La Biodiversidad marina como fuente de nuevos agentes anticáncer

Transcription

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

2 Talk verview 1. Facts about cancer 2. Marine environments and biodiversity 3. Marine organisms as source of natural products and anticancer compounds 4. Stories of success. MP in the market 5. MP in preclinical 6. Role of symbiotic microorganisms as source of MP 7. Conclusions

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

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 The main types of cancer are: lung (1.37 million deaths) stomach ( deaths) liver ( deaths) colorectal ( deaths) breast ( deaths) cervical cancer ( 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 World ealht rganization, Fact sheet 297, January 2013.

5 Why to search for anticancer compounds in the oceans?

6 ceans cover over 70 % of earth surface

7 Why Marine rganisms? 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 owadays we have more access to the marine biodiversity (SCUBA, Submarines)

8 Marine rganisms are a rich source of natural products Sponges Cnidarians Ascidians Echinoderms Mollusks Microorganisms Cyanobacteria Bryozoans

9 ot spots of marine biodiversity Amarillo = poca riqueza de especies/ naranja = rico/ rojo = muy rico/ rojo oscuro = regiones con muchas especies endémicas (= hotspots)

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

11 Temporal trend in the number of new 1300 MP ( ) More access to the oceans Powerful spectroscopic techniques (MR, MS ) Growing interest from scientists Blunt, J. et al., Marine atural Products, at. Prod. Rep

12 ovel compounds isolated between 1985 and 2008 u, G.P., et al., Mar. Drugs, 2011, 9,

13 Marine atural products isolated in 2011 Blunt, J. W. et al., at Prod. Rep 2013, 30,

14 What happened with all these marine compounds?

15 Stories of success: There are four anticancer MP in the market!

16 Status: FDA Approved Cytarabine (Ara-C) 2 Criptotethya crypta Arabinofuranosyl Cytosine Ara-C, MP derivative Approved 1969 Spongouridine MP Isolated in early 50s Source: Sponge (Criptotethya crypta) Disease area: Acute myeloid leukemia and non-odgkin lymphoma. Molecular target: DA polimerase

17 Status: FDA Approved Trabactedin (ET743) S Ac Ecteinascidin-743 (Yondelis ) Ecteinascidia turbinata Isolated 1986 Approved 2007 There was gap of 38 years in anticancer MP drug discovery! Source: Tunicate (Ecteinascidia turbinata) Disease area: Soft tissue sarcoma and ovarian cancer Molecular target: Minor groove of DA

18 Status: FDA Approved Eribulin Mesylate (alaven) 2 alichondrin B E7389 (Eribulin) Isolated in 1986 (32 stereocenters) Marketed in 2010 (19 stereocenters) Source: Sponge (alichondria okadai) Disease area: Late stage matastatic breast cancer Molecular target: Microtubules

19 Status: FDA Approved Brentuximab vedotin (SG-35) Abm S Monomethylauristatin E 2 Approved 2011 S Dolastatin 10 Isolated in 1987 Source: Mollusk (Dolabella auricularia) Disease area: odgkin s lymphoma, anaplastic large cell lymphoma Molecular target: CD30 and microtubules

20 Brentuximab vedotin Structure

21 Brentuximab vedotin mechanism of action

22 Compounds in phase I-III Clinical trials 11 MP under study

23 Status: Phase III Plitidepsin (Aplidine) Source: Tunicate (Aplidium albicans) Disease area: solid tumors and non-odgkin s lymphoma Molecular target: Rac1 and JK activation

24 Status: Phase III Brentuximab vedotin (SG-35) Abm S MMAE 2 ECEL-1: front-line odgkin lymphoma in combination with chemotherapy ECEL-2: front-line CD30-positive mature T-cell lymphomas in combination with chemotherapy ALCAZA : trial for relapsed CD30-positive cutaneous T-cell lymphoma

25 Status: Phase II Brentuximab vedotin (SG-35) Abm S MMAE 2 1. Relapsed/refractory CD30-positive non-odgkin lymphomas 2. Frontline odgkin lymphoma in patients Frontline diffuse large B-cell lymphoma (+ RCP) 4. CD30-positive non-lymphoma malignancies 5. Retreatment of CD30-positive hematologic malignancies

26 Status: Phase II ADC with MMAF Abm S Monomethylauristatin F 2 S Dolastatin 10 SG-75:Renal cell carcinoma (+ everolimus) (descontinuado) SG CD19A: Acute lympoblastic leukemia, on-odgkin lymphoma

27 Status: Phase II Plinabulin (PI 2358) Phenylahistin (P) Source: Fungus(Aspergillus ustus) Disease area: non-small cell lung cancer Molecular target: Microtubules and JK stress protein

28 Status: Phase II Zalypsis (PM00104) Ac A B C F F F C Ac S Yondelis Source: udibranch (Jorunna funebris) Disease area: Multiple mieloma, bladder and Ewing sarcoma Molecular target: Plasma membrane fluidity

29 Status: Phase II Trabactedin analog (PM01183) S Ac Ac S Source: Tunicate (Ecteinascidia turbinata) Disease area: Resistant ovarian cancer, lung, breast and pancreatic cancer Molecular target: Minor groove of DA, ucleotide Excision Repair

30 Status: Phase I Marizomib (Salinosporamide A) C l Source: Bacteria(Salinispora tropica) Disease area: multiple myeloma Molecular target: 20S proteasome

31 Status: Phase I ASG-22ME Abm S 2 Monomethylauristatin E Source: Mollusk (Dolabella auricularia) Disease area: Solid tumors Molecular target: ectin-4

32 Status: Phase I emiasterlin derivative (E7974) C 2 C 2 emiasterlin Source: Sponge (emiasterella minor) Disease area: solid tumors Molecular target: Microtubules

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

34 Role of symbiotic microorganisms as source of MP

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

36 Entotheonella sp. is responsible for the natural product families isolated from the sponge Theonella swinhoei Wilson, M.C., et al., ature, 2014, doi: /nature12959

37 Yondelis Ac S Eitenascidia turbinata ET-743 Soft tissue sarcoma and ovarian cancer

38 S Candidatus Endoecteinascidia frumentensis 2 2 C Streptomyces lavendulae Myxococcus xanthus Pseudomonas fluorescens Rath, C. M. et al., ACS Chem. Biol. 2011, 6,

39 Marine atural products and MP derivatives that are FDA approved are most likely produced by microorganisms Compound name Collected source organisms Predicted biosynthetic source Disease area Cytarabine (Ara-C) Sponge Bacterium Cancer Eribulin Mesylate Sponge Bacterium Cancer Trabactedin (Yondelis) Tunicate Bacterium Cancer Brentuximab vedotin Mollusk Cyanobacterium Cancer Virabidine (Ara-A) Sponge Bacterium Antiviral Ziconotide Cone Snail Mollusk Pain mega-3-acid ethyl esters Fish Microalgae ypertrigliceridemia Gerwick, W..; Moore, B.S. Chemistry & Biology 2012, 19,

40 Gerwick, W..; Moore, B.S. Chemistry & Biology 2012, 19,

41 Conclusions 1. f approximately 22,000 MP isolated, there are 7 drugs in the market. This means about 1 drug per 3140 MP described. 2. There is a very rich pipeline of MP/MP-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. ew genomic tools indicate that natural products are not an exhausted recourse. Rather, there is still a universe of molecules just waiting to be discovered.

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