Oncologia: dalla ricerca all applicazione clinica

Transcription

1 Oncologia: dalla ricerca all applicazione clinica Prof. Sabino De Placido Dip. di Endocrinologia ed Oncologia Molecolare e Clinica Università Federico II --- Napoli, Italia

2 Leading Causes of Death 30,00% Heart Diseases 49,4 % Cancer 25,00% Cerebrovascular Pneum & Influ 20,00% Accidents Diabetes 15,00% Alzheimer Nephritis 10,00% Septicemia Suicide 5,00% Liver diseases... 0,00%

3 Burden of cancer in the world 12.7 million new cases of cancer / million deaths from cancer / million people living with cancer / 2008 * Includes all types of cancer except nonmelanoma skin cancer Jemal et al. Ca Cancer J Clin; 61, (2011)

4 Progressi della Ricerca e Pratica Clinica in Oncologia Avanzamenti della ricerca Pratica clinica e risultati Difficoltà e prospettive

5 Progressi della Ricerca e Pratica Clinica in Oncologia Avanzamenti della ricerca Pratica clinica e risultati Difficoltà e prospettive

6 Molecular Histologic Clinical MULTISTEP CARCINOGENIC PROGRESSION Hyperplasia Mild Dysplasia Severe Cancer 3p, 9p loss; RAR-b loss; p16 inactivation 4q, 8p, 13q, 14q, 17p loss; p53 mutation; FHIT loss; cyclin D 1 amplification; DNA aneuploidy 6p, 8q, 13p, 18q loss

7 Tumorigenesis in humans A succession of genetic changes, each conferring one or another type of growth advantage, leads to the progressive conversion of normal cells into cancer cells Taken together, observations of human cancers argue that tumor development proceeds via a process formally analogous to Darwinian evolution.

8 21 st Century quest Biomedical research is revealing the processes of life and disease The Human Genome Project Cancer is a disease involving dynamic changes in the genoma Weinberg RA, 2000 image courtesy of Nature

9 Evading apoptosis Self-sufficiency in growth signals Insensitivity to anti-growth signals Sustained angiogenesis Limitless replicative potential Tissue invasion & metastasis

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12 Progressi della Ricerca e Pratica Clinica in Oncologia Avanzamenti della ricerca Pratica clinica e risultati Difficoltà e prospettive

13 Evading apoptosis Self-sufficiency in growth signals Insensitivity to anti-growth signals

14 HRG (NRG1) The EGFR/HER Family Ligand binding domain Transmembrane Tyrosine kinase domain erb-b1 EGFR HER1 neu Erb-b2 HER2 Erb-b3 HER3 Erb-b4 HER4 Mendelsohn and Baselga. Oncogene. 2000;19:6550. Olayioye et al. EMBO J. 2000;19:3159. Prigent and Lemoine. Prog Growth Factor Res. 1992;4:1. Harari and Yarden. Oncogene. 2000;19:6102. Earp et al. Breast Cancer Res Treat. 1995;35:115.

15 Trastuzumab: Humanized Anti-HER2 Antibody HER2 epitopes recognized by hypervariable murine antibody fragment Human IgG-1 Targets HER2 protein High affinity (K d = 0.1 nm) and specificity 95% human, 5% murine Decreases potential for immunogenicity Increases potential for recruiting immune effector mechanisms

16 More than patients were recruited in 4 international clinical trials HERA (ex-usa) BCIRG 006 (global) IHC / FISH (n=5,090) Observation 1 year 2 years FISH (n=3,222) 1 year 1 year NCCTG N9831 (USA) NSABP B-31 (USA) IHC / FISH (n=3,505) 1 year IHC / FISH (n=2,030) 1 year 1 year Standard CTx Doxorubicin + cyclophosphamide Docetaxel Docetaxel + carboplatin Trastuzumab Paclitaxel IHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, chemotherapy Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006

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18 Adjuvant Setting Results of individual studies are supported by a recent meta-analysis that included six randomized clinical trials and showed that the combination of trastuzumab with adjuvant chemotherapy produced a significant benefit in: DFS: odds ratio [OR] = 0.69 Overall survival: odds ratio [OR] = 0.78 Locoregional recurr: odds ratio [OR] = 0.53 Distant recurr: odds ratio [OR] = 0.62

19 Adjuvant Setting What we know Trastuzumab has changed the natural history of early HER2+ BC

20 Adjuvant Trastuzumab predicted to prevent recurrence in almost 28,000 patients over a 10-year period in the 5 major EU countries No. of patients prevented from developing metastases Patients, n 20,000 18,000 Herceptin introduced Incidence of MBC without Herceptin 16,000 14,000 12,000 27,737 10, Year Weisgerber-Kriegl et al, ASCO 2008

21 T-DM1: first-in-class antibody drug conjugate (ADC) Target expression: HER2 Monoclonal antibody: trastuzumab Cytotoxic agent: DM1 Highly potent chemotherapy (maytansine derivative) Linker Systemically stable Breaks down in target cancer cell T-DM1

22 T-DM1 selectively delivers a highly toxic payload to HER2-positive tumour cells T-DM1 binds to the HER2 protein on cancer cells Receptor-T-DM1 complex is internalised into HER2- positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positive tumour cell UNIQUE DUAL MOA Trastuzumab-like activity by binding to HER2 Targeted intracellular delivery of a potent antimicrotubule agent, DM1 MOA = mode of action

23 Inducing angiogenesis

24 ANGIOGENESIS Angiogenesis is the generation of new vessels from the existing vasculature and is essential for tumor growth and metastasis

25 VEGF AND BEVACIZUMAB Bevacizumab (Avastin TM ): an anti-vegf antibody Vascular Endothelial Growth Factor Recombinant humanised monoclonal antibody targeting the angiogenic factor VEGF Similar to Herceptin : 93% human, 7% murine

26 Pharmaceuticals Survival Hazard ratio = 0.66, p= Avastin Introduction WE GM Conference, June 2003

27 Targeting the EGFR pathway TGF-α EGFR overexpression: CRC (27 77%) Pancreatic cancer (30 50%) Lung cancer (40 80%) NSCLC (14 91%) EGFR* EGFR mutation: NSCLC (10%) Glioblastoma (20%) Sos Grb2 Ras* Raf* MEK MAPK Ras mutation: CRC (~50%) Pancreatic cancer (90%) Papillary thyroid cancer (60%) NSCLC (30%) B-Raf mutation: CRC (10%) Melanoma (70%) Papillary thyroid cancer (50%) *Mutated in human cancers Adapted from Roberts Der. Oncogene 2007

28 Months Use at best all drugs to increase 1980s 1990s 2000s 2008 BSC BSC: best supportive care survival of mcrc patients 5-FU Irinotecan Xeloda Oxaliplatin Bevacizumab Cetuximab Panitumumab

29 Metastatic renal cell cancer Front-line Therapy IL-2 INF-α SOR, TEM, BEV/IFN-α SUN, PAZ, EVER. AXIT, TIV Several drugs in the last 6 years

30 Metastatic renal cell cancer Front-line Therapy IL-2 INF-α SOR, TEM, BEV/IFN-α SUN, PAZ, EVER. AXIT, TIV OS (mos) Doubling and more. in Overall Survival

31 Progressi della Ricerca e Pratica Clinica in Oncologia Avanzamenti della ricerca Pratica clinica e risultati Difficoltà e prospettive

32 Problematiche attuali della Ricerca e Pratica Clinica in Oncologia Alto costo Carenze di investimenti Competenze

33 National Health Expenditures (billions of $) NHE

34 Cancer Drug Expenditures (billions of $)

35 Cost Effectiveness of Colon Cancer Treatment

36 EUROCARE -3 Trends in age-standardised 5-year relative survival

37 EUROCARE -3 Trends in age-standardised 5-year relative survival

38 Cancer Prevalence and Treatment

39 Problematiche attuali della Ricerca e Pratica Clinica in Oncologia Alto costo Carenze di investimenti Competenze

40 Molecular diagnosis profile of the patients and the tumor Gene microarray Signal network profile Microdissection Biopsy Protein microarray Personalized medicine Risk assessment and earlier detection Enhanced diagnosis Individualized intervention from Dr. E. Kohn. NCI

41 Molecular imaging diagnosis and monitoring in "real-time" Earlier detection Prevention Accurate diagnosis Targeted therapy Real-time monitoring Pharmacokinetic modeling CT PET PET-CT Synthetic and protein chemistry

42 Transformational technologies exponential expansion of knowledge Genomics Proteomics Metabolomics Molecular imaging Nanotechnology Bioinformatics

43 What is Targeted Therapy? A smart bomb versus a cluster bomb Chemotherapy Radiotherapy Surgery Target therapy