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AVANCES EN MODELOS PRECLÍNICOS Luis de la Cruz Merino Hospital Universitario Virgen Macarena (Sevilla)
Transcript of AVANCES EN MODELOS PRECLÍNICOS - geicam.org · Índice introducciÓn perfiles mutacionales ruta...
AVANCES EN MODELOS PRECLÍNICOS Luis de la Cruz Merino
Hospital Universitario Virgen Macarena
(Sevilla)
ÍNDICE
INTRODUCCIÓN
PERFILES MUTACIONALES
RUTA PI3K-akt-mTOR
CICLO CELULAR. iKDC
POTENCIALES NUEVAS DIANAS EN TNBC
ABORDAJE INMUNOLÓGICO
Alexandrov et al. Nature. Aug 2013
Alexandrov et al. Nature. Aug 2013
Nik-Zainal et al. Cell. May 2012
Algoritmo - firmas mutacionales
Análisis completo genoma 21
carcinomas de mama
Modelo de desarrollo molecular
temporal cáncer de mama
Petrocca et al. Cancer Cell. Aug 2013
Petrocca et al. Cancer Cell. Aug 2013
Inhibidores proteosoma
(bortezomib) posible terapia TNBC
Regulation of the G1/S Checkpoint
Lange et al. Endocrine-Related Cancer 2011;18:C19–C24
RB
RB
Gene
transcription G2 S
M
G1
G0
P P P
P
Inactive
Active tumor
suppressor
E2F
E2F
R
CDK4/6 Cyclin D
Pl3K/Akt
STATs MAPKs
(ER/PR/AR) Wnt/β-catenin
NF-κB
p16
p21
p53
R = restriction point
Hagen. Cell Division. 2013
iKDCs efecto
agonista con
RT mediante
inducción
apoptosis
McClendon et al. Cell Cycle. 2012
Inhibidores KDCs antagonizan efectos agentes
anti-DNA (QT- Carbo/antraciclinas…)
Rodon. Nature Rev 2013
Serra et al. Journal Clin Invest 2013
Familia RSK
represores de
función inhibitoria
de PI3Kinhibitors
Doble bloqueo
BEZ235+MEK
inhibe fosfo rpS6
BEZ235 activo en TNBC
BEZ235 sinérgico
con QT- Carbo
Montero. Oncogene. 2014
Elkabets. Sci Transl Med. 2013
Resistencias a
BYL719 pueden
revertirse con
combos mTORi
Chen. Mol Cancer Res 2013
Sinergias entre
Tam+Everolimus
+LY29402
(inhibidor PI3K)
Brown. Genome Res. April 2014
Brown. Genome Res. April 2014
Chen & Mellman. Immunity. Jul 2013
Chen & Mellman. Immunity. Jul 2013
Chen & Mellman. Immunity. Jul 2013
• Association of increased tumor-infiltrating lymphocytes (TILs) with immunomodulatory (IM) triple-negative breast cancer (TNBC) subtype and response to neoadjuvant platinum-based therapy in PrECOG0105. Abstract No: 1000. Shaveta Vinayak MD
• Expression of novel immunotherapeutic targets in triple-negative breast cancer. Abstract No: 1001. Barbara Pockaj
• Association of genomic analysis of immune function genes and clinical outcome in the NCCTG (Alliance) N9831 adjuvant trastuzumab trial. Abstract No: 509 Edith A. Perez , MD
• Expression of immunologic genes in triple-negative and HER2-positive breast cancer in the neoadjuvant GEPARSIXTO trial: Prediction of response to carboplatin-based chemotherapy. Abstract No: 510 Carsten Denkert , MD, PhD
• Tumor-Host Immune System Interactions: Prognostic and Therapeutic Implications. Sylvia Adams MD Extended Education Session. Immunology for non-immunologists
Loi JCO 2013
Loi Ann Oncol 2014
Tumor-Host Immune System Interactions: Prognostic and Therapeutic Implications. Sylvia Adams MD Extended Education Session.
Immunology for non-immunologists
Expression of novel immunotherapeutic targets in triple-negative breast cancer. Abstract No: 1001. Barbara Pockaj
Tumor-Host Immune System Interactions: Prognostic and Therapeutic Implications. Sylvia Adams MD Extended Education Session.
Immunology for non-immunologists
Conclusiones • Firmas mutacionales: heterogeneidad cáncer mama
• Vía del proteosoma, nuevo target en TNBC
• Inhibidores KDC, potencial sinergia con RT (no QT)
• Vía PI3K-akt-mTOR: valor de las combinaciones de PAMi entre ellos, inhibidores MEK, QT (carbo-TNBC)…
• Inmunoedición- nuevo “hallmark” del cáncer. Nueva estrategia terapéutica a incorporar en cáncer de mama
