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
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
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
McClendon et al. Cell Cycle. 2012
Inhibidores KDCs antagonizan efectos agentes
anti-DNA (QT- Carbo/antraciclinas…)
Serra et al. Journal Clin Invest 2013
Familia RSK
represores de
función inhibitoria
de PI3Kinhibitors
Doble bloqueo
BEZ235+MEK
inhibe fosfo rpS6
• 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
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