Translational Program for Evaluating Novel Therapies in Disseminated and Metastatic Human Tumor Models in NOD/SCID Mice

Research in the laboratory, particularly into hematopoietic malignancies (leukemia, lymphoma and multiple myeloma) as well as into the process of metastasis in various solid tumor systems, continues to identify potential therapeutic targets. Consequently a program has been established to validate these targets and identify novel therapeutic agents that can be moved into clinical trial.

The laboratory is involved in a number of translational projects using human tumor xenografts models of orthotopic or disseminated human tumor cell lines in NOD/SCID mice in conjunction with whole body luciferase imaging technology. We are currently employing panels of human hematopoietic tumor lines (lymphoma, multiple myeloma, acute myeloid leukemia) and solid tumors (ovarian, breast, colorectal) and evaluating therapeutic antibodies directed against receptors (VEGF receptors, Insulin-like growth factor receptors, FGFR, Flt3 receptor, cKit receptor). We are also evaluating small molecules targeting telomerase or tyrosine kinases, antagonists of HSP90 or CXCR4, and synthetic analogs of epothilone and migrastatin.

Flasshove M, Leonard JP, Bardenheuer W, Moore MAS. Increased resistance and selection in paclitaxel for peripheral blood progenitor cells following transduction with the MDR1 gene. Tumor Diagnostik & Therapie 2000; 21:51-58.

Kikuchi T, Moore MAS, Crystal RG. Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against pre-existing murine tumors. Blood 2000, 96; 91-99.

Fushimi T, Kojima A, Moore MAS, Crystal RG. Macrophage inflammatory protein 3? attracts dendritic cells to established murine tumors and suppresses tumor growth. J Clin Invest 2000, 105:1383-93.

Dias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W, Wu Y, Chadburn A, Hyjek E, Gill M, Hicklin DJ, Witte L, MAS Moore, Rafii S. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest. 2000, 106;511-21.

Kikuchi T, Worgall S, Singh R, Moore MAS, Crystal RG. Dendritic cells genetically modified to express CD40 ligand and pulsed with antigen can initiate antigen-specific humoral immunity independent of CD4-T cells. Nature Medicine 2000, 6;1154-59.

Kikuchi T, Miyazawa N, Moore MAS, Crystal RG. Tumor regression induced by intratumor administration of adenovirus vector expressing CD40 ligand and naïve dendritic cells. Cancer Res. 2000, 60:6391-5.

Hattori K, Dias S, Heissig B, Hackett NR, Lyden D, Tateno M, Hicklin DJ, Zhu Z, Witte L, Crystal RG, Moore MA, Rafii S. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med. 2001;193:1005-1014.

Dias S, Hattori K, Heissig B, Zhu Z, Wu Y, Witte L, Hicklin DJ, Tateno M, Bohlen P, Moore MA, Rafii S. Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci USA, 2001, 98: 10857-62.

Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MAS, Hajjar KA, Manova K, Benezra R, Rafii S. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med 2001, 7;1194-1201.

Lane WJ, Hattori K, Dias S, Peerschke EI, Moore MA, Blanset DL, Lang PC, Petrone M, Rafii S. Anagrelide metabolite induces thrombocytopenia in mice by inhibiting megakaryocyte maturation without inducing platelet aggregation. Exp Hematol. 2001, Dec; 29:1417-24.

Takebe N, Li-Cheng X, MacKenzie KL, Bertino JR, Moore MAS. Methotrexate selection of long term culture initiating cells following transduction of CD34+ cells with a retrovirus containing a mutated human of dihydrofolate reductase gene. Cancer Gene Therapy 2002;9:308-320.

Wang E, O’Connor O, She Y, Zelenetz A, Sirotnak FM, Moore MAS. Activity of a novel anti-folate (PDX, 10-propargyl-10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression. Leukemia & Lymphoma 2003, 44:1027-1035.

Moldenhauer A, Nociari MM, Dias S, Lalezari P, Moore MAS. Optimized culture conditions for the generation of dendritic cells from peripheral blood monocytes. Vox Sanguinis 2003, 84:228-236.

Sommer G, Agosti V, Ehlers I, Rossi F, Corbacioglu S, Farkas J, Moore M, Manova K, Antonescu CR, Besmer P. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc National Acad Science 2003. 100:6706-6711.

Wang E, Teruya-Feldstein J, Wu Y, Zhu Z, Hicklin DJ, Moore MAS. Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenographs in vivo. Blood. 2004. 104:2893-902.

Budak-Alpdogan T, Alpdogan O, Banerjee D, Wang E, Moore MA, Bertino JR. Methotrexate and cytarabine inhibit progression of human lymphoma in NOD/SCID mice carrying a mutant dihydrofolate reductase and cytidine deaminase fusion gene. Mol Ther. 2004 Sep;10(3):574-84.

Gaul C, Njardarson JT, Shan D, Dorn DC, Wu KD, Tong WP, Huang XY, Moore MA, Danishefsky SJ. The migrastatin family: discovery of potent cell migration inhibitors by chemical synthesis. J Am Chem Soc. 2004,126:11326-37.

Project Members