• Overview
• Researchers
• Selected Publications
• Simmons Cancer Center: Clinical Research Office

Overview

UT Southwestern is one of the leading research institutions in the world with four Nobel laureates (more than any other institution) and fifteen members of the National Academy of Sciences.  The Blood and Marrow Stem Cell Transplant/Hematologic Malignancies Program takes advantage of the institution’s outstanding research environment to carry out both laboratory and clinical research aimed at improving understanding and treatment of hematologic malignancies.  Program accomplishments include:

• Preclinical and clinical studies of stem cell transplant immunology.  Stem cell transplantation is one of the most effective treatments for hematologic malignancies.  However, its ultimate success is limited by complications involving the immune system.  Our Program aims to improve the precision of stem cell transplantation by increasing our understanding of the fundamental issues of transplant immunology, including immune system recovery, graft-versus-host disease, and graft-versus-leukemia.  Accomplishments include:
  • In-depth study of immune system recovery after allogeneic stem cell transplantation.
  • Isolation and monitoring of individual T-cells capable of causing graft-versus-host disease.
  • Separation of T-cells with potential for causing graft-versus-host disease from T-cells with potential for specifically attacking cancer cells.
  • Preclinical investigation of new techniques for removing harmful T-cells from allogeneic stem cell transplants, leaving beneficial T-cells intact.
  • Extensive clinical studies of donor leukocyte infusion, an approach used to treat successfully patients who have relapsed after transplantation.
  • Clinical studies of nonmyeloablative stem cell transplantation.  This new approach is significantly less toxic than traditional transplant approaches.

• Preclinical laboratory studies of the molecular biology of hematologic malignancies.  Improved understanding of the basic molecular biology of hematologic malignancies leads to appreciation of molecular (“Achilles’ heels”) that can be targeted by new drugs, resulting in less toxic, more effective cancer treatments.  UT Southwestern research in this area includes:
  
  • Dissection of molecular pathways involved in acute myelogenous leukemia and chronic myelogenous leukemia
  • Development of animal models of leukemia to allow methodical testing of novel therapeutic agents
  • Studying molecular pathways involved in the pathogenesis of myelodysplastic syndromes (MDS) and other bone marrow failure disorders.
  • Evaluating novel MAP kinase inhibitors as potential therapeutic strategies in MDS.
  • Collaborating with Dr. Gazdar and his team in correlating methylation levels of novel genes as predictors of leukemic transformation of MDS.
  • Conducting a CALGB sponsored trial evaluating a novel oral VEGF inhibitor in MDS.
  • Conducting Phase I clinical trial of Immunotoxin Combotox©, (a combination of anti-CD19 and CD22 antibodies conjugated with ricin) in patients with relapsed or refractory Acute Lymphoblastic Leukemia.
  • Dissection of pathways involved in apoptosis.

• Clinical studies of new drugs for hematologic malignancies.  Laboratory research leads to new drugs, which are then tested in the laboratory. UT Southwestern Ongoing Clinical Trials of new agents include:
  

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Researchers

Robert Collins, M.D. 
Simrit Parmar, M.D.

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Selected Publications

1. Chaudhary, P.M., Eby, M., Jasmin, A., and Hood, L. (1999). Activation of the c-Jun N-terminal Kinase/Stress activated Protein Kinase pathway by overexpression of Caspase 8 and its homologs. J. Biol. Chem. 274 (27), 19211-19219.
2. Chaudhary, P.M., Eby, M., Jasmin, A., Gimmell, A and Hood, L. (1999). Modulation of the NF-kB pathway by virally encoded Death Effector Domains-containing proteins. Oncogene. 18(42):5738-46.
3. Eby, M.T., Jasmin, A., Kumar, A., Sharma, K., and Chaudhary, P.M. (2000). TAJ, a novel member of the Tumor Necrosis Factor Receptor family, activates the c-Jun N-terminal Kinase pathway and mediates caspase-independent cell death. J. Biol Chem. 275 (20), 15336-15342.
4. Chaudhary, P.M., Eby, M., Jasmin, A., Kumar, A., Liu, L., and Hood, L. (2000). Activation of the NF-kB pathway by Caspase 8 and its homologs. Oncogene. 19(39):4451-60.
5. Kumar A, Eby MT, Sinha S, Jasmin A, and Chaudhary PM. (2001) Ectodermal dysplasia receptor activates the nuclear factor kappa B, c-Jun N-terminal kinase and cell death pathways and binds to ectodysplasin A. J. Biol Chem. 276 (4) 2668-2677.
6. Kumar, A., Jasmin, A., Eby, M.T., and Chaudhary, P.M. (2001). Cytotoxicity of Tumor Necrosis Factor Related Apoptosis-Inducing Ligand Towards Ewing’s Sarcoma cell lines. Oncogene. 20, 1010-1014.
7. Taylor, M.A., Chaudhary, P.M., Klem, J., Kumar, V., Schatzle, J.D., and Bennett, M (2001). Inhibition of the death receptor pathway by cFLIP confers partial engraftment of MHC class I-deficient stem cells in perforin-deficient mice. J. Immunology. 167(8):4230-7.
8. Shivapurkar, N., Toyooka, S., Eby, T.M., Huang, C.X., Sathyanarayana, U.G., Cunningham, T., Reddy, J.L., Minna, J.D., Chaudhary, P.M. and  Gazdar, A.F. (2002) Differential inactivation of caspase 8 in lung cancer. Cancer biology and therapy. 1(1) 65-71 .
9. Liu L, Eby TM, Rathore N, Sinha S and Chaudhary P.M. (2002). The human herpes Virus 8 encoded viral FLICE inhibitory protein physically associates with and persistently activates the IkappaB kinase complex. J. Biol Chem. 277(16):13745-51.
10. Kenichi Harada, Shinichi Toyooka, Narayan Shivapurkar, Anirban Maitra, Jyotsna L. Reddy, Hittu Matta, Charles F. Timmons, Gail E. Tomlinson1, Domenico Mastrangelo, Robert J. Hay, Preet M. Chaudhary and Adi F. Gazdar. (2002) Deregulation of Caspase 8 and 10 expression in Pediatric Tumors and cell lines; Cancer Research; 15;62(20):5897-901
11. Sun, Q., Matta, H and Chaudhary, P.M. (2002) The human herpes Virus 8 encoded viral FLICE inhibitory protein protects against growth factor withdrawal-induced apoptosis via NF-kB activation. Blood. (In press).
12. Shivapurkar, N., Toyooka, S., Eby, T.M., Huang, C.X., Sathyanarayana, U.G., Matta, H., Cunningham, T., Reddy, J.L., Minna, J.D., Chaudhary, P.M. and  Gazdar, A.F. (2002) Loss of expression of components of Death Inducing Signaling Complex in lung cancer and correlation with Myc expression. Oncogene. 21(55):8510-4.
13. Sinha S, Zachariah S, Shindo M, Quinones H and Chaudhary P.M. (2002). Role of TRAF-3 and 6 in the activation of the NF-kB and JNK pathways by X-linked Ectodermal Dysplasia Receptor. J. Biol Chem. 277(47): 44953-44961
14. Porter DL, Collins RH, Shpilberg O, Drobyski W, Connors J, Sproles A, Antin J.  Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions for relapse after allogeneic bone marrow transplantation.  Biology of Blood and Marrow Transplantation 5:253-61, 1999
15. Porter DL, Collins RH, Hardy C, Kerman N, Giralt S, Flowers M, Casper J, Drobyski W, Leahey A, Parker P, Mick R, Bate-Boyle B, King R, Antin JH.  Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions.  Blood 95:1214-21, 2000
16. Douek DC, Vescio RA, Betts MR, Brenchley JM, Zheng L, Berenson JR, Collins RH, Koup RA.  Contribution of the thymus to immune reconstitution following autologous hematopoietic stem cell transplant in adults.  Lancet 355:1875-81, 2000
17. Collins R, Goldstein S, Giralt S, Levine J, Porter D, Drobyski W, Barrett J, Johnson M, Kirk A, Horowitz M, Parker P.  Donor leukocyte infusions in acute lymphocytic leukemia.  Bone Marrow Transplantation 26:511-516, 2000
18. Gatlin J, Douglas J, Collins R, Wendel G, Garcia V.  In vitro selection of lentivirus vector transduced human CD34 cells.  Hum Gene Ther 11(13):1949-57, 2000
19. Salama M, Nevill T, Marcellus D, Parker P, Johnson M, Kirk A, Porter D, Giralt S, Levine J, Drobyski W, Barrett J, Horowitz M, Collins R.  Donor leukocyte infusions for multiple myeloma.  Bone Marrow Transplantation 26:1179-84,2000
20. Malik AH, Collins RH, Saboorian MH, Lee WM.  Acute hepatitic presentation of chronic graft versus host disease (GVHD) of the liver following hematopoietic cell transplantation (HCT).  Am J Gastroenterol 96: 588-590, 2001
21. Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M, Koup RA, Betts MR, Collins RH, Douek DC.  Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation.  Blood 97:1458-66, 2001
22. Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Rodrigo M, Drobyski WR, Barrett AJ, Porter DL, Giralt S, Leis J, Holmes HE, Johnson M, Horowitz M, Collins Jr. RH.   Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation.  Journal of Clinical Oncology 20:405-412, 2002
23. Collins RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R, Goodman SA, Wolff SN, Hu W, Verfaillie C, List A, Dalton W, Ognoskie N, Chetrit A, Antin JH, Nemunaitis J.  Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation.  Classic Papers and Current Comments: Highlights of Bone Marrow Transplant Research 5:(3) 598, 2001.
24. Xu Y, McKenna RW, Hoang MP, Collins RH, Kroft SH.  Composite angioimmunoblastic T-cell lymphoma and diffuse large B-cell lymphoma: A case report and review of the literature.  American Journal of Clinical Pathology 118:1-5, 2002
25. Aquino VM, Douek DC, Berryman B, Johnson M, Jain VK, Collins RH.  Evaluation of Thymic Output in patients who have received Fludarabine-containing chemotherapy.  Leukemia and Lymphoma 44 (2): 343-348, 2003.
26. Michalek J, Collins RH, Vitetta ES.  Clinical-scale selective depletion of alloreactive T cells using and anti-CD25 immunotoxin.  Neoplasma 50(4):296-9, 2003.
27. Michalek J, Collins RH, Durrani HP, Vaclavkova P, Ruff LE, Douek DC, Vitetta ES.  Definitive Separation of graft-versus-leukemia and graft-versus-host specific CD4 T cell clones by virtue of their T cell receptor b locus sequences. Proceedings of the National Academy of Sciences 100:1180-1184, 2003.
28. Michalek J, Collins RH, Hill BJ, Brenchley JM, Douek DC.  Pre-transplant identification of graft-versus-host specific T-cell clone and quantitative monitoring after allogeneic hematopoietic stem cell transplantation.  Lancet 361(9364):1183-5, 2003.
29. Bhushan, V, Collins, R.  Chronic Graft-versus-Host Disease.  JAMA 290 (19):2599-2603, 2003.
30. Butcher B., Wilson K, Kroft S, Collins R, Bhushan, V.  Acute Leukemia with B-lymphoid and Myeloid Differentiation Associated with an inv(5)(q13q33) in the Adult Patient.  Cancer Genet Cytogenet 157:62-66, 2005.
31. Verma A, Sassano A, Deb D, Wickrema, A., VanBesien K., and Platanias L. “Blockade of p38 MAP kinase reverses cytokine mediated inhibition in aplastic anemia.” Journal of Immunology 2002, 168 (12) (Cutting edge)
32. Kambhampati S, Li Y, Verma A, Sassano A, Majchrzak B, Deb DK, Parmar S, Giafis N, Kalvakolanu DV, Rahman A, Uddin , Minucci, Tallman MS, Fish EN, Platanias LC. “Activation of protein kinase C-delta (PKC-delta) by All-trans-retinoic acid.” 1999 Journal of Biological Chemistry 2003 epub June 13th
33. Miller M, Levinson B, Bhushan V, Kent S, Kroft S. Zinc Induced Copper Deficiency: A Report of Three Cases Initially Recognized on Bone Marrow Examination.  American Journal of Clinical Pathology (In press).
34. Liu LQ, Ilaria R Jr., Kingsley PD, Iwama A, Van Etten RA, Palis J, Zhang DE.  Novel Ubiquitin-specific protease UBP46, cloned from leukemia fusion protein AML1-ETO-expressing mice, functions in hematopoietic cell differentiation.  MCB 1999; 19:4 3029-3038.
35. Li Shaoguang, Ilaria RL Jr., Million RP, Daley GQ, Van Etten RA.  The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity.  J Exp Med 1999; 189:1399-1412.
36. Ilaria RL Jr., Hawley RG, Van Etten RA.  Dominant negative mutants implicate STAT5 in myeloid cell proliferation and neutrophil differentiation.  Blood, 1999; 93(12): 4154-4166.
37. Tomasson MH, Sternberg DW, Williams IR, Carroll M, Cain D, Aster JC, Ilaria RL Jr., Etten RA, and Gilliland DG.  Fatal myeloproliferation, induced in mice by TEL/PDGFbetaR expression, depends on PDGFbetaR tyrosines 579/581. J Clin Invest, 2000; 105(4): p. 423-32.
38. Spencer JA, Eliazer S, Ilaria RL Jr, Richardson JA, Olson EN.  Regulation of Microtubule Dynamics and Myogenic Differentiation by MURF, a Striated Muscle RING-Finger Protein. J Cell Biol, 2000; 150(4):771-784.
39. Roumiantsev S, de Aos IE, Varticovski L, Ilaria RL Jr., and Van Etten RA.  The SH2 domain of Bcr/Abl is required for efficient induction of CML-like disease in mice but not for lymphoid leukemogenesis or activation of phosphatidylinositol 3-kinase.  Blood, 2001;97(1):4-13.
40. Silvany RE, Eliazer S, Wolff NC, and Ilaria RL Jr.  Interference with the Constitutive Activation of ERK1 and ERK2 Impairs EWS/FLI-1-dependent Transformation.  Oncogene, 2000; 19:4523-4530.
41. Wolff NC and Ilaria RL Jr. Establishment of a Murine Model for Therapy-treated CML Using the Tyrosine Kinase Inhibitor STI571.  Blood, 2001; 98(9):2808-16.
42. Ilaria RL Jr. STAT isoforms: mediators of STAT specificity or leukemogenesis? Leuk Res., 2001. 25(6): p. 483-4.
43. Ilaria RL, Jr. Bcr/Abl, leukemogenesis, and genomic instability: a complex partnership.  Leuk. Res., 2002; 26(11):971-973.
44. Eliazer S. Spencer JA, Olson E, and Ilaria RL Jr.  Alteration of Mesodermal Cell Differentiation by EWS/FLI-1, the Oncogene Implicated in Ewing’s Sarcoma, MCB, 2003; 23(2):482-492.
45. Ilaria RL Jr. Animal models of chronic myelogeneous leukemia. Hematol Oncol Clin North Am., 2004 Jun;18(3):525-43.
46. Wolff NC, Randle DE, Egorin MJ, Minna JD, Ilaria RL Jr.  Imatinib mesylate efficiently achieves therapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small cell lung cancer.
    Clin Cancer Res. 2004 May 15;10(10):3528-34.
47. Ilaria RL Jr. Tyrosine kinases in AML: where do they fit in?  Leuk Res. 2004 Mar;28(3):217-8. No abstract available.
48. Ye D, Maitra A, Timmons CF, Leavey PJ, Ashfaq R, Ilaria RL Jr. The epidermal growth factor receptor HER2 is not a major therapeutic target in Ewing sarcoma.  J Pediatr Hematol Oncol. 2003 Jun;25(6):459-66.
49. Wolff NC, Richardson JA, Egorin M, Ilaria RL Jr.  The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia.  Blood. 2003 Jun 15;101(12):5010-3. Epub 2003 Feb 20.
50. Roumiantsev S, de Aos IE, Varticovski L, Ilaria RL, Van Etten RA.  The src homology 2 domain of Bcr/Abl is required for efficient induction of chronic myeloid leukemia-like disease in mice but not for lymphoid leukemogenesis or activation of phosphatidylinositol 3-kinase.  Blood. 2001 Jan 1;97(1):4-13.
51. Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS, Peeters P, Van Rompaey L, Van Etten RA, Ilaria R Jr., Marynen P.  Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes. EMBO J. 1998 Sep 15;17(18):5321-33.
52. Ilaria RL Jr, Van Etten RA.  P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members.  J Biol Chem. 1996 Dec 6;271(49):31704-10.
53. Ilaria RL Jr, Komaroff AL, Fagioli LR, Moloney WC, True CA, Naides SJ.  Absence of parvovirus B19 infection in chronic fatigue syndrome.  Arthritis Rheum. 1995 May;38(5):638-41.
    
    
    
    Book Chapters

1. Collins, RH. "Gastrointestinal Lymphomas." Sleisenger and Fordtran’s Gastrointestinal and Liver Disease.  Feldman M, Friedman LS, Sleisenger MH (eds.). 7th Edition Vol. 1. Philadelphia: Saunders Press, 2002. 453-472.
2. Collins, RH.  "Donor Leukocyte Infusions."  In Lazarus HM and Laughlin MJ (eds.) Allogeneic Stem Cell Transplantation Human Press. Lazarus HM and Laughlin MJ (eds.). Totowa NJ. Human Press, 2003. 287-310.
3. Collins, RH. "Management of Relapse After Allogeneic Transplantation."  Thomas’ Hematopoietic Cell Transplantation.  Blume K, Forman S, Appelbaum F (eds.).  3rd edition.  Malden, MA.  Blackwell Press, 2004. 1150-1163.
4. Collins, RH.  Gastrointestinal Lymphomas.  Sleisenger and Fordtran's Gastrointestinal and Liver Disease 8th Edition (in press)

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