1. La Biodiversidad marina como fuente de nuevos agentes anticáncer Marcelino Gutiérrez G. Centro de Biodiversidad y Descubrimiento de Drogas, INDICASAT, Panamá Segundo Simposio Iberoamericano de Investigación en Cáncer 27-30 de Octubre, 2014, Ilhéus-Ba, Brasil

2. Talk Overview 1.Facts about cancer 2.Marine environments and biodiversity 3.Marine organisms as source of natural products and anticancer compounds 4.Stories of success. MNP in the market 5.MNP in preclinical 6.Role of symbiotic microorganisms as source of MNP 7.Conclusions Marcelino Gutiérrez-INDICASAT-AIP

3. Definition Cancer is the uncontrolled growth and spread of cells. It can affect almost any part of the body. The growths often invade surrounding tissue and can metastasize to distant sites Marcelino Gutiérrez-INDICASAT-AIP

4. Facts about cancer Cancer is a leading cause of death worldwide and accounted for 7.6 million deaths (around 13% of all deaths) in 2008. The main types of cancer are: – lung (1.37 million deaths) – stomach (736 000 deaths) – liver (695 000 deaths) – colorectal (608 000 deaths) – breast (458 000 deaths) – cervical cancer (275 000 deaths) About 70% of all cancer deaths occurred in low- and middle-income countries. Deaths from cancer worldwide are projected to continue to rise to over 13.1 million in 2030. World Healht Organization, Fact sheet N°297, January 2013. Marcelino Gutiérrez-INDICASAT-AIP

5. Why to search for anticancer compounds in the oceans? Marcelino Gutiérrez-INDICASAT-AIP

6. Oceans cover over 70 % of earth surface

7. Why Marine Organisms? Life started in the oceans There are 11 terrestrial phyla and 28 marine phyla -15 are exclusively marine Marine ecosystems are still a unexplored frontier specially deep-sea and polar regions which comprise 95% of the biosphere. Sessile organisms have evolved developing powerful chemical defenses against predators Nowadays we have more access to the marine biodiversity (SCUBA, Submarines) Marcelino Gutiérrez-INDICASAT-AIP

8. Marine Organisms are a rich source of natural products Sponges Cnidarians AscidiansEchinoderms Mollusks Microorganisms CyanobacteriaBryozoans Marcelino Gutiérrez-INDICASAT-AIP

9. Hot spots of marine biodiversity Amarillo = poca riqueza de especies/ naranja = rico/ rojo = muy rico/ rojo oscuro = regiones con muchas especies endémicas (= hotspots) Marcelino Gutiérrez-INDICASAT-AIP

10. Marine organisms have provided more than 20,000 compounds over last 50 years All main types of natural products found in land can be found in marine environments More than 500 new compounds/year were isolated from marine sources over the last decade, and about 1000 were reported since 2008 to the present. Several terpenoid-carbon skeletons are exclusively marine Marcelino Gutiérrez-INDICASAT-AIP

11. Temporal trend in the number of new MNP (2001-2012) Blunt, J. et al., Marine Natural Products, Nat. Prod. Rep. 2002-2014 More access to the oceans Powerful spectroscopic techniques (NMR, MS ) Growing interest from scientists Marcelino Gutiérrez-INDICASAT-AIP 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

12. Novel compounds isolated between 1985 and 2008 Hu, G.P., et al., Mar. Drugs, 2011, 9, 514-525 Marcelino Gutiérrez-INDICASAT-AIP

13. Marine Natural products isolated in 2011 Blunt, J. W. et al., Nat Prod. Rep 2013, 30, 237-323 Marcelino Gutiérrez-INDICASAT-AIP

14. What happened with all these marine compounds? Marcelino Gutiérrez-INDICASAT-AIP

15. Stories of success: There are four anticancer MNP in the market! Marcelino Gutiérrez-INDICASAT-AIP

16. Cytarabine (Ara-C) Status: FDA Approved Arabinofuranosyl Cytosine Ara-C, MNP derivative Source: Sponge (Criptotethya crypta) Disease area: Acute myeloid leukemia and non-Hodgkin lymphoma. Molecular target: DNA polimerase Spongouridine MNP Criptotethya crypta Isolated in early 50s Approved 1969 Marcelino Gutiérrez-INDICASAT-AIP

17. Trabactedin (ET743) Status: FDA Approved Ecteinascidin-743 (Yondelis®) Source: Tunicate (Ecteinascidia turbinata) Disease area: Soft tissue sarcoma and ovarian cancer Molecular target: Minor groove of DNA Ecteinascidia turbinata Isolated 1986 Approved 2007 There was gap of 38 years in anticancer MNP drug discovery! Marcelino Gutiérrez-INDICASAT-AIP

18. Eribulin Mesylate (Halaven) Status: FDA Approved Halichondrin B E7389 (Eribulin) Source: Sponge (Halichondria okadai) Disease area: Late stage matastatic breast cancer Molecular target: Microtubules Isolated in 1986 (32 stereocenters)Marketed in 2010 (19 stereocenters) Marcelino Gutiérrez-INDICASAT-AIP

19. Brentuximab vedotin (SGN-35) Status: FDA Approved Monomethylauristatin E Dolastatin 10 Isolated in 1987 Source: Mollusk (Dolabella auricularia) Disease area: Hodgkin’s lymphoma, anaplastic large cell lymphoma Molecular target: CD30 and microtubules Approved 2011 Marcelino Gutiérrez-INDICASAT-AIP

20. Brentuximab vedotin Structure Marcelino Gutiérrez-INDICASAT-AIP

21. Brentuximab vedotin mechanism of action Marcelino Gutiérrez-INDICASAT-AIP

22. Compounds in phase I-III Clinical trials 11 MNP under study Marcelino Gutiérrez-INDICASAT-AIP

23. Plitidepsin (Aplidine) Status: Phase III Source: Tunicate (Aplidium albicans) Disease area: solid tumors and non-Hodgkin’s lymphoma Molecular target: Rac1 and JNK activation Marcelino Gutiérrez-INDICASAT-AIP

24. ECHELON-1: front-line Hodgkin lymphoma in combination with chemotherapy ECHELON-2: front-line CD30-positive mature T-cell lymphomas in combination with chemotherapy ALCANZA : trial for relapsed CD30-positive cutaneous T-cell lymphoma Brentuximab vedotin (SGN-35) Status: Phase III MMAE Marcelino Gutiérrez-INDICASAT-AIP

25. 1.Relapsed/refractory CD30-positive non-Hodgkin lymphomas 2.Frontline Hodgkin lymphoma in patients 60+ 3.Frontline diffuse large B-cell lymphoma (+ RCHOP) 4.CD30-positive non-lymphoma malignancies 5.Retreatment of CD30-positive hematologic malignancies Brentuximab vedotin (SGN-35) Status: Phase II MMAE Marcelino Gutiérrez-INDICASAT-AIP

26. ADC with MMAF SGN-75:Renal cell carcinoma (+ everolimus) (descontinuado) SGN CD19A: Acute lympoblastic leukemia, Non-Hodgkin lymphoma Status: Phase II Dolastatin 10 Monomethylauristatin F Marcelino Gutiérrez-INDICASAT-AIP

27. Plinabulin (NPI 2358) Status: Phase II Source: Fungus(Aspergillus ustus) Disease area: non-small cell lung cancer Molecular target: Microtubules and JNK stress protein Phenylahistin (NP) Marcelino Gutiérrez-INDICASAT-AIP

28. Zalypsis (PM00104) Status: Phase II C CA B Source: Nudibranch (Jorunna funebris) Disease area: Multiple mieloma, bladder and Ewing sarcoma Molecular target: Plasma membrane fluidity Yondelis Marcelino Gutiérrez-INDICASAT-AIP

29. Trabactedin analog (PM01183) Status: Phase II Source: Tunicate (Ecteinascidia turbinata) Disease area: Resistant ovarian cancer, lung, breast and pancreatic cancer Molecular target: Minor groove of DNA, Nucleotide Excision Repair Marcelino Gutiérrez-INDICASAT-AIP

30. Marizomib (Salinosporamide A) Status: Phase I Source: Bacteria(Salinispora tropica) Disease area: multiple myeloma Molecular target: 20S proteasome Marcelino Gutiérrez-INDICASAT-AIP

31. ASG-22ME Status: Phase I Monomethylauristatin E Source: Mollusk (Dolabella auricularia) Disease area: Solid tumors Molecular target: Nectin-4 Marcelino Gutiérrez-INDICASAT-AIP

32. Hemiasterlin derivative (E7974) Status: Phase I Hemiasterlin Source: Sponge (Hemiasterella minor) Disease area: solid tumors Molecular target: Microtubules Marcelino Gutiérrez-INDICASAT-AIP

33. Bryostatin 1 Status: Phase I Source: Briozoan (Bugula neritina) Disease area: Solid tumors, colorectal metastatic cancer Molecular target: Microtubules Marcelino Gutiérrez-INDICASAT-AIP

34. Role of symbiotic microorganisms as source of MNP Marcelino Gutiérrez-INDICASAT-AIP

35. Same chemotype from organisms so distant? Paederus sp. Theonella swinhoei

36. Entotheonella sp. is responsible for the natural product families isolated from the sponge Theonella swinhoei Wilson, M.C., et al., Nature, 2014, doi:10.1038/nature12959 Marcelino Gutiérrez-INDICASAT-AIP

37. Yondelis ® Eitenascidia turbinata ET-743 Soft tissue sarcoma and ovarian cancer Marcelino Gutiérrez-INDICASAT-AIP

38. Streptomyces lavendulaeMyxococcus xanthusPseudomonas fluorescens Candidatus Endoecteinascidia frumentensis Rath, C. M. et al., ACS Chem. Biol. 2011, 6, 1244–1256 Marcelino Gutiérrez-INDICASAT-AIP

39. Gerwick, W. H.; Moore, B.S. Chemistry & Biology 2012, 19, 85-98. Compound nameCollected source organisms Predicted biosynthetic source Disease area Cytarabine (Ara-C)SpongeBacteriumCancer Eribulin MesylateSpongeBacteriumCancer Trabactedin (Yondelis)TunicateBacteriumCancer Brentuximab vedotinMolluskCyanobacteriumCancer Virabidine (Ara-A)SpongeBacteriumAntiviral ZiconotideCone SnailMolluskPain Omega-3-acid ethyl esters FishMicroalgaeHypertrigliceridemia Marine Natural products and MNP derivatives that are FDA approved are most likely produced by microorganisms Marcelino Gutiérrez-INDICASAT-AIP

40. Gerwick, W. H.; Moore, B.S. Chemistry & Biology 2012, 19, 85-98. Marcelino Gutiérrez-INDICASAT-AIP

41. Conclusions 1.Of approximately 22,000 MNP isolated, there are 7 drugs in the market. This means about 1 drug per 3140 MNP described. 2.There is a very rich pipeline of MNP/MNP-derivatives in cancer with 11 compounds in preclinical trials 3.Drugs from the sea have indeed became a reality and oceans and their organisms have proven to be a rich source of drugs 4.There are many niches and marine organisms unexplored and for sure there are many more drugs in the oceans waiting to be discovered 5.New genomic tools indicate that natural products are not an exhausted recourse. Rather, there is still a universe of molecules just waiting to be discovered. Marcelino Gutiérrez-INDICASAT-AIP

42. Obrigado Marcelino Gutiérrez-INDICASAT-AIP