Productos naturales marinos como fuente de agentes anticáncer · Productos naturales marinos como fuente de agentes anticáncer ... Talk Overview 1. Facts about cancer 2. Marine

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


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)Marcelino Gutiérrez-INDICASAT-AIP

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 (2001-2011)

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


Novel compounds isolated between

1985 and 2008

Hu, G.P., et al., Mar. Drugs, 2011, 9, 514-525


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 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


Trabactedin (ET743)


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!


Eribulin Mesylate (Halaven)


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)


Brentuximab vedotin

(SGN-35)


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


Brentuximab vedotin Structure


Brentuximab vedotin mechanism of action


Compounds in phase I-III Clinical trials

11 MNP under study


Plitidepsin (Aplidine)Status: Phase III

Source: Tunicate (Aplidium albicans)

Disease area: solid tumors and non-Hodgkin’s lymphoma

Molecular target: Rac1 and JNK activation


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


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


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


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)


ElisidepsinStatus: Phase II

F3C O-

O

NH3+

Source: Mollusk (Aplidium albicans)

Disease area: non-small cell lung cancer

Molecular target: Plasma membrane fluidity


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


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


Marizomib (Salinosporamide A)Status: Phase I

NH

OO

Cl

O

HO

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 tumors

Molecular target: Nectin-4


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



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



Role of symbiotic microorganisms as

source of MNP


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


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


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


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


Obrigado


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Productos naturales marinos como fuente de agentes anticáncer · Productos naturales marinos como fuente de agentes anticáncer ... Talk Overview 1. Facts about cancer 2. Marine