Targeted therapy in oncology (basic principles, main categories and adverse events) Targeted therapy in oncology (basic principles, main categories and adverse events) Regina Demlova, MD, Ph.D. Cancer epidemiologyCancer epidemiology • Czech republic – population: 10 266 646 (2006) – life expectancy: men: 73,45 / women: 79,67 years – mortality: 107 938 (2005) – Incidence - 521,3 / 100 000 (2004) – Mortality - 28 255 (26,2%) Cancer epidemiologyCancer epidemiology Deaths by selected dg. causes of death and age, CR, 2005 Cancer epidemiologyCancer epidemiology The most common solid tumors in czech men (2005): • 1. prostatic cancer (4 846) • 2. colorectal cancer (4 746) • 3. lung cancer (4 632) Cancer epidemiologyCancer epidemiology The most common solid tumors in czech women (2005): • 1. breast cancer (5 533 / 5 790 + TIS) • 2. colorectal cancer (3 236) • 3. endometrial Ca – corpus uteri (1 782) Genetic instability own production of growth factors, loss of sensitivity to inhibiting signals Getting unlimited replication potential Induction of angiogenesis Demage of the death cells (apoptosis) Invasion and metastatic process Cancer cellCancer cell Anticancer treatmentAnticancer treatment Fighting against cancer cell is aimed especially to: 1) Reduce its continued proliferation x cell cycle x growth factors and their receptors 2) avoidance of necessary nutrients x angiogenesis x of nucleic acids in the cell and the formation of DNA Classification of cytostaticsClassification of cytostatics BUSULFAN CYTOSIN ETOPOSID BLEOMYCIN L-ASPARAGINASA CARMUSTIN ARABINOSID TENIPOSID DACTINOMYCIN HYDROXYUREA CHLORAMBUCIL FLOXURIDIN VINBLASTIN DAUNORUBICIN PROCARBAZIN CISPLATIN FLUOROURACIL VINCRISTIN DOXORUBICIN CYKLOFOSFAMID MERCAPTOPURIN VINDESINE MITOMYCIN-C IFOSFAMID METHOTREXAT TAXANY MITOXANTRON MELFALAN PLICAMYCIN Alkylating agents antimetabolites Mitotic agents Anticancer antibiotics others Targeted therapy - is designed to target cells with specific receptors for treatment Targeted therapy - is designed to target cells with specific receptors for treatment Increasing of efficacy different mechanism of action different profile of adverse events different mechanism of resistance activity safety Principles of targeted therapyPrinciples of targeted therapy 1. Influence/disruption the binding of natural ligand to the receptor – monoclonal antibodies Example: e.g. Bevacizumab - binds to VEGF and prevents it from binding to VEGF-R receptors. Targeted therapy – receptor signaling pathways Cell membrane Ligand bindingl Receptor´s activation Proliferation Migration Tumor growth and matastases Survival Signal transduction Receptors with TKI activities Tyrosin- Kinases domain (TKI) Monoclonal antibodies Principles of targeted therapyPrinciples of targeted therapy Principles of targeted therapyPrinciples of targeted therapy 1. Influence/disruption the binding of natural ligand to the receptor 2. Direct binding of antibodies to the receptor – monoclonal antibodies (e.g. cetuximab) Targeted therapy – receptor signaling pathways Cell membrane Ligand bindingl Receptor´s activation Proliferation Migration Tumor growth and matastases Survival Signal transduction Receptors with TKI activities Tyrosin- Kinases domain (TKI) Monoclonal antibodies Principles of targeted therapyPrinciples of targeted therapy 1. Disposal of the signal from binding to receptor (e.g. bevacizumab) 2. Direct binding of antibodies to the receptor (e.g. cetuximab) 3. Disposal of the intracellular signaling pathway (e.g. lapatinib, sunitinib, sorafenib) Targeted therapy – receptor signaling pathways Cell membrane Ligand bindingl Receptor´s activation Proliferation Migration Tumor growth and matastases Survival Signal transduction Receptors with TKI activities Tyrosin- Kinases domain (TKI) Monoclonal antibodies Tyrozin-kinases inhibitors Basic terminologyBasic terminology Monoclonal antibodies have the suffix „mab“ (e.g. cetuximab, trastuzumab) Inhibitors of enzymatic reactions (Tki) have the suffix „nib“ (e.g. imatinib, erlotinib) Nomenclature of monoclonal antibodies Nomenclature of monoclonal antibodies Nomenclature of monoclonal antibodies Nomenclature of monoclonal antibodies Marking and identification of monoclonal antibody according to the origin is secured by inserting the letter: o - mouse (-o-mab) abagovomab a - rat (-a-mab) e - hamster (-e-mab) i - primates (-i-mab) cetuximab mu - human (-mu-mab) panitumumab zu - humanized (-zu-mab) trastuzumab xi - chimeric (-xi-mab) rituximab Nomenclature of Tki - what does „nib“ mean? Nomenclature of Tki - what does „nib“ mean? „nib“ refers to the pharmacologic action of the drug „nibs“ are inhibitors the letters before “nib” tell you what is being inhibited • a-nib – angiogenesis inhibitor pazopanib • ti-nib – tyrosine kinase inhibitor lapatinib • rafe-nib – raf kinase inhibitor sorafenib Example : breast carcinoma - The most common cancer in czech women - High mortaliy Decreasing of mortality - CZ: 1994-2003 o 19,5% - USA :1989-2003 25% Reference: 1www.SVOD.cz, 2 Jatoi I., et al. JCO 2007;25(12) HER-2 positive breast cancer 1985 – identification of the human Her-2/neu gene as a negative prognostic marker Methods : IHC, FISH Incidence: worldwide: 10-25% european: 17% czech: 14,2% Yang-Feng et al. Cytogenet. Cell Genet. 1985; Slamon et al, Science 1987; Pegram et al, JCO 1998; Owens et al. Clin Breast Can 2004; Al-Kuraya K et al. Mod Pathol 2000; Fabian et al, Sborník BOD 2006, HER-2 SIGNALING PATHWAY INHIBITION APOPTosis AKTIVATION TRANSKRIPTION AKTIVATION PROLIPHERATION AKTIATION ANGIOGENESIS HOMODIMERIZATION: HER-2/HER-2 Akt MEK MAPK RAS PI3-K mTOR PDK1 Shc/GRB2/ SOS PDK2 S6K GSK3β NFκB Kaspázy CCND1 MNK ELK Jun/Fos STAT ER RAF PI3K/Akt signaling pathway RAS/MAPK Signaling pathway P DIMERIZATION OF RECEPTOR = ACTIVATION OF RECEPTOR HER-2 TARGETING 1. Monoclonal antibodies TRASTUZUMAB – monoklonal antibody 1st line treatment of metastatic breast carcinoma Marty, JCO 2005 • INDICATIONS: treatment of locally advanced and metastatic HER-2 positive breast cancer • ADVERSE EVENTS: allergic reaction, fever, chills, hypotension cardiotoxicity diarrhea, nausea, vomiting, rash muscle and joint pain pulmonary infiltrates, penumonitis TRASTUZUMAB (Herceptin®) HER-2 TARGETING 2. Tyrozikinases inhibitors Reversible inhibitor EGFR (HER-1), HER-2 Activity in trastuzumab-rezistent tumors Oral administration, well tolerated INDICATION: Metastatic breast carcinoma after trastuzumab failure Konecny et al, 2006, Allen et al, 2002 LAPATINIB (Tyverb®) – tyrosinkinase inhibitor MAIN ADVERSE EVENTS: • Gastrointestinal toxicity (diarrhea, dehydration, abdominal pain, nausea, vomiting) • dermal toxicity - rash, pruritus, dry skin LAPATINIB (Tyverb®) Targeted therapy - other drugs targeting EGFR Targeted therapy - other drugs targeting EGFR • Monoclonal antibodies (e.g. cetuximab, panitumumab • Tyrosin-kinases inhibitors (e.g gefitinib /EGFR Cetuximab (ERBITUX®)Cetuximab (ERBITUX®) INDICATION: • Anti - EGFR Mab • metastatic colorectal cancer AE: • Akneiform rash 76 – 90% Prognostic marker ??? !!! • Alergic reaction • Diarrhoea • Fatigue Panitumumab (VECTIBIX®)Panitumumab (VECTIBIX®) INDICATION: • Anti - EGFR Mab • metastatic colorectal cancer AE: • Akneiform rash • Diarrhoea • Fatigue Erlotinib (TARCEVA®)Erlotinib (TARCEVA®) INDICATION: • Inhibitor of EGFR-kinases inhibitor • NSCLC after chemotherapúy failure • Metastatic pancreatic cancer AE: • akneiform rash • anorexie, diarrhoea • conjunctivitis • pneumonitis Example : colorectal carcinoma and VEGF targeting Example : colorectal carcinoma and VEGF targeting • The growth of malignant tumor needs the continuous supply of oxygen and nutrients • Simple diffusion and not enough nutrition to the cells under the influence of hypoxia • Tumor produced a series mediators, particularly VEGF (vascular endothelial factor). VEGF - bevacizumabVEGF - bevacizumab • VEGF binds to receptors (VEGF-R) on the surface of normal endothelial cells. • The result is the formation of blood vessels in the tumor and its vascularization, tumor growth and metastasis. VEGF - bevacizumabVEGF - bevacizumab • Antibody against VEGF, Avastin (bevacizumab), binds to VEGF and prevents it from binding to receptors. • This induced inhibition of angiogenesis and its long-term use leads to regression of tumor vasculature, the normalization of surviving tumor vessels and inhibition of recovery and growth of new blood vessels Bevacizumab (AVASTIN®)Bevacizumab (AVASTIN®) INDICATION: • Metastatic colorectal carcinoma • Metastatic breast Ca, renal Ca, NSCLC ADVERSE EVENTS: • Akceleration of hypertenzion • proteinurie • Trombembolic complication Targeted therapy - other drugs targeted to VEGFR, PDGFR, c-kit Targeted therapy - other drugs targeted to VEGFR, PDGFR, c-kit • Tyrosin-kinases inhibitors (e.g sunitinib and sorafenib (VEGFR, PDGFR, c-kit), imatinib (c-kit) Sunitinib maleát (SUTENT®)Sunitinib maleát (SUTENT®) • Multikinases inhibitor (PDGFR, VEGFR, c-KIT…) INDICATION: • Renal CA after failure of INF • GIST after failure of imatinib AE: • hand-foot syndrom (cca 13% pts.) • Diarrhoea, nausea • bronchospasm • neutropenia, trombocytopenia • hypertension Sorafenib (NEXAVAR®)Sorafenib (NEXAVAR®) • Multikinases inhibitor (PDGFR, VEGFR, c-KIT…) INDICATION : • Metastatic renal cancer • Inoperable hepatic cancer AE: • hand-foot syndrom • alopecia, • diarrhoea, vomiting • headache Current possibilities and using of targeted therapy Current possibilities and using of targeted therapy • Breast carcinoma – trastuzumab, bevacizumab, lapatinib • Colorectal cancer – bevacizumab, cetuximab, panitumumab • Non-small cell lung cancer - erlotinib , bevacizumab, cetuximab • Renal carcinoma – sunitinib, sorafenib, bevacizumab, temsirolimus, everolimus • GIST – imatinib, sunitinib • Pancreatic cancer • erlotinib • Head and neck cancer – cetuximab • Hepatocellular carcinoma – sorafenib SummarySummary • Targeted therapy = a modern form of an active anticancer therapy • Well tolerated • A different toxicity profile • Expensive • The future of anticancer treatment