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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 Cáncer27-30 de Octubre, 2014, Ilhéus-Ba, Brasil
Talk Overview
1. Facts about cancer 2. Marine environments and biodiversity3. Marine organisms as source of natural products
and anticancer compounds4. Stories of success. MNP in the market 5. MNP in preclinical6. Role of symbiotic microorganisms as source of
MNP7. Conclusions
Marcelino Gutiérrez-INDICASAT-AIP
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
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
Why to search for anticancer compounds in the oceans?
Marcelino Gutiérrez-INDICASAT-AIP
Oceans cover over 70 % of earth surface
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
Marine Organisms are a rich source of natural products
Sponges Cnidarians Ascidians Echinoderms
Mollusks Microorganisms Cyanobacteria Bryozoans
Marcelino Gutiérrez-INDICASAT-AIP
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
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
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
1 2 3 4 5 6 7 8 9 10 11 12600
700
800
900
1000
1100
1200
1300
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Novel compounds isolated between 1985 and 2008
Hu, G.P., et al., Mar. Drugs, 2011, 9, 514-525Marcelino Gutiérrez-INDICASAT-AIP
Marine Natural products isolated in 2011
Blunt, J. W. et al., Nat Prod. Rep 2013, 30, 237-323Marcelino Gutiérrez-INDICASAT-AIP
What happened with all these marine compounds?
Marcelino Gutiérrez-INDICASAT-AIP
Stories of success:There are four anticancer MNP in
the market!
Marcelino Gutiérrez-INDICASAT-AIP
Cytarabine (Ara-C)Status: FDA Approved
O
OH
HOOH
N
N
O
NH2
Arabinofuranosyl CytosineAra-C, MNP derivative
Source: Sponge (Criptotethya crypta)Disease area: Acute myeloid leukemia and non-Hodgkin lymphoma.Molecular target: DNA polimerase
O
OH
HOOH
N
HN
O
O
SpongouridineMNP
Criptotethya crypta
Isolated in early 50sApproved 1969
Marcelino Gutiérrez-INDICASAT-AIP
Trabactedin (ET743)Status: FDA Approved
N
N
OO
HO
O
OH
NH
HO
O
SO
O
AcO H
Ecteinascidin-743 (Yondelis®)
Source: Tunicate (Ecteinascidia turbinata)Disease area: Soft tissue sarcoma and ovarian cancerMolecular target: Minor groove of DNA
Ecteinascidia turbinata
Isolated 1986Approved 2007
There was gap of 38 years in anticancerMNP drug discovery!
Marcelino Gutiérrez-INDICASAT-AIP
Eribulin Mesylate (Halaven)
Status: FDA Approved
O
OO
O
O
O
HO
HOHO
H
H
H
H
H O
OO
O
O
OO O
OH
HO
O
O
O
OO O
OH
HO
O
H2N OH
Halichondrin B E7389 (Eribulin)
Source: Sponge (Halichondria okadai)Disease area: Late stage matastatic breast cancerMolecular target: Microtubules
Isolated in 1986 (32 stereocenters) Marketed in 2010 (19 stereocenters)
Marcelino Gutiérrez-INDICASAT-AIP
Brentuximab vedotin (SGN-35)
Status: FDA Approved
Monomethylauristatin E
HN
NN
HN
OO
O
N
O
O
O
NH
HN
NH
O
NH
H2N O
O
O
NO O
OH
O
O
SAbm
HN
NN
HN
OO
O
N
O O O
N
S
Dolastatin 10Isolated in 1987
Source: Mollusk (Dolabella auricularia)Disease area: Hodgkin’s lymphoma, anaplastic large cell lymphomaMolecular target: CD30 and microtubules
Approved 2011
Marcelino Gutiérrez-INDICASAT-AIP
Brentuximab vedotin Structure
Marcelino Gutiérrez-INDICASAT-AIP
Brentuximab vedotin mechanism of action
Marcelino Gutiérrez-INDICASAT-AIP
Compounds in phase I-III Clinical trials11 MNP under study
Marcelino Gutiérrez-INDICASAT-AIP
Plitidepsin (Aplidine)Status: Phase III
Source: Tunicate (Aplidium albicans)Disease area: solid tumors and non-Hodgkin’s lymphomaMolecular target: Rac1 and JNK activation
Marcelino Gutiérrez-INDICASAT-AIP
ECHELON-1: front-line Hodgkin lymphoma in combination with chemotherapyECHELON-2: front-line CD30-positive mature T-cell lymphomas in combination with chemotherapyALCANZA : trial for relapsed CD30-positive cutaneous T-cell lymphoma
Brentuximab vedotin (SGN-35)HN
NN
HN
OO
O
N
O
O
O
NH
HN
NH
O
NH
H2N O
O
O
NO O
OH
O
O
SAbm
Status: Phase III
MMAE
Marcelino Gutiérrez-INDICASAT-AIP
1. Relapsed/refractory CD30-positive non-Hodgkin lymphomas2. Frontline Hodgkin lymphoma in patients 60+3. Frontline diffuse large B-cell lymphoma (+ RCHOP) 4. CD30-positive non-lymphoma malignancies5. Retreatment of CD30-positive hematologic malignancies
Brentuximab vedotin (SGN-35)HN
NN
HN
OO
O
N
O
O
O
NH
HN
NH
O
NH
H2N O
O
O
NO O
OH
O
O
SAbm
Status: Phase II
MMAE
Marcelino Gutiérrez-INDICASAT-AIP
ADC with MMAF
SGN-75:Renal cell carcinoma (+ everolimus) (descontinuado)SGN CD19A: Acute lympoblastic leukemia, Non-Hodgkin lymphoma
HN
NN
OO
O
N
O
O
O
NH
HN
NH
O
NH
H2N O
O
O
NO O
O
O
SAbm
HN OH
O
Status: Phase II
HN
NN
HN
OO
O
N
O O O
N
S
Dolastatin 10
Monomethylauristatin F
Marcelino Gutiérrez-INDICASAT-AIP
Plinabulin (NPI 2358)Status: Phase II
Source: Fungus(Aspergillus ustus)Disease area: non-small cell lung cancerMolecular target: Microtubules and JNK stress protein
Phenylahistin (NP)
Marcelino Gutiérrez-INDICASAT-AIP
Zalypsis (PM00104)Status: Phase II
N
N
OO
HO
O
OH
NH
HO
O
SO
O
AcO HN
N
OO
HO
O
OH
AcOH
NH
OF
F
FC
CA
B
Source: Nudibranch (Jorunna funebris)Disease area: Multiple mieloma, bladder and Ewing sarcomaMolecular target: Plasma membrane fluidity
Yondelis
Marcelino Gutiérrez-INDICASAT-AIP
Trabactedin analog (PM01183)Status: Phase II
N
N
OO
HO
O
OH
NH
HO
O
SO
O
AcO H
N
N
OO
HO
O
OH
NH
SO
O
AcO H
NH
O
Source: Tunicate (Ecteinascidia turbinata)Disease area: Resistant ovarian cancer, lung, breast and pancreatic cancerMolecular target: Minor groove of DNA, Nucleotide Excision Repair
Marcelino Gutiérrez-INDICASAT-AIP
Marizomib (Salinosporamide A)Status: Phase I
NH
OO
Cl
OHO
Source: Bacteria(Salinispora tropica)Disease area: multiple myeloma Molecular target: 20S proteasome
Marcelino Gutiérrez-INDICASAT-AIP
ASG-22MEStatus: Phase I
Monomethylauristatin E
HN
NN
HN
OO
O
N
O
O
O
NH
HN
NH
O
NH
H2N O
O
O
NO O
OH
O
O
SAbm
Source: Mollusk (Dolabella auricularia)Disease area: Solid tumorsMolecular target: Nectin-4
Marcelino Gutiérrez-INDICASAT-AIP
Hemiasterlin derivative (E7974)Status: Phase I
NH
N CO2H
N NH
O
ONH
N CO2H
O
O
N
Hemiasterlin
Source: Sponge (Hemiasterella minor)Disease area: solid tumorsMolecular target: Microtubules
Marcelino Gutiérrez-INDICASAT-AIP
Bryostatin 1Status: Phase I
O O
O O O
HO
O
O
OH
O
OOH
O
OO
O
HO
Source: Briozoan (Bugula neritina)Disease area: Solid tumors, colorectal metastatic cancerMolecular target: Microtubules
Marcelino Gutiérrez-INDICASAT-AIP
Role of symbiotic microorganisms as source of MNP
Marcelino Gutiérrez-INDICASAT-AIP
Same chemotype from organisms so distant?
Paederus sp.Theonella swinhoei
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
Yondelis®
Eitenascidia turbinata
ET-743
N
N
OO
HO
O
OH
NH
HO
O
SO
O
AcO H
Soft tissue sarcoma and ovarian cancer
Marcelino Gutiérrez-INDICASAT-AIP
N
N
OO
O
OHO
O
OO
NH
O
S
OHH
HH
HO
N
N
O
O
O
O
CNH
HH
O
O
NH
O
O
N
N
O
O
O
OHH
HH
ONH
O
HO
OH
O
NH2
N
N
O
O
O
OHH
HH
ONH
O
HO
NH2
Streptomyces lavendulae Myxococcus xanthus Pseudomonas fluorescens
Candidatus Endoecteinascidia frumentensis
Rath, C. M. et al., ACS Chem. Biol. 2011, 6, 1244–1256 Marcelino Gutiérrez-INDICASAT-AIP
Gerwick, W. H.; Moore, B.S. Chemistry & Biology 2012, 19, 85-98.
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
Omega-3-acid ethyl esters
Fish Microalgae Hypertrigliceridemia
Marine Natural products and MNP derivatives that are FDA approved are most likely produced by microorganisms
Marcelino Gutiérrez-INDICASAT-AIP
Gerwick, W. H.; Moore, B.S. Chemistry & Biology 2012, 19, 85-98. Marcelino Gutiérrez-INDICASAT-AIP
Conclusions1. 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
Obrigado
Marcelino Gutiérrez-INDICASAT-AIP
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