GENETIC PROFILES AND TARGETED TREATMENT OF CANCER - PERSONALIZED MEDICINE

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1 GENETIC PROFILES AND TARGETED TREATMENT OF CANCER - PERSONALIZED MEDICINE Branko Zakotnik MD, PhD Department of Medical Oncology Institute of Oncology Ljubljana 1

2 I have no conflict of interest to declare

3 Content Introduction What is a targeted drug? Where and what are the targets for these drugs? Mechanisms of target inhibition Personalized medicine Registered targeted drugs What is the efficacy of these drugs in everyday clinical practice? Side effects of targeted therapy Conclusion 3

4 What is a targeted drug? 4

5 Where are the targets for these drugs in the tumor? 5

6 Where and what are the targets in the cells? a. Membrane receptors 1. Epitelial Growth Factor Receptors (EGFR or HER1,2,3,4) 2. Vascular Growth Factor Receptors (VEGFR 1,2,3) 3. Other receptors and molecules (c-kit, PDGFR, CD20, CD52, IGFR-1, HGF,...) b. Intracelular signaling pathways (braf, kras, met, PI3K, mtor, ) c. Nucleus - DNA 6

7 PARP inh. Reyevi dnevi

8 Mechanisms of target inhibition? monoclonal antibodies (...mab) Binding to receptors/molecules on the surface of cell mebranes Binding to growth factors To the monoclonal antibody attached a toxic molecule (isotope, cytotoxic agents, toxin) released when MoAB binds to cancer cell small molecules Tyrosine Kinase Inhibitors TKI (...nib) other targeted drugs TKI 8

9 Inhibition of receptors on cell membrane MoAb GF Binding of GF to the receptor Receptor TKI MoAb - monoclonal antibody GF - growth factor TKI tyrosine kinase inhibitor 9

10 BUT!

11 Personalized medicine 1 Molecular diagnostics: multiple answers on a single microarray chip Prognosis? Is there a BRCA1 mutation? Will tumor respond to mtor inhibitors? Will tumor respond to trastuzumab? Will tumor respond to cross-linking agents? Will tumor respond to hormonal therapy?

12 Personalized medicine 2 Genetic polymorphisms, pharmacokinetics and pharmacodynamics of drugs Yamayoshi Y et al. Int J Clin Oncol

13 Personalized cancer treatment: Molecular diagnostics Treatment Which pathways are active? Pharmacogenomic profile? Pathway targeted therapy + patient s pharmakogenomic profile

14 Registered targeted drugs (EMA, FDA) Inhibit signaling pathways Imatinib, Trastuzumab, Pertuzumab, Lapatinib, Gefitinib, Erlotinib, Cetuksimab, Panitumumab, Temsirolimus, Everolimus, Vandetanib, Vemurafenib, Crizotinib Modify protein function Vorinostat, Romidepsin, Beksarotene, Aliretinoin, Induce apoptosis cell death Bortezomib, Carfilzomib, Pralatrexate, Block growth of tumor blood vessels Bevacizumab, Ziv-aflibercept, Sorafenib, Sunitinib, Pazopanib, Regorafenib, Cabozantinib Help the immune system destroying cancer cells Rituksimab, Alemtuzumab, Ofatumumab, Ipilimumab Transport toxic molecules to cancer cells 131I-tositumomab, Ibritumomab tiuksetan, Denileukin diftitoks, Brentuximab vedotin, T-DMI

15 What is the efficacy of targeted drugs in everyday clinical practice? 15

16 Trastuzumab (HER2 MoAb) in adjuvant treatment of HER2+ breast cancer ChT+trastuzumab Only ChT Only ChT Relapse ChT+trastuzumab Reyevi dnevi

17 ChT (CVP) ± retuximab (MoAb CD20) in patients with follicular NHL: time to disease progression retuksimab retuksimab 17

18 GIST abdominal metastases Before treatment 1 month on imatinib 18

19 Survival of patients with metastatic GIST treated with imatinib (TKI ) compared to historical controls IMATINIB IMATINIB 19

20 Metastatic colorectal cancer Bevacuzimab (MoAb VEGF) Hurwitz H. et al. NEJM, 2004 Jun 3;350(23):

21 Metastatic colorectal cancer Cetuximab (MoAb EGFR) Van Cutsem E et al. JCO 2011

22 METASTATIC LUNG CANCER bevacuzimab + ChT ChT HR=0.79 ( ); p=0.003 Preživetje meseci ChT=carboplatin+paclitaxel, HR = hazard ratio Sandler, et al. NEJM 2006

23 METASTATIC LUNG CANCER Reck M et al. Ann Oncol 2010;21:

24

25 Metastatic lung cancer Mok T. et al, NEJM 2009

26 Side effects of targeted therapy Changes of general well being: fatigue, tiredness, mood changes, sleep disorders Gastrintestinal disturbances: taste changes, vulneable mucous membranes, loss of apetite, nausea, vomiting, meteorism, diarrhea, constipation Vascular disturbances: high blood pressure, heart failure, trombembolic events, bleeding Skin and hair changes: skin eruptions, dry ichy and sensitive skin, hiperkeratosis, skin discolorations, nail and hair changes Hormonal disturbances: hipotireosis Other: hepatotoxicity, lung toxicity, infections

27 21. centuary 22. centuary Conclusion 20. centuary Farmakogenomics 19. centuary DNA micro arrays Surgery Radiotherapy Chemotherapy Hormonal th. Proteomics Targeted therapy? Immunotherapy 27

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