Molecularly targeted therapy AKA Designer therapy

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

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

3. 3 Therapeutic concepts in oncology: Clasics & Contemporary Surgery Radiotherapy Chemotherapy Photodynamic therapy Immunotherapy Gene therapy Combinations

4. 4 Concepts of chemotherapy Chemoprevention Conventional therapy Epigenetic chemotherapy Hormonal therapy Induction of differentiation �Targeted� (designer) therapy

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

6. 6 Conventional chemotherapy: trying to fight cancer stem cell Hard to kill 1:1000000 �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

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

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

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

10. 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�

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

12. 12 Here is the beef!

13. 13 Q1: Why Cancer cell needs �advantage�: Activation of pathways responsible for Proliferation Resistance against apoptosis

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

15. 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)

16. 16 Challenge: tailored medicine Specific precise reliable marker Diagnosis of individual patient Specific targeted individual therapy

17. 17 Philosophy Level Ligand Receptor Xxxxxxx Transcription factor Molecular mechanism (ant)agonist tyr-kinase inhibitor Antisense olig siRNA mAbs etc

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19. 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

20. 20 The Notch-?-Secretase Pathway

21. 21 Wnt � inhibition of b-catenin Wnt soluble local mediator - embryogenesis, morphogenesis, SC 7pass R (through G, inositol, or others..) Wnt blocks catenin hydrolysis in proteasome ie upregulates IC [catenin] Block of negative regulation of catenin � multiple tumors Catenin adhesion and/or transcription factor accumulates in the nucleus Induces Wnt regulated gene transcription Stimulates proliferation (among others via c-myc)

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

23. 23 Inhibitors of proliferation of progenitors

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25. 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

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27. 27 How to fight mAbs against the receptor domain: Erbitux � colon, Herceptin - breast Low molecular weight inhibitors Blocking IC kinase domain � Iresa � NSCLG, pancreas

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

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

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31. 31 RAS �> cascade of serine/threonine phosphorylation

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

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

35. 35 NFkB NFkB inhibited by IkB NFkB activated by: TNFa and IL1 Phosphorylated (IkB kinase - IKK), ubikvitination � IkB degradation Facilitated by MAPK, JAK/STAT, stress Active nuclear localization signal - NFkB Transcription of about 60 antiapoptotic genes (IL1, 6, 8, IFgamma,etc) FB � synthesis of IkB

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

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

38. 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

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40. 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

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42. 42 Inhibition of inva and meta

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

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

45. 45 Transport Blood or lymph 1 g of tu -> 106 meta cells/day -> just 0.1% survives in systemic circulation Extravasation, homing: :�seed and soil�

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

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