RECEPTOR DE FOLATO Y CANCER XIV Congreso Nacional Salamanca Octubre de 2013

Simposio Científico Especial MSD 13-14,15h

Andres Poveda, MD Fundación Instituto Valenciano de Oncología

acog@fivo.org

Origen del folato en humanos

pteroylmonoglutamic acid

FOLATO= vitamina B9

ÁCIDO FÓLICO

British Journal of Nutrition(2001), 85, Suppl. 2,

S115±S124

60% legumbres + cereales

ALIMENTACIÓN= FUENTE EXTERNA

ENFERMEDADES ASOCIADAS DÉFICIT FOLATO

1) Anemia megaloblástica

2) Malformaciones recién nacido: maduración tubo neural

3) Homocisteinemia (¿?)

1) Acumulación de homocisteina

2) Efectos: factor riesgo cardiovascular: infartos,….

British Journal of Nutrition(2001), 85, Suppl. 2,

S115±S124

Folato: Key Points

Se come

Básico en la Síntesis de DNA

Parece pueda tener una relación con el

tratamiento del cáncer

Premio Nobel 2004 Química

Angew. Chem. Int. Ed.2005, 44, 5944 – 5967

Historia de la inhibición de folatos

en cáncer

Drogas clásicas antifolato:

Metrotexate

Indicaciones: LLA, Osteosarcoma, Coriocarcinoma

(ETG), CM,Ca Vejiga,

Inmunosupresor: Art Reumatoidea, Enf Autoinmune,

Nuevos antifolatos:

Pemetrexed

Expresión de RFA en cáncer

0

10

20

30

40

50

60

70

80

90

100

Ova

rian

Uterin

e

Brain/C

NSLu

ng

Kidn

ey

Head/

Neck

Breas

t

Gar

tric

Color

ecta

l

Test

icular

Endo

crine

Pamcr

eatic

% F

R E

xpre

ssio

n b

y IH

C

1. Low. Current Opin Chem Biol. 2009; 13:256-262

Positividad FRA en cáncer ovario (IHQ)

K.R. Kalli et al. / Gynecologic Oncology 108 (2008) 619–626

PRIMARY TUMOR

(72%) primary tumors

Muestra no representativa:

infraestimación

PRIMARY VS RELAPSED

K.R. Kalli et al. / Gynecologic Oncology 108 (2008) 619–626

FRA positivity at relapse

(81.5%) 22 of 27

Positividad FRA en cáncer ovario (IHQ)

B-2 What are the promising targets for future therapeutic approaches?

4th Ovarian Cancer Consensus Conference

June 25 – 27, 2010

UBC Life Sciences Institute, Vancouver, BC

• The most promising targets in clinical trials are angiogenesis and homologous

recombination deficiency.

• To select patients for trials investigating these targets, predictive biomarkers are

required. Understanding mechanisms of resistance is a priority.

• Other promising targets currently being studied based on ovarian cancer biology

include:

• PI3-Kinase and Ras/Raf pathways

• Folate receptor

• Immune targets/cytokines, Notch/hedgehog, IGF merit further investigation.

• Targeted agents should be studied both as single agents and in combination based

on appropriate preclinical data.

Resumen: por qué RFA es una diana

interesante

1) LOCALIZACIÓN TEJIDO TUMORAL (no en sano)

2) ADQUIRIDO CON LA AGRESIVIDAD cáncer ovario

ESTADÍOS AVANZADOS

ALTO GRADO

3) Modelos in vitro/ in vivo inhibición inhibe crecimiento

4) MECANISMO ENDOCITOSIS PRESERVA MOLÉCULA

ASOCIADA

RECEPTOR DE FOLATO Y CANCER

• Journal of Clinical Oncology 2013 by R. Wendel Naumann et al.

• In a randomized phase II trial the addition of vintafolide to pegylated liposomal doxorubicin improved progression-free survival in women with recurrent platinum-resistant ovarian cancer.

• PFS benefit was most marked in patients with 100% of lesions positive for folate receptors as identified by the folate receptor-targeted imaging agent 99mTc-etarfolatide.

Let´s go…