Substrate Specificity. Mol Pharm, 9(4), 986-95, 2012.
- Eckrich, MJ, Yang, E, Domm, J, Ho, R, Calder, C, Manes, B, Bleesing, J, Frangoul, H A unique clinical presentation of X-linked lymphoproliferative syndrome with a novel mutation in SH2D1A and review of the literature. J Pediatr Hematol Oncol, 33(1), e39-42, 2011.
- Esbenshade, AJ, Ho, RH, Shintani, A, Zhao, Z, Smith, LA, Friedman, DL Dapsone-induced methemoglobinemia: a dose-related occurrence. Cancer, 117(15), 3485-92, 2011.
- Ho, RH, Leake, BF, Urquhart, BL, Gregor, JC, Dawson, PA, Kim, RB Functional characterization of genetic variants in the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). J Gastroenterol Hepatol, 26(12), 1740-8, 2011.
- Schwarz, UI, Meyer zu Schwabedissen, HE, Tirona, RG, Suzuki, A, Leake, BF, Mokrab, Y, Mizuguchi, K, Ho, RH, Kim, RB Identification of novel functional organic anion-transporting polypeptide 1B3 polymorphisms and assessment of substrate specificity. Pharmacogenet Genomics, 21(3), 103-14, 2011.
- Ho, RH, Leake, BF, Kilkenny, DM, Meyer Zu Schwabedissen, HE, Glaeser, H, Kroetz, DL, Kim, RB Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet Genomics, 20(1), 45-57, 2010.
- Eckrich, MJ, Domm, J, Ho, R, Whitlock, JA, Frangoul, H Autologous stem cell transplant in a patient with Down syndrome and relapsed Hodgkin lymphoma. Pediatr Blood Cancer, 53(7), 1327-8, 2009.
- Piro, CC, Crossno, CL, Collier, A, Ho, R, Koyama, T, Frangoul, H Initial vancomycin dosing in pediatric oncology and stem cell transplant patients. J Pediatr Hematol Oncol, 31(1), 3-7, 2009.
- Frangoul, H, Wang, L, Harrell, FE, Ho, R, Domm, J Preengraftment syndrome after unrelated cord blood transplant is a strong predictor of acute and chronic graft-versus-host disease. Biol Blood Marrow Transplant, 15(11), 1485-8, 2009.
- Urquhart, BL, Ware, JA, Tirona, RG, Ho, RH, Leake, BF, Schwarz, UI, Zaher, H, Palandra, J, Gregor, JC, Dresser, GK, Kim, RB Breast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe. Pharmacogenet Genomics, 18(5), 439-48, 2008.
- Meyer zu Schwabedissen, HE, Tirona, RG, Yip, CS, Ho, RH, Kim, RB Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. Cancer Res, 68(22), 9338-47, 2008.
- Lavin, VA, Hamid, R, Patterson, J, Alford, C, Ho, R, Yang, E Use of human androgen receptor gene analysis to aid the diagnosis of JMML in female noonan syndrome patients. Pediatr Blood Cancer, 51(2), 298-302, 2008.
- Ho, RH, Choi, L, Lee, W, Mayo, G, Schwarz, UI, Tirona, RG, Bailey, DG, Michael Stein, C, Kim, RB Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenet Genomics, 17(8), 647-56, 2007.
- Bagatell, R, Gore, L, Egorin, MJ, Ho, R, Heller, G, Boucher, N, Zuhowski, EG, Whitlock, JA, Hunger, SP, Narendran, A, Katzenstein, HM, Arceci, RJ, Boklan, J, Herzog, CE, Whitesell, L, Ivy, SP, Trippett, TM Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17-demethoxygeldanamycin in pediatric patients with recurrent or refractory solid tumors: a pediatric oncology experimental therapeutics investigators consortium study. Clin Cancer Res, 13(6), 1783-8, 2007.
- Ho, RH, Tirona, RG, Leake, BF, Glaeser, H, Lee, W, Lemke, CJ, Wang, Y, Kim, RB Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology, 130(6), 1793-806, 2006.
- McRae, MP, Lowe, CM, Tian, X, Bourdet, DL, Ho, RH, Leake, BF, Kim, RB, Brouwer, KL, Kashuba, AD Ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibit bile acid transport in human and rat hepatocytes. J Pharmacol Exp Ther, 318(3), 1068-75, 2006.
- Jones, E, Koyama, T, Ho, RH, Kuttesch, J, Shankar, S, Whitlock, JA, Cartwright, J, Frangoul, H Safety and efficacy of a continuous infusion, patient-controlled antiemetic pump for children receiving emetogenic chemotherapy. Pediatr Blood Cancer, 48(3), 330-332, 2005.
- Calder, C, Hays, SR, Manes, B, Lavin, VA, Ho, RH, Frangoul, H Successful bone marrow harvest during pregnancy. Bone Marrow Transplant, 35(6), 631-2, 2005.
- Ho, RH, Kim, RB Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther, 78(3), 260-77, 2005.
- Ho, RH, Johnson, J, Dev, VG, Whitlock, JA A novel t(2;20)(q35;p12) in embryonal rhabdomyosarcoma. Cancer Genet Cytogenet, 151(1), 73-7, 2004.
- Ho, RH, Leake, BF, Roberts, RL, Lee, W, Kim, RB Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J Biol Chem, 279(8), 7213-22, 2004.