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.