Young Innovators 2009 Prostate-Specific Membrane Antigen (PSMA)-Targeted Imaging, Diagnosis, and Therapy of Prostate Cancer using a PSMA inhibitor as a.

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Presentation transcript:

Young Innovators 2009 Prostate-Specific Membrane Antigen (PSMA)-Targeted Imaging, Diagnosis, and Therapy of Prostate Cancer using a PSMA inhibitor as a Homing Ligand Sumith A. Kularatne Philip S. Low Purdue University Part III

Design of PSMA-Targeted Chemotherapeutic Agents IC50 = 1 nM (to LNCaP cell) Low, P. S. & Kularatne, S. A. PCT/WO2009026177 IC50 = 0.8 nM (to LNCaP cells)

Relative Binding Affinity of DUPA-TubH for LNCaP Cells + 100 nM DUPA-99mTc Relative affinity ~ 0.27 DUPA-TubH

LC-MS Analysis of Disulfide Carbonate Mediated Drug Release DUPA-TubH DTT = Dithiothreitol t = 0 min DTT DUPA-Linker t =60 min DUPA-TubH

Potency of DUPA-TubH to LNCaP Cells in Culture Competition with excess PMPA DUPA-TubH Kularatne, S. A., Wang, K., Santhapuram, H-K. R. & Low, P. S. Mol Pharm. 2009, 6, 780-789

Effects of DUPA-TubH I on Growth of LNCaP Tumors

Pathological Analysis of DUPA-TubH I Treated Mice Saline Treated DUPA-TubH I Treated Treatment Group % of tumor dead mass Saline < 10 % xs PMPA + DUPA-TubH I > 95% H & E (Hemotaxylin and Eosin) stain (400 x) NL – no lesion identified Treatment Group Liver Kidney Spleen Lung Heart Muscle Intestine Skin Bone marrow Saline NL xs PMPA + DUPA-TubH I minor Kularatne, S. A., Subramanian, B., van Alstine, W.& Low, P. S. (unpublished data)

Conclusions Developed PSMA-targeted imaging agents Locate primary and metastatic disease Detect CTCs in blood samples of prostate cancer patients Monitor response to therapy Detect disease recurrence following surgery Select patients for subsequent DUPA-targeted chemotherapy (B) Developed highly potent PSMA-targeted therapeutic agents (C) Developed Folate-targeted PET imaging and immunotherapeutic agents

Acknowledgements Prof. Philip S. Low Prof. Philip L. Fuchs Prof. Ei-chi Negishi Prof. Hilkka I. Kenttämaa Collaborators: Dr. Z. Zhou (Purdue) Dr. C. Post (Purdue) Dr. W. Alstine (Purdue) Dr. W. He (Purdue) Dr. L. Hartmann (Mayo Clinic) Dr. G. Klee (Mayo Clinic) Dr. K. Wang (Endocyte Inc) Dr. H-K. Santhapuram (Endocyte Inc) Dr. R. Amato (The Methodist Hospital, TX) Dr. Paul McQuade (Merck Research Laboratories, PA) Special Thanks: Group members Funding: Endocyte Inc, West Lafayette Department of Chemistry, Purdue University

References Ghosh A, Heston, WDJ. Cell Biochem. 2004, 91, 528-539. Mesters JR, Barinka C, Li W. EMBO J. 2006, 25, 1375-1384. Kozikowski AP, Zhang J, Nan FJ. Med. Chem. 2004, 47, 1729-1738. Jackson PF, Slusher BS. Curr. Med. Chem. 2001; 8, 949-957 Low, P. S. & Kularatne, S. A.. PCT/WO2009026177 Kularatne, S. A., Zhou, Z., Young, J., Post, C. B. & Low, P. S. Mol. Pharm. 2009, 6, 790–800 Kularatne, S. A., Wang, K., Santhapuram, H-K. R. & Low, P. S. Mol. Pharm. 6, 781-790 Slusher, B.S. et al J. Comp. Neurol. 315, 217-229 Ghosh, A. et al Cell. Biochem. 91, 528-539 Sodee, D.B. et al The Prostate 37, 140-148 Thomas, M. A. ;Kularatne, S. A., et. Al. Ann. N.Y. Acad. Sci. 2009, 1175: 32–3 Low, P. S., Wei, H. & Kularatne, S. A. PCT/WO2008057437 He, W., Kularatne, S. A., et. al. Int. J. Cancer, 2008, 123, 1968-1973 Kularatne, S. A., Chelvam V., Low P. S. et al. (Manuscript in submission Kularatne, S. A., Subramanian, B., van Alstine, W.& Low, P. S. (unpublished data) Young Innovators 2009

BIOS/Contact info Born in Kandy, Sri Lanka, Sumith A. Kularatne graduated from the University of Peradeniya, Sri Lanka, with a B.S. (honors) in the Chemistry Honors program. He earned a master’s degree in organic chemistry from Wichita State University, Kansas, conducting research on synthesis of endo-[n.m.n.m] (n,m ≥ 3) metacyclophanes using Cu(I)-catalyzed cross-coupling/ Grignard system and elucidating of solvent effects in anion binding selectivity and stoichiometry of synthetic anion binding receptors using tri- & tetra-urea picket porphyrins as model systems (supramolecular chemistry). Sumith then earned a Ph.D. in organic/medicinal chemistry from Purdue University in October 2009, conducting research on receptor-mediated drug delivery using small molecular ligands for treatment of cancer and inflammatory diseases under the guidance of Ralph C. Corley Distinguished Professor Philip S. Low. Based on his current research work, he is an inventor on 5 pending patents and a co-author of 10 peer reviewed publications, 2 book chapters, and 12 proceedings/ paper presentations in meetings. He will be working with Prof. Peter G. Shultz at Scripps Research Institute, San Diego for his postdoctoral fellowship from November 2009. Young Innovators 2009