targeted therapy AKA

Transcription

1 Molecularly targeted therapy AKA Designer therapy Signal transduction elements as therapeutic targets in oncology 1

2 Cancer Self-initiated proliferation Evasion of apoptosis Invasion Avoidance of immune surveilance Sustain new blod wessels 2

3 Therapeutic concepts in oncology: Clasics & Contemporary Surgery Radiotherapy Chemotherapy Photodynamic therapy Immunotherapy Gene therapy Combinations Understanding the molecular pathogenesis of cancer may lead to a rational development of new therapies 3

4 Concepts of chemotherapy Chemoprevention Conventional therapy Epigenetic chemotherapy Hormonal therapy Induction of differentiation Targeted (designer) therapy Understanding of biochemistry and pathophysiology of the CANCER cell 4 itself as well as STROMAL cell (plus their INTERACTIONS) is the key!

5 Chemoprevention: : just in early phases Retinoids antiproliferative Antiestrogens COX2 inhibitors D3 vitamin derivatives Natural compounds Green tea Curcumin Resveratrol Lycopen antiproliferative,, differentiation, proapoptotic many more 5

6 Conventional chemotherapy: trying to fight cancer stem cell Hard to kill 1: Deregulated stem cell and the surrounding niche :: Microenvironment Conventional therapy is preferential, but not specific for transformed cells (and mostly empiric) Replication, transcription, translation, mitosis, proteosynthesis..immortality, self-renewal: benefits and risks 6

7 Chemotherapy: : Combating Antimetabolites proliferating cells Antimetabolites (inhibition of DNA synthesis) Antifolates - impairing ing the function of folic acids Purine and pyrimidine analogs Genotoxic compounds compounds (inhibition of replication and transcription) Alkylating agents Intercalating agents DNA breaking ( radiomimetics( radiomimetics ) Inhibitors of topoisomerase Antimitotics (affecting cytoskeleton) Novel forms of old friends distribution, prodrugs,, stability etc.. 7

8 Epigenetic therapy: not only sequence, but also folding Methylation of DNA (promotors( promotors) Cancer: hypermethylation and thus silencing of promotors of oncosupressors Acetylation/deacetylation of histons Remodelation of chromatin 8

9 Hormonal therapy Sex hormons hormons: tissue specific, mostly pro- proliferative effect (breast, prostate..) Glucocortikoids: Typically antioncogenic effect Peptidic hormons: depends Ablative therapy (castration) Competitive therapy (antiestrogens, antiandrogens) 9

10 Immunotherapy Immune-surveilance Cancer antigens Tumour specific (pathogenetic cause or just consequence of genomic instability Tumour associated Proteins of oncogenic DNA viruses.. Ideal in ideal, still awaits for full success 10

11 Monoclonal antibodies: Start from 1997 Membrane proteins (CDs) Receptors (EGFR, VEGFR) GFs (VEGF, IL6) Adhesion molecules Ab Dependent Cellular Cytotoxicity Cytotoxicity (recruitment and activation of immune cells) Complement Dependent Direct cytotoxic effect effect (also due to the blocks of signaling via ligand neutralization or receptor blocking) Overlap with concept of targeted therapy 11

12 Here is the beef! Targeted therapy 12

13 Q1: Why Cancer cell needs advantage :: Activation of pathways responsible for Proliferation Resistance against apoptosis The dream: increase specific efficacy And minimize toxicity 13

14 Q2: How Mutated or overexpressed protein initiating activation of the downstream signaling elements: Achilles heel Initial stage of transformation: oncogene or pathway addiction ion Problem: subsequent accumulation of mutations one could be blocked, but more redundant weapons: Multitargeted And multimodality treatments needed 14

15 Targeted therapy: : Rational Signal transduction pathways involved in control of Cell cycle Invasion Metastasizing Differentiation Neoangiogenesis Apoptosis Pblms: Less (but still) toxic: on-target, off-target One disease differing causes (although within one pathway) - resulting individual sensitivity) 15

16 Challenge: tailored medicine Specific precise reliable marker Diagnosis of individual patient Specific targeted individual therapy Despite the genetic heterogeneity of malignant tumours (even within single tumour), common aberrations in the signaling elements of the growth and survival pathways are found 16

17 Philosophy Level Ligand Receptor Xxxxxxx Transcription factor Molecular mechanism (ant)agonist tyr-kinase inhibitor Antisense olig sirna mabs etc Functional endpoint: Cancer cell itself: : block of selfrenewal,, proliferation inhibitors, apoptosis inductors Microenvironment: immunomodulation,, block of neovascularization, inhib of inva and meta 17

18 Block of selfrenewal of CSC : El Dorado Selfrenewal: an attribute of the CSC Proliferation: an attribute of progenitors 18

19 Inhibition of telomerases Telomers (TTAGGG)n are consumed during cycling, senescence Telomerase: reverse transcriptase, absent in differentiated cells Reexpression in transformed cells Inhibitors sirnas 19

20 The Notch-γ-Secretase Pathway Cleavage products of Notch converts transcription inhibitor CSL to the activator Initiation of transcription of additional transcription factors Activated in cancer: Inhibitors of gamma secretase 20

21 Wnt inhibition of β-catenin Wnt soluble loca cal mediator - embryogenesis, morphogenesis, SC 7pass R (through( G, inositol,, oro others..) Wnt blocks catenin hydrolysis Wnt upregulates IC [catenin atenin] is in proteasome ie Block of negative regulation of catenin multiple tumors Catenin adhesion and/or transcrip ription factor accumulates in the nucleus Induces Wnt regulated gene transcrip ription Stimulates proliferation (among others via c-mycc myc) retinoids, COX2 inhibitors 21

22 Sonic Hedgehog Hedgehog (sonic, desert, indian hedgehog Secreted eted growth and development regulators, morphogenesis esis, limbs,, CNS Blocks IC downstream Cubitus interruptus (Ci) and several others molecules cleavage in proteasomes Ci fragments are transcrip ription represors Excess of Hedgehok signaling ng in basocellul ular,, lung, prostate, stomach etc CA Th Concept: low molecullar weight inhibitors of HH pathway 22

23 Inhibitors of proliferation of progenitors 23

24 Inhibition of (constitutive activated) growth factor receptors and intracellular effectors (downstream signaling molecules) 24

25 Receptor Tyr-kinases EGFR colon, lung HGFR stomach, kidney IGFR prostate, lung, kidney, multiple myeloma PDGFR breast, sarcomas FGFR - multiple Many others Often MULTITARGETED needed 25

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27 How to fight mabs against the receptor domain: Erbitux colon, Herceptin - breast Low molecular weight inhibitors Blocking IC kinase domain Iresa NSCLG, pancreas Multitargeted, combinations, multimodality 27

28 Non-receptor kinases Oncogene products Integrators Downhill partners: MAPK adhesion, invasion, migration 28

29 RAS (homologues H,K,N): switch Mutation: ligand independent signaling Frequent in many human cancers Promising target, but 29

30 30

31 RAS > cascade e of serine/threonin threonine phos osphorylation = Raf = MEK Motility, angiogenesis, meta, inva. In collab with FAK family Low molecular weight inhibitors tested 31

32 JAK, STAT Preclinical studies: Inhibition of activation Inhibition of dimerization 32

33 PTEN Pathway SIGMA-ALDRICH Aberant activation of AKT pathway in numerous tumors: Targets: PI3K (preclinical) PDK-1 1 (phosphoinositide( dependent kinase) Multilevel combinations 33

34 PKC inhibition Natural staurosporin curcumin resveratrol Synthetic so far off-target 34

35 NFκB NFκB inhibited ited by IκB NF NFκB activated by: TNFα and IL1 Phosphoryla rylated (IκB kinase - IKK), ubikvitination tion IκB degradation Facilitated ated by MAPK, JAK/STAT, stress Active nucle lear localiza alization signal al - NFκB Transcrip ription of about 60 antiapoptotic genes es (IL1, 6, 8, IFgamma,etc etc) FB synthes esis of IκB Therapeutic inhibitors of proteasome 35

36 Induction of apoptosis: separate lecture Agonists of death receptors Targeted Induction of ROS Inhibition of antiapoptotic Bcl-2 2 proteins Inhibition of HSP Induction of p53 36

37 Stroma/microenvironment targeted therapy Hard life of transformed cell Dirty collaboration paracrine deal Th Targets: biological processes participating on tumorigenesis: Neovascularization Invasion Metastasizing 37

38 Angiogenesis Cancer vessels - atypical Circulating endothelial precursors (from bone marrow) Mobilized by VEGF, MMP9, TGF-beta, HGF, bfgf Sprouting, Angiogenic cascade, Angiogenis switch Trigger: hypoxia Hypoxia Incucible Factor (HIF) transcription factor of VEGF and Angiopoetins VEGFR tyrosine kinase 38

39 Events Leading to Angiogenesis and Metastasis SIGMA-ALDRICH 39

40 Antiangiogenic factors Trombospodin 1 (induced by p53 cascade) Angiostatin (fragment of plasmin) Endostatin (fragment of collagen) Recombinant endostatin Syntetic Trombospodin Inhibition of endothelia proliferation Interferons Natural compounds Inhibition of VEGF cascade Neutralization of ligand Inhibition of receptor 40

41 41 Sathornsumetee S. et al, Cancer 110: 13-24, 2007

42 Inhibition of inva and meta 42

43 Metastatic cascade invasion (ECM, vessels) transport homing proliferation in new site 43

44 Decreased adhesion: Downregulation of E-cadherin Invasion Increased motility: Epithelial to mesenchymal transition (dediferentiation, dereg signaling) Facilitated integrin signaling: Facilit RAS, inhib p53, block of apoptosis Miscommunication : both outside-in in and inside out 44

45 Transport Blood or lymph 1 g of tu -> > 10 6 meta cells/day -> > just 0.1% survives in systemic circulation Extravasation,, homing: : seed: and soil 45

46 Th targets in inva and meta Anti-integrin integrin mabs MMP inhibitors Endogeneous Tissue Inhibitors of MMP Synthetic RTK inhibitors (FGFR, VEGFR, PDGFR etc) Inhibition of TGFbeta signaling: MAbs, inhibs 46

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