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Productos naturales marinos como
fuente de agentes anticáncer
Marcelino Gutiérrez G.
Centro de Biodiversidad y Descubrimiento de Drogas, INDICASAT,
Panamá
Primer Simposio Iberoamericano de Investigación en Cáncer
UNICAMP, Campinas, Brasil
Septiembre 24-25, 2013
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
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 (2001-2011)
Blunt, J. et al., Marine Natural Products, Nat. Prod. Rep. 2002-2013
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
• More access to the oceans
• Powerful spectroscopic techniques (NMR, MS )
• Growing interest from scientists
Marcelino Gutiérrez-INDICASAT-AIP
Novel compounds isolated between
1985 and 2008
Hu, G.P., et al., Mar. Drugs, 2011, 9, 514-525
Marcelino 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 Cytosine
Ara-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
Spongouridine
MNP
Criptotethya crypta
Isolated in early 50sApproved 1969
Marcelino Gutiérrez-INDICASAT-AIP
Trabactedin (ET743)
Status: FDA Approved
N
N
O
O
HO
O
OH
NH
HO
O
SO
O
AcO H
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
Eribulin Mesylate (Halaven)
Status: FDA Approved
O
OO
O
O
O
HO
HO
HO
H
H
H
H
H O
OO
O
O
O
OO
O
H
H
OO
O
O
O
OO
O
H
HO
O
H2N OH
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
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 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
Brentuximab vedotin Structure
Marcelino Gutiérrez-INDICASAT-AIP
Brentuximab vedotin mechanism of action
Marcelino Gutiérrez-INDICASAT-AIP
Compounds in phase I-III Clinical trials
11 MNP under study
Marcelino Gutiérrez-INDICASAT-AIP
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
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)
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 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)
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)
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 cancer
Molecular target: Microtubules and JNK stress protein
Phenylahistin (NP)
Marcelino Gutiérrez-INDICASAT-AIP
ElisidepsinStatus: Phase II
F3C O-
O
NH3+
Source: Mollusk (Aplidium albicans)
Disease area: non-small cell lung cancer
Molecular target: Plasma membrane fluidity
Marcelino Gutiérrez-INDICASAT-AIP
Zalypsis (PM00104)Status: Phase II
N
N
O
O
HO
O
OH
NH
HO
O
SO
O
AcO H
N
N
O
O
HO
O
OH
AcO
H
NH
O
F
F
FC
CA
B
Source: Nudibranch (Jorunna funebris)
Disease area: Multiple mieloma, bladder and Ewing sarcoma
Molecular target: Plasma membrane fluidity
Yondelis
Marcelino Gutiérrez-INDICASAT-AIP
Trabactedin analog (PM01183)Status: Phase II
N
N
O
O
HO
O
OH
NH
HO
O
SO
O
AcO H
N
N
O
O
HO
O
OH
NH
S
O
O
AcO H
NH
O
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
Marizomib (Salinosporamide A)Status: Phase I
NH
OO
Cl
O
HO
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 tumors
Molecular target: Nectin-4
Marcelino Gutiérrez-INDICASAT-AIP
Hemiasterlin derivative (E7974)Status: Phase I
NH
N CO2H
N NH
O
O
NH
N CO2H
O
O
N
Hemiasterlin
Source: Sponge (Hemiasterella minor)
Disease area: solid tumors
Molecular target: Microtubules
Marcelino Gutiérrez-INDICASAT-AIP
Bryostatin 1Status: Phase I
O O
O O O
HO
O
O
OH
O
OOH
O
O
O
O
HO
Source: Briozoan (Bugula neritina)
Disease area: Solid tumors, colorectal metastatic cancer
Molecular target: Microtubules
Marcelino Gutiérrez-INDICASAT-AIP
Role of symbiotic microorganisms as
source of MNP
Marcelino Gutiérrez-INDICASAT-AIP
Yondelis®
Eitenascidia turbinata
ET-743
N
N
O
O
HO
O
OH
NH
HO
O
SO
O
AcO H
Soft tissue sarcoma
and ovarian cancer
Marcelino Gutiérrez-INDICASAT-AIP
N
N
O
O
O
OHO
O
O
O
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
O
NH
O
HO
OH
O
NH2
N
N
O
O
O
OHH
HH
O
NH
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 rre 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
Sources of compounds in Market or
clinical trials (20 total-7 in market)
Gerwick, W. H.; Moore, B.S. Chemistry & Biology 2012, 19, 85-98.
Collected source Predicted source
Marcelino Gutiérrez-INDICASAT-AIP
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
Marcelino Gutiérrez-INDICASAT-AIP
Obrigado
Marcelino Gutiérrez-INDICASAT-AIP
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