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Molecular_Imaging_2017-1.ppt
- 1. Marcelo Tatit Sapienza Medical Imaging Workshop Molecular Imaging INFIERI Summer School Intelligent signal processing for FrontIER Research and Industry
- 2. • Overview • Imaging Modalities • Clinical Applications – e.g. breast cancer Molecular Imaging
- 3. Molecular Imaging visualisation, characterization and quantification of normal / pathological biological processes at the cellular and molecular level MOLECULAR BIOLOGY In vivo Imaging
- 4. MOLECULAR BIOLOGY Abnormal cells with pathological phenotypes Molecular expression Molecular paradigm of diseases
- 5. Hallmarks of cancer – Cell 2000 Hanahan & Weinberg
- 6. Probes / ligands may be detected and allow Diagnosis Identification of targets for drugs Therapy planning Therapy with labeled compounds Therapy response Abnormal cells with pathological phenotypes Molecular expression
- 7. • Study of mechanisms of disease development and progression • Detection and activity of receptors and pathways • Pharmacokinetics / pharmacodynamics of target drugs Molecular Imaging • Understanding pathophysiological mechanisms • Diagnosis / Staging • Response to target drugs /individualized therapies CLINICAL APPLICATIONS BASIC / PRECLINICAL RESEARCH
- 8. Translational research Preclinical • Molecular Target Identification • Development of ligands • Experimental / preclinical evaluation Clinical • Image in humans validation • Approval by regulatory agencies • Clinical application
- 9. Translational research from BENCH to BEDSIDE to public health
- 10. Molecular Imaging • Overview • Imaging Modalities • Clinical Applications – e.g. breast cancer
- 11. Differences in • Spatial resolution • Depth of evaluation • Ionizing / non-ionizing radiation • Available molecular markers or probes • Detection threshold Optical systems Nuclear Medicine: PET / SPECT MRI Ultrasonography Computed tomography Imaging Modalities
- 13. Imaging modalities Willmann Nature Reviews 2008 Optical Imaging: lower cost high-throughput screening for targets low depth penetration limited clinical translation Nuclear Medicine: higher cost than optical unlimited depth penetration clinical translation MRI: high resolution and soft tissue contrast / cost and imaging time US: high spatial and temporal resolution / low cost / limited targets CT: high spatial resolution / no target specific imaging
- 14. Spectrum of wavelenghts High energy Low energy Eletromagnetic radiation MRI Infra red Ultra violet CT / NM Optical
- 15. Optical Imaging fluorescence and bioluminescence Green fluorescent protein Near Infrared fluorphores (NIR) Reporter gene (luciferase) Prescher Current Opinion in Chemical Biology 2010
- 16. NM Radiopharmaceuticals • radiolabeled molecules designed for in vivo application: 1. PHARMACEUTICAL= molecular structure determining the fate of the compound within the organism 2. RADIO= radioactive nuclide responsible for a signal detectable outside of the organism e.g. technetium-99m half life 6 hours gamma-ray photon 140 keV
- 17. Scintillation camara Sorenson and Phelps,27 1987 W.B.Saunders
- 18. SPECT Single Photon Emission Computed Tomography
- 19. Positron emitters Nuclides half life • F-18 110 min • C-11 20 min • N-13 10 min • O-15 1 2 min • Ga-68 68 min • Rb-82 1.3 min Positron: -Same mass as electron -opposite electrical charge -annihilation generates a pair of gamma-ray photons – 180º
- 20. Zanzonico Semin Nucl Med 2004 PET
- 21. 511 keV 511 keV 140 keV SPECT SPECT / CT PET / CT PET
- 22. PET SPECT PET > SPECT • Spatial resolution (human studies) • Temporal resolution • Sensitivity • Cost
- 23. Molecular Imaging Requirements - Imaging equipment - Target selection - Development of imaging probe / tracer
- 24. < 5% of in vitro targets allow development of an in vivo tracer • High TARGET concentration – Affinity and specificity – Absence of biological barriers (i.e. endothelium, blood brain barrier, ...) – Stable labeling of compound Development of in vivo probes
- 25. < 5% of in vitro targets allow development of an in vivo tracer • High TARGET activity / concentration – Affinity and specificity – Absence of biological barriers (i.e. endothelium, blood brain barrier, ...) – Stable labeling of compound • Low BACKGROUND activity – Non-specific accumulation, – Circulating or interstitial activity – Renal or hepatic elimination Development of in vivo probes
- 26. < 5% of in vitro targets allow development of an in vivo tracer • High TARGET activity / concentration – Affinity and specificity – Absence of biological barriers (i.e. endothelium, blood brain barrier, ...) – Stable labeling of compound • Low BACKGROUND activity – Non-specific accumulation, – Circulating or interstitial activity – Renal or hepatic elimination • Signal amplification – Cell trapping – Enzymatic conversion – "Reporter" molecules: fluorescence, radiation, magnetic Development of in vivo probes
- 27. EXAMPLE: 18FDG fluorodeoxyglucose = glucose analogue • Transport (Glut) • Phosphorylation (hexokinase) • Metabolism
- 28. MOST TUMORS: Increased Aerobic glycolysis (Warburg effect ) Vander Heiden Understanding the Warburg Effect Science 2009 Phenotype common to most tumors •Lower production of energy / mol X •NADPH Production - Synthesis •Hypoxia and acidosis select cells resistant to apoptosis •Acid pH associated with invasion
- 30. Hanahan & Weinberg Cell 2011
- 31. Molecular Imaging • Overview • Imaging Modalities • Clinical Applications – e.g. breast cancer
- 32. Breast cancer •Brazil Most incident in women ~ 50 /100,000 57.120 new cases ( 2014 – INCA ) deaths: 13.345 ( 2011 – SIM ) 5 y survival ~ 60 % LOBULAR DUCTAL
- 33. Therapy choices considers also : - Clinical conditions, Age , Menopause, Histology of the tumor - Hormone Receptors and HER2 Breast cancer Staging - T 1 < 2 cm T2 2-5 cm T3 > 5 cm T4 thoracic wall / skin - N0, 1 axillary I-II mobile, N2 axillary fixed or int.thoracic, N3 infra (III) / supraclavicular / axillary+int. thoracic - Metastases M0, M1 PROGNOSIS and CONDUCT AJCC Cancer Staging Manual. 7th ed. 2010,
- 34. Hormone and Growth Factor Receptors expression variation PREDICTIVE biomarker = susceptibility of the tumor before indicating the therapy
- 35. Biomarker-driven personalized cancer therapy Precision medicine BUT… BIOPSY: TU hormone receptor ++ susceptible to treatment with drugs that blocks either the estrogen receptors or hormonal synthesis
- 36. Establishing genetic and molecular profile by biopsy may not be sufficient: Gerlinger, Intratumor heterogeneity NEJM 2012 Tumor heterogeneity
- 37. Linden JCO 2006 FDG FES FDG post- therapy 18FES – FLUOROESTRADIOL target = hormone receptor PREDICTIVE biomarker in breast cancer ( indicates susceptibility to treatment )
- 38. Linden JCO 2006 FDG FES FDG post- therapy 18FES – FLUORO ESTRADIOL
- 39. PET- FDG in the metabolic evaluation after lymphoma chemotherapy EARLY RESPONSE biomarker = post-therapy prognosis Kasamon JNM 2007 • Reduce or increase # chemotherapy cycles • Change / add therapy
- 40. Crippa F Eur J Nucl Med Mol Imaging 2015 18F-FES – FLUOROTHYMIDINE target = DNA synthesis uptake after 1st cycle identifies responders ( p 0.001 ) - ( n= 15 ) EARLY RESPONSE biomarker in breast cancer
- 41. Crippa F Eur J Nucl Med Mol Imaging 2015 18F-FES – FLUORO THYMIDINE EARLY RESPONSE biomarker in breast cancer uptake after 1st cycle identifies responders ( p 0.001 ) - ( n= 15 )
- 42. Conclusion • Molecular imaging is a multidiciplinary field in the intersection of molecular biology and in vivo imaging • Main pillars of MI are : – Use of imaging modalities with different performances – Development of probes/ligands detectable in vivo • MI is part of translational research and may be applied for biomarker-driven personalized therapy ( precision medicine )
Editor's Notes
- Molecular Imaging emerged as a discipline at the intersection of molecular biology and in vivo imaging
- In a medical research context, it aims to "translate" findings in fundamental research into medical practice and meaningful health outcomes
- The same authors revisited the main molecular factors related to cancer, increased glycolisis is part of deregulated cellular energetics
- It is well known that gene expression may vary in different areas of the same tumor in a single patient. This publication from 2012 shows a primary renal cell tumor with differences in tumor grade from well differentiated to undifferentiated tumor – the metastases may also present marked heterogeneity. This heterogeneity results from the interaction of the tumor cells with its surrounding, acting in a Darwinian selection of clones, form which some are capable of dissemination and metastatic progpagation, others may be quiescent but resistant to a specific therapy, others may act as tumor stem cells.