Modality onkologické terapie - chemoterapie Vypnětě / ztlumte laskavě svoje mobilnín telefony vyplatí se to !!! scan0005 scan0006 scan0007 Vznik nádorového onemocnění scan0008 scan0004 Vznik nádorového onemocnění a jeho léčba 800px-Cerberus-Blake[1] CHIRURGIE RADIOTERAPIE CHEMOTERAPIE a HORMONOTERAPIE Modality onkologické terapie ØLokoregionální Ø Ø chirurgie Ø radioterapie Ø Ø Systémové Ø Ø chemoterapie Ø hormonoterapie Ø imunoterapie Ø scan0004 Chemoterapie - historie ØAplikace cytotoxických látek –antiproliferační neselektivní Ø ( kolchicin - Dioscorides l.st.před Kristem ) Ø Ødusíkatý yperit , aktinomycin ( 40 -léta ) Øantimetabolity ( 60 - léta ) Øantracykliny, platinové deriváty ( 70 - léta ) Øtaxany ( 90 léta ) Øcílená terapie ( Herceptin®, inhibirory VEGF) Øgenová terapie Ø Ø minimálně 10 let, průměrně 12 let, maximálně 16 let THE STORY OF A MEDICINE Mini 10 years / Average 12 years / Maxi 16 years Research for Chemical Targets Conception Synthesis Screening Optimisation Potential medical candidates Preclinical Evaluation in vitro in vivo Preparation and submission of the registration dossier for the medicine Marketing •Pharmacovigilance •Renewals •R&D new indications assessment of quality, efficiency and safey Life Cycle Management 1 to 2 yr 1 to 2 yr 1 to 3 yr 1 to 2 yr Life cycle management 6 to 8 yr Safety and Pharmacokinetics search for the therapeutic effect Confirmation of the therapeutic effect and safety Phase 2 Phase 3 RESEARCH DEVELOPMENT BIRTH LIFE 10 000 molecules Phase 1 INVESTMENT 50 10 3 1 PATENT PROTECTION 3 0 1 to 3 yr 7 to 10 yr 12 PRECLINICAL DEVELOPMENT CLINICAL DEVELOPMENT MOLECULE IDENTIFIED Registration Patent submission Data protection 10 years (cent) or 6 or 10 years (decent) Generics Bolar + 1 year if new therapeutic indication Phase 4 € Patent 20 years SPC 5 years Investment € 1 YEAR € (Supplementary Protection Certificate) Chemoterapie Ø systémová terapie Ø Ø limitující faktor - počet buněk, velikost tumoru, stádium onemocnění,heterogenita Ø chemosenzitivita/ chemorezistence Ø celkový stav pacienta, komorbidita Ø Ø 5 % trvalé vyléčení INV&ME~1 Heterogenita nádorových buněk primární tumor Metastázy TRANSFORMACE VÝVOJ TUMORU VÝVOJ A A JEHO PROGRESE PROGRESE METASTÁZ 2. Cancer Biology: Emergence of Tumor Cell Heterogeneity The heterogeneity of tumor-cell populations, including primary neoplasms and metastases, is well recognized. The development of biological diversity within a clonal population derived from a single transformed cell is a reflection of genetic and epigenetic instability in the cell line. Metastases from a primary neoplasm can further drive tumor evolution and progression so that most neoplastic diseases comprise multiple subpopulations of tumor cells by the time of diagnosis. Počet nádorových buněk – jejich růst adetekce 1012 109 čas Diagnostický limit (1cm) Nedetekovatelné onemocnění Detekce nemoci Limit klinické detekce smrt 11. Cancer Biology: Tumor Growth and Detection The growth of tumors follows a sigmoidal curve, from a single transformed cell through billions of cancerous cells. With current limitations of clinical detection, tumors may remain undetectable until they reach the diagnostic threshold of approximately 1 cm in diameter and contain 1 billion cells. If the steep rate of tumor growth continues, progression from detection of cancer to host death will occur within the period of time required for the tumor mass to reach 10^12 cells. Doubling Zdvojovací proces Normální buňka Dělení Maligní transformace 2 nádorové buňky zdvojení 4 buňky zdvojení 8 buněk zdvojení 16 nuněk 1 million buněk (20 zdvojení) nedetekovatelný 1 billion buněk (30 zdvojení) detekce 1 trillion buněk (40 zdvojení –1kg) 41 – 43 zdvojení — Smrt 10. Cancer Biology: The Doubling Process Tumors grow exponentially, since after the malignant transformation of a single cell, each cell divides to produce two daughter cells. Cells in rapidly-growing tumors may double every one to four weeks, whereas slowly-growing tumors may double every six months. Tumor cells that double every three months will have undergone the doubling process 20 times in 5 years; this tumor would then contain approximately 1 million cells and only have grown to the size of a pin head. After 30 doublings, the tumor will be detectable as a lump and by 41 to 43 doublings the tumor will overwhelm the patient, resulting in death. Citlivost k chemoterapii M.Hodgkin, NHL,Burkit.l.,testikulární, ovariální tumory, choriokarcinom,Wilms.,Ewing,ALL NHL,Myelom,karcinom prsu,bronchogenní SCLC ORL , GIT Grawitz,moč.měchýř,pankreas,bronchogenní NSCLC,št.žláza Chemoterapie - typ léčby Økurativní Ø Øpaliativní Ø Øsymptomatická Øneoadjuvantní Ø Øadjuvantní Chemoterapie v kombinaci Ø kombinace s chirurgií Ø předoperační ( neoadjuvantní ) Ø pooperační ( adjuvantní, paliativní ) Ø kombinace s radioterapií Ø neoadjuvantní Ø adjuvantní Ø sandwich Ø konkomitantní chemoradioterapie Chemoterapie - aplikační cesty Systémová - perorální,parenterální- i.v. bolus, kontinuálně,i.m.,s.c., rektální Regionální - intrakavitální CL/PA ( intrathékálně, intraperitoneálně,intrapleurálně,intraperikardiálně ) - intraarteriální CL/ Qt ( 1 - E ) - intraluminální ( moč. měchýř, střeva) Lokální - zevní aplikace ( Efudix, Miltex ) Farmakokinetika Ø Resorpce ( aplikační cesta, forma, průnik membránami ) Ø Ø Distribuce ( vazba na bílkoviny, krev. elementy ) Ø Ø Biotransformace ( anabolická – Ø antimetabolity , katabolická inaktivace ) Ø Ø Vylučování ( ledviny , játra ) Mechanismus účinku cytostatik ØInhibice syntezy nukleových kyselin ( antimetabolity ) ØPoškození struktury nukleových kyselin ( alkylace , interkalace, radiomimetický efekt,inhibice topoizomerázy I. a II.) ØAlterace mikrotubulů ( inhibice polymerace, depolymerace) Ø ØInhibice proteosyntézy Ø ( L asparagináza ) Ø ØKombinované účinky Ø ØPoškození buněčné membrány Øsyntheza DNA Antimetabolity DNA DNA transkripce DNA duplikace Mitosa Alkylační látky Mitotické jedy Interkalační látky Mechanismus účinku cytostatik 5. Principles of Chemotherapy: Action Sites of Cytotoxic Agents/Cellular Level Most cytotoxic drugs target the DNA. Two exceptions are the poisons of the mitotic spindle—vinca alkaloids and taxoids—that target the tubulin. ØAntibiotika Antimetabolity S (2-6h) G2 (2-32h) M (0.5-2h) Alkylační látky G1 (2-¥h) G0 Vinca alkaloidy Inhibitory mitozy Taxany Mechanismus účinku cytostatik buněčný cyklus 4. Principles of Chemotherapy: Action Sites of Cytotoxic Agents/Cell Cycle Level Understanding the cell cycle is important because chemnicals with different modes of action may be rationally combined to increase antitumor effects at different times in the cell cycle. Interfáze Profáze Dceřinné buňky fáze Anafáze Metafáze Mitoza 1. Principles of Chemotherapy: The Stages of Mitosis Mitosis (=cell division) is divided into well-defined stages; the prophase (chromosomes become visible and spindle begins to form); the metaphase (spindle is completed, chromosomes begin to separate); the anaphase (the cell begins to divide in two); and the telophase (the final step of mitosis). Nežádoucí účinky cytostatik Øhematologické Økožní adnexa a kůže ØGIT Øplicní Øsrdeční Ømočový systém Øgonády Øimunitní reakce Ø Øbezprostřední (hodiny-dny: alergické, GIT ) Øčasné ( dny- týdny : hematologické,stomatitidy ) Øoddálené ( týdny-měsíce : plic.fibroza,kardiotoxicita,neuro-,nefro-,hepatopatie) Øpozdní ( měsíce- roky : sterilita,cirhoza, sekundární malignity,katarakta) ØMukositdas Ø Ø ØNausea/zvracení ØPrůjmy ØCystitida ØSterilita ØMyalgie ØNeuropatie Alopecie Plicní fibrosa Kardiotoxicita Lokální reakce Nefrotoxicita Myelosuprese Flebitida Nežádoucí účinky cytostatik 10. Principles of Chemotherapy: Side Effects of Chemotherapy There are multiple side effects of chemotherapy. Some are common, such as alopecia, neutropenia. Some are rare such as cardiotoxicity. The side effects are generally the consequence of the cytotoxic effect of chemotherapy on normal cells, however they can also be related to the direct toxicity of the drug. Podpůrná léčba během chemoterapie Øhematologické Ø Øinfekční Ø Øgastrointestinální Øantidota ( mesnum -Uromitexan, calcium folinát-Leukovorin, natrium thiosulfát- Devenan, amifostin-Ethyol ) Økardioprotektiva ( dexrazoxan-Cardioxan ) Ø Příčiny selhávání chemoterapie Øheterogenita nádoru (velikost nádoru ) Ø Ø Ø Øgenetická instabilita Ø (rezistence -přirozená, získaná- MDR ) Ø Ø medici medici INV&ME~1 Ovlivnění efektivity chemoterapie Ødávkování ( dávka, intenzita dávky, vysokodávkovaná chemoterapie ) Ø ESKALACE DÁVKY Ø ú… ú … ú ú… ú … ú Ø DOSE DENSE režimy Ø ú… ú … ú ú. ú. ú Ø DOSE INTENSIVE režimy Ø ú… ú … ú ú.ú. ú Ø Ø Ønačasování chemoterapie - timing Ovlivnění efektivity chemoterapie ØTiming Ø ØDávkování Ø Ø STANDARD DOSE Ø ú… ú … ú Ø 50mg/m2 q. 3 weeks Ø Ø DOSE ESCALATION Ø ú… ú … ú ú… ú … ú Ø 75mg/m2 q. 3 weeks Ø DOSE DENSE Ø ú… ú … ú ú. ú. ú Ø 50mg/m2 q.2 weeks Ø DOSE INTENSIVE Ø ú… ú … ú ú.ú. ú Ø 75mg/m2 q. 2 weeks FASG 05: FEC 100 improves DFS compared with FEC 50 Number of patients at risk 6 FEC 50 248 204 169 143 104 51 17 6 FEC 100 248 215 194 171 126 63 23 1.0 0.8 0.6 0.4 0.2 0 0 12 24 36 48 60 72 84 96 Time since randomisation (months) FEC 100 FEC 50 The French Adjuvant Study Group. J Clin Oncol. 2001;19:602-611. FASG = French Adjuvant Study Group; FEC = 5-fluorouracil, epirubicin, cyclophosphamide; DFS = disease free survival G-CSF Filgrastim days 3–10 CMF 500/40/600 days 1 and 8 Q4W Paclitaxel 250 mg/m² Q2W Epirubicin 150 mg/m² Q2W ET 90/175 mg/m² Q3W Surgery Surgery R A N D O M I S A T I O N Dose-dense 12 weeks ET standard 12 weeks Radiotherapy Untch M, et al. Proc Am Soc Clin Oncol. 2002;21:34a. Abstract 133. Neoadjuvant dose-dense chemotherapy: AGO protocol AGO = Arbeitsgemeinschaft Gynäkologische Onkologie; Q4W = once every 4 weeks; ET = epirubicin, paclitaxel Radiotherapy Dose-dense neoadjuvant chemotherapy phase 3 study: ³T2 tumours ØDose-dense sequential application of epirubicin and paclitaxel as pre-operative treatment for primary breast cancer resulted in a significant increase in the rates of lmeasurable response 68% vs 59% lpathological complete response 19% vs 10% lhistologically negative nodes 50% vs 41% lbreast conservation 61% vs 50% ØAll toxicities were comparable between treatment arms lexcept anaemia, which was higher in the dose-dense arm Ø Untch M, et al. Proc Am Soc Clin Oncol. 2002;21:34a. Abstract 133. ØZVÝŠENÍ EFEKTIVITY Rozdílnost mechanismu účinku Vedlejší účinky Rozdílnost mechanismu rezistence ÚČINNOST BEZPEČNOST Zásady aplikace chemoterapie 9. Principles of Chemotherapy: Aim of Combination Therapy The aim of combination therapy is to increase efficacy while keeping an acceptable safety profile. For example, two drugs in a combination therapy may have different mechanisms of action, and/or limiting drug resistance. Zásady aplikace chemoterapie Ømultimodální terapie Ø Øvhodnost chemoterapie Ø Øtiming Ø Ødávkování Ø Økombinace cytostatik Ø Ø Ø Øpodpůrná terapie Ø Ødůsledná kontrola pacientů Ø Øléčba po dosažení CR Ø Øalternativní kombinace při ztrátě citlivosti Ø Ø Ø Ø Proč je chemoterapie neefektivní ? Doubling INV&ME~1 heterogenita počet buněk chemorezistece PATHOF~1 Proč je chemoterapie neefektivní ? TRANSFORMATION ANGIOGENESIS MOTILITY & INVASION Capillaries, Venules, Lymnphatics ADHERENCE ARREST IN CAPILLARY BEDS EMBOLISM & CIRCULATION EXTRAVASATION INTO ORGAN PARENCHYMA RESPONSE TO MICROENVIRONMENT TUMOR CELL PROLIFERATION & ANGIOGENESIS METASTASES METASTASIS OF METASTASES TRANSPORT Multicell aggregates (Lymphocyte, platelets) 7. Cancer Biology: Pathogenesis A series of complex, interdependent, and interactive steps must take place before a single tumor cell evolves into cancer metastasis. Following neoplastic transformation, the proliferation of cancer cells must first be supported by the host organ. In order for the tumor mass to exceed 1 to 2 mm in diameter, angiogenesis must take place. Some tumor cells develop motility and are then able to invade the host stroma, typically gaining entry to the circulation system through capillaries and thin-walled venules (eg, lymphatic channels). While the vast majority of circulating cells die, the detachment and embolization of single tumor cells or multicell aggregates occurs, and the surviving cells arrest in the capillary cells of distant organs, where they adhere to either capillary endothelial cells or to exposed endothelial membranes. This is followed by the extravasation of tumor cells into organ parenchyma, where tumor cell receptors respond to paracine growth factors and proliferate. For metastases to progress, the tumor cells must continue to evade host defenses and angiogenesis must again take place. Co nyní ? Cílená léčba Cílená ( biologická ) léčba Ø epidermal grow factor receptors EGFR Ø Ø Ø vascular endothelial grow factor receptors VEGFr bez viditelného terče nelze zasáhnout cíl ligandy Trastuzumab blokáda ErbB2 interakce Textové pole: Pertuzumab blokáda Erb2 a ErbB3 interakce Pertuzumab blokáda Erb2 a ErbB3 interakce Bevacizumab blokáda VEGR interakce Cetuximab blokáda Erb1 interakce Erlotinib/gefitinib inhibice ErB1 fosforylace Lapatinib inhibice ErB1a ErbB2 fosforylace Sunitinib/pazopanib inhibice VEGFR fosforylace membrána endioteliální buňky buněčná progrese, proliferace,přežití,apoptoza diferenciace angiogeneze Proces aktivace receptoru 7 1 2 3 4 6 5 Degradace nebo reexprese Uzavření receptoru Přenos signálu TK activace a tyrosin transfosforylace Hetero/homo dimerizace Interakce ligandu Exprese receptoru P P P P P P P P P P P P Přežití buňky Proliferace Buněčná progrese Degradace Ligand Signal transduction through the ErbB receptors proceeds through an ordered, multistep process.^1 1.The first step requires expression of the receptor on the cell surface as well as expression of the appropriate ligand, either by the same cell or by a neighboring cell. 2.When both ligand and receptor are in close proximity, binding can occur. 3.Interaction of ligand with the receptor causes receptor pairing, or dimerization. This interaction can occur between 2 of the same receptor (homodimerization) or between 2 different ErbB family members (heterodimerization). 4.Receptor dimerization leads to activation of the intrinsic tyrosine kinase activity of the receptors, which results in transphosphorylation of the cytoplasmic tails, creating docking sites for downstream signaling molecules. 5. The interaction of downstream signaling molecules with the receptor tails leads to the formation of a signaling complex. This triggers additional phosphorylation events and sets off a signaling cascade that activates downstream pathways including MAPK/ERK and PI3K/Akt, producing outcomes such as cell-cycle progression, proliferation, and survival. 6. Activation of the ErbB receptors also triggers receptor internalization in a process that involves endocytosis in clathrin-coated pits. 7. Internalized receptors are either degraded within endosomal compartments, or recycled and returned to the cell surface. Sorting is based primarily on dimer composition. Homo- or heterodimers containing ErbB-1 are generally targeted for degradation, those containing ErbB3 are recycled, and those containing ErbB2 experience slower rates of endocytosis and increased recycling to the cell surface. The sorting process involves the ubiquitin ligase c-Cbl, which preferentially polyubiquitinates ErbB1 homodimers targeted for degradation within the lysosomal compartment. 1. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:127-37. ErbB Tyrosin Kinásové receptory lErbB-1 (EGFR/HER1) lErbB-2 (HER2) lErbB-3 (HER3) lErbB-4 (HER4) Ø extracellulární doména (navázání ligandu) transmembránová doména Cytoplasmatická doména (TK akctivita) The ErbB family is composed of 4 evolutionarily related receptor tyrosine kinases: ErbB-1 (also known as the epidermal growth factor receptor [EGFR] or HER1), ErbB-2 (also known as HER2/neu), ErbB-3 (HER3), and ErbB-4 (HER4). The 4 members of this family share a similar conserved structure––an extracellular ligand-binding domain, a single transmembrane-spanning domain, and an intracellular tyrosine kinase domain. MAPK MEK Genová transkripce Aktivace buněčného cyklu PI3-K RAS RAF SOS GRB2 PTEN AKT STAT R K pY R pY pY K proliferace/ maturace buněk přežití/ anti-apoptoza angiogenesa metastazování DNA myc Myc cyclin D1 Cyclin D1 Jun Fos P P chemo/ radio rezistence Strategie inhibice ErbB ØMoAbs –monoklonální protilátky blokují receptor-extracelulární doména TK ØTK inhibitory-malé molekuly (intracelulární doména ) ØKonmpetitivné receptoroví antagonisté ØToxiny -Ligandů Ø Antagonist MoAb Kinase Inhibitor Ligand- toxin trastuzumab lapatinib There are multiple strategies that could potentially be used to block signaling through the ErbB receptors: • Monoclonal antibodies (MoAbs) directed toward the extracellular domain of the receptor can be used to prevent interactions with ligands. This approach might also modulate signaling, dimerization, or receptor expression on the cell surface, as well as potentially triggering antibody-dependent cellular cytotoxicity or complement-mediated cytotoxicity. • Small molecules directed toward the kinase domain can inhibit phosphorylation and activation of downstream signaling pathways. • Receptor antagonists can be used to competitively block ligand binding. • Ligands or receptor-specific antibodies can be conjugated to lethal toxins. Following binding to the receptor, the toxin is internalized and kills the tumor cells. • Antisense oligonucleotides can be used to downregulate the expression of ErbB receptors or ligands. • Vaccines can be made to trigger the immune system to attack tumor cells overexpressing normal or mutant ErbB receptors. While all of these strategies could potentially be used to inhibit ErbB receptors, so far MoAbs and small-molecule kinase inhibitors have been developed to the greatest extent in a clinical setting. Akt Lapatinib - mechanismus účinku gsk-req2 > Ras Raf MAPK P Sos Shc Grb2 ATP Akt MAPK PI3K Lapatinib proliferace přežívání buněk normální aktivace pomocí ATP blokáda lapatinibem přežívání buněk proliferace Xia W, et al. Oncogene 2002;21:6255-63. Rusnak DW, et al. Mol Cancer Ther 2001;1:85-94. Lapatinib is a reversible small-molecule dual-kinase inhibitor targeting both ErbB1 and ErbB2 receptors. It works inside the cell by blocking the kinase activity of the receptor, and for this reason lapatinib can inhibit signaling through receptors that have lost or mutated their extracellular domains. In addition, as a dual-kinase inhibitor, lapatinib can potentially work against multiple receptor combinations. By inhibiting signaling through more than one complex, multiple-kinase inhibitors such as lapatinib could potentially be more effective at blocking tumor growth than single-target agents. Two of the major downstream pathways activated following stimulation of ErbB receptors are involved in cell proliferation (ERK1/2) and survival (PI3K/Akt).^1 Preclinical studies with lapatinib have demonstrated that this kinase inhibitor effectively blocks phosphorylation and activation of both ErbB1 and ErbB2, thereby simultaneously blocking activation of both of these downstream pathways.^2,3 ^PTEN must be present (inhibiting PI3K) for Herceptin to work 1. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:127-37. 2. Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 2002; 21:6255-63. 3.Rusnak DW, Lackey K, Affleck K, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 2001; 1:85-94. MORE Ligand-mediated dimerization of the ErbB receptors and subsequent autophosphorylation or transphosphorylation leads to their association with a variety of cytoplasmic phosphotyrosine binding proteins. This results in the initiation of a phosphorylation cascade and activation of several downstream pathways involved in cell growth and survival, including the Ras/Raf/MAPK and PI3K/Akt pathways.^1 Stimulation of these pathways transmits a signal to the nucleus resulting in modification of gene transcription patterns that ultimately affects processes such as cell division, apoptosis, adhesion, migration, and/or differentiation. Although the various dimer combinations activate overlapping downstream pathways, each receptor exhibits a unique phosphorylation pattern. The profile of the adaptor proteins that interact with each family member, and thus the quality and potency of the output signal, is distinct. For example, Erb-B-3 contains 6 binding sites for a PI3K subunit, leading to particularly potent activation of the Akt survival pathway through dimers containing this receptor.^2 In addition, the same receptor can also exhibit a different phosphorylation pattern and bind a unique subset of adaptor proteins dependent on ligand and dimerization partner. To illustrate, while EGF-activated ErbB1 homodimers recruit Shc and Grb2 and display rapid internalization, ErbB-1/ErbB-4 heterodimers activated by NRG-1 recruit Shc but not Grb2 and internalize more slowly.^3 This combinatorial diversity allows for exquisite control and fine tuning of signal transmission and cellular responses through the ErbB family of receptors. 1. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:127-37. 2. Prigent SA, Gullick WJ. Identification of c-erbB-3 binding sites for phosphatidylinositol 3′-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J 1994; 13:2831-41. 3. Olayioye MA, Graus-Porta D, Beerli RR, et al. ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol Cell Biol 1998; 18:5042-51. VEGF VEGF bFGF TGFb-1 VEGF bFGF TGFb-1 PlGF VEGF bFGF TGFb-1 PlGF PD-ECGF Pleiotrophin VEGF bFGF TGFb-1 PlGF PD-ECGF PlGF = placental growth factor. Relf et al. Cancer Res. 1997;57:963; DeVita et al (eds). Cancer: Principles and Practice of Oncology. 7th ed. 2005. Růst tumoru Exprese Angiogeního faktoru u karcinomu prsu ØVEGF je exprimován během celého života nádoroých buněk Additional information: •Angiogenesis is a significant prognostic factor in breast cancer, but the factors that control angiogenesis in vivo are not well defined. •Expression of 7 angiogenic peptides was determined in primary human breast cancers. •All tumors expressed at least six different vascular growth factors. VEGF was most abundant, and the transcript for the 121-amino acid form predominated. •Other angiogenic factors produced at different stages in the tumor lifecycle may be a reason why we have difficulty with maintaining the durability of response and tumor regression with Avastin. Perhaps if we also inhibit other factors in the tumor lifecycle we may be able to improve upon our results. Reference: Relf et al. Cancer Res. 1997;57:963. VEGF receptory Migrace, permeabilita, syntheza DNA ,přežití buňky Lymphangiogenesa – P – P P– P– – P – P P– P– – P – P P– P– VEGF-A VEGF-B PlGF VEGFR-1 VEGF-A VEGF-C VEGF-D VEGFR-2 VEGF-C VEGF-D VEGFR-3 Angiogenesa VEGFR = VEGF receptor Ferrara et al. Nature Med, 2003 Endothelial cell Bevacizumab - Three Proposed Mechanisms of Action Regrese Normalizace 1 2 Inhibice 3 Časný efekt Pozdní efekct Key Points •Based on what is known about tumor vasculature, there are many possible hypothetical mechanisms that could account for the effects of Avastin. We believe there are 3 that are predominant and at any one time, one may be more active than another, but likely all are at work simultaneously. •Summarize the 3 mechanisms of action of Bevacizumab with the potential clinical implications of the action of each mechanism.