Daruka Mahadevan, MD, PhD

Professor of Medicine

Director, Drug Development and Translational Research

Director, Phase I Program

E-Mail Address: 
dmahadevan@azcc.arizona.edu
Phone Number: 
520-626-0191
Fax: 
520-626-2225
Short Bio: 
Dr. Mahadevan is a Professor of Medicine and the Director of the Phase I Program at the University of Arizona – Arizona Cancer Center.  He received his medical degree from the University of London, England, UK. He is certified by the American Board of Internal Medicine, subspecialty of Medical Oncology.
 
Dr. Mahadevan’s major area of clinical interest is in the treatment and management of patients with Pancreatic cancer, Gastrointestinal Stromal Tumors (GIST), Myelodysplastic Syndromes (MDS) and non-Hodgkin’s lymphoma (NHL) including Chronic Lymphocytic Leukemia (CLL).
 
As Director of the Phase I Program, he conducts first-in-human clinical trials with new drugs for patients with all solid tumor types as well patients with MDS, CLL and NHL. His research interest focuses on discovering novel therapeutic targets through a rigorous validation process and then design drugs to these targets using a structure-based drug discovery algorithm.
 
Dr. Mahadevan’s expertise in the above tumor types is that he conducts both Phase I and II first-in-human therapeutic trials in patients who have failed front line therapies. The Phase I Drug Development Program includes Dr. Mahadevan as team director, a nurse practitioner, a program manager, two senior research nurses, two clinical research coordinators and a pharmakokinetics lab specialist.
 
Multiple new drugs are available for patients with both solid and hematologic malignancies. Clinical research interests are to develop the drug alone and in combination for novel Phase I combination studies to enhance survival. Laboratory interests are focused on understanding resistance mechanisms in Pancreas Cancer, GIST, CLL and NHL.
 
Dr. Mahadevan's laboratory expertise is to discover novel therapeutic targets by a rigorous validation process and then design drugs to these targets using a structure-based drug discovery algorithm. To this end he has been successful in taking a small molecular inhibitor to c-Kit/PDGFR all the way from the bench to the clinic. MP470 (Amuvatinib) a c-Kit/PDGFR tyrosine kinase inhibitor is now in Phase I clinical trials.
 
Since the AZCC received the prestigious Lymphoma SPORE grant in 2008 from the NCI/NIH to evaluate drugs targeting Aurora Kinases in NHL, major strides have been made in treating both B- and T-cell NHL patients where significant clinical activity has been observed. Currently, novel combination therapies for NHL are in the process of being developed for future clinical trials.
 
Other areas of translation research include identifying novel cell surface therapuetic targets in pancreatic cancer and new drugs and combinations for gleevec and sutent resistant GIST. For pancreas cancer the translational component involves the design and humanization of murine antibodies as a therapeutic as well as elucidating the mechanism of action of the therapeutic antibody. Pre-clinical research involves in vivo and mouse pancreatic cancer models to demonstrate safety and efficacy of the therapeutic. For GIST, CLL and NHL novel drug combinations are being evaluated for future clinical trials.
 
Clinical Information
Specialty: 
Medical Oncologist
Clinical Practice Sites: 
The University of Arizona Cancer Center - North Campus
Research Information
Research Program: 
1. Therapeutic Development
Member Status: 
Member
Year of Membership Acceptance: 
2006
Selected Publications: 

1. Rausch MP, Hahn T, Ramanathapuram L, Bradley-Dunlop D, Mahadevan D, Mercado-Pimentel ME, Runyan RB, Besselsen DG, Zhang X, Cheung HK, Lee WC, Ling LE, Akporiaye ET. An Orally Active Small Molecule TGF-{beta} Receptor I Antagonist Inhibits the Growth of Metastatic Murine Breast Cancer. Anticancer Res. 2009 Jun;29(6):2099-109.

2. Qi W, Cooke LS, Stejskal A, Riley C, Croce KD, Saldanha JW, Bearss D, Mahadevan D. MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer. BMC Cancer. 2009 May 11;9:142.

3. Mahadevan D, Dreisbach L, Kristedja T, Williams D, Obregon Y, Kurtin S, Von Hoff D. Phase I study of fixed dose gemcitabine plus epirubicin in patients with advanced solid malignancies. AJCO. 2008. Accepted for publication.

4. Mahadevan D, Choi J, Cooke L, Simons B, Riley C, Klinkhammer T, Sud R, Maddipoti S, Hehn S, Garewal H, Spier C. Gene Expression and Serum Cytokine Profiling of Stage 0/I CLL Patients Identifies WNT/PCP, Flt-3L/Flt-3 and CXCL9/CXCR3 Pathways as Regulators of Cell Proliferation, Survival and Migration..Human Genomics and Proteomics. 2008. Accepted for publication.

5. Riley CJ, Engelhardt K, Saldanha JW, Qi W, Cooke LS, Zhu Y, Narayan S, Shakalya K, Della Croce K, Georgiev I, Nagle RB, Garewal H, Von Hoff DD, Mahadevan D. Design and activity of a Murine and Humanized anti-CEACAM6 scFv in the Treatment of Pancreatic Cancer. 2008. Accepted for publication in Cancer Research.

6. Mahadevan D, Powis G, Mash EA, George B, Gokhale VM, Zhang S, Shakalya K, Du-Cuny L, Berggren M, Ali MA, Jana U, Ihle N, Moses S, Franklin C, Narayan S, Shirahatti N, Meuillet EJ. Discovery of a novel class of AKT pleckstrin homology domain inhibitors.Mol Cancer Ther. 2008 Sep;7(9):2621-32.

7. Qi W, Shakalya K, Stejskal A, Goldman A, Beeck S, Cooke L, Mahadevan D. NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells.Oncogene. 2008 Jul 10;27(30):4210-20.

8. Myers CE, Dionne SO, Shakalya K, Mahadevan D, Smith MH, Lake DF. Variation in cytotoxic T-lymphocyte responses to peptides derived from tyrosinase-related protein-2. Hum Immunol 2008 Jan;69(1):24-31.

9. Mlcochová P, Plechanovová A, Barinka C, Mahadevan D, Saldanha JW, Rulísek L, Konvalinka J. Mapping of the active site of glutamate carboxypeptidase II by site-directed mutagenesis. FEBS J. 2007 Sep;274(18):4731-41.

10. Mahadevan D, Beeck S. Aurora kinase targeted therapeutics in oncology: past, present and future. Expert Opinion on Drug Discovery 2007 Jul; 2(7):1011-1026.

11. Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K, Wisner L, Iorio M, Shakalya K, Garewal H, Nagle R, Bearss D, A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 2007 Jun 7;26(27):3909-19. 

12. Mahadevan D & Von Hoff DD, Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2007 Apr;6(4):1186-97.

13. Bunch TA, Kendall TL, Shakalya K, Mahadevan D, Brower DL. Modulation of Ligand binding by alternative splicing of the alphaPS2 integrin subunit. J Cell Biochem. 2007 Mar 19; [Epub ahead of print] 

14. Engelhardt K, Riley C, Cooke L, Mahadevan D. Monoclonal antibody therapies targeting pancreatic ductal adenocarcinoma. Curr Drug Discov Technol. 2006 Dec;3(4):231-43. 

15. Mahadevan D, Will MDR-1/P-gp modulators provide clinical benefit in hematologic malignancies? Leuk Res. 2006 Sep;30(9):1077-8. 

16. Mahadevan D, DiMento J, Della Croce K, Riley C, George B, Fuchs D, Matthews T, Wilson C and Lobell M. Transcriptosome and Serum Cytokine Profiling of an Atypical case of MDS with Progression to AML Am J Hematol. 2006 Jul 12; [Epub ahead of print] 

17. Warner S, Bashyam S, Vankayalapati H, Bearss D, Han H, Mahadevan D, Von Hoff D, Hurley L. Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach. Mol Cancer Ther.2006 Jul;5(7):1764-73. 

18. Bunch TA, Helsten TL, Kendall TL, Shakalya K, Mahadevan D, Shattil SJ, Brower DL.Amino Acid Changes In DrosophilaaPS2bPS Integrins That Affect Ligand Affinity J Biol Chem. 2006 Feb 24;281(8):5050-7. 

19. Falsey RR, Marron MT, Gunaherath K, Shirahatti N, Mahadevan D, Gunatilake AAL and Whitesell L. Actin microfilament aggregation induced by withaferin A is mediated by Annexin II. Nature Chemical Biology 2005; 2:33-38. 

20. Mahadevan D, Spier C, Della Croce K, Miller S, George B, Riley C, Warner S, Grogan T, Miller T. Transcript Profiling in Peripheral T-cell lymphoma (NOS) and Diffuse Large B-cell lymphoma identifies distinct ‘Tumor Profile Signatures’: Biological Implications and Novel Therapeutic Interventions. Mol Cancer Ther. 2005 Dec;4(12):1867-79. 

21. Zhang X, Shirahatti N, Mahadevan D. and Wright S. A conserved glutamate residue in transmembrane helix 10 influences substrate specificity of rabbit OCT2 (SLC22A2). J Biol Chem. 2005 Oct 14;280(41):34813-22. 

22. Cooke L, Grill M, Shirahatti N, Mahadevan D. MDR Transporters as Therapeutic Targets in Cancer. Science & Medicine. 2005; 10(1):30-41. 

23. Mahadevan D. andShirahatti N.Strategies for Targeting the Multidrug Resistance-1 (MDR1)/P-gp Transporter in Human Malignancies. Current Cancer Drug Targets. 2005; 5(6): 445-455. 

24. List A, Kurtin S, Roe D, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R,Knight R, Zeldis J. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005, 352(6):549-57. 

25. Meuillet EJ, Ihle N, Baker AF, Gard JM, Stamper C, Williams R, Coon A, Mahadevan D, George BL, Kirkpatrick L, Powis G. In vivo pharmacology and antitumor activity of the targeted Akt inhibitor PX-316. Oncol Res. 2004;14(10):513-27. 

26. Meuillet E, Mahadevan D, Berggren M, Coon A, and Powis G. Thioredoxin-1 binds to the C2 domain of PTEN’s lipid phosphatase activity and membrane binding: A mechanism for the functional loss of PTEN’s tumor suppressor activity. Arch Biochem Biophys. 2004;429(2):123-33. 

27. Mahadevan D and List A. Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies. Blood.2004;104(7):1940-51. 

28. Mahadevan D and Garewal H. Advances in the diagnosis and treatment of Chronic Lymphocytic Leukemia. American College of Physicians-American Board of Internal Medicine PIER Module ACP-ASIM website. (July 2003).

29. Meuillet E, Mahadevan D, Vankayalapati H, Berggren M, Williams R, Coon A, Kozikowski A, Powis G. Specific Inhibition of the AKT1 Pleckstrin Homology Domain by D-3-Deoxy-Phosphatidyl-myo-Inositol Analogues. Mol Cancer Ther. 2003;2:389-399.

30. Vankayalapati H, Rojanala S, Saldanha J, Munoz R, Bearss D, Hurley L, Von Hoff DD and Mahadevan D. Targeting Aurora Kinase 2 in Oncogenesis: A Structural Bioinformatics Approach to Target Validation and Rational Drug Design. Mol Cancer Ther. 2003;3:283-294. 

31. Mahadevan D, Bearss D and Vankayalapati H. Structure Based Design of Novel Anti-Cancer Agents Targeting Aurora Kinase. Curr Med Chem – Anti-Cancer Agents. 2003;3:25-34. 

32. Von Hoff DD, Mahadevan D and Bearss DJ. New Developments in the Treatment of Patients with Pancreatic Cancer. Clin Oncol Updates. 2001;4(4):1-15. 

33. Mahadevan D, Chattopadhay T, Palmer R, O’Brien R, and Saldanha J. A predicted fold for the ABri amyloid subunit: A model for Amyloidogenesis in Familial British Dementia. Protein and Peptide Letters. 2001;8(2): 139-143. 

34. Mahadevan D and Saldanha J. The extracellular region of PSMA and the transferrin receptor contain an aminopeptidase domain: Implications for drug design. Protein Science.1999;8(11):2546-2549. 

35. Saldanha J, Singh J and Mahadevan D. Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases. Protein Science. 1998;7(7):1632-1635. 

36. Aroca P, Mahadevan D and Santos E. Functional interactions between SH2 domains and Insulin/Ras signaling pathways of Xenopus oocytes: opposite effects of the C- and N-terminal SH2 domains of p85 PI-3 kinase. Oncogene. 1996;13:1839-1846. 

37. De Mora J, Guerrero C, Mahadevan D, Coque J, Rojas J, Esteban L, Rebecchi M and Santos E. Isolated Sos1 PH domain exhibits germinal vesicle breakdown-inducing activity in Xenopus oocytes. J.Biol. Chem., 1996;271, 18272-18276. 

38. Uren, A., Yu, J.-C., Li, W., Chung, I.-Y., Mahadevan, D., Pierce, J. and Heidaran, M.A Identification of a domain within the C-terminal region of the b-Platelet derived growth factor receptor (PDGFR) that mediates the high transforming activity of PDGF. J. Biol. Chem.1996;271:11051-11054. 

39. Xu, N., Coso,O., Mahadevan, D., DeBlasi, A., Goldsmith, P., Simmonds, W. and Gutkind, J. The PH domain of Ras-GAP is sufficient for in vitro binding to bg subunits of heterotrimeric G proteins. Cell. and Molec. Neurobiology. 1996;16(1):51-59. 

40. Mahadevan, D., Yu, J.-C., Saldanha, J., Thanki, N., McPhie, P., Uren, A., LaRochelle, W. and Heidaran, M. Structural role of extracellular domain 1 of a-Platelet derived growth factor in PDGF-AA and -BB binding. J. Biol., Chem., 1995;270, 27595-27600. 

41. Mahadevan, D., Heidaran, M., and LaRochelle, W. b-PDGFR-IgG chimera demonstrates that human b-PDGFR Ig-like domains 1-3 are sufficient for high affinity PDGF-BB binding. FASEB J. 1995;9:140-145. 

42. Mahadevan, D., Thanki, N., Aroca, P., McPhie, P., Beeler, J.F., Yu, J.-C., Santos, E., Wlodawer, A. and Heidaran, M. A divalent metal ion binding site in the kinase insert domain of the a-PDGFR regulates its association with SH2 domains. Biochemistry.,1995;34:2095-2106. 

43. Mahadevan, D., Thanki, N., Singh, J., Zangrilli, D., McPhie, P., Wang, L.-M., Guererro, C., LeVine, H., Humblet, C., Saldanha, J., Gutkind, S. and Haske,T. Structural studies on the PH domains of Dbl, Sos1, IRS-1 and ARK and their differential binding to Gbg subunits. Biochemistry.,1995;34:9111-9117.

44. Chattopadhay, T., Palmer, R. and Mahadevan, D. Molecular and absolute crystal structure of Pindolol-1-(1H-indol-4-yloxy)-3-[(1-methylethyl) amino]-2-propanol: A specific b-adrenoceptor antagonist with partial agonost activity. J. Chem. Cryst., 1995;25, 195-199. 

45. Yu, J.-C., Gutkind,S., Mahadevan, D., Li, W., Myers, K., Pierce, J. and Heidaran, M. Biological function of receptor associated PI-3 kinase activity: its role in a-PDGFR mediated mitogenic or chemotactic signaling. J. Cell Biol., 1994;127, 479-487. 

46. Yu, J.-C., Mahadevan, D., LaRochelle, W., Pierce, J. and Heidaran, M. Structural coincidence of a-PDGFR epitopes binding to platelet derived growth factor-AA and a potent neutralizing monoclonal antibody. J. Biol. Chem., 1994;269:10668-10674. 

47. Mahadevan, D., Thanki, N., McPhie, P., Beeler, J., Yu, J.-C., Wlodawer, A. and Heidaran, M. Comparison of calcium dependent conformational changes in the N-terminal SH2 domain of p85 and GAP defines distinct properties for SH2 domains. Biochemistry.,1994;3:746-754. 

48. Driessen, H., Bax, B., Slingsby, C., Lindley, P., Mahadevan, D., Nalini, V., Moss, D., Blundell, T. and Tickle, I.. The structure of oligomeric B2crystallin: an application of theT2 translation function to an asymmetric unit containing two dimers. Acta Cryst., 1991;B47:987-997. 

49. Saldanha, J. and Mahadevan, D. Molecular model building of amylin and a -CGRP hormones using a combination of knowledge sources. Protein Engineering.,1991;4:539-544. 

50. Bax, B., Lapatto, R., Nalini, V., Driessen, H., Lindley, P., Mahadevan, D., Blundell, T. and Slingsby, C. X-ray analysis of beta B2-crystallin and evolution of oligomeric lens proteins. Nature.,1990;347:776-779. 

51. Banga, P., Mahadevan, D., Barton, G., Sutton, B., Saldanha, J., Odell, E. and McGregor, A. Prediction of domain organization and secondary structure of thyroid peroxidase: a human auto-antigen involved in destructive thyroiditis. FEBS Lett., 1990;266, 133-141. 

52. Banga, P., Ewins, D., Barnett, P., Tomlinson, R., Mahadevan, D., Barton, G., Sutton, B., Saldanha, J., Odell, E. and McGregor, A. Thyroid peroxidase auto-antigen: Localization of autoantigenic epitopes on recombinant protein and prediction of secondary structure. Thyroperoxidase and Thyroid Autoimmunity, 1990;207, 351-358. 

53. Collison, K., Mahadevan, D., Barnett, P., Doble, N., Tomlinson, R., Banga, J. and McGregor, A. Thyroid peroxidase studies on auto-antibody recognition, gene expression and secondary structure prediction. Nato ASI Series H: Cell Biology, 1990;38, 379-390. (In Molecular Biology of Autoimmune disease, Springer-Verlag). 

54. Mahadevan, D., Ndirika, A., Vincent, J., Chambers, A. and Pasternak, C. Protection against membrane mediated cytotoxicity by calcium and zinc ions. American J. Pathology, 1990;136, 513-520. 

55. Banga, P., Barnett, P., Mahadevan, D. and McGregor, A. Immune recognition of antigen and its relevance to auto-immune disease: recent advances at the molecular level. European J. of Clinical Investigation, 1989;19, 107-116. 

56. Slingsby, C., Driessen, H., Mahadevan, D., Bax, B. and Blundell, T. Evolutionary and functional relationships between acidic and basic b-crystallins. Experimental Eye Research, 1988;46, 375-413. 

57. Pasternak, C. and Mahadevan, D. Novel role of extracellular calcium and zinc: protection against membrane damage induced by cytotoxic agents. Indian J. of Biochemistry and Biophysics, 1988;25, 1-7. 

58. Summers, L., Slingsby, C., White, H., Narebor, M., Moss, D., Miller, L., Mahadevan, D., Lindley, P., Driessen, H., Blundell, T. et.al. The molecular structures and interactions of bovine and human g-crystallins. Ciba Symposium, 1984;106, 219-236. 

Book Chapters Published

1. Mahadevan D. Shakalya K. Anti-proliferation Inhibitors Targeting Aurora Kinases. Wei D,(ed) Checkpoint Responses in Cancer Therapy. New York, Humana Press, 2007. 

Submitted for Publication

1. Welsh J. Mahadevan D. Cooke L, Bearss D. Stea B. A c-Met Receptor Tyrosine Kinase Inhibitor Radiosensitizes Glioblastoma Cells by inhibiting dsDNA Repair (Submitted to Cancer Res. 2009).

2. TrevorK, CombsD, Al-ObeidiA, MahadevanD, WelshJ, BearssD, CranmerL. MP470, A novel agent for the treatment of synovial sarcoma (Submitted to Clin Cancer Res. 2009).

3. Mahadevan D. et al. AT7519, a Cyclin-dependent Kinase Inhibitor in Patients with Refractory Solid Tumors: Dose Escalation, Pharmacokinetic and Pharmacodynamic Study (To be submitted to JCO, 2009).

4. Mahadevan D. et al. AT7519, a Cyclin-dependent Kinase Inhibitor Promotes Apoptosis in Chronic Lymphocytic Leukemia by Inhibiting Transcription Independent of Rai Stage (To be submitted to Br J. Haem, 2009). 

5. Mahadevan D. Carcinoma of Unknown Primary Site (CUPS).Greene HL,(ed) Decision Making in Medicine, 3rd Ed. St. Louis, Mosby, Inc. 2007.
 

Bio sketch: 
application/msword iconDM-biosketch - Webpage.doc
Professional Information
Board Certifications: 

1998    Diplomate, American Board on Internal Medicine
2003    Diplomate, American Board of Medical Oncology

Professional Affiliations: 

2002  Southwest Oncology Group (SWOG) – Lymphoma Committee Member
2002  American Association for Cancer Research (AACR) – Active member
2002  American Society of Oncology (ASCO) – Active- Junior Member
2003  Current Medicinal Chemistry–Editorial Board (Anti-Cancer Drug Design)
2004  Supergen Pharmaceuticals, Inc. – Scientific Advisor
2005  American Society of Hematology (ASH) – Active Member, Abstract Reviewer (2007)

Honors: 

2000-2002  AMGEN Fellow of the Year Award
                Arizona Cancer Center
                Tucson, Arizona 

9/91–10/94 Fogarty International Fellowship
                Laboratory of Cellular and Molecular Biology
                National Cancer Institute
                National Institutes of Health
                Bethesda, MD
 
1998–1990 Dane Foundation Fellowship
                British Medical Council
                British Medical Association
                BMA House, England
 
  • US Patent #920214.00004 Inhibitors of C-Kit and PDGF Receptor Tyrosine Kinases 
  • US Patent #920214.00003 Aurora 2 Kinase Inhibitors
  • US Patent #263922US-2204-2204-96  Anti-CEACAM6 antibodies for the treatment of cancer
  • US Patent #7,326,713 Substituted Tricyclic Compound as Protein Kinase Inhibitors
  • US Patent #7,326,712 Substituted Tricyclic Compound as Protein Kinase Inhibitors
  • US Patent #7,335,662 Substituted Tricyclic Compound as Protein Kinase Inhibitors

 

Academic Information
Fellowship: 
Hematology/Oncology: Arizona Health Science Center, University of Arizona
Residency: 
Internal Medicine: University of Connecticut Health Center
Doctorate: 
Doctorare in Science (PhD): "Protein Crystallography": Birkbeck College
Medical School: 
Kings College Hospital Medical Center, University of London, UK
Undergraduate School: 
Bachelor of Honors (BSC), "Physiology and Biochemstry with Chemistry, University of Reading, UK