Molecular Targets for Targeted Radionuclide Therapy
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Molecular targets for Targeted Radionuclide Therapy Stephen J Mather Barts and the London School of Medicine and Dentistry, Queen Mary University of London. [email protected] Changes in malignancy Levels may go up é or down ê What are we trying to achieve? • Selective Radiation dose delivery –é as high as possible to the tumour –ê as low as possible to normal tissues ê as low as possible to ‘important’ normal tissues How can we achieve this? • Choose the best target • Produce the best radiopharmaceutical • Use the best delivery strategy • Treat the best patients Features of the best targets • High expression in tumour – High density – High incidence – Good access • Low ‘expression’ in normal tissues Types of Targets • Extracellular • Transporters • Neurotransmitter receptors • Hormone receptors • Neuropeptide receptors • Growth Factor receptors • Tumourassociated Antibody epitopes • Intracellular • Metabolic pathways • DNA/RNA • Other organelles. Types of Targets • Extracellular • Transporters Radioiodine • Neurotransmitter receptors • Hormone receptors • Neuropeptide receptors • Growth Factor receptors • TAA epitopes • Intracellular • Metabolic pathways • DNA/RNA • Other organelles Types of Targets • Extracellular • Transporters • Neurotransmitter receptors – peripheral e.g.mIBG • Hormone receptors • Neuropeptide receptors • Growth Factor receptors • TAA epitopes • Intracellular • Metabolic pathways • DNA/RNA • Other organelles Noradrenaline transporter LeuT Phaeochromocytoma vs neuroblastoma mIBG Na + LAT1 Tumour expression Kyoichi Kaira Pathology, Research and Practice 2008, 204,553561 Types of Targets • Extracellular • Transporters • Neurotransmitter receptors • Hormone receptors • Neuropeptide receptors Somatostatin • Growth Factor receptors • TAA epitopes • Intracellular • Metabolic pathways • DNA/RNA • Other organelles Gprotein coupled receptors Nature (2009) 459, 356363 In vitro detection of somatostatin receptors in carcinoids. SSTR2 immunohistochemistry in ileal carcinoid A, Hematoxylineosin. B, Autoradiogram. C, nonspecific D, Hematoxylineosin. E, Autoradiogram showing sst 2 mRNA in the tumor by use of a 33P labeled probe. F, Control section Reubi, J. C. Endocr Rev 2003;24:389427 Copyright ©2003 The Endocrine Society Somatostatin receptor expressing tumours • GHproducing pituitary Meningioma (sst ) adenoma (sst , sst ) 2 2 5 Neuroblastoma (sst ) • Nonfunctioning pituitary 2 Medulloblastoma (sst 2 ) adenoma (sst 3 > sst 2 ) Astrocytoma • Gut carcinoid (sst 2 > sst 1 , sst 5 ) Gastric carcinoma • Gastrinoma (sst 2 ) Hepatocellular carcinoma • Insulinoma Renal cell carcinoma Prostate carcinoma (sst ) • Paraganglioma (sst ) 1 2 Breast carcinoma • Pheochromocytoma (sst 2 ) Ovarian carcinoma • Medullary thyroid carcinoma Lymphoma • Small cell lung cancer (sst 2 ) Leiomyoma Endocrine Reviews (2003) 24 (4): 389427 111 InDOTATOC 68G aDOTATOC 177 LuDOTATATE Kwekkeboom DJ et al Eur J Nucl Med Mol Imaging 2003 Mar;30(3):41722. Tumour expression of neuropeptides Peptide Tumor type Somatostatin neuroendocrine tumors, nonHodkgin lymphoma, melanoma, breast, aMSH melanoma LHRH prostate, breast VIP/PACAP SCLC, colon, gastric, pancreatic CCK2/Gastrin MTC, SCLC, pancreatic, astrocytoma, stromal ovarian cancer Opioid SCLC, neuroblastoma, breast Neurotensin SCLC, colon, exocrine pancreatic Bombesin/GRP SCLC, breast, colon, glioblastoma, prostate Substance P glioblastoma, astrocytoma, MTC, breast, intra and peritumoral blood vessels Reubi et al JNM 2005: 46: 67S Peptide autoradiography in breast cancer Reubi, J. C. Endocr Rev 2003;24:389427 Copyright ©2003 The Endocrine Society CCKR2 radioscintigraphy Reubi, J. C. Endocr Rev 2003;24:389427 Copyright ©2003 The Endocrine Society Types of Targets • Extracellular • Transporters • Neurotransmitter receptors • Hormone receptors • Neuropeptide receptors • Growth Factor receptors • TAA epitopes • Intracellular • Metabolic pathways • DNA/RNA • Other organelles Antibodies e.g. MUC1 µ MUC1 is a protein found on the surface of epithelial cells • Normal epithelial cells cover the protein with sugar residues • Tumour cells produce MUC1 lacking normal sugar coat µ MUC1 is the target for antibodies in the HMFG1 family • Only accessible in tumour cells, where protein core exposed Normal mucin Cancer mucin HMFG1 Immunohistochemisty Breast cancer HMFG1 vs SM3 R1549 phase II data in ovarian cancer • Significant survival benefit vs standard care (historical controls) Hird, V. et al. (1993) Adjuvant therapy of ovarian cancer with radioactive monoclonal antibody. Br. J. Cancer 68, 403406. R1549 in ovarian cancer – phase III ‘SMART’ trial µ Phase III ‘SMART’ study examining survival benefit • R1549 (Pemtumomab) 30mCi i.p. + best std care vs best std care alone • Patients like those shown to benefit in phase II study µ Single pivotal study including ~ 420 patients µ Results published 2004 • No added benefit from RIT Phase II Trial of Pretargeted Yttrium90DOTABiotin 1. NRLU10 Antibody/Streptavidin 2. BiotingalactoseHSA clearing agent 3. 110mCi/m2 Y90DOTABiotin Responses: 2 PR (8%); 4 SD (16%) Toxicity: Diarrhoea: 88% (up to grade IV) Nausea and Vomiting: 70% (mostly grade III) Fatigue and Anorexia: 70% (mostly grade III) Haematological: 100% (mostly grade III) HAMA, HASA. HACA: 100% Susan J. Knox, Clinical Cancer Research Vol. 6, 406–414, 2000 Some Molecular Targets for RIT in Haematology Antibody Radionuclide (Specificity Target Isotype antigen) cell/disease AntiB1 I131 CD20 NHL Murine IgG2a (Tositumomab) antigen (Bexxar TM ) LYM1 I131 HLADR NHL Murine IgG2a antigen LL2 I131 CD22 antigen NHL Murine IgG2a (Epratuzumab) Y90 (transferrin R) AntiCD33 I131, CD33 antigen Acute/chronic Humanized (HuM195) Bi213 myelogenous murine Mab leukemia Ibritumomab Y90 CD20 antigen NHL Murine IgGI Tiuxetan, (Zevalin TM IDEC Y2B8) . CD20 • Restricted to Bcell lineage • >90 % of Bcell malignancies • Highly expressed (100 200,000 copies per cell) • Not shed/modulated • No clonal selection • Direct induction of apoptosis NonHodgkin’s Lymphoma CT before and after Radioimmunotherapy 90 Y Zevalin Versus Rituximab Therapy: Response 100 90 80 ORR 70 80 80 PP==0.00.00022 60 CR 50 Patients 56 56 (%) 40 30 3030 20 PP==0.00.04 4 10 16 16 0 90Y Zevalin Rituximab Type I and II antibodies Antibody Type Apoptosis CDC ADCC adhesion Lipid rafts Rituximab I + +++ +++ + +++ B1 II +++ ++ +++ Contributions of radiation and cell signalling • Radiation: – External – 131I anti MHC(II) • Signalling: – AntiId – AntiCD19 Yong Du et al, Blood (2004) 103, 14851494 EBRT + antiId BCL1 A31 I131 + antiId BCL1 A31 I131 + CD19 HER receptor family EGF receptor Epidermal Growth Factor Receptor Inhibition Modulates the Nuclear Localization and Cytotoxicity of the Auger Electron–Emitting Radiopharmaceutical 111InDTPA–Human Epidermal Growth Factor. Journal of Nuclear Medicine (2007); 48: 15621570 Kristy E. Bailey, Danny L. Costantini, Zhongli Cai, Deborah A. Scollard, Zhuo Chen, Raymond M. Reilly and Katherine A. Vallis TABLE 1 Effect of Gefitinib on Binding, Internalization, and Nuclear Localization of 111I nDTPAhEGF in MDAMB468 Human Breast Cancer Cells Proportion (%) Proportion of cellbound 111I n DTPAhEGF (%) Treatment Radioactivity Cellbound Radioactivity Radioactivity bound to cells radioactivity within within nucleus internalized by cytoplasm cells 111 InDTPA 54.7 ± 8.6 76.9 ± 5.9 62.3 ± 9.5 14.6 ± 4.0 hEGF 111 InDTPA 58.1 ± 2.8 81.1 ± 1.0 55.0 ± 6.2 26.0 ± 5.5 * hEGF + gefitinib * P < 0.05. Bailey et al: Journal of Nuclear Medicine (2007); 48: 15621570 Bailey et al: Journal of Nuclear Medicine (2007); 48: 15621570 Conclusions • A variety of targets have been successfully exploited for TRT • Many interesting targets remain • Expression on normal tissues may not be a limiting factor nonreceptor mediated mechanisms may dominate • Intrinsic radiosensitivity of tissues is important • Synergistic effects of radiation and cell signalling may be advantageous Thank you.