Actualización en el Tratamiento del Mesotelioma Pleural ... · Actualización en el Tratamiento...

Actualización en el Tratamiento del Mesotelioma Pleural MalignoMesotelioma Pleural Maligno

B MassutíB.MassutíHospital Universitario Alicante

ContenidoContenido• Datos epidemiológicosDatos epidemiológicos

• Etiopatogenia

• Diagnóstico

• Estadificación y pronóstico• Estadificación y pronóstico

• Tratamiento quirurgico

• Tratamiento radioterápico

• Tratamiento quimioterápico• Tratamiento quimioterápico

• Tratamientos combinación

• Perspectivas

Antecedentes epidemiológicosAntecedentes epidemiológicos

Tumores torácicos infrecuentesRARECANCER working group EU

EJC 2012;48:949‐960

• Mesotelioma:Mesotelioma:– 19/1.000.000/a

– 7 964 casos anuales7.964 casos anuales pleura

– 617 casos anuales perit.p

• Traquea: 2008:Traquea:– 1.3/1.000.000/a

670 casos anuales

2008:Cáncer Pulmón EU:– 670 casos anuales

• Timo:/ 000 000/

Cáncer Pulmón EU:- 390.900 casos

– 1.7/1.000.000/a

– 829 casos anuales - 342.100 muertes

The Europeanmesotheliomamesothelioma epidemic (Peto BJC 1999)(Peto, BJC, 1999)

Methodology:• British mesothelioma• British mesothelioma

register and male death rates for cancer of the pleura from p6 European countries

• Statistical modeling taking into account asbestos legislation and long latency period


• Etiopatogenia

• Diagnóstico






• Perspectivas

AsbestoAsbesto• Amianto o asbesto: conjunto de minerales fibrosos muy resistentes al calor, tracción y abrasión

• Silicatos complejos constituidos por haces de fibrasfibras

• Dos tipos de fibras: – Serpentinas (magnesio): crisotilo o amianto blancoblanco

– Anfiboles (hierro y magnesio): crocidolita (amianto azul); amosita (amianto marrón)(amianto azul); amosita (amianto marrón), tremolita, antofilita, actinolita

Comportamiento diferencial fibras asbesto

Molecular biologyMolecular biologyMULTISTEP CARCINOGENESIS OF PLEURAL MESOTHELIOMA

Risk factorsHealthy

mesotheliumMalignant

transformationPreneoplastic

lesions

30-40 years

ASBESTOS

Latency

lti

ASBESTOS

SV40 VIRUS ???multiSV40 VIRUS

RADIATIONS

???EPITHELIAL

MESOTHELIOMA

RADIATIONS

MESOTHELIUM

Testa JR. Molecular Biology (2000)

Factores riesgo carcinogenético exposición laboralFactores riesgo carcinogenético exposición laboral British Journal of Cancer (2012) 107, S56 – S70

Efectos de la regulación del asbesto

World Asbestos Production from 1900 through 2003 (Virta, 2006)


• Etiopatogenia

• Diagnóstico






• Perspectivas

Poblaciones de riesgo: cribajePoblaciones de riesgo: cribaje• Exposición laboral

• Dificultad diagnóstica

• Potencial diagnóstico biomarcadores:Potencial diagnóstico biomarcadores:– Mesotelina: alta especificidad, baja sensibilidad (J Clin Oncol 2012;30:1541‐1549) ; )

– Osteopontina: superior precisión que mesotelina (Lung Cancer 74 (2011) 55–60)

– miR‐625‐3p: niveles plasmáticos elevados y desregulado en tejido (J Thorac Oncol. 2012;7: 1184–1191)

– Fibulina‐3: sensibilidad 96.7%, especificidad 95.5% (N Engl J Med 2012;367:1417‐27. DOI: 10.1056/NEJMoa1115050)

Guidelines for Pathologic Diagnosis of Malignant Mesothelioma

2012 Update of the Consensus Statement from IMIG2012 Update of the Consensus Statement from IMIG

Arch Pathol Lab Med. 2012;136:1–21; doi: 10.5858/ arpa.2012‐0214‐OA


• Etiopatogenia

• Diagnóstico






• Perspectivas

Estadificación: TNM/IMIG/IASLCEstadificación: TNM/IMIG/IASLC

Factores pronósticospEuropean Journal of Cardio‐thoracic Surgery 33 (2008) 307—313

J Thorac Oncol. 2012;7: 1631–1639

Fig. 2. Kaplan—Meier survival curves according to tumor cell t ype (n = 366).Cell type could not be determined in 28 pat ients.

Grupos pronósticos en Mesotelioma


• Etiopatogenia

• Diagnóstico






• Perspectivas

Stages I / II / III / IV = 11 / 21 / 48 / 20%

EPP 51 4% P/D 12 9%EPP 51.4%, P/D 12.9%

Correlation between cTNM and pTNM:Correlation between cTNM and pTNM:<30% for stages I / II, >65% for stages III / IV

Rusch ‐ IASLC, Amsterdam 2011

Impacto de la cirugíaJ Thorac Oncol. 2010;5: 1649–1654

Estadificación para eventual cirugía: Guidelines ERS‐ESTS

Eur Respir J 2010; 35: 479–495

Procedimientos quirúrgicos en MMPJ Thorac Oncol 2011;6: 1304 1312J Thorac Oncol. 2011;6: 1304–1312

• EPP:enbloc resection of the parietal and visceral pleura with the ipsilateral lung, pericardium, and diaphragm. In cases where the pericardium and/or diaphragm are not involved by tumor, these structures may be left intact.

• Extended P/D: parietal and visceral pleurectomy to remove all gross tumor with resection of the diaphragm and/or pericardium. The IASLC Mesothelioma Domain suggests use of the

“ d d” h h “ di l” i hi i h l i li l fterm “extended” rather than “radical” in this instance as the latter implies a completeness of resection with added therapeutic benefit. There is currently insufficient evidence that resection of the pericardium and diaphragm provides either.

• P/D: parietal and visceral pleurectomy to remove all gross tumor without diaphragm or• P/D: parietal and visceral pleurectomy to remove all gross tumor without diaphragm or pericardial resection.

• Partial pleurectomy: partial removal of parietal and/or visceral pleura for diagnostic or palliative purposes but leaving gross tumor behind. p p p g g

Procedimientos quirurgicos en MPMProcedimientos quirurgicos en MPM

• Paliativos: Drenaje pleural / ¿Pleurodesis?

• Pleurectomia / Decorticación (P/D):Pleurectomia / Decorticación (P/D):– P/D extendida vs tto soporte (14.5 vs. 4.5 m)

P/D did P/D (15 3 7 1 )– P/D extendida vs P/D (15.3 vs. 7.1 m)

– P/D extendida mortalidad 9.1%, morbilidad 30%, EM 12 días , Sup 1‐a 65% Sup 3‐a 0–24

– MesoVATS CT (UK): 196 p P/D vs Pleurodesis( ) p /

• Neumonectomia extrapleural (EPP) (Butchart Thorax 1976; 31: 15 24)Thorax 1976; 31: 15–24)– MARS trial

Extensión de la Cirugía

Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignantpleural mesothelioma: Results in 663 patients

Stage I: 8%, Stage II: 21%Stage III: 62% Stage IV: 9%Stage III: 62%, Stage IV: 9%

Flores – J Thorac and Card Surg 2008

Patrón de recaídas y extension de la cirugíay g

Flores – J Thorac and Card Surg 2008

EC MARSLancet Oncol 2011; 12: 763–72

EC MARSlLancet Oncol 2011; 12: 763–72

Impacto tipo cirugía en CDVLung Cancer 77 (2012) 151–155


• Etiopatogenia

• Diagnóstico






• Perspectivas

Evolución de la RT en el Mesotelioma

• EPP + EBRT, con mediana superv. 17 m (Est I‐II 34m, Est III‐IV 10 m), con 4% recidiva local y 55% recaída a distancia. (Rusch – J Thor Cardiovasc Surg 2001)

• P/D + EBRT (retrospectivo), con mediana superv. 13.5 m, con 33% recidiva local y 24% recaida a distancia. Elevada neumotoxicidad (1 6% G5) (Gupta I J Radiot Oncol Biol Phys 2005)(1.6% G5) (Gupta – I J Radiot Oncol Biol Phys 2005)

• EPP + IMRT, obtiene mediana superv. 14m, 4% recidiva local. (Rice –, p , (Ann T Surg 2007), con excesiva neumotoxicidad (Rice – I J Radiat Oncol Biol Phys 2007).

• EPP seguida de IMRT, reduce recidiva local comparada con EPP seguida de EBRT (14% vs 42%, p=0.03). (Buduhan – Ann Thorac Surg 2009).


• Etiopatogenia

• Diagnóstico






• Perspectivas

Quimioterapia en mesotelioma:Quimioterapia en mesotelioma: el pasado

(Tiong y Vogelzang JCO 1997)(Tiong y Vogelzang, JCO 1997)

• Pequeños estudios Fase II, habitualmente < 40 p

• Antraciclinas (Doxorrubicina y Epirrubicina): RG 5%‐15%

• Platinos (Cisplatino y carboplatino): RG 7%‐16%p y p

• Antifolatos (methotrexate, edatrexate, trimetrexate): RG 12‐37%

• Esquemas de combinación– Agentes alquilantes y antraciclinas: RG 11‐30%– Cisplatino y antraciclinas: RG 14‐22%

QT inicial o diferidaAnnals of Oncology 17: 270–275, 2006 doi:10.1093/annonc/mdj073

Mejoría síntomas en mesotelioma: experienciaMejoría síntomas en mesotelioma: experiencia con MVP

(Middleton Ann Oncol 1998; Andreopoulou Ann Oncol 2004)(Middleton, Ann Oncol 1998; Andreopoulou, Ann Oncol 2004)

• 150 pacientes

( )• RG 15% (95% i.c. 9%‐21%)

• Mejoría sintomática 69%– Disnea 50%

– Tos 62%

– Dolor 71%

– Astenia 39%

• Mediana supervivencia 7 meses

• Prob Superv 1 y 2 años : 31% y 11%• Prob. Superv. 1 y 2 años : 31% y 11%

Impacto sintomático de QT en Mesotelioma / Lancet 2008

Control de síntomas:Tto sintomatico activo (ASC) vs ASC + MVP (7% vs. 11%, P 0 0017)P=0.0017)

Ttto sintomático activo ASC vs ASC + Vinorelbina (4% vs. 7%,

P=0.047).

Impacto sintomático de QT en Mesotelioma / Lancet 2008

Q i i i li ú iQuimioterapia en mesotelioma: agente únicoRG MST

Vi lbiVinorelbina:‐ Steele, JCO 2000 21% 10.6 meses(mejoría sintomatica)

G it biGemcitabina:‐ Bischoff, ASCO 1998 31% n/a ‐ v. Meerbeck, Cancer 1999 7% 8.0 meses‐ Kinder, Lung Cancer 2001 0% 4.1 mesesKinder, Lung Cancer 2001 0% 4.1 meses

Edatrexate:‐ Kindler, Cancer 1999 25% 9.6 meses

R ltit dRaltitrexed‐ Baas, EJC 2003 21% n/a

Pemetrexed:Scagliotti JCO 2003 14% 10 7 meses‐ Scagliotti, JCO 2003 14% 10.7 meses

Taxanos:4 estudios con RG 0%‐10%

Campthotecinas:Topotecan y CPT‐11 inactivos

Temozolamida: Inactiva

Quimioterapia en mesotelioma:combinaciones platino y gemcitabina

ByrneJCO 1999

NowakBJC 2002

v. Haarst BCJ 2002

Favaretto Cancer 2002

Pacientes 21 53 25 501000Gemcitabina 1000

d1,8,151000

d1,8,151250d1,8

1000 d1,8,15

Pl ti Ci 100 Ci 100 Ci 80 C bPlatino Cis 100 Cis 100 Cis 80 Carbo (AUC 5)

Respuesta 48% 33% 16% 26%

Superv. (mediana)

9.5 ms 11.2 ms 9.6 ms 15 ms

EC Fase III en mesotelioma:EC Fase III en mesotelioma:

• Pemetrexed + cisplatino vs cisplatino(Vogelzang, JCO 2003)

MST 12.1 vs 9.3 meses (p<0.001)

R ltit d i l ti i l ti• Raltitrexed + cisplatino vs cisplatino(v. Meerbeeck, JCO 2005)

( )MST 11.2 vs 8,8 meses (p=0.048)

EC Fase III Cisplatino‐Pemetrexed vs Cisplatino Respuesta y Supervivencia

Vogelzang et al. J Clin Oncol 21: 2636, 2003

EC Fase III Cisplatino +/‐ Raltitrexed. EORTC‐NCIC / JCO 05


• Etiopatogenia

• Diagnóstico






• Perspectivas

Rusch ‐ IASLC, Amsterdam 2011

TMT en MPM con QT adyuvanteTMT en MPM con QT adyuvante1980-1995 Post-op OS

NMortalidadMorbilidad

QT

OS

(m)

OS EPP

FP Negat.

Sugarbaker 183 3.8% ‐ 50%CAP

Cb/taxol21 m

HistolR1N+

Riesgo relativo muerte:S bti it li l (OR 3 0 0001)-Subtipo no epitelial (OR 3, p < 0.0001)

-Márgenes positivos (OR 1.7, p=0.0082)-Ganglios positivos (OR 2 p=0 0026)-Ganglios positivos (OR 2, p=0.0026)

Pacientes con las 3 variables pronósticas favorables conMediana superv. 51 mesesSugarbaker – J Thorac Cardiovasc S 1999 * Sugarbaker – Ann of Surgery 1996

TMT en MPM con QT adyuvante

NEPP

(%)

Post-opMortalidadMorbilidad

RT (%)

QT

Compl

TMT

(%)

OS

(m)FP

Neg(%) Compl. (%)OS EPP

Neg.

Batirel20

80%5% ‐ 55%

54GyCis/PemCis/Gem 60

17.2N+*

T1-3 N0-220

R1:70%5% 55%

75%Cis/Gem75%

6023.9

N+

Pagan54 81% 4.5% ‐ 36%

50Gy Cb/Taxol57

20**T1-3 N0-2

54 81% 4.5% 36%74% 70%

575y:50%**

HasaniT1 3 N0 1

36 74% 11% / ‐‐ 88% 80% 39 19***T1-3 N0-1

OkuboII-IV

16 100% ‐‐ 93% 88% 8128.1sIII: 38II-IV sIII: 38

*Batirel: OS N+ vs N0: 13m vs 24 m, p=0.052**5yOS=50% en Epitelial, N0‐1, con resección completa

Batirel – JTO 2008 * Pagan –J Cardiovasc S 2006 * Hasani – JTO 2009 * Okubo – Gen T CV s 2009

***Hasani (análisis retrospectivo), OS EPP vs no EPP: 20.4 vs 20,7, p=NS

TMT con P/D en MPMP/D, adjuvant chemotherapy, and adjuvant radiation

A th Y N St d D i P/D Ch XRT OS di ( ) l ti ll

/

Author Year N StudyDesign P/D Chemo XRT OSmedian(mos.) completingall

Bolukbas[26] 2009 35 Prospective 35/35 35/35 33/35 30 94%

Maggi[29] 2001 32 Retrospective 32/32 32/32 27/30 not reported 84%Maggi[29] 2001 32 Retrospective 32/32 32/32 27/30 not reported 84%

Mediana supervivencia elevada:‐Estadio patológico: 75% pT1a‐3 N0 5% N1 9% N2/‐Estadio patológico: 75% pT1a‐3 N0, 5% N1, 9% N2/‐Sv 2a 51%‐ Sv 3a 31% * no diferencias est I vs III/ 36% recidiva local y 24% a distancia‐ Pacientes tratados con P/D mantienen mejor PS a la progresión Posible 2ª L QT

Zauderer – Curr Treat Options Oncol 2011 * Bolukbas – Lung Cancer 2011

Quimioterapia Platino/Gem

N QTRR a NEO

EPP

(%)

Post-opMortalidad

RT (%) TMT

(%)

OS

(m)

OS

FP

Negat(%)

(%) Morbilidad (%) OS EPP

Negat.

Weder19

C/Gem32 84 0% / -- 30-60Gy 68 23(T1-3 N0-2) 19

(95%)32 84 0% / -- 30-60Gy 68 23

Weder(T1-3 N0-2) 61

C/Gem(95%)

-- 74 2.2% / -- 50-60Gy 5919.823

Histol*EORTC( )

Rea(I-III) 21

Cb/Gem(50%)

PR 33SD 67

81 0% / 52.4% 45+10Gy 7125.527.5

Flores(II-IV)

21C/Gem(53%)

PR 26SD 32

42 0% / -- 54Gy 4219

33.5No S**

Bille Cis/G 54GyBilleT1-3 N0-1

25Cis/G

Cis/Pem -- 92 4% / 60%54Gy81%

81 12.8

* OS Epitelial vs Sarcomatoide/mixto 21 9 m vs 11 1m p=0 259

Weder – JCO 2004 * Weder – Ann Oncol 2007 * Rea ‐ Lung Cancer 2007 * Flores – J T Oncol 2006 * Bille – GTCVS 2012

OS Epitelial vs Sarcomatoide/mixto 21.9 m vs 11.1m, p 0.259** OS Tumores resecables vs no resecables: 33.5 mo vs 9 mo, p=0.01

Combinaciones platinos con antifolatos

OS

N QTRR a NEO

(%)

EPP

(%)

Post-opMortalidadMorbilidad

RT (%) TMT

(%)(m)

OS EPP

FP

NegatEPP

Estudios retrospectivosC/Pem

EBRT 63 pN2Buduhan 55 CMV

C/GemNR 84 4.3% / 80%

EBRT 63IMRT 34*

69 24pN2R1

C/V noTM

De Perrot 60C/PemC/RaltiC/Gem**

nNR 75 6.7% / --EBRTIMRT

50 14T

pN2Histol

* Incidencia recidiva loca IMRT vs EBRT: 14.3% vs 41.7%, p=0.03, pero diferentes dosis 50Gy+24Gy vs 30 Gy** El esquema de QT en induccion NO muestra impacto significativo en superv: C/P 16 C/Vi lbi 14 ( 0 2)C/Pem 16 m vs C/Vinorelbine 14m, (p=0.2)

Buduhan – Ann Thorac Surg 2009 * de Perrot – J Clin Oncol 2009

Platinum doublets with modern antifolate regimens

pN0/N1: Completion of TMT vs no TMT completion: 59 mo vs 8 mo, p<,0.0001pN2: Completion of TMT vs no TMT completion: 12 mo vs 14mo, p=0.9

Histology: Epithelial vs Biphasic: 18 mo vs 12 mo, p=0.002Stage, age and T status no prognostic factors

de Perrot – J Clin Oncol 2009

Combinaciones Cisplatino‐Pemetrexed

N QT(Compl)

RR a NEO

EPP

(%)

Post-opMortalidad

RT (%) TMT

(%)

OS /

OS

FP

Negat( p )

(%)(%)

Morbilidad(%) OS

TMT

Negat.

Prospective TrialsProspective Trials

Krug(cT1-3 N0-2)

77C/Pem(83%)

PR 31pCR 5%

SD 4770.1 4% EBRT54Gy 52

16.829.1 No RR

SD 47

Van Schil(cT1-3 N0-1)

58C/Pem(93%)

CR 5PR 43SD 42

74 6.5% / 83% EBRT54Gy(65%)

6518.433( ) SD 42

Rea(cT1-3 N0-2)

54C/Pem(96%)

PR 30SD 57 83.3 -- EBRT54Gy 41 15.5

Krug Trial:‐OS correlacion con respuesta radiologica: PR/CR 26m vs SD/PD 13.9mo (p=0.05)‐pCR 5% Sv 2 a 37%

Krug – J Clin Oncol 2009 * van Schil – Eur Resp J 2010 * Rea – ASCO 2011 (Abst 7090)

‐pCR 5% Sv 2 a 37%‐No diferencias en OS segun: status gangl, histología, sexo, estadio clinico inicial

TMT with EPP in MPMA. EPP, adjuvant chemotherapy, and adjuvant radiation

Author Year N Study Design EPP Chemo XRT OS median (mos ) complete allAuthor Year N Study Design EPP Chemo XRT OS median (mos.) complete all

Pagan[20] 2006 54 Prospective 44/54 31/42 31/42 20 57%

Hasani[17] 2009 36 Retrospective 18/22 15/16 14/16 19 39%

Batirel[13] 2008 20 Prospective 16/20 12/12 12/16 17.2 60%

Okubo[19] 2009 16 Retrospective 16/16 14/16 13/14 28.1 81%

B. Neoadjuvant chemotherapy, EPP, and adjuvant radiation

Author Year N Study Design Chemo EPP XRT OS (mos.) complete all

Krug[18] 2009 77 Prospective 64/77 57/64 40/44 16.8 52%

dePerrot[15] 2009 67 Retrospective 56/60 45/60 30/45 14 67%dePerrot[15] 2009 67 Retrospective 56/60 45/60 30/45 14 67%

Weder[24] 2007 61 Prospective 58/61 45/61 24/36 19.8 39%

Van Schil[22] 2010 59 Prospective 55/58 42/58 37/38 18.4 63%

Buduhan[14] 2009 55 Retrospective 55/55 46/55 38/46 24 69%

Flores[16] 2006 21 Prospective 10/21 9/10 7/8 19 33%

Rea[21] 2007 21 Prospective 20/21 17/21 13/15 25.5 62%

Weder[23] 2004 19 Prospective 18/19 16/19 6/13 23 32%

Curr Treat Options Oncol. 2011


• Etiopatogenia

• Diagnóstico






• Perspectivas

Tratamientos biológicosInhibidores HDAC : Vorinostat

Tratamientos biológicos•Agentes anti-mesotelina: MORAb009, SS1PInhibidores HDAC : Vorinostat,

PXD101Inhibidores IGF-1R : IMC-A12, OSI-906

Agentes anti mesotelina: MORAb009, SS1P•Inhibidores AXL: Foretinib, Amuvatinib, Bosutinib, BMS-777-607

OSI-906Inhibidores mTor : EverolimusInhibidores Src : Dasatinib

•Inhibidores BCL-2: ABT-263•Inhibidores CDK : CBP501•Anti EGFR: Cetuximab ErlotinibInhibidores TGF-B : GC1008

Inhibidores Flk1-KDR: Semaxinib

•Anti-EGFR: Cetuximab, Erlotinib, Gefitinib•Inhibidores HGF : AMG 102

Inhibidores RET, tRNA: RanpirnasaAntiangiogénicos:

•Inhibidores PDGF: Imatinib•Inhibidores proteosoma: BortezomibA i t t 2 CS 100Antiangiogénicos:

Bevacizumab, Cediranib, Pazopanib, Vatalanib, Sorafenib, Sunitinib,

•Agonistas receptor-2 : CS-100•Otras dianas potenciales: c-met, AKT, aurora -quinasas, efrinas, hedgehog, PARP…., ,

Vandetanibq , , g g,

Resultados fármacos biológicos en MPMResultados fármacos biológicos en MPM

• Vorinostat: EC Fase III: NS respecto placebo; 660 p; HR 0.86p

• Sunitinib: RP 12%, EE 65%, SLP 3.5 m, SG 6.1 mm

J Thorac Oncol. 2012;7: 1449–1456

• Bortezomib: RP 4 8% EE 4 8% SLP 2 1 m SG• Bortezomib: RP 4.8%, EE 4.8%, SLP 2.1 m, SG 5.8 J Thorac Oncol. 2012;7: 1466–1470

• Vatalanib: RP 6%, EE 72%, SLP 4.1 m, SG 10 m Lung Cancer 76 (2012) 393–396

• Cediranib: RP 10%, EE 34%, SLP 1.8 m, SG 4.4 m Lung Cancer 78 (2012) 76–80

Disrupted pathways in MPM, the relevance of the

•Precise control of cell number is

HIPPO signaling pathway

•Precise control of cell number is essential function of multicellular organims.

•Impairment of this function leads to human disease as cancer.

•Hippo pathway has been shown to have a critical role in controlling organ size by regulating both cell proliferation and egu at g bot ce p o e at o a dapoptosis

•Alterations in several components of the pHIPPO signaling pathway are found in MPMs, including mutations in NF2, LATS1 and increased expression of YAP and BMI-1.

Zhao et al 2008Kango-Singh 2009

BMI‐1 overexpressing cancer cell enhance YAP expression

•An 11-gene BMI signature has

A Ewing sarcoma cell

An 11 gene BMI signature has been identified as related with survival in many different primary tumors

line in wich BMI‐1 inhibition decreases

primary tumors

•In mesothelioma patients with positive BMI-1 signature

levels of YAPp gmedian survival was 16.4 months vs 39 months for negative BMI signature (P=.0002)

Glinsky 2005

Disrupted pathways in MPM, NF 2 pathway

• The neurofibromatosis type 2 gene (NF2) is mutated in more than 40% of MPMs The NF2than 40% of MPMs. The NF2 gene encodes a protein called Merlin (moesin‐ezrin‐radixin‐like protein)protein)

• The protein kinase C potentiated phosphatase inhibitor of 17 KDaphosphatase inhibitor of 17 KDa(CPI‐7) is overexpressed in several tumors and abrogates Merlin activity.y

• Integrin‐linked kinase (ILK) phosphorylates CPI‐17 leading

Cheng 1999S

to inhibition of downstream phosphatases including Merlin.

Sekido 2008Lopez-Lago 2009

Disrupted pathways in MPM, NF 2 pathway

•It has been shown that ILK is highly expressed in 90% of MPM samples, regardless of histological subtype, whereas healthy pleural and lung tissue does not express g pILK.

•The contribution of the ILKThe contribution of the ILK signaling pathway in loss of Merlin expression has been identified as conferring sensitivity to mTORconferring sensitivity to mTOR inhibitors such as rapamycin.

Hannigan 2011Watza 2011Cabodi 2010

Disrupted pathways in MPM, the relevance of the HIPPO signaling pathway: LATS 2

•MPM quite often harbors mutations and

HIPPO signaling pathway: LATS 2

MPM quite often harbors mutations and has loss of LATS2 expression. LATS2 deletions show negative or weak LATS2 staining and, by contrast, strong YAP staining in the y , g gnucleus.

•The HIPPO signaling pathway has recently g g p y ybeen shown to be central in mesothelioma and liver cancer.

•Upstream components of the HIPPO‐YAP pathway include the mammalian Ste20‐like kinase 1/2 (MST1/2) and LATS1/2 which phosphorylate and activate YAP.

Murakani 2011Yokoyama 2008

Disrupted pathways in MPM, the relevance of the HIPPO signaling pathwayHIPPO signaling pathway

•The HIPPO signaling pathway hasThe HIPPO signaling pathway has recently been shown to be central in mesothelioma and liver cancer.

•Of interest is the fact that AXL expression was observed to be stronger in mesothelioma than in other primarin mesothelioma than in other primary tumors. YAP nuclear translocation acts as a transcriptional coactivator increasing expression of genes including AXL

Nuevas estrategias: inhibición Mesotelina( ) d / lPLoS ONE 7(4): e33214. doi:10.1371/journal.pone.0033214

AgradecimientosAgradecimientos

• Rafael Rosell

• Enric CarcerenyEnric Carcereny

• Pilar Lianes

• Felipe Cardenal

• Rosana MontoyoRosana Montoyo

• Cristina Velasco

[email protected]

El futuro de los servicios públicos en 2012‐2013

Grupo de trabajo Mesotelioma GECP

Actualización en el Tratamiento del Mesotelioma Pleural ... · Actualización en el Tratamiento...

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