Translational science in neuroendocrne tumors: opportunities and pitfalls - Birmingham - December 2019
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The biology of neuroendocrine tumors remains poorly understood. Thanks to the United Kingdom & Ireland Neuro-Endocrine Tumor Society for inviting me to overview current knowledges during its yearly meeting. Enclosed, please find attached the slides that were used for this lecture. I hope this will generate insights for pushing forward the discovery of novel targets and biomarkers.
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Translational science in neuroendocrne tumors: opportunities and pitfalls - Birmingham - December 2019
- 1. UKINETS 17th Annual Conference Birmingham 2 December 2019 Translational science in NETS: opportunities and pitfalls
- 2. Translational science in NETS: opportunities and pitfalls Prof Eric Raymond, MD, PhD Head of Medical Oncology & Department of Specialized Medicines – Scientific Director of the Vessels & Blood Institute (IVS) Saint-Joseph Hospital – 75014 Paris - France UKINETS 17th Annual Conference – 2 December 2019
- 3. Characteristics of neuroendocrine malignancies • High levels of heterogeneity across tumor types (NET/NEC), organs, and patients • High variability in tumor biology – Genetic background – Proliferation & doubling time – Metastatic potential – Angiogenesis – Metabolic activation – Tumor microenvironment
- 4. NET GENETIC BACKGROUND Translational science in NETS: opportunities and pitfalls UKINETS 17th Annual Conference – 2 December 2019
- 5. MS Lawrence et al. Nature, 1-5 (2013) Mutational loads in cancers Somatic mutation frequencies observed in exomes from 3,083 tumor–normal pairs
- 6. Genome alterations in NET Top Alterations in Neuroendocrine Tumor Most Commonly Altered Genes in Neuroendocrine Tumor Gene transcription Transcriptional enhancer Tumor suppressor of proliferation P27 cyclin dependent kinase Histone methyltransferase
- 7. Genetic alterations in PanNETs and associated targeted therapies de Wilde, R. F. et al. (2012) Gastroenterol. Hepatol. doi:10.1038/nrgastro.2012.9
- 8. Cholecystokinin, Muscarinic adenosine (AdoR-A) Pituitary adenylate cyclase-activating Polypeptide (PACAP) GABA receptors MAPK/PKC PKA/cAMP/CREB NFkb PI3K Glutamate receptor family Somatostatin receptors Protein interactomes involved in neuroendocrine malignancies
- 9. TGF-β R1 & R2 SMAD7 AKT1 TGF-α EGFR RAS/RAF MEK/ERK PI3K AKT MEN1 Protein interactome involved in neuroendocrine neoplasm proliferation
- 10. > 50% unknown somatic mutations Neuroendocrine tumors Diseases are characterized by loss of tumor suppressor genes and/or external activation of growth signaling by the microenvironment
- 11. Genetic changes are different among various NETs
- 12. Consequences of pathway activation in NET Metabolism/angiogenesis Genomic instability Journal of Endocrinology (2018) 236, R161–R167
- 13. X X X CDKN1A/CDKN2A depended Loss of cell cycle control X Loss of apoptosis TGF-β & NOTCH Increased invasiveness X TGF-β Common genetic mutations and impacted signal transduction pathways in pancreatic neuroendocrine tumors
- 14. NET MICROENVIRONMENT Translational science in NETS: opportunities and pitfalls UKINETS 17th Annual Conference – 2 December 2019
- 15. F1000Research 2018, 7(F1000 Faculty Rev):326 Last updated: 15 AUG 2018 NETs are paradigm tumors for the study of angiogenesis
- 16. A Couvelard et al. British Journal of Cancer (2005) 92, 94 – 101 Low CA9 High CA9 High MVD Low MVD Low CA9 - a marker of hypoxia - is more frequently expressed in WHO 1-3 and corelate with high microvascular density (and better overall prognosis) As NETs progress, VEGF expression is lost and MVD significantly decreases. The neuroendocrine paradox in angiogenesis
- 17. Faivre S et al. Endocrinol Metab Clin N Am 39 (2010) 811–826 VEGFR/PDGFR inhibitors VEGF inhibitors mTOR inhibitors Somatostatin analogues ? Drugs that can affect vessel maintenance & metabolism in NETs Angiogenesis and cancer metabolism can be affected by targeted therapies
- 18. Distribution of TILs in pNEN, PDAC, and NEC Lymphocytes Macrophages Cold ‘non inflammatory’ tumors Hot ‘inflammatory’ tumors Cold ‘non inflammatory’ tumors Hot ‘inflammatory’ tumors
- 19. Distribution of TILs (PD-1+) in NETs according to tumor grades (G1/G2/G3) Lymphocytes Macrophages
- 20. PD-1 expression is associated with a poor outcome Cold tumor low PD-1 expression Hot inflammatory tumor with local immunosuppression High PD-1 expression Decreased angiogenesis Increased mutational burden Higher neoantigen expression Inflammatory Switch
- 21. Frequency and metastatic potential of GEP-NET Neuroendocrine tumors are slowly proliferative at initial stages Metastatic potentials are different in various neuroendocrine tumors Angiogenesis patterns are different in various neuroendocrine tumors
- 22. First hit Differences between carcinomas and neuroendocrine tumors Activating oncogenic mutation Leading to and Increased Proliferation Loss of cell cycle control and apoptosis Genomic instability Repair enzyme deficiency and loss of apoptosis Third hit loss of migration control Acquired metastatic capacity VHL-HIF activation AngiogenesisCarcinoma stepwise oncogenic cascades Neuroendocrine tumors backward oncogenic cascades
- 23. SUMMARY OF BIOLOGY AND TRANSLATIONAL MEANS Translational science in NETS: opportunities and pitfalls UKINETS 17th Annual Conference – 2 December 2019
- 24. Summary of main biological characetristics in NET/NEC NET NEC Mutational load / p53 Low / non mut High /mut Proliferation (Ki67, doubling time) low high Metastatic spread high high Angiogenesis (HIF-VEGF/VEGFR) high low Metabolic pathway activation (mTOR) high high Immune microenvironment Chronic (non inflammatory) Acute (inflammatory) T-cell activation No Yes – but with local immunosuppression
- 25. Hypoxic conditions Metastatic spreading Increased angiogenesis Lactic acid metabolism Chronic inflammation NET - Indolent state Low proliferation No p53mut / cell cycle control Decreased angiogenesis Inflammatory reaction high proliferation p53mut/loss of cell cycle control Increased metastatic spreading Glycolysis Low mutation loads NET activated state & NEC Acquired activating mutations P53mut + Genome instability Time & therapies Biological landscape in NET
- 26. Present & Future of targeted therapies in neuroendocrine tumors mTOR inhibition Everolimus VEGFR/PDGFR inhibition Sunitinib Somatostatin analogues Octreotide Lanreotide Primary targets mTOR inhibition Others VEGFR/PDGFR inhibition Others Somatostatin analogues Others Analog targets TT with checkpoint inhibitors TT with chemotherapy TT with PRRT TT with nanoparticles Combinations TGF-beta R1/2 inhibitors CXCR4 inhibitors EGFR inhibitors PI3K/MEK/ERK inhibitors NOTCH inhibitors Novel targets MET inhibitors PD-1/PD-L1 – CTLA4 inhibitors
- 27. • Primary biopsy • Differentiation (pathology, expression of somatostatin receptors, Chromogranin A / NSE • Proliferation index (Ki67 – Mitotic index) and tumor doubling time (CT-Scan) Translational evolution in NET i.e. better identifying at which level of tumor progression an individual patient stands prior selecting specific therapies 2019 • At progression biopsy for proliferation index and genome instability • Angiogenesis changes using pathological specimens and imaging • Mutational loads and oncogene expression in circulating tumor cells • Oncogenic mutations (p53 and others) in liquid biopsy • Changes in metabolism (18-FDG-TEP scan) • PD1/PD-L1 expression and other microenvironment biomarkers of immune inflammation Beyond
- 28. Conclusions Pitfalls Serendipity in drug identification and development Opportinities Progresses will derive from using current knowledges of tumor biology in individuals at various stages of malignant progression
- 29. Thanks for you attention and welcome to the PAMM winter meeting in Stockholm, Sweden in 2020 UKINETS 17th Annual Conference – 2 December 2019