Regina Demlova, 2019 AACR Cancer Progress Report 2012 Cancer epidemiology - incidence and mortality in the Czech Republic 0 20 40 60 80 100 120 140 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 Početna100000žen Rok ZN prsu (C50) u žen 0 10 20 30 40 50 60 70 80 90 1977197919811983198519871989199119931995199719992001200320052007 Početna100000osob Rok ZN kolorekta (C18-C21) 0 10 20 30 40 50 60 70 1977197919811983198519871989199119931995199719992001200320052007 Početna100000osob Rok ZN plic (C34) 0 20 40 60 80 100 120 1977197919811983198519871989199119931995199719992001200320052007 Početna100000mužů Rok ZN prostaty (C61) 0 5 10 15 20 25 30 1977197919811983198519871989199119931995199719992001200320052007 Početna100000osob Rok ZN ledviny (C64) 0 2 4 6 8 10 12 14 16 18 20 1977197919811983198519871989199119931995199719992001200320052007 Početna100000osob Rok ZN slinivky břišní (C25) incidence mortalita Breast Ca Colorectal Ca NSCLC Prostatic Ca Renal ca Pancreatic Ca Czech Cancer Care in Numbers 2009 Complex Cancer Treatment ̶ Surgery ̶ Radiotherapy ̶ Pharmacoterapy ̶ Psychotherapy, physiotherapy, nutrition care Pharmacotherapy ̶ cytostatic agents ‒classification according to the mechanism of action ̶ endocrine (hormonal) therapy ̶ targeted therapy ‒monoclonal antibodies ‒tyrosine kinase inhibitors ‒intracellular signaling cascades inhibitors ‒others ̶ targeted immunotherapy ̶ pain management, supportive care 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 cell „Cancer hallmarks“ (Hannahan D., Weinberg RA.) Cell; 2011 – terapeutic targets ̶ therapeutic intention: curative, palliative ̶ route of administration: ̶ parenterally (i.v. bolus, infusion, intrathecally, intravesically…) ̶ orally ̶ posology: dose in mg/m2 or mg/kg ̶ monotherapy and combination regimens ̶ repeated administration in cycles pause = patient‘s recovery, prevention of severe AE + „waking“ dormant cells in G0 phase 1. Cytostatic drugs Different efficacy according to the cell cycle phase: ̶ Cell cycle non-specific cytostatics (e.g., busulfan) ̶ Cell cycle specific cytostatics: −Phase-nonspecific (e.g., some of alkylating agents) −Phase-specific (e.g., antimetabolites, taxanes) http://csls-text3.c.u-tokyo.ac.jp/active/13_01.html Cytostatic drugs A C T G synthesis THF DHF metabolism of nucleic acids DNA structure DNA replication tubulin Intracelullar targets of cytostatics A C T G syntesis THF DHF antimetabolites platinum derivatives topoisomerase inhibitors alkylating agents intercalating agents alkaloids Mechanisms of action Cytostatics according to their MoA 1. Drugs that damage the structure of DNA a) Alkylating agents b) Platinum derivatives c) Intercalating agents d) Bleomycin 2. Drugs that inhibit key enzymes of DNA metabolism a) Antimetabolites: i. Purine analogues ii. Pyrimidine analogues iii.Folic acid analogues iv.Hydroxyurea b) Topoisomerase inhibitors: i. Inhibitors of topoisomerase I – camptothecins ii. Inhibitors of topoisomerase II – podophyllotoxins 3. Drugs that alter microtubules a) Inhibitors of tubulin polymerization – Vinca alkaloids b) Inhibitors of tubulin depolymerization – taxanes 4. Others a) Drugs that inhibit protein synthesis – L-asparaginase Drug groups overview A C T G syntesis THF DHF DNA structure Intracelullar targets of cytostatics alkylating agents Alkylating agents • MoA: transfer of the alkyl group on nitrogen in nucleobases, covalent bond between two guanines of one or two DNA strands – Inhibition of replication, cell cycle arrest • 50s: first derivatives of sulphur mustard in the clinical practice • AE – typical toxicity: secondary malignancies – hematological ALKYLATING AGENTS Nitrosourea derivatives: CYCLOPHOSPHAMIDE LOMUSTINE MITOMYCIN CBUSULFANTEMOZOLOMIDE DACARBAZINE IFOSFAMIDECHLORAMBUCIL MELPHALANE CARMUSTINE Alkylating agents Melphalane • i.v., p.o. administration • treatment of hematological malignancies and solid tumors Cyclophosphamide • i.v., p.o. administration • prodrugs → CYP450 → cytotoxic metabolites • AE: urotoxicity, emetogenity • low doses – immunosuppressant • hematological malignancies and solid tumors Lomustine • p.o. administration • lipophilic, crosses BBB → treatment of brain tumors Alkylating agents Temozolomide • 100% bioavailability after oral administration • crosses BBB → treatment of brain tumors Busulfan • i.v., p.o. administration • bone marrow transplantation • treatment of hematological malignancies A C T G syntesis THF DHF DNA structure Intracelullar targets of cytostatics platinum derivatives Platinum derivatives • MoA: binding on DNA, cross-linking of DNA strands, inhibition of topoisomerases • AE – most important: emetogenity, nephrotoxicity – AE are dose-dependent – prevention of nephrotoxicity: i.v. hydration, forced diuresis • cisplatin – high nephrotoxicity – treatment of solid tumors • others: – carboplatin – oxaliplatin – typical neurotoxicity A C T G syntesis THF DHF DNA structure Intracelullar targets of cytostatics intercalating agents Intercalating agents Anthracyclines • MoA: intercalation = insertion between base pairs, binding of DNA strands • AE – typical toxicity: acute and chronic cardiotoxicity • cardioprotective cumulative dose = restraint of therapy (e.g., doxorubicin 550 mg/m2) • i.v., intravesical administration • doxorubicin – treatment of hematological malignancies and solid tumors – modern dosage form (PEGylated liposomes) – higher cumulative dose (860 mg/m2) • others: epirubicin… Bleomycin • mixture of glycopeptides • MoA: intercalation between base pairs + inhibition of thymine incorporation → breaks → DNA fragmentation („radiomimetic“ effect) • i.v. administration • treatment of solid tumors • typical AE: fever, hyperkeratosis and hyperpigmentation of skin (flagellate = whip-like) • risk of anaphylactic reaction A C T G syntesis THF DHF metabolism of nucleic acids Intracelullar targets of cytostatics antimetabolites Antimetabolites • MoA: false substrates = affinity to target structure, loss of endogenous effect → blockade of nucleic acid synthesis, inhibition of nucleotides metabolism enzymes, production of non-sense DNA sequences • prodrugs: intracellular activation mostly by phosphorylation a) purine analogues – mercaptopurine, azathioprine, fludarabine… b) pyrimidine analogues – fluorouracil, capecitabine, gemcitabine… c) folic acid analogues – methotrexate, pemetrexed… Antimetabolites – purines Mercaptopurin • MoA: inhibition of purine nucleobases biosynthesis de novo, inhibition of mutual conversion of purine nucleotides • thiopurin methyltransferase (TPMT): MP → MeMP – genetic polymorphism – ↑ toxicity / ↓ efficacy – available pharmacogenetic testing of TPMT • p.o. administration, treatment of hematologic malignancies • azathioprine – prodrug of MP, immunosuppressant inactive Antimetabolites – pyrimidines Fluorouracil • MoA: incorporation to RNA + inhibition of thymidylate synthetase • combined chemotherapeutic regimens of solid cancers (i.v.) • AE – typical toxicity: GIT toxicity (mucositis) • biochemical modulation of effect: leucovorin (folinic acid) enhances binding on thymidylate synthetase, i.v. administered before FU – „FUFA“ regimen = colorectal carcinoma • capecitabine – prodrug Antimetabolites – folic acid Methotrexate – intracellular mechanism of action: MTX MTXPG TYMS DHFR other enzymes dUMP TMP Pyrimidine nucleotides biosynthesis: DHF THF 5-Me-THF homocysteine methionine Purine nucleotides biosynthesis: SAM polyglutamylation One-carbon metabolism Antimetabolites – folic acid Methotrexate • MoA: inhibition of dihydrofolate reductase, thymidylate synthetase and other enzymes • i.v., intrathecal administration, p.o. • leucovorin (folinic acid) – „rescue therapy“, antidote – forces free MTX out of healthy cells ; in cancer cells, polyglutamylation is more intensive → more MTXPG → MTXPG cannot be forced out • TDM – calculation of time interval from MTX administration, frequently in pediatric patients, less frequent in adults • AE – typical toxicity: – nephrotoxicity – precipitation (acute renal failure) • prevention: hydration, urine alkalinization (pH 7–7,5) – pneumotoxicity • low-dose MTX = immunosuppressant (p.o.) • high-dose MTX = hematological malignancies and aggresive solid tumors A C T G syntesis THF DHF DNA replication Intracelullar targets of cytostatics topoisomerase inhibitors Topoisomerase inhibitors Topoisomerase I inhibitors – camptothecins • plant-derived drugs – identification in bark of the tree Camptotheca acuminata • derivatives: irinotecan, topotecan – treatment of solid tumors Topoisomerase II inhibitors – podophyllotoxins • plant-derived drugs – identification in Podophyllum peltatum • derivatives: etoposide, teniposide – treatment of solid tumors (etoposide) and hematological malignancies (teniposid) ETOPOSIDE A C T G syntesis THF DHF tubulin Intracelullar targets of cytostatics Vinca alkaloids and taxanes TAXANES VINCA ALK. Cytostatics that alter microtubules Vinca alkaloids • plant-derived drugs • MoA: inhibition of tubuline dimers polymerization – inhibition of mitotic spindle formation, depolymerization prevails • i.v. administration, some for p.o. (vinorelbine) • treatment of hematological malignancies and solid tumors • AE – typical toxicity: peripheral neuropathy • original alkaloids: vincristine, vinblastine • semisynthetic derivatives: vinorelbine, vindesin, vinflunine ‒ increased affinity to mitotic spindle tubulin, ↓ AE VINBLASTINE Vinca alkaloids • identification: lesser periwinkle (Vinca minor) • isolation: Cataranthus roseus Taxanes • plant-based drugs • MoA: inhibition of tubulin depolymerization • i.v. administration – treatment of solid tumors • AE – typical toxicity: neurotoxicity • paclitaxel, docetaxel, cabazitaxel • modern dosage form: paclitaxel conjugated with albumine nanoparticles – transporter protein for albumine in cancer cells = better distribution from circulation into the tissues – ↓ toxicity, ↑ efficacy PACLITAXEL Taxanes • identification and isolation: Taxus brevifolia (Pacific yew) a Taxus baccata (European yew) Combination of cytostatics • monotherapy • combination regimens – examples: FUFA fluorouracil, folinic acid FOLFOX folinic acid, fluorouracil, oxaliplatin ABVD doxorubicin, bleomycin, vinblastine, dacarbazine BEACOPP bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristin, procarbazine, prednisone 2. Targeted therapy in oncology ̶ „target“ in cancer cell - Extracellular part of receptors - Intracellular part of receptors - Intracellular signaling pathway ̶ „target“ in immune system (T-cell) ̶ Immune check-point inhibitors (CTLA-4) Targeted therapy – „mAbs and –nibs“ 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 B-Raf Cancer signaling pathway inhibitor Current „targets“ Receptors • EGFR (epidermal growth factor receptor) • VEGF(vascular endothelial growth factor receptor) • PDGF (platelet derived growth factor receptor) • FGF (fibroblast growth factor receptor) ….on example of breast cancer 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 1 EGFR ErbB1 HER 2 ErbB2 Neu Her 3 and 4 ErbB3 ErbB4 EGF TGFalpha Amphiregulin Betacellulin Epiregulin Epiregulin Neuregulins No known ligand HER-2 TARGETING 1. Monoclonal antibodies HER2 HER1-4 Trastuzumab binds to subdomain IV and inhibits downstream signalling Trastuzumab (HERCEPTIN): Mechanisms of Action Cell membrane Franklin MC, et al. Cancer Cell. 2004;5(4):317-328. • 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®) HER2 HER1-4 Pertuzumab binds to a specific domain II and inhibits ligand-activated dimerization Trastuzumab binds to subdomain IV and inhibits downstream signalling Pertuzumab (PERJETA): Mechanisms of Action The combined regimen of pertuzumab and trastuzumab offers the potential for a more comprehensive HER blockade Cell membrane Franklin MC, et al. Cancer Cell. 2004;5(4):317-328. Cell membrane T-DM1: Antibody Drug Conjugate trastuzumab + emtansin conjugate Intracellular emtansine release → inhibition of microtubule polymerization LoRusso PM, et al. Clin Cancer Res. 2011;17(20):6437-6447. HER2 HER2 HER-2 TARGETING – tyrosinkinase 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 RARE ADVERSE EVENTS: • cardiotoxicity (2,5% pts.) • neutropenia • lung toxicity • hepatotoxicity • LAPATINIB (Tyverb®) Current „targets“ Receptors • EGFR (epidermal growth factor receptor) • VEGF (vascular endothelial growth factor receptor) • PDGF (platelet derived growth factor receptor) • FGF (fibroblast growth factor receptor) ….on example of colorectal cancer 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 - bevacizumab • Antibody against VEGF, Avastin (bevacizumab), binds to VEGF and prevents it from binding to receptors. • This induced inhibition of angiogenesis and its longterm 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®) INDICATION: • Metastatic colorectal carcinoma • Metastatic breast Ca, renal Ca, NSCLC ADVERSE EVENTS: • Akceleration of hypertenzion • proteinurie • Trombembolic complication Current „targets“ Receptors • EGFR (epidermal growth factor receptor) • VEGF(vascular endothelial growth factor receptor) • PDGF (platelet derived growth factor receptor) • FGF (fibroblast growth factor receptor) ….on example of colorectal cancer (overexpressed up to 90% of metastatic colorectal Ca) EGFR inhibition in mCRC • Monoclonal antibodies antiEGFR – Cetuximab, panitumumab • Tyrosine kinase inhibitors (TKIs) – regorafenib Venook A. Oncologist. 2005;10:250-261 Mayer A, et al. Cancer. 1993;71:2454-2560. Cetuximab (ERBITUX®) EGFR overexpression up to 90% of metatatic colorectal Ca INDICATION: • Anti - EGFR Mab • metastatic colorectal cancer AE: • Akneiform rash 76 – 90% Prognostic marker ??? !!! • Alergic reaction • Diarrhoea • Fatigue Panitumumab (VECTIBIX®) INDICATION: • Anti - EGFR Mab • metastatic colorectal cancer AE: • Akneiform rash • Diarrhoea • Fatigue PDGFR a c-KIT inhibitory • PDGFR – endothelial growth • C-KIT – formation of blood cells, melanocytes, intestinal cells • Mutation of c-KIT – leukemia (CML), GIST…. Philadelphia Chromosome (BCR-ABL Translocation) Imatinib mesylát (GLIVEC®) • Bcr-abl inhibitor – chronic myeloid leukémia • c-KIT inhibitor – 1st line treatment of GIST (mutation c-KIT in 85% pts.) – 70% of the pts. Are responders!!! AE: - neutropenia, trombocytopenia • diarrhoea, vomiting - joint pain – anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) – ipilimumab, tremelimumab – anti-PD-1 (programmed death-1 receptor) - nivolumab, pembrolizumab – anti-PD-L1 – BMS-936559, MPDL3280A Immunotherapy in oncology „Checkpoint“ inhibitors – CTLA-4 a PD-1/PD-L1 antagonists Activation of T lymfocytes through TCR and co-stimulating molecule CD28 Dendritic cell T lymfocyte MHC B7 TCR CD28 Antigen CTLA-4 Up-regulation of CTLA-4 receptors after T- cell activation Dendritic cell T lymfocyte MHC B7 TCR CD28 Antigen CTLA-4 CTLA-4 receptor inhibition Dendritic cell T lymfocyte MHC B7 TCR CD28 Antigen CTLA-4 Antagonisation of CTLA-4 receptors Ipilimumab Dendritic cell T lymfocyte MHC B7 TCR CD28 Antigen CTLA-4 Leach DR, Science 1996;271:1734-1736. Ipilimumab anti-CTLA-4 mAbs • Tremelimumab (IgG2, Pfizer) – Phase III ongoing – Tremelimumab 15 mg/kg vs DTIC/Temozolomid • Ipilimumab (IgG1, Bristol-Myers Squibb) – EMA registration – I. line treatment of melanoma • Ipilimumumab (10 mg/kg) – II. line • Ipilimumab (3 mg/kg) vs Ipilimumab/gp100 vs gp100 Kirkwood JM et al., JCO 2008;26:3445-3455 Ribas A et al., JCO 2008;26:,abstr.9011 Robert C et al., NEJM 2011;364:2517-2526 Hodi FS et al., NEJM 2010;363:711-723 Ipilimumab: Managing Immune-Related Adverse Events System Symptoms Management GI tract Diarrhea Abdominal pain Dark, bloody stools Moderate enterocolitis: hold ipilimumab, administer antidiarrheal. Persistent diarrhea (> 1 wk): systemic corticosteroids. 7+ stools/day: start methylprednisone, permanently discontinue ipilimumab. Consider infliximab for corticosteroid-refractory patients Skin Rash (± itching) Blistering/peeling Oral sores Moderate/nonlocalized rash: hold ipilimumab, start topical or systemic corticosteroids. Severe dermatitis: permanently discontinue ipilimumab, start corticosteroids Liver Jaundice Nausea/vomiting Assess ALT/AST, bilirubin, and thyroid function before each dose and as necessary. Hold ipilimumab if ALT/AST > 2.5 x but ≤ 5 x ULN; permanently discontinue if AST/ALT > 5 x ULN or bilirubin > 3 x ULN. The immunosuppressant mycophenolate can be used for hepatotoxicity in corticosteroid-refractory patients CNS Weakness in extremities Numbness/tingling Sensory changes Moderate neuropathy: hold ipilimumab. New or worsening neuropathy: permanently discontinue ipilimumab. Consider corticosteroids Endocrine Headaches Fatigue Behavior/mood changes Menstruation changes Dizziness/light-headedness Moderate endocrinopathy: hold ipilimumab, start corticosteroids. Endocrine abnormalities can be difficult to detect, due to nonspecific symptoms. Consider having an endocrinologist follow the patient Eyes Vision problems Irritation Monitor for redness suggesting uveitis, treat with topical steroidal eye drops Ipilimumab adverse reaction management guide. Gajewski TF, et al. Curr Opin Immunol. 2011;23:286-292. Spranger S, Gajewski T. J Immunother cancer. 2013;1:16. Checkpoint inhibitors – PD-(L)-1 ▪ T cell recruitment – High levels of innate immune signals – Chemokine expression ▪ Nevertheless, negative immune regulators dominate ▪ Blocking PD1:PD-L1 binding might activate immunity within the tumor microenvironment Cytotoxic T cell Chemokines Migration T reg Tumor PD-L1 Anergy MDSC PD1 Clinical Development of Inhibitors of PD-1 Immune Checkpoint Target Antibody Molecule Development stage PD-1 Nivolumab (BMS-936558) Fully human IgG4 Phase III multiple tumors (melanoma, RCC, NSCLCa, HNSCC) Pembrolizumab (MK-3475) Humanized IgG4 Phase I-II multiple tumors Phase III NSCLC/melanoma Pidilizumab (CT-011) Humanized IgG1 Phase II multiple tumors PD-L1 MEDI-4736 Engineered human IgG1 Phase I-II multiple tumors MPDL-3280A Engineered human IgG1 Phase I-II multiple tumors Phase III NSCLC MSB0010718C Fully human IgG1 Phase I solid tumors Eventsper 100person-years Observation period (no. pts; P-Y) Nivolumab Exposure-adjusted irAEs: Toxicity Is Not Cumulative ▪ Multiple occurrences of all-cause select AEs in individual pts are included in this exposure-adjusted analysis. ▪ Treatment-related Gr 3-4 AEs occurred in 17% of pts, including select AEs in 6%. 0-6 mo. (n = 306; P-Y = 138) 6-12 mo. (n = 189; P-Y = 59) 12-24 mo. (n = 85; P –Y = 49) 140 120 100 80 60 40 20 0 Topalian SL, et al. J Clin Oncol. 2014;32:1020-1030. Thank you for your attention