Advanced Drug Targeting & Therapeutic Responses in Complex Signaling Pathways

1. Σηματοδοτική Πολυπλοκότητα, Φαρμακευτική Στόχευση και Θεραπευτικές Αποκρίσεις Καθηγητής ΑΘ. Γ. ΠΑΠΑΒΑΣΙΛΕΙΟΥ, MD, PhD Διευθυντής Εργαστηρίου Βιολογικής Χημείας ΙΑΤΡΙΚΗΣ ΣΧΟΛΗΣ ΠΑΝΕΠΙΣΤΗΜΙΟΥ ΑΘΗΝΩΝ

2. A human colon polyp (an early stage of colon cancer)

3. Ras activation by growth factor signaling

4. Ras (hyper)activation of the ERK MAP kinases Cyclic AMP-inducible gene expression

5. Inhibition of tumor growth by targeting downstream signaling elements Konstantinopoulos, Karamouzis & Papavassiliou Nature Reviews Drug Discovery 6 (2007)

6. The MAPKKK-MAPKK-MAPK … zoo

7. Anti-breast tumor chemotherapy with an anthracycline cytotoxic agent

8. EGFR HER-3 HER-4 HER-2 TK X TK TK TK TK TK TK TK X TK TK RAS TK TK Cbl X X PLC PKB RAF TK TK JAK TK X MEK PKC Hsp90 PI-3K PAC MAPK STAT C y t o p l a s m AKT TFs DNA N u c l e u s Gene transcription Apoptosis Proliferation Angiogenesis Differentiation The ErbB receptors signaling modules Karamouzis & Papavassiliou Int J Biochem Cell Biol 39 (2007) Karamouzis et al. Oncotarget 7 (2016)

9. A biological interaction network of phosphotyrosine proteins identified as novel EGF targets Papavassiliou Mol Med 14 (2008)

10. A mammalian signaling network Cyclic AMP-inducible gene expression

11. Cross-talk of signal transduction pathways [“c h a o t i c” ?]

12. NF-kB signaling Cyclic AMP-inducible gene expression

13. Feedback inhibition of NF-kB Cyclic AMP-inducible gene expression

14. Velcade and its effects on proteasome

15. Inhibition of NF-kB action by Velcade: apoptosis of myeloma cells within bone marrow

16. Use of expression arrays to predict cancer progression

17. S1 S2 S2 S1 R1 R2 R2 R1 TF TF Where to target? Konstantinopoulos & Papavassiliou JAMA 305 (2011) Karamouzis & Papavassiliou Cancer 120 (2014)

18. How to target a Transcription Factor? Cyclic AMP-inducible gene expression

19. The ‘enigma’ of Transcription Factor phosphorylation (I) Cell Proliferation

20. The ‘enigma’ of Transcription Factor phosphorylation (II) Cell Differentiation - Homeostasis

22. … and here we are! (start to) Approaching cellular reality…

23. Mode of action of small-molecule drugs targeting Transcription Factors & Co-factors Karamouzis et al. Clin Cancer Res 8 (2002) Grivas & Papavassiliou Trends Mol Med 17 (2011) Grivas & Papavassiliou Cancer 119 (2013)

24. Mode of action of small-molecule drugs targeting Transcription Factors & Co-factors Karamouzis et al. Clin Cancer Res 8 (2002) Grivas & Papavassiliou Trends Mol Med 17 (2011) Grivas & Papavassiliou Cancer 119 (2013)

25. GFRs Kinases AP-1 PROTEIN DIMERS Transcription Co-factors CYCLIN D1 COX-2 Prostaglandins PPARγ RARβ RXRs FasL / TNF-α APOPTOSIS CELL PROLIFERATION NF-κB PTEN / Akt IGF-1R ERβ AP-1 signaling network in colon carcinogenesis Karamouzis et al.Mol Cancer Res 5 (2007) Gargalionis et al.Carcinogenesis 36 (2015)

26. AP-1/PPARγ/NF-κB cross talk and COX-2 overexpression in colon adenocarcinomas Konstantinopoulos et al. Cell Oncol 29 (2007) Gargalionis et al. Int J Cancer 136 (2015) Gargalionis et al. Int J Cancer 134 (2014)

27. GFRs Kinases C y t o p l a s m Degradation N u c l e u s AP-1 PROTEINS HAT / HDAC Transcription Co-factors BTM Other Transcription Factors AP-1 PROTEIN DIMERS DNA TREs Transcription of target genes Multifaceted targeting of AP-1 Gargalionis et al. Int J Biochem Cell Biol 44 (2012)

28. The intracellular signaling circuitry and collaboration between cancer-associated genes

29. The Tokyo subway network…

30. The molecular ‘socio-biochemistry’ approach … 1990 1990 … Biochemistry in the post-genomic era