la biodiversidad marina como fuente de nuevos agentes anticáncer marcelino gutiérrez g. centro de...

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


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?


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)


Marine Organisms are a rich source of natural products

Sponges Cnidarians Ascidians Echinoderms

Mollusks Microorganisms Cyanobacteria Bryozoans


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


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


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?


Stories of success:There are four anticancer MNP in

the market!


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


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!


http://www.pharmamar.com/grafico.aspx

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)


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


http://1.bp.blogspot.com/-dD8FN1V4JzE/Uc7GVkB-pLI/AAAAAAAABTc/DQFYuPHFZpk/s390/Dolabella+auricularia.jpg

Brentuximab vedotin Structure


Brentuximab vedotin mechanism of action


Compounds in phase I-III Clinical trials11 MNP under study


Plitidepsin (Aplidine)Status: Phase III

Source: Tunicate (Aplidium albicans)Disease area: solid tumors and non-Hodgkin’s lymphomaMolecular target: Rac1 and JNK activation


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


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


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


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)


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


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


Marizomib (Salinosporamide A)Status: Phase I

NH

OO

Cl

OHO

Source: Bacteria(Salinispora tropica)Disease area: multiple myeloma Molecular target: 20S proteasome


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


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


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


Role of symbiotic microorganisms as source of MNP


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


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


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.


Obrigado


la biodiversidad marina como fuente de nuevos agentes anticáncer marcelino gutiérrez g. centro de...

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