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Impact of radiopharmaceutical development on the management of cancer Mike Sathekge
University of Pretoria & Steve Biko Academic Hospital
Impact of radiopharmaceutical development on the management of - - PowerPoint PPT Presentation
Impact of radiopharmaceutical development on the management of - - PowerPoint PPT Presentation
Impact of radiopharmaceutical development on the management of cancer Mike Sathekge University of Pretoria & Steve Biko Academic Hospital Acknow ledgments IAEA Morgenstern A, Bruchertseifer F, Betti M Vorster M, Lawal I, Knoesen O,
SLIDE 2
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- Metabolism
–Glucose –Cell membrane –Proteins –Bone
- Tumor specific agents
- Proliferation
- Angiogenesis
- Apoptosis
- Vascularization
- Hypoxia
Hanahan & Weinberg, Cell 2011
Characterization of tumor biology - image-based “biomarker” Identification of therapy targets - Theranostics and treatment planning Early Indicator of Tumor Response - patient-specific effect on outcome
Radiopharmaceuticals: Targeting of the Hallmarks of Cancer
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Process of New Drug Development
Phase 1 Phase 2 Phase 3
Application Review approval Seeds Clinical trial Preclinical
pharmacodynamics pharnacokinetics toxicity Candidate compounds Safety effect Safety effect Phase IV Safety dose In vitro Animal study Volunteer Patients Patients-large scale Side effects in patients
Duration of new drug development: 12 years Cost of new drug development: ???>R800million Successful compounds: only 8% of candidate compounds
Clinical use
effectiveness Screening of patients Dose setting Pharmacokinetics urinary or biliary excretion unexpected accumulation Screening
- f compounds
Jun Hatazawa – Drug Development
SLIDE 5
Schematic Representation of a Drug for Imaging and Targeted Therapy Molecular Address
- Antibodies, minibodies,
Affibodies, aptamers
- Regulatory peptides
(agonists & antagonists)
- Amino Acids
Targets
- Antigens
e.g. CD20, HER2)
- GPCR e.g. SSTR
- Enzymes & inhibitors
e.g. PSMA
- Transporters
Reporting Unit
- 99mTc, 111In, 67Ga
- 64Cu, 18F, 68Ga
- Gd3+
Cytotoxic Unit
- 225Ac, 177Lu, 213Bi, 131I
- 105Rh, 67Cu, 188Re, 90Y
Modified form: Helmut Mäcke & Rich Baum
THERANOSTIC PAIRS Targeted Molecular Imaging and Therapy The Key-Lock Principle
Lock Key
68Ga, 225Ac, 177Lu
pharmacokinetics/biodistribution modifier
Chelator Linker Ligand Target
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Cell Membrane Proteins metabolism Bone Proliferation Angiogenesis
18F-NAF/68Ga-ZOL 18F‐CHOLINE 68Ga‐ RGD 18F‐Fluoro‐L‐DOPA
Estrogen Receptors Androgen Receptors PARP inhibitors Glucose metabolism
68Ga‐PSMA‐11
Prostate Cancer
68Ga‐DOTATATE 18F‐ FDG 18F‐PARPi 18F‐ FDHT
Somatostatin Receptor Cancer-Fibroblasts
68Ga‐ FAPI 18F‐FLT 18F‐Estradiol
Lee et al. Sem Nucl Med 2019
Tumor
- Detection
- Staging
- Recurrence
Tumor
- Biology
- Targets
- Response
SLIDE 7
Kratochwil et al. J Nucl Med 2019
SNMMI Image of the Year: 2019
68Ga-FAPI PET/CT in patients reflecting 15 different Cancers
Fibroblast activation protein (FAP) is overexpressed in cancer associated fibroblasts of several tumor entities (15). 90% of the gross tumor-mass can consist from stromal but not tumor cells FAPI-tracers contain the universal DOTA-chelator: theranostic approach
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Planned clinical management altered in 52%
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Theranostics
Find Fight Follow-up
68Ga-DOTATATE/PSMA Lu-177/Bi213 DOTATATE/PSMA 68Ga- DOTATATE/PSMA
M Sathekge: CME 2013
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Yordanova et a 2017
Theranostics: Personalized Medicine
Cancer type Radioconjugate Patients Reference Leukemia
213Bi-HuM195mAb
49 [38,39]
225Ac-HuM195mAb
36 [40] Lymphoma
213Bi-anti-CD20-mAb
12 [41] Melanoma
213Bi-9.2.27mAb
54 [42-44] Bladder Cancer
213Bi-anti-EGFR-mAb
12 [32,45] Glioma
213Bi-Substance P
68 [46-48]
225Ac-Substance P
19 [48] Neuroendocrine tumors
213Bi-DOTATOC
25 [4]
225Ac-DOTATOC
39 [49] Prostate cancer
225Ac-PSMA-617
190 [5,50,51]
A Morgernstern et al. 2018
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Post-Tx
Remission for 26 Months
Pre-Tx
SLIDE 12
Hanahan & Weinberg, Cell 2011
Characterization of tumor biology - image-based “biomarker” Identification of therapy targets - Theranostics and treatment planning Early Indicator of Tumor Response - patient-specific effect on outcome
Radiopharmaceuticals: Targeting of the Hallmarks of Cancer
Sathekge……………….…………….Kratochwil …………………………..Heck…………………. Morgenstern & Bruchertseifer