Ana Ramírez de Molina-El impacto de las ciencias ómicas en la medicina, la nutrición y la biotecnología
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El 29 de marzo de 2016 celebramos un Simposio Internacional sobre el 'Impacto de las ciencias ómicas en la medicina, nutrición y biotecnología'. Organizado por la Fundación Ramón Areces en colaboración con la Real Academia Nacional de Medicina y BioEuroLatina, abordó cómo un mejor conocimiento del genoma humano está permitiendo notables avances hacia una medicina de precisión.
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Ana Ramírez de Molina-El impacto de las ciencias ómicas en la medicina, la nutrición y la biotecnología
- 1. Cancer therapies: more precise personalized approaches Impacto de las ciencias ómicas en la medicina, nutrición y biotecnología Fundacion Ramon Areces 29 Marzo de 2016 Ana Ramírez de Molina Grupo de Oncología Molecular y Genómica Nutricional del Cáncer Instituto IMDEA Alimentación
- 2. Cancer Cancer is caused by genetic alterations that lead to cellular malfunction. Despite first tumor was resected 200 years ago, cancer currently constitutes the second leading cause of death and disability in developed countries
- 3. Cancer Research • Discovery of the first cellularoncogene H. E. Varmusand M. Bishop. 1976 • Relationshipbetween virus andcancer. P. Rous. 1910 •”The Seed an Soil Hypothesis”. StevenPaget. 1889 • Cancer caused in laboratory animals.1915 • Relationshipbetween mutations andcancer. Theodor Bovery. 1914 •Isolationof the first tumor suppressor gene. Stephen H. Friend. 1986 1950 1900 2013 1975 1800 1825 1850 1875 1925 • Extirpation of the first ovarian tumor. E. McDowell. 1809 • First uses of cancer radiotherapy. • First uses of cancer chemotherapy. Using nitrogen mustards (1943) and Folic acid antagonists(1948) Developmentof anesthetic techniques.1846 Developmentof antiseptic techniques.1867 Discovery of X-rays (1895) andRadium (1898) Technologydevelopmentfor the productionof antibiotics. 1975 S U R G E R Y R A D I O T H E R A P Y C H E M O T H E R A P Y I N M U N O T H E R A P Y Anticancerdrugs based on genetic alterations 1976: Src cellular oncogene 1981: Human oncogenes 1984: erbB2 truncated growth factor 1986: Rb tumor supressor 1993: Ras signalling pathway 1996: Cloning telomerase 1999: Tumor molecular profiling (OMICS) 2001: First specific therapies (Gleevec FDA Approval) Oncología traslacional: De la biología Molecular a la Clínica Ramos R et al., 2013. In Applications of Advanced Omics Technologies, Elsevier, 2013
- 4. Cancer is a genetic disease, but also a metabolic disease, immune disease, environmental disease…. Comprises more than 100 different diseases that share common features The hallmarks of cancer: the next generation, Hannahan & Weinberg, Cell 2011 Cancer Different mutations in different patients and different cancer subtypes
- 5. Image adapted from http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/pmc_age_of_pmc_factsheet.pdf. Li et al. J Clin Oncol. 2013;31(8):1039. Traditional “One-Size-Fits All” Approach All patients with the same diagnosis receive same treatment Precision Medicine Approach Treatment strategy based on patient’s unique genetic profile Genetic Profile A Targeted Therapy Genetic Profile B Standard Therapy Precise Treatment Approach Based on Molecular Features -omics Treatment decisions based on tumour phenotype and genomic profile maximize efficacy and minimize toxicity
- 6. • Molecular alterations are PRE- clinical manifestation: early detection (DIAGNOSTIC AND PROGNOSTIC BIOMARKERS) • Tumors with different molecular alterations respond to different therapeutic strategies: personalization of treatment (TARGETED THERAPIES) First mutation Second mutation Third mutation Additional mutations Uncontrolled growth Clinical manifestation Molecular mechanism of the disease ---- Molecular mechanism of treatment
- 7. Revolution in Cancer Molecular Diagnosis Involves High- Throughput Technology Old New Li et al. J Clin Oncol. 2013;31(8):1039. Molecular profiling: OMICS
- 9. Molecular Understanding Affecting Treatment Decisions
- 10. Disease Main Genetic Determinations with Clinical Relevance in Cancer Therapy
- 11. Targeted therapy Complexity of Signaling pathways in cancer Adapted from Hanahan and Weinberg, Cell 2000, vol. 100:57-70 Complementary approacches
- 12. LIPID METABOLISM ALTERATIONS IN CANCER Metabolic alterations sustain increased energetic and structural demands of tumor cells for uncontrolled growth Lipid metabolism Membranes synthesis Membranes saturation Lipid dropplets NADPH oxidation Lipid hormones Cell growth Oxidative stress resistance Survival Redox balance Proliferation and invassionAdipose tissue Tumor microenviroment Warbourg effect The hallmarks of cancer: the next generation Hannahan & Weinberg, Cell 2011 Adaptado de Santos y Schulze, 2012 Glucose metabolism Energy
- 13. 12, 829–846 , 2013 Including personalized nutrition for prevention and treatment improvement of patients with gastric cancer Gastric cancer Lipid metabolism Molecular Epidemiological evidence evidence Therapeutic nutritional intervention 54,4% preventable Targeted therapy Molecular biomarkers LIPID METABOLISM ALTERATIONS IN CANCER
- 14. FOOD and HEALTH The problem of chronic diseases, NIH, 2012 Population suffering from more than one chronic conditions
- 15. The evolution of Food Science Research Diet, body maintenance, epidemiological studies, healthy nutrition Disease prevention, bioactive ingredient, molecular mechanisms, genotype-phenotype Targeted personalized nutritional strategies that promote health Efficiently improve prevention and treatment of chronic diseases based on: • The molecular mechanisms of the effects of bioactive compounds and nutrients • Genetic profiles involved in the inter-individual differential susceptibility to disease and response to diet The human genome project -omic technologies GENETIC FACTOR + ENVIRONMENTAL FACTOR
- 16. Lipid metabolism Colon cancer development and progression Bioactive compounds Metabolic reprograming to substain increased energetic and structural requirements of tumoral cells Metabolic homeostasis restoration Characteristics nº of Patients (%) nº of Patients (%) nº of Patients (%) T otal sample size (n) 77 (100) 119 (100) 120 (100) Age at Diagnosis (years) Mean 68·22 66·08 --- Median 69 66 --- Age Range 32-86 26-91 33-88 ≤50 3 (3·90) 15 (12·60) 15 (12·5) 50-70 39 (50·65) 58 (48·74) 63 (52·5) ≥70 35 (45·45) 46 (38·66) 42 (35) Sex Female 33 (42·86) 54 (45·38) 60 (50) Male 44 (57·14) 65 (54·62) 60 (50) Stage IIA (T3 N0 M0) 56 (72·73) 70 (58·82) 99 (82·5) IIB (T4 N0 M0) 21 (27·27) 49 (41·18) 21 (17·5) Regional Lymph Node M etastasis No Lymph node involvement (N0) 77 (100) 119 (100) 120 (100) 1-3 Lymph node involvement (N1) Training group Validation group I Validation group II Stage II CRC Training set Hospital La Paz (2000-2004) Validation set Hospital La Paz (2004-2008) Validation set II GEMCAD (H. Clinic, H. La Fe, IVO) Validation set III GSE39582 series Gene Expression Omnibus Database (n=264) Global metabolic analysis of colon cancer tumors (early stage) of different sets of patients from different hospitals: Clinic Hospital La Fe University Hospital IVO LIPID METABOLISM ALTERATIONS IN CANCER
- 17. Fatty acid biosynthesis Oleate Biosynthesis n-3 n-6 FADS2 FADS3 FADS6 FADS1 SCD5 SCD Fatty Acid Elongation Saturated FASN ACACA ACACB LPL Lipid metabolism in peroxisomes β-oxidation ACOT8 HSD17B4 ACOX2 ACOX3 AMACR α-oxidation Plasmalogen synthesis GNPAT AGPS FAR1 FAR2 ACSL 1 ACSL 3 ACSL 4 Intestinaltract Intestinaltract Intestinaltract PPAR signaling Adipocytokine signaling PLIN1 ApoAIV ApoB ApoCI ApoCIIA poD ApoE LDLR LDL FATP CD36 ABCA1 ABCG5 Cholesterol Metabolism FABP4 Lipid transport ApoAI ApoAII ApoCIII Phospholipids Metabolism PPARD ACADM ECHS1 HADH ACAT1 HMGCS2 HMGCL Fatty Acid Activation PPA1 ACSS2 Fatty Acid Saturated acyl CoA Carbohydrate metabolism ACLY Acyl-CoA Gall bladder ABCB11 ACSM4 CYP7A1 LIPH SLCO1A2SL CO1B1SLC1 0A2 SLC25A20 PPARG MBOAT1 MBOAT2 Triacylglycerol metabolism AGPAT 1 AGPAT2 AGPAT3 AGPAT4 AGPAT5 DGAT1 Biosyntesis Degradation triacylglycerol diacylglycerol monoacylglycerol Glycerol LIPE LIPG MGLL LIPE Glycerol-3-phophate triacylglycerol diacylglycerol LEP LEPR POMC AGRP PPARGC1A ADIPO ADIPOR SLC2A4 Fatty acid β-oxidation VLDL Chylomicron Apoliporotins SCP2 KREBS 16 genes de regulación e interconexión metabólica Lipid metabolism quantitative gene expression screening RT-PCR_ 96 genes pannel
- 18. ColoLipidGene: lipid metabolism profile associated to early-stage colon cancer progression
- 19. 1.- ABCA1: Cholesterol efflux (tumor microenviroment) 3 key pathways: Lipid metabolism Colon cancer development and progression Tumor metabolic reprograming 2.- ACSL/SCD network: fatty acid activation (invasiveness) 3.- GCNT3: protein glycosilation (response to treatment)
- 20. ACSL / SCD network Confers migratory and invasive properties to cancer cells Fatty acid activation (ACSL) to enter into metabolic pathways SCD to avoid lipotoxicity 0 20 40 60 80 0.00.20.40.60.81.0 x3 - Training group Time (months) Disease-freesurvival P.Log < 0.001 Low Risk High Risk 0 20 40 60 80 0.00.20.40.60.81.0 x3 - Validation group Time (months) Disease-freesurvival P.Log < 0.001 Low Risk High Risk OVEREXPRESSED ACSL/SCD NETWORK HIGH RISK OF RELAPSE Molecular biomarkers
- 21. Normal colonocytes CCD18Co Combination of low doses Triacsin C/A939572 5-FU resistant Colon Cancer Cells Targeting of ACSL1/ACSL4/SCD axis on colon cancer cells by chemical inhibitors means could represent a promising therapeutic strategy (Triacsin C: vasodilator); Drug repurposing? SYNERGISTIC EFFECT OF ACSLS AND SCD INHIBITORS ON CRC CELLS 1µM T + 0.1µM A1µM TDMSO 0.1µM A No ORF x3 Targeted Therapy
- 22. Protein glycosilation (GCNT3) Low GCNT3 (deficient protein glycosilation): deficient cell function; bad prognosis DOWNREGULATION OF GCNT3 HIGH RISK OF RELAPSE Different antitumoral treatments increase GCNT3 (dose-dependent) Effect no observed under cell resistance
- 23. NATURAL COMPOUNDS Clinical trials in specific subgroups of patients Phytochemicals Basal structure for drug development Plant extracts: Therapeutic complement Molecular targets: ACSL/SCD GCNT3 Validación y análisis funcional -In vitro -In vivo (animal models) ANTITUMORAL EFFECT (cancer subtype) Non invasive biomarkers of response (ie miRNAs) (OMICS) i Combination with current treatments Clinical trials (healthy volunteers) Screening (OMICS) RE Therapeutic nutritional intervention (Standarized composition)
- 24. Lipid metabolism Bioactive compounds RE: Rosemary Supercritical Fluid Extracts (determined composition, EFSA approval) CARNOSIC ACID CARNOSOL * * * Display antitumoral properties * Sensitizies chemoresistant cells to treatment * Sinergizes with chemotherapy In vivo tumor volume RE González-Vallinas et al. Nutrition and Cancer, 2015 Oct 9:1-9 González-Vallinas et al. PLoS One. 2014, 3;9(6):e98556. González-Vallinas et al. Electrophoresis. 2014; 35(11):1719-27. González-Vallinas et al. Pharmacological Research, 2013, 1;72C:61-68. Vicente G et al. The Journal of Supercritical fluids, 2013, 79: 101–108. FORCANCER: Personalizednutritionforpreventionandtreatment ofpatientswithgastriccancer ACSL/SCD; GCNT3 RE Célula tumoral de colon humano (SW620) 1 mg/mL (≈ 150 mg/kg/día) H2O + RE Adm. oral Ratón portador de xenografía de cáncer de colon
- 25. Lipid metabolism Bioactive compounds RE: Rosemary Supercritical Fluid Extracts (determined composition, EFSA approval) CARNOSIC ACID RE miR-15b González-Vallinas et al. Nutrition and Cancer, 2015 Oct 9:1-9 González-Vallinas et al. PLoS One. 2014, 3;9(6):e98556. González-Vallinas et al. Electrophoresis. 2014; 35(11):1719-27. González-Vallinas et al. Pharmacological Research, 2013, 1;72C:61-68. Vicente G et al. The Journal of Supercritical fluids, 2013, 79: 101–108. FORCANCER: Personalizednutritionforpreventionandtreatment ofpatientswithgastriccancer ACSL/SCD; GCNT3 dUMP TS dTMP dTTP DNA synthesis Timidina TK1 OMICS CARNOSOL Plasma ACSL1/SCD: fatty acid activation Invasion and migration 0 20 40 60 80 100 0.00.20.40.60.81.0 Grupo Inicial Tiempo (meses) Supervivenicalibredeenfermedad P = 0.0006 Alta expresión de GCNT3 Baja expresión de GCNT3 Response to treatment GCNT3 Colon cancer patients ↑GCNT3 ↓GCNT3 * Display antitumoral properties * Sensitizies chemoresistant cells to treatment * Sinergizes with chemotherapy
- 26. Different formulations to increase bioavailability * Clinical trial in healthy volunteers Security, lipidic profile modulation, risk factors (prevention), genetic profile determining differential responses, metabolic and biochemical biomarkers, plasmatic miR15b Development of RE bioactive nutritional supplements • Study completed (80 volunteers) • No sign of toxicity • Currently: data analyis
- 27. *Clinical trial in colon cancer patients CRC resectable patients (target population), ColoLipidGene / miRNA Biomarkers, GCNT3, clinico- pathological characteristics, Synergism with chemotherapy (2 phase) First Targeted nutritional supplement as complementary therapeutic approach (colon cancer) • CEIC (FJD) approval: march 2016 • Trial: April – December 2016 Development of RE bioactive nutritional supplements
- 28. Lipid metabolism alterations might determine early-stage colon cancer patients relapse Supports metabolic drug repurposing Supports nutritional-based targeted strategies as complementary personalized therapeutic approaches for gastric cancer patients Conclusion OMICS: Molecular mechanism of disease ---- Molecular mechanism of treatments
- 29. Margarita González-Vallinas Teodoro Vargas Ruth Sánchez Marta Gómez de Cedrón Cristina Aguirre Lara Fernández Silvia Cruz Jorge Martínez Romero Ana Ramírez de Molina Molecular Oncology Group IMDEA Food Institute Paloma Cejas Marta Mendiola Ana B Custodio Emilio Burgos Jaime Feliu Hospital La Paz Joan Maurel Jorge Aracicio Carlos Fernández-Martos Ricardo Yaya Hospital Clinic, Hospital La Fe, IVO http://www.alimentacion.imdea.org/oncologia-molecular Isabel Espinosa Elena Aguilar Susana Molina Mónica Gómez Clara Ibáñez Jesús Herranz Viviana Loria Plataforma GENYAL Tiziana Fornari Mónica García-Risco Marta Corzo Carlos Torres Guillermo Reglero CIAL (UAM-CSIC) Ana Jiménez César Gómez Raposo Maria Sereno Maria Merino Juan Moreno Enrique Casado Hospital Infanta Sofía Victor Moreno Start Madrid Mónica Álvarez Mirna Pérez Moreno Marcos Malumbres Spanish National Cancer Research Centre
Editor's Notes
- Combined pharmacological treatment targeting the ACSL/SCD network synergy to selectively inhibit cancer cells viability and mesenchymal features The robust protumor action of ACSL1/ACSL4/SCD network, together with the fact that all three of them are lipid metabolism enzymes, makes these druggable proteins attractive targets for cancer therapy. For this reason, we evaluated the effect on colon cancer cell viability of Triacsin C, a specific inhibitor of ACSL, and the SCD inhibitor A939572. Accordingly, both Triacsin C and A939572 were able to decrease cell viability in DLD-1 and SW620 cell lines in a dose- dependent manner. Given that the use of high concentrations of pharmacological inhibitors may cause side effects and affect other pathways, we combined both compounds using lower doses that per se has little or no effect on the viability of a panel of colon cancer cell lines. Very importantly, the combined action of both inhibitors caused a strong cancer cell viability reduction even in the colon cell lines that do not easily respond to these compounds, such as HT-29 or LS174T. We used as well a subclone of SW620 cells resistant to 5-Fluorouracil, the most used chemotherapeutic agent in colorectal cancer. The drugs had little (Triacsin C), or no effect (A939572) on SW620-5FU-R when applied separately. Nonetheless, a strong cooperative effect was found upon simultaneous treatment of chemotherapy resistant cells with ACSL and SCD inhibitors (Figure 5D). Finally and very importantly, the same inhibitors concentrations that caused a massive loss of viability of colon cancer cell lines were totally ineffective when applied to normal colonocytes CCD18Co Thus, the targeting of ACSL1/ACSL4/SCD axis by means of the selective effect of these drugs on cancer cells arises as a promising therapeutic strategy.
- El estudio de los compuestos naturales antitumorales puede dar lugar, por un lado a la identificación fitoquímicos tanto para su aplicación directa como para su utilización como estructuras que sirvan de base para el desarrollo de nuevos fármacos. Por otro lado, los extractos naturales se pueden como terapia complementaria en cáncer, y este uso puede ser eficaz en los pacientes, siempre que se establezcan adecuadamente las bases científicas que demuestren su utilidad en cada situación clínica concreta, determinada por el tipo de cáncer, el tratamiento antitumoral utilizado, y las alteraciones moleculares que presente el tumor. Además, la identificación de las dianas moleculares de estos compuestos antitumorales puede servir para establecer nuevas dianas y biomarcadores con potencial utilidad en cáncer.