Donald Small, M.D., Ph.D.
Phone: (410) 955-8817
Fax: (410) 955-8897
Interests:
- Hematopoietic Growth Factors and Receptors
- Leukemia
Titles
Kyle Haydock Professor of Oncology
Professor of Oncology, Pediatrics, Cellular and Molecular Medicine
Director, Division of Pediatric Oncology
Schools/Degrees
M.D., The Johns Hopkins University School of Medicine
Ph.D., The Johns Hopkins University School of Medicine
Training
Intern in Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD
Resident in Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD
Clinical Fellow in Pediatric Hematology/Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD
Certifications
Pediatrics, Pediatric Hematology/Oncology
Clinical Interests
Pediatric Oncology
Research Summary
My laboratory is interested in how the normal signal transduction pathway goes awry and leads to the development of leukemia and lymphoma. Most of our efforts are concentrated on FLT3, which codes for a type III receptor tyrosine kinase normally restricted to expression by CD34+hematopoietic stem/progenitor cells. The gene is aberrantly expressed by most B-lineage acute lymphoblastic leukemia and acute myeloid leukemia patients’ blast cells, most of which co-express FLT3 ligand. In addition, about one-third of patients with AML express a mutated form of the receptor, which results in its constitutive activation in the absence of ligand.
We are studying the anti-apoptotic and antidifferentiation signals transduced by the activated receptor in leukemic cells. We are also studying the control elements that are responsible for regulating FLT3 expression. We have discovered several small-molecule tyrosine kinase inhibitors that interfere with FLT3 kinase activity fairly specifically. These inhibitors are able to induce cell death in cells transformed with the constitutively activated FLT3 while not interfering with the normal proliferative pathways in these cells. Thus, these new drugs are true examples of molecularly targeted therapy. We have moved one of these drugs into the clinics in patients with relapsed/refractory AML with FLT3 mutations and have seen clinical responses in these patients. We have studied how FLT3 inhibitors best combine with chemotherapeutics and have used this data to design the next generation clinical trial now under way at Johns Hopkins and more than 20 other institutions. We continue to perform correlative and surrogate assays on material from the patients on these trials to try to understand the factors that determine response to this new class of agents. We have also demonstrated that infant leukemias and others with high- level expression of wild-type FLT3 respond in vitro to these inhibitors. This forms the basis for the preclinical work to support trials of these drugs in leukemias other than FLT3-mutant AML.
Journal Citations
Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P, Witte L, Burrow C, Ratajczak M, Gewirtz A and Civin C. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc. Natl. Acad. Sci. 91: 459-463, 1994.
Carow C, Kim E, Hawkins A, Webb,H, Griffin C, Jabs E, Civin C and Small D. Localization of the human FLT3 (STK-1/FLK-2) gene to 13q 12-13. Cytogenetics and Cell Genetics 70: 255-257, 1995.
Civin C and Small D. Purification and expansion of human hematopoietic stem/progenitor cells. Annals of the New York Academy of Sciences 770: 91-98, 1995.
Carow C, Levenstein M, Kaufmann S, Chen J, Amin S, Rockwell P, Witte L, Borowitz M, Civin C and Small D. Expression of hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 87: 1089-96, 1996.
Tse K-F, Mukherjee G and Small D. Constitutive activation of FLT3 stimulates multiple signaling pathways and results in leukemic transformation. Leukemia 14: 1766-1776, 2000.
Tse K-F, Novelli E, Civin C, Bohmer F and Small D. Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor. (Lead article) Leukemia 15:1001-1010, 2001.
Levis M, Tse K-F, Smith B, Garrett E and Small D. A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to AML blasts harboring FLT3/ITD mutations. Blood 98:885-887, 2001.
Tse K-F, Allebach J, Levis M, Smith B, Bohmer F and Small D. Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. Leukemia 16:2027-2036, 2002.
Lumkul R, Gorin N, Malehorn M, Hoehn, G, Zheng R, Baldwin B, Small D, Gore S, Smith D, Meltzer P and Civin C. Human AML cells in NOD/SCID mice: engraftment potential and gene expression. Leukemia 16:1818-1826, 2002.
Levis M, Allebach J, Tse, K, Zheng R, Baldwin B, Smith D, Jones-Bolin S, Ruggeri B, Dionne C and Small D. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. (Plenary Paper)Blood 99:3885-91, 2002.
Zheng R, Friedman A and Small D. Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dc13 caused by expression of FLT3/ITD mutants. Blood 100:4154-4161, 2002.
Levis M, Zheng R, Baldwin B, Smith D, Malehorn M, Civin C, Gorin C and Small D. Prognostic implications of FLT3 mutations in patients treated by 2 disparate treatment regimens. Journal of Applied Research 3: 296-303, 2003.
Brown P, Mesinchi S, Levis M, Alonzo T, Gerbing R, Lange B, Arceci R and Small D. FLT3 inhibitors preferentially induce cytotoxicity in pediatric AML samples expressing FLT3/ITD mutations. Blood 104:1841-1849, 2004.
Zheng R, Levis M, Piloto O, Brown P, Baldwin B, Gorin N, Beran M, Zhu Z, Ludwig D, Hicklin,D, Witte L, Li Y and Small D. FLT3 ligand causes autocrine signaling in Acute Myeloid Leukemia cells. Blood 103: 267-274, 2004.
Zheng R, Friedman A, Levis M, Li L, Weir E and Small D. Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBP expression. Blood 103: 1883-1890, 2004.
Smith B, Levis M, Beran M, Giles F, Kantarjian H, Murphy K, Dauses T, Allebach J and Small D. Single Agent CEP-701, a novel FLT3 inhibitor, shows biologic response and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103: 3669-3676, 2004.
Levis M, Smith D, Pham R and Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood 104:1145-1150, 2004.
Li Y, Li H, Wang M, Lu D, Wu Y, Bassi R, Zhang H, Balderes P, Ludwig D, Pytowski B, Kussie P, Piloto O, Small D, Bohlen P, Witte L, Zhu Z and Hicklin D. Suppression of leukemia expressing wild-type or ITD-mutant FLT3 receptor by a fully human anti-FLT3 neutralizing antibody. Blood 104:1137-1144, 2004.
Brown P, Downing J, Campano D, Levis M and Small D. FLT3 inhibition selectively induces cytotoxicity in infant and childhood ALL samples expressing high levels of FLT3. Blood 105:812-820, 2005.
Kim K-T, Baird K, Ahn J, Levis M, Meltzer P, Lilly M and Small D. Pim-1 is upregulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival. Blood 105:1759-1767, 2005.
Chen P, Allebach J, Kim K-T and Small D. FLT3/ITD mutation signaling includes suppression of SHP-1 phosphatase activity. JBC 280: 5361-5369, 2005.
Piloto O, Levis M, Li Y, Li H, Wang M-N, Lu D, Wu Y, Bassi R, Balderes P, Zhang H, Ludwig D, Pytowski B, Kussie P, Bohlen P, Witte L, Zhu Z, Hicklin D and Small D. FLT3 antibodies are capable of inhibiting FLT3 signaling and engraftment of human AML blasts in NOD/SCID mice. Cancer Research 65:1514-22, 2005.
Levis M, Murphy K, Pham R, Kim K-T, Stine A, Li L, McNiece I, Smith B and Small D. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood 106:673-680, 2005.
Whartenby K, Calabresi P, McCadden E, Nguyen B, Allebach J, Mosse C, Pardoll D, and Small D. Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease. PNAS 102:16741-16746, 2005.
Zheng R and Small D. Mutant FLT3 signaling contributes to a block in myeloid differentiation. Leukemia and Lymphoma 46: 1679-1687, 2005.
Radomska H, Basseres D, Zheng R, Yamamoto Y, Sternberg D, Lokker N, Sullivan C, Giese N, Bohlander S, Schnittger S, Davis R, Small D, Hiddemann W, Gilliland D and Tenen D. Inactivation of C/EBP function by serine 21 phosphorylation in acute myeloid leukemia with FLT3 activating mutations. J. Ex. Med. 203:371-381, 2006.
Piloto O, Nguyen B, Huso D, Kim K-T, Li Y, Witte L, Hicklin D, Brown P and Small D. IMC-EB10, an anti-FLT3 monoclonal antibody, prolongs survival and reduces NOD/SCID engraftment of some ALL cell lines and primary leukemic samples. Cancer Research 66:4843-51, 2006.
Brown P, Levis M, McIntyre E, Griesemer M and Small D. Combinations of the FLT3 inhibitor CEP-701 and chemotherapy synergistically kill infant and childhood MLL-rearranged ALL cells in a sequence-dependent manner. Leukemia 20: 1368-76, 2006.
Kim K-T, Levis M and Small D. Constitutively activated FLT3 phosphorylates BAD partially through Pim-1. British Journal of Hematology 134(5):500-9, 2006.
Levis M, Stine A, Pham R, Smith B, Karp J, Stone R, Estey E, Giles F, Kantarjian H, Cohen P, Wang Y, Small D. Pharmacokinetic and Pharmacodynamic Studies of Lestaurtinib (CEP-701) and PKC-412: Cytotoxicity Is Often Dependent on Non-FLT3-Mediated Effects. Blood 108(10):3477-83, 2006.
Knapper S, Burnett A, Kell J, Mills K, Gilkes A, Walsh V, Levis M and Small D. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 108(10):3262-70, 2006.
Piloto O, Griesemer M, Brown P, Kim K, Levis M and Small D. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood 109:1643-52, 2007.
Li L, Piloto O, Ye Z, Kim K-T, Nguyen B, Yu X, Levis M, Cheng L and Small D. FLT3/ITD expression increases expansion, survival and entry into cell cycle of human hematopoietic stem cells. Brit J of Haematol 137(1): 64-75, 2007.
Baldwin B, Li L, Tse K, Small S, Collector M, Tyszko S, Whartenby K, Sharkis S, Huso D, Racke F, and Small D. Transgenic mice expressing a constiutively activated FLT3 receptor display a myeloproliferative disease phenotype. Leukemia 21(4):764-71, 2007.
Brown P, McIntyre E, Rau R, Meshinchi S, Lacayo N, Dahl G, Alonzo T, Chang M, Arceci R and Small D. The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood 110(3):979-85, 2007.
Kim K, Baird K, Davis S, Piloto O, Levis M, Li L, Chen P, Meltzer P, and Small D. Constitutive FLT3 activation results in specific changes in gene expression in myeloid leukemic cells. Br J Haematol 135: 603-615, 2007.
Sallmyr A, Fan, J, Datta K, Kim K-T, Grosu D, Shapiro P Small D and Rassool F. Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage and misrepair: implications for poor prognosis in AML. Blood 111: 3173-82, 2008. PMID18192505
Zhang W, Konopleva M, Shi Y-X, McQueen T, Harris D, Ling X, Estrov Z, Quintas-Cardama, Small D, Cortes J and Andreeff M. Mutant FLT3: A direct target of sorafenib in acute myelogenous leukemia. Journal of the National Cancer Institute 100: 184-98, 2008. PMID18230792
Li L, Piloto O, Nguyen H, Greenberg K, Takamiya K, Racke F, Huso D and Small D. Knock-in of an internal tandem duplication into murine FLT3 confers myeloproliferative disease in a mouse model. Blood 111: 3849-58, 2008. PMID18245664
Small D. Targeting FLT3 as Therapy for Leukemia. Seminars in Hematology 45: S17-21, 2008. PMID18760705
Whartenby K, Small D and Calabresi P. FLT3 inhibitors for the treatment of autoimmune disease.
Expert Opin Investig Drugs 17:1685-92, 2008. PMID18922105
Skarica M, Wang T, McCadden E, Kardian D, Levis M, Calabresi P, Small D and Whartenby K. Signal transduction inhibition of APCs diminishes th17 and Th1 responses in experimental autoimmune encephalomyelitis. Journal of Immunology 182: 4192-9, 2009. PMID 19299717
Chu H and Small D. Mechanisms of resistance to FLT3 inhibitors. Drug Res Update 12: 8-16, 2009. PMID19162530
Pratz K, Cortes J, Roboz G, Rao N, Stine A, Shiotsu Y, Akinaga S, Small D and Levi M. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood 113: 3938-46, 2009. PMID19029442
Chuk M, McIntyre E, Small D and Brown P. Discordance of MLL-rearranged (MLL-R) infant ALL in monozygotic twins with spontaneous clearance of preleukemic clone in unaffected twin. Blood, 2009. [Epub ahead of print] PMID 19411627
