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Review Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma Mrinali Patel 1 , Elizabeth Smyth 1 , Paul B. Chapman 1 , Jedd D. Wolchok 1 , Gary K. Schwartz 1 , David H. Abramson 2 , and Richard D. Carvajal 1 Abstract Uveal melanoma represents the most common primary intraocular malignancy in adults. Although uveal and cutaneous melanomas both arise from melanocytes, uveal melanoma is clinically and biolo- gically distinct from its more common cutaneous counterpart. Metastasis occurs frequently in this disease, and once distant spread occurs, outcomes are poor. No effective systemic therapies are currently available; however, recent advances in our understanding of the biology of this rare and devastating disease, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, hold the promise for novel and effective therapies in the foreseeable future. Herein, we review our rapidly growing understanding of the molecular biology of uveal melanoma, including the pathogenic roles of GNAQ (guanine nucleotide binding protein q polypeptide)/11, PTEN (phosphatase and tensin homolog), IGF (insulin-like growth factor)/IGF-1 receptor, MET (hepatocyte growth factor), BAP1 [breast cancer 1, early onset (BRCA1)-associated protein-1], and other key molecules, potential therapeutic strategies derived from this emerging biology, and the next generation of recently initiated clinical trials for the treatment of advanced uveal melanoma. Clin Cancer Res; 17(8); 2087–100. Ó2011 AACR. Introduction Although uveal melanoma represents only 5% of all melanomas, this disease is the most common primary intraocular malignancy of the adult eye, affecting 6 indi- viduals per million per year (1, 2). These tumors arise from melanocytes within the uveal tract, which consists of the iris, ciliary body, and choroid of the eye. Several features of the primary tumor have been associated with poor prog- nosis, including location in the ciliary body or choroid (as opposed to the iris), diffuse configuration, and larger size (3–6). Histologically, uveal melanomas with epithelioid morphology fare worse than those with spindle cells (7), as do those with higher mitotic activity, extrascleral invasion, or the presence of microvascular networks (3, 8, 9). Genetic features, including monosomy of chromosome 3 and amplification of chromosome 8q, have also been identified as poor prognostic indicators (10, 11). Two independent groups have identified microarray gene expression profiles which accurately segregate uveal melanomas into 2 tumor classes by risk of metastasis (12–15). Class I tumors appear to have a low risk of metastasis, whereas class II tumors are more aggressive, correspond with monosomy in chromo- some 3, and are associated with a higher rate of metastatic death. The natural history of uveal melanoma is characterized by the frequent development of metastases, with over 50% of patients developing metastatic disease at any time from the initial diagnosis of the primary to several decades later (2, 16–21). A broad spectrum of therapies, including systemic therapies (22), hepatic artery infusion of che- motherapy, hepatic embolization, and metastastectomy, have been used to treat patients with metastatic uveal melanoma. However, a recent meta-analysis showed no compelling evidence that these interventions confer any survival benefit (23). Although a recently completed phase III trial that randomized 93 patients with hepatic metas- tases from uveal (n ¼ 82) or cutaneous (n ¼ 11) melanoma to percutaneous hepatic perfusion with melphalan to standard of care met its primary end point of hepatic progression-free survival (PFS), no survival advantage was observed (24). Due to the lack of effective therapies for this disease, prognosis after the development of metastasis is poor. In the largest published series of patients with uveal mela- noma, the median survival after diagnosis of metastatic disease was 3.6 months, with a 5-year cumulative survival of less than 1% (16). In this series, only 39% of patients received treatment for metastatic disease. In contrast, a smaller single institutional series of 119 cases treated at Memorial Sloan-Kettering Cancer Center (New York, NY) showed a 22% 5 year survival for patients with metastatic uveal melanoma (13, 18). In this study, 81% of patients received treatment for stage IV disease, including 20% who Authors' Affiliations: Departments of 1 Medicine and 2 Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York Note: M. Patel and E. Smyth contributed equally to the manuscript. Corresponding Author: Richard D. Carvajal, 1275 York Avenue, New York, NY 10065. Phone: 212-639-5096; Fax: 212-717-3342; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-10-3169 Ó2011 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 2087 on March 12, 2021. © 2011 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169

Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma · primary uveal melanoma to the development of metas-tases, surgical resection of metastases, and lung

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Page 1: Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma · primary uveal melanoma to the development of metas-tases, surgical resection of metastases, and lung

Review

Therapeutic Implications of the Emerging Molecular Biologyof Uveal Melanoma

Mrinali Patel1, Elizabeth Smyth1, Paul B. Chapman1, Jedd D. Wolchok1, Gary K. Schwartz1,David H. Abramson2, and Richard D. Carvajal1

AbstractUveal melanoma represents the most common primary intraocular malignancy in adults. Although

uveal and cutaneous melanomas both arise from melanocytes, uveal melanoma is clinically and biolo-

gically distinct from its more common cutaneous counterpart. Metastasis occurs frequently in this disease,

and once distant spread occurs, outcomes are poor. No effective systemic therapies are currently available;

however, recent advances in our understanding of the biology of this rare and devastating disease,

combined with the growing availability of targeted agents, which can be used to rationally exploit these

findings, hold the promise for novel and effective therapies in the foreseeable future. Herein, we review our

rapidly growing understanding of the molecular biology of uveal melanoma, including the pathogenic

roles of GNAQ (guanine nucleotide binding protein q polypeptide)/11, PTEN (phosphatase and tensin

homolog), IGF (insulin-like growth factor)/IGF-1 receptor, MET (hepatocyte growth factor), BAP1 [breast

cancer 1, early onset (BRCA1)-associated protein-1], and other key molecules, potential therapeutic

strategies derived from this emerging biology, and the next generation of recently initiated clinical trials

for the treatment of advanced uveal melanoma. Clin Cancer Res; 17(8); 2087–100. �2011 AACR.

Introduction

Although uveal melanoma represents only 5% of allmelanomas, this disease is the most common primaryintraocular malignancy of the adult eye, affecting 6 indi-viduals per million per year (1, 2). These tumors arise frommelanocytes within the uveal tract, which consists of theiris, ciliary body, and choroid of the eye. Several features ofthe primary tumor have been associated with poor prog-nosis, including location in the ciliary body or choroid (asopposed to the iris), diffuse configuration, and larger size(3–6). Histologically, uveal melanomas with epithelioidmorphology fare worse than those with spindle cells (7), asdo those with higher mitotic activity, extrascleral invasion,or the presence of microvascular networks (3, 8, 9). Geneticfeatures, including monosomy of chromosome 3 andamplification of chromosome 8q, have also been identifiedas poor prognostic indicators (10, 11). Two independentgroups have identified microarray gene expression profileswhich accurately segregate uveal melanomas into 2 tumorclasses by risk of metastasis (12–15). Class I tumors appearto have a low risk of metastasis, whereas class II tumors are

more aggressive, correspond with monosomy in chromo-some 3, and are associated with a higher rate of metastaticdeath.

The natural history of uveal melanoma is characterizedby the frequent development of metastases, with over 50%of patients developing metastatic disease at any time fromthe initial diagnosis of the primary to several decades later(2, 16–21). A broad spectrum of therapies, includingsystemic therapies (22), hepatic artery infusion of che-motherapy, hepatic embolization, and metastastectomy,have been used to treat patients with metastatic uvealmelanoma. However, a recent meta-analysis showed nocompelling evidence that these interventions confer anysurvival benefit (23). Although a recently completed phaseIII trial that randomized 93 patients with hepatic metas-tases from uveal (n¼ 82) or cutaneous (n¼ 11) melanomato percutaneous hepatic perfusion with melphalan tostandard of care met its primary end point of hepaticprogression-free survival (PFS), no survival advantagewas observed (24).

Due to the lack of effective therapies for this disease,prognosis after the development of metastasis is poor. Inthe largest published series of patients with uveal mela-noma, the median survival after diagnosis of metastaticdisease was 3.6 months, with a 5-year cumulative survivalof less than 1% (16). In this series, only 39% of patientsreceived treatment for metastatic disease. In contrast, asmaller single institutional series of 119 cases treated atMemorial Sloan-Kettering Cancer Center (New York, NY)showed a 22% 5 year survival for patients with metastaticuveal melanoma (13, 18). In this study, 81% of patientsreceived treatment for stage IV disease, including 20% who

Authors' Affiliations: Departments of 1Medicine and 2Surgery, MemorialSloan-Kettering Cancer Center, New York, New York

Note: M. Patel and E. Smyth contributed equally to the manuscript.

Corresponding Author: Richard D. Carvajal, 1275 York Avenue, NewYork, NY 10065. Phone: 212-639-5096; Fax: 212-717-3342; E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-10-3169

�2011 American Association for Cancer Research.

ClinicalCancer

Research

www.aacrjournals.org 2087

on March 12, 2021. © 2011 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169

http://clincancerres.aacrjournals.org/
Page 2: Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma · primary uveal melanoma to the development of metas-tases, surgical resection of metastases, and lung

underwent complete surgical metastastectomy. Factorsrelating to improved outcomes included female gender,age less than 60 years, longer time from treatment for theprimary uveal melanoma to the development of metas-tases, surgical resection of metastases, and lung or softtissue as sole site of metastasis.

Given these unsatisfactory outcomes, there is a compel-ling need for novel and effective therapeutic strategies forthe management of metastatic uveal melanoma. As currenttreatment for localized disease often leads to visual loss,whether due to enucleation or the local effects of radiationwithin the eye, the identification of active pharmacologicagents may obviate the necessity for these locally destruc-tive therapies. Innovation in pharmacotherapy dependslargely upon elucidating the molecular mechanisms under-lying uveal melanoma pathogenesis. Recent advances inour understanding of the biology of this rare and devastat-ing disease, combined with the growing availability oftargeted agents, which can be used to rationally exploitthese findings, hold the promise for novel and effectivetherapies in the foreseeable future. Herein, we review recentdevelopments in our understanding of the pathogenesis ofuveal melanoma as well as the associated potential ther-apeutic implications.

Mitogen-activated protein kinase pathwayEighty-six percent of primary uveal melanoma tissue

exhibits activation of the mitogen-activated protein kinase(MAPK) pathway (25). In this signaling pathway, ligandbinding to cell surface tyrosine kinase receptors leads toexchange of GDP for GTP on Ras. Activated in its GTP-bound state, Ras activates Raf, which subsequently activatesMAP/ERK (extracellular signal-regulated kinase) kinase

(MEK). MEK phosphorylates and activates ERK, whichdimerizes and translocates to the nucleus, where it med-iates cell proliferation, survival, differentiation, and apop-tosis. Preclinical studies show that inhibition of the MAPKpathway in uveal melanoma cell lines results in decreasedcell proliferation (26, 27), suggesting that several keymolecules in this pathway, including BRAF (v-raf murinesarcoma viral oncogene homolog B1) GNAQ (guaninenucleotide binding protein q polypeptide)/11, and MEK,may serve as potential therapeutic targets (Fig. 1).

BRAF as a therapeutic target. Cutaneous and uvealmelanomas differ in many ways, including pattern ofspread and responsiveness to chemotherapy; however,given their common melanocytic origin and the signifi-cantly larger body of knowledge about cutaneous mela-noma, observations made in cutaneous melanoma haveserved to guide investigation into the molecular biology ofuveal melanoma. BRAF has been shown to be of greatsignificance in cutaneous melanoma, with up to 62% ofcases harboring activating mutations in BRAF (28). Ninety-five percent of such cases result in a V600E mutation whichinvolves a valine to glutamic acid substitution at position600.

Based upon these findings in cutaneous melanoma,several groups have investigated the mutational status ofBRAF in primary uveal melanomas (29–32), as well as inliver metastases of uveal melanoma (25). These studieshave been overwhelmingly negative, with only 1 caseharboring a BRAF V600E mutation (30). Several groups,however, have posited that uveal melanoma exhibitssignificant intratumoral heterogeneity and that conven-tional PCR techniques are insufficiently sensitive to iden-tify BRAFmutations that may be present in a small subsetof cells within a tumor. Using nested PCR and pyrophos-phorolysis-activated polymerization techniques, thesegroups showed that subsets of tumor tissue, but notthe entire tumor, harbor a BRAF mutation (33, 34). Thisobservation, in part, may explain the identification ofseveral uveal melanoma cell lines that harbor a BRAFmutation (29, 33, 35–37). Interestingly, Calipel andcolleagues showed that uveal melanoma cell lines exhibitsimilar MAPK pathway activation and proliferationregardless of BRAF mutational status, indicating thatother mechanisms of MAPK pathway activation are pre-sent in uveal melanoma (35).

Preclinical studies have shown that sorafenib, a smallmolecule inhibitor of the RAF family of kinases, PDGFR-b(platelet-derived growth factor receptor, beta polypeptide),VEGF receptor (VEGFR)-1 and VEGFR-3, and KIT, inhibitsMAPK signaling and decreases proliferation, even in BRAFwild-type cell lines. Interestingly, studies of PLX4270, aninhibitor with relative selectivity for V600E BRAF, in uvealmelanoma cell lines showed that only the BRAF mutantlines exhibited decreased cell viability with therapy,whereas no effect was observed in the wild-type cells(unpublished data). This is consistent with recent dataindicating that effective RAF inhibition in BRAF wild-typecells may activate rather than inhibit MAPK pathway

Translational Relevance

Uveal melanoma is a unique clinical and molecularsubtype of melanoma that has no known effectivetherapy in the metastatic setting. Significant advancesin our understanding of the biology of this disease,combined with the growing availability of agents whichcan be used to rationally target these findings, have ledto the development of a number of clinical trials testingvarious treatment strategies for advanced disease.Herein, we present an overview of the current knowl-edge of the molecular biology of uveal melanoma, withparticular attention paid to tumor-specific aberrationswhich can be exploited for therapeutic benefit. Wediscuss the pathogenic roles of guanine nucleotidebinding protein q polypeptide (GNAQ)/11, PTEN(phosphatase and tensin homolog), IGF (insulin-likegrowth factor)/IGF-1 receptor MET (hepatocyte growthfactor receptor), BAP1 [breast cancer 1, early onset(BRCA1)-associated protein-1], and other key mole-cules, review potential therapeutic strategies, and reviewthe next generation of recently initiated clinical trials forthe treatment of advanced uveal melanoma.

Patel et al.

Clin Cancer Res; 17(8) April 15, 2011 Clinical Cancer Research2088

on March 12, 2021. © 2011 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169

http://clincancerres.aacrjournals.org/
Page 3: Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma · primary uveal melanoma to the development of metas-tases, surgical resection of metastases, and lung

signaling (38–40), and that, although both BRAF mutantand wild-type uveal melanomas may require MAPK signal-ing for growth, inhibition of this pathway likely hasdifferent consequences depending upon the genetic back-ground of the cell.To date, there are a number of clinical trials evaluating

various BRAF inhibitors such as PLX4032 (RO5185426,also known as RG7204), XL281, and GSK2118436 inmelanoma (Table 1). Several of these have enrolledpatients with uveal melanoma, and 1 trial of the combina-tion of carboplatin, paclitaxel, and sorafenib is specifically

enrolling patients with ocular melanoma. The ongoingphase I study of XL281 in patients with advanced solidtumors included 1 patient with uveal melanoma whoachieved a confirmed partial response lasting for 4 months(41). It will be critical to carefully assess any clinical benefitobserved in patients treated on these trials in relationshipto tumor mutational status to optimally assess the role andfuture of BRAF inhibition as a therapeutic strategy for thetreatment of uveal melanoma.

GNAQ/11 as therapeutic targets. Despite the absence ofBRAFmutations, 86% of primary uveal melanomas exhibit

© 2011 American Association for Cancer Research

P

P

P

G�

DAGPI3K

PTENPIP2P

−

P

PIP2PIP3

ERK ERK

Raf Raf

GNAQQ209L

GDPGTP

GPCR

Perifosine

Rapamycin

17 – AAG

AZD6244

Tumorgrowth andproliferation

PLX4032

XL147

PPP

Akt

IP3

PKC

IRS

MEK MEK

mTOR

PLC�

IMC – A12

IGF1–R

EC

IC

G�G��

IGF1

Figure 1.Major signaling pathways in uveal melanoma. The MAPK, P13K (phosphatidylinositol-3-kinase), mTOR, and IGF-1R pathways intersect significantlyin uveal melanoma pathogenesis. Briefly, stimulation of GPCR (G-protein–coupled receptor) results in replacement of GDP for GTP on the Ga subunit.Ga-GTP is the active form andmediates activation of PLCb, which promotes cleavage of PIP2 [phosphatidylinositol (4,5)-bisphosphate] to inosol triphosphate(IP3) and diacyl glycerol (DAG). DAG goes on to activate PKC, which stimulates the MAPK signaling pathway. MAPK signaling leads to tumor growthand proliferation. The GNAQ Q209L mutation inactivates the intrinsic phosphatase of the Ga protein, thus preventing hydrolysis of GTP to GDP and enablingconstitutive downstream MAPK signaling. PI3K mediates phosphorylation of PIP2 to PIP3 [phosphatidylinositol (3,4,5)-trisphosphate], and PTEN(phosphatase and tensin homolog) antagonizes this process. PIP3 activates AKT, which promotes tumor growth and proliferation. Both ERK and AKTalso activate the mTOR-signaling pathway, which also mediates tumor growth and proliferation. IGF-1 simulation of IGF-1R leads to dimerization andautophosphorylation of the receptor, resulting in recruitment and activation of IRS, which can then activate both the PI3K and MAPK pathways. mTOR alsoexerts inhibitory effects on IGF-1R, such that mTOR blockade disinhibits IGF-1R signaling to paradoxically promote tumor proliferation. There arenumerous points at which these pathways can be manipulated, including inhibition of IGF-1 levels with somatostatin analogues or IGF-1R signaling bypicropodophyllin (PPP). PI3K inhibition by LY294002 or wortmannin, mTOR inhibition by rapamycin, everolimus, or temsorilimus, or MAPK pathwayinhibition with BAY-439006, AZD6244, U0126, 17-AAG (17-allylamino-17-demethoxygeldanamycin), or 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin).

Molecular Biology and Therapeutics of Uveal Melanoma

www.aacrjournals.org Clin Cancer Res; 17(8) April 15, 2011 2089

on March 12, 2021. © 2011 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169

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Page 4: Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma · primary uveal melanoma to the development of metas-tases, surgical resection of metastases, and lung

Tab

le1.

Rec

eptortyrosine

kina

seinhibito

rsan

dinhibito

rsof

theMAPkina

sean

dPI3K/AKTpathw

aysof

interest

inuv

ealm

elan

oma

Signa

ling

pathw

ayTarget

Agen

tDev

elopmen

tstag

eTrial

status

Clin

icalTrials.gov

iden

tifier

MAPKinas

eBRAF

PLX

4032

(RO51

8542

6)Pha

seIII

trialin

cutane

ousmelan

oma

Acc

rual

completed

NCT0

1006

980

XL2

81Pha

seItrialinso

lidtumors

Ong

oing

NCT0

0451

880

Sorafen

ib(BAY43

-900

6)FD

Aap

prove

dforrena

lcell

andhe

patoce

llularca

rcinom

an/a

n/a

MEK

AZD62

44(ARRY-142

886)

Pha

seIItrialinuv

ealm

elan

oma

Ong

oing

NCT0

1143

402

GSK11

2021

2Pha

seIII

trialincu

tane

ousmelan

oma

Ong

oing

NCT0

1245

062

AS70

3026

Pha

seItrialinhe

matolog

icmaligna

ncies

Ong

oing

NCT0

0957

580

MSC19

3636

9BPha

seItrialinso

lidtumors

Ong

oing

NCT0

0982

865

PI3K/AKT

mTO

RRap

amyc

inApprove

dforpos

t-rena

ltrans

plant

immun

osup

press

ion

n/a

n/a

Temso

rilim

usFD

Aap

prove

dforrena

lcellc

arcino

ma

n/a

n/a

Eve

rolim

us(RAD00

1)Pha

seIIwith

paclita

xel/c

arbop

latin

instag

eIV

melan

oma

Ong

oing

NCT0

1014

351

Ridaforolim

us(AP23

573)

Pha

seI/IIin

adva

nced

/refractorymaligna

ncies

Acc

rual

completed

NCT0

0112

372

TORC1/2

AZD80

55Pha

seIin

adva

nced

solid

maligna

ncies

Ong

oing

NCT0

0973

076

OSI027

Pha

seIin

adva

nced

solid

maligna

ncies/lympho

ma

Ong

oing

NCT0

0698

243

INK12

8Pha

seIin

adva

nced

solid

maligna

ncies

Ong

oing

NCT0

1058

707

PI3K

XL1

47Pha

seIin

adva

nced

solid

tumors/lympho

ma

Ong

oing

NCT0

0486

135

PI3Kþ

mTO

RXL7

65Pha

seIin

patie

ntswith

solid

tumors

Ong

oing

NCT0

0485

719

AKT

Perifo

sine

Pha

seIin

solid

tumors/lympho

ma

Acc

rual

completed

NCT0

0389

077

GSK21

4179

5Pha

seIin

solid

tumors/lympho

ma

Ong

oing

NCT0

0920

257

GSK69

0693

Pha

seIin

solid

tumors/lympho

ma

Ong

oing

NCT0

0493

818

MK22

06Pha

seIin

loca

llyad

vanc

edor

metas

tatic

solid

tumors

Ong

oing

NCT0

1071

018

Rec

eptorTy

rosine

Kinas

esIG

F-1R

IMC-A

12Pha

seIwith

temsirolim

usin

adva

nced

canc

ers

Ong

oing

NCT0

0678

769

R15

07Pha

seIin

adva

nced

solid

tumors

Ong

oing

NCT0

0400

361

MK06

46Pha

seIin

adva

nced

solid

tumors

Acc

rual

completed

NCT0

0635

778

OSI-90

6Pha

seIin

adva

nced

solid

tumors

Ong

oing

NCT0

0514

007

BIIB

022

Pha

seIin

adva

nced

solid

tumors

Ong

oing

NCT0

0555

724

CP-751

,871

Pha

seIwith

sunitin

ibin

adva

nced

solid

tumors

Ong

oing

NCT0

0729

833

AXL1

717

Pha

seIin

adva

nced

solid

tumors

Ong

oing

NCT0

1062

620

AMG47

9Pha

seIwith

biolog

ics/ch

emoin

adva

nced

solid

tumors

Ong

oing

NCT0

0974

896

(Con

tinue

don

thefollo

wingpag

e)

Patel et al.

Clin Cancer Res; 17(8) April 15, 2011 Clinical Cancer Research2090

on March 12, 2021. © 2011 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169

http://clincancerres.aacrjournals.org/
Page 5: Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma · primary uveal melanoma to the development of metas-tases, surgical resection of metastases, and lung

Tab

le1.

Rec

eptortyros

inekina

seinhibito

rsan

dinhibito

rsof

theMAPkina

sean

dPI3K/AKTpathw

aysof

interest

inuv

ealm

elan

oma

(Con

t'd)

Signa

ling

pathw

ayTarget

Agen

tDev

elopmen

tstag

eTrial

status

Clin

icalTrials.gov

iden

tifier

c-Kit

Imatinib

Pha

seIIin

metas

tatic

uvea

lmelan

oma

Ong

oing

NCT0

0421

317

Sun

itinib

Pha

seIIwith

cisp

latin

and

tamox

ifenin

ocular

melan

oma

Ong

oing

NCT0

0489

944

Sorafen

ibPha

seIIwith

carbop

latin

/pac

litax

elin

uvea

lmelan

oma

Ong

oing

NCT0

0329

641

Das

atinib

Pha

seIwith

beva

cizu

mab

inmetas

tatic

solid

tumors

Ong

oing

NCT0

0792

545

Nilo

tinib

Pha

seIIin

c-kitmutated

oram

plifiedmelan

oma

Ong

oing

NCT0

1168

050

c-Met

PF-02

3410

66Pha

seIin

solid

tumors

othe

rthan

NSCLC

Not

yetop

enNCT0

1121

588

GSK13

6308

9Pha

seIin

solid

tumors

Acc

rual

completed

NCT0

0742

261

XL-18

4Ran

dom

ised

disco

ntinua

tion

inad

vanc

edso

lidtumors

Ong

oing

NCT0

0940

225

ARQ

197

Pha

seIin

refrac

tory/

adva

nced

solid

tumors

Ong

oing

NCT0

0609

921

EMD

1204

831

Pha

seIin

adva

nced

solid

tumors

Ong

oing

NCT0

1110

083

PRO14

3966

Pha

seIin

adva

nced

solid

tumors

Acc

rual

completed

NCT0

1068

977

Abbreviation:

n/a,

notap

plicab

le.

Molecular Biology and Therapeutics of Uveal Melanoma

www.aacrjournals.org Clin Cancer Res; 17(8) April 15, 2011 2091

on March 12, 2021. © 2011 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

Published OnlineFirst March 28, 2011; DOI: 10.1158/1078-0432.CCR-10-3169

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activation of the MAPK pathway as evidenced by activationof phospho-ERK (26–32). In cutaneous melanoma, MAPKpathway activation has also shown to be mediated bymutations in NRAS (42); however, these mutations havenot been found in uveal melanoma (29). Thus, whereasuveal melanoma, such as cutaneous melanoma, is char-acterized by MAPK activation, the mechanism of MAPKactivation differs between these 2 unique subtypes ofmelanoma.

Recent studies have identified G-proteins as potentialdrivers of MAPK activation in uveal melanoma. Geneticscreens have shown that 46% to 53% of uveal melanomaexhibit mutations in GNAQ (26, 43–45). These mutationsare not associated with clinical, pathologic, immunohisto-chemical, or genetic factors associated with advanced uvealmelanoma, indicating that this alteration may represent anearly event in disease pathogenesis (43). Recent data sug-gest that over half of uveal melanomas lacking a mutationin GNAQ exhibit a mutation in GNA11 (44). GNAQ is a qclass G-protein a-subunit. G proteins are a family ofheterotrimeric proteins (Gabg) coupled to cell surface,7-transmembrane spanning receptors. Upon ligand bind-ing to these receptors, the GDP bound to the Ga subunit ofGabg is exchanged for GTP, resulting in a conformationalchange and the subsequent dissociation of the Ga from theGbg subunits. These 2 subunits are then able to regulatevarious second messengers. Ga activation is terminated bya GTPase intrinsic to the Ga subunit. The q class Ga (Gqa)mediates its activity through stimulation of phospholipaseC-b (PLCb), which cleaves PIP2 to IP3 and DAG. DAG goeson to activate protein kinase C (PKC), which ultimatelyactivates downstream pathways including the MAPK sig-naling pathway.

Van Raamsdonk and colleagues showed that transfectionof GNAQ Q209L in human melanocytes results in ancho-rage-independent growth, with cells able to grow in theabsence of the DAG analogue 12-O-tetradeconoyl phorbol-13-acetate, presumably due to high levels of DAG produc-tion by constitutively activated PLCb. GNAQ Q290L trans-fected melanocytes have increased ERK activation ascompared tomelanocyteswithwild-typeGNAQ(26). Inter-estingly, small interfering RNA (siRNA) targeting GNAQnormalizes phospho-ERK levels, increases the number ofresting cells, decreases cell number, and decreases ancho-rage-independent growth. Injection of nude mice withmelanocytes harboring GNAQ Q209L, but not wild-typeGNAQmelanocytes, leads to thedevelopment of pigmentedtumors at the injection site (26). GNA11 has similarly beenvalidated as an oncogene that results in MAPK activation,comparable to that achieved with GNAQ (44).

The somaticGNAQ exon 5Q209L andQ209Pmutationsmost commonly identified lead to a glutamine-to-lysineand glutamine-to-proline substitution, respectively, atposition 209, which lies in the Ras-like domain of GNAQ.The GNA11 exon 5 mutation most commonly observedresults in a Q209L substitution that is analogous to theQ209L substitution observed in GNAQ. Mutations at thissite cause loss of the intrinsic GTPase activity, similar to that

seen in Ras family members (46). Because Ga inactivationis mediated by this intrinsic GTPase, suchmutations lead toconstitutive Ga activation and downstream signaling. Exon4 mutations in GNAQ and GNA11 have also been identi-fied in 4.8% of uveal melanomas that lead to alterations atarginine 183 (R183; ref. 44). In all but one of the tumorstested, exon 5 Q209 and exon 4 R183 mutations weremutually exclusive. Interestingly, tumors characterized bythese mutations display distinct biological activity. Injec-tion of GNA11 Q209L transfected melanoma cells inimmunocompromised mice produced rapidly growingtumors at all injection sites, whereas injection of R183C-transfected cells produced tumor growth at only one half ofinjection sites with a longer latent period. Furthermore,whereas all mice injected with the GNA11 Q209L variantdeveloped visceral metastases, this was not observed withmelan-a cells transfected with GNAQ Q209L, supportingthe hypothesis that GNA11 Q209 mutations are moreoncogenic than the GNAQ Q209 variant. Indeed, a recentstudy showed an inverse relationship of the frequency ofGNAQ mutations and GNA11 mutations when comparingblue nevi, uveal melanoma, and uveal melanoma metas-tases. Whereas GNA11 mutations were observed in 7% ofblue nevi, 32% of uveal melanoma, and 57% of uvealmelanoma metastases, GNAQ mutations were present in55% of blue nevi, 45% of uveal melanoma, and 22% ofuveal melanoma metastases. This also suggests that muta-tions in GNA11 connote a greater risk of distant metastasisin uveal melanoma than GNAQ mutations.

Thus, in vitro and in vivo studies support the hypothesisthat GNAQ/11 mutations result in MAPK activation andplay an essential role in the development of uveal mela-nomas. There is currently a significant interest in investi-gating inhibition of the GNAQ/11 pathway for thetreatment of uveal melanoma; however, whether inhibi-tion of this pathway will be an effective strategy is yet to bedetermined. Importantly, it is also not known whetherpathway inhibition at the level of GNAQ/11 or furtherdownstream will be optimal. Currently, there are no clini-cally available specific inhibitors of GNAQ/11, PLCb, orthe various PKC isoforms with which to investigate thesecritical questions.

MEK as a therapeutic target. An alternative therapeuticstrategy for these patients is the targeting, not of GNAQ/11,but rather of the downstream effector MEK. Treatment ofuveal melanoma cell lines bearing GNAQ mutations withU0126, a small molecule inhibitor of MEK, leads to adecrease in phospho-ERK and cell number, a loss of ancho-rage-independent growth, and an increase in the sub-G0/G1

subpopulation. Moreover, in these cell lines, U0126 resultsin lower cell numbers than siRNA-mediated knockdown ofGNAQ, suggesting that targeting the downstream targetMEK may be more effective than inhibiting GNAQ itself(26). Additional in vitro studies indicate that uveal mela-noma cell lines bearing the GNAQ Q209L mutation aresensitive toMEK inhibitionwith AZD6244, another potent,selective, orally available, and non–ATP-competitive smallmolecule inhibitor of MEK1/2 (47). MEK inhibition in

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these cells is associated with decreased signaling throughboth the MAPK and PI3K pathways, as shown by inhibitionof phospho-ERK and phospho-AKT. Although these effectsare not observed in wild-type cells for GNAQ or BRAF,transfection of GNAQ wild-type cell lines resistant toAZD6244 with GNAQ Q209L leads to the induction ofsensitivity to AZD6244 in terms of both ERK inhibition anddecreased proliferation.We have observed clinical efficacy of MEK inhibition in

subset analysis of patients with metastatic uveal melanomatreated with AZD6244 on 3 completed trials (48–50). On arandomized phase II study of AZD6244 versus temozolo-mide for patients with melanoma, of the 20 patients withuveal melanoma, 17 received AZD6244 during the study: 7received AZD6244 upfront whereas 10 received AZD6244following progression on temozolomide (49). PFS hazardratio (HR) was 0.76 (80% CI, 0.38–1.53) in favor ofAZD6244, with a median PFS of 50 days for those rando-mized to temozolomide [80%confidence interval (CI)¼ 43days, 83 days; 12 events/13 patients] and 114 days for thoserandomized to AZD6244 (80% CI ¼ 70 days, 202 days; 5events/7 patients). Insufficient numbers of patients havebeen treated thus far with AZD6244 to conclude a benefitover chemotherapy and to assess whether GNAQ/11 statusis predictive of response; however, these questions arecurrently being assessed in a randomized phase II trial oftemozolomide versus AZD6244 in patients with advanceduveal melanoma, with patients stratified by GNAQ/11

mutational status (Table 2). This study is powered to testthe hypothesis that AZD6244 will decrease the 4-monthprogression rate by 40% when compared with temozolo-mide in the GNAQ/11-mutant patient population that istemozolomide/dacarbazine (DTIC) na€�ve. This study willalso assess the efficacy of AZD6244 in temozolomide/DTICnaive patients regardless of genetic background, as well aspatients with tumor characterized by a GNAQ/11mutationwho have previously been treated with temozolomide/DTIC.

PI3K/AKT pathway. PI3K signaling is also implicated inuveal melanoma. PI3K is activated by G-protein–coupledreceptors and by receptor tyrosine kinases. Upon activa-tion, PI3K catalyzes the conversion of PIP2 to PIP3. PIP3mediates translocation of AKT (also known as proteinkinase B) to the cell membrane, where it is activated.AKT mediates several key proliferation and cell survivalpathways. PI3K signaling is antagonized by PTEN, a proteinthat stimulates conversion of PIP3 to PIP2, and thus,decreases AKT activation.

A relative decrease in PTEN expression in aggressiveprimary uveal melanomas compared with less aggressivetumors was previously reported, with either decreased orcomplete loss of PTEN expression as measured by immu-nohistochemistry observed in 58.7% of cases evaluated(51). Loss of PTEN was associated with a less favorableprofile for patients presenting with primary uveal mela-noma, where patients with a total loss of PTEN have a

Table 2. Currently accruing clinical trials for advanced uveal melanoma

ClinicalTrials.govidentifier

Agent Phase Sponsor/study lead

NCT01034787 CP-675,206 II Alberta Health Services (Edmonton, Alberta, Canada)NCT00506142 Liposomal vincristine II Hana Biosciences, Inc. (South San Francisco, CA)NCT01143402 AZD6244 vs. temozolomide II Memorial Sloan-Kettering Cancer CenterNCT01200342 Genasense (Genta), carboplatin

and paclitaxelII MD Anderson Cancer Center (Houston, TX)

NCT00738361 Paclitaxel albumin-stabilizednanoparticle formulation

II Arthur G. James Cancer Hospital (Columbus, OH)

NCT00110123 i.v. vs. hepatic arterial infusionof fotemustine

III EORTC

NCT01217398 Temozolomide and bevacizumab II Institut Curie (Paris, France)NCT00313508 Vaccine therapy and autologous lymphocyte

infusion with or without fludarabineI/II H. Lee Moffitt Cancer Center (Tampa, FL)

NCT00471471 Multi-epitope peptide vaccine I University of Pittsburgh (Pittsburgh, PA)NCT01005472 Temozolomide and sunitinib I/II University of California, Los AngelesNCT00168870 Gemcitabine and treosulfan vs. treosulfan II Charite University (Berlin, Germany)NCT01200238 STA-9090 II Dana-Farber Cancer Institute (Boston, MA)NCT00421317 Imatinib II Centre Oscar Lambret (Lille, France)NCT01252251 SOM230 and RAD001 II Memorial Sloan-Kettering Cancer CenterPending IMC-A12 II MD Anderson Cancer Center

Abbreviations: EORTC, European Organization for Research and Treatment of Cancer.

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median survival of 60 months compared with more than120 months for patients with normal or nearly normalPTEN expression.

PI3K and AKT as therapeutic targets. Several uvealmelanoma cell lines exhibit PI3K activation (51–53). Afew of these cell lines exhibit submicroscopic chromosomaldeletions leading to loss of expression of PTEN, represent-ing one mechanism of pathway activation (51). Inhibitionof PI3K with LY294002 in uveal melanoma cell lines resultsin decreased proliferation that is observed even in cell linesharboring a BRAF mutation (53, 54). Although LY294002and the related nonreversible PI3K inhibitor wortmanninhave limited clinical utility due to their poor solubility andhigh toxicity, more tolerable PI3K inhibitors such as XL147are currently undergoing clinical investigation. In addition,inhibition of the PI3K/AKT pathway at the level of AKT iscurrently being investigated with agents such as perifosine,GSK2141795, GSK690693, and MK2206 now in clinicaltrials (Table 1).

mTOR as a therapeutic target. mTOR is a downstreameffector of the PI3K pathway that stimulates cell prolifera-tion through translational control of cell-cycle progressionregulators. There exist 2 structurally and functionally dis-tinct mTOR complexes: mTORC1 (mTOR complex 1,rapamycin sensitive) and mTORC2 (mTOR complex 2rapamycin insensitive; ref. 55). mTORC1 is activatedmainly via the PI3K pathway through AKT and the tuberoussclerosis complex (56). Activated AKT phosphorylatesTSC2, which leads to dissociation of the TSC1/TSC2 com-plex, thus inhibiting the ability of TSC2 to act as a GTPaseactivating protein. This allows Rheb, a small G-protein, toremain in a GTP-bound state and activate mTORC1. AKTcan also activate mTORC1 by PRAS40 phosphorylation,thereby relieving the PRAS40-mediated inhibition ofmTORC1 (57, 58).

Several mTOR inhibitors, including everolimus and tem-sirolimus, are being evaluated in clinical trials for mela-noma, and a new class of compounds targeting bothTORC1 and TORC2 complexes is also under investigationfor advanced cancers (Table 1). No significant single-agentactivity has thus far been shown in melanoma (59). Ofsignificant clinical relevance, treatment of uveal melanomacell lines with the mTOR inhibitor rapamycin at levels thatinhibit downstream mTOR signaling by 100% results inonly 9% to 21% inhibition of cell proliferation (53). Thisphenomenon is explained, in part, by the finding thatmTOR inhibition induces AKT activation through loss ofthe mTOR pathway–dependent inhibition of IGF-1Rsignaling (discussed in more detail below; refs. 60, 61).IGF-1R blockade abrogates mTOR inhibition–mediatedAKT activation and confers sensitivity to mTOR inhibitionin cancer cells (60). Thus, IGF-1R–mediated feedback acti-vation of PI3K signaling appears to confer resistance tomTOR inhibitors, and mTOR inhibition alone is likelyinsufficient for the successful treatment of uveal mela-noma. Interestingly, it has been shown that activation ofAKT due to mTOR blockade can be inhibited in vitro bypretreatment with an IGF-1R antibody (61, 62), suggesting

that combination therapy targeting both mTOR and theIGF-1R pathway may produce more favorable results thanthose of mTOR inhibition alone.

Therapeutic targets upstream of the MAPK and PI3K/AKTpathways. Preclinical data show that simultaneous inhi-bition of both the MAPK and PI3K/AKT pathways result inthe synergistic inhibition of cell proliferation (53), suggest-ing that dual-pathway inhibition may be necessary for theoptimal management of uveal melanoma. Such inhibitionmay be achieved by combining 2 or more inhibitorstargeting components of both pathways. Alternatively, asseveral key cell-surface receptors activate both pathwayssimultaneously, effective inhibition of such receptors mayserve as an alternative therapeutic strategy.

KIT as a therapeutic target. A member of the PDGFRfamily of kinases, KIT is a receptor tyrosine kinase thatmediates growth differentiation, as well as attachment,migration, and proliferation of cells. Binding of the KITligand stem cell–derived factor (SCF) results in receptordimerization and autophosphorylation. Docking sites forseveral Src homology-2 signaling proteins such as thosemediating PI3K, MAPK, and JAK/STAT pathway activationare subsequently revealed.

KIT expression has been identified in up to 87% ofprimary uveal melanomas by immunohistochemistry;however, less than 40% exhibit strong staining (63–65).Uveal melanoma cell lines as well as normal uveal mela-nocytes produce SCF; however, only uveal melanoma celllines secrete SCF, suggesting the presence of a relevantautocrine loop in the setting of malignancy (66). Stimula-tion of normal uveal melanocytes with SCF results inactivation of both ERK1/2 and AKT; however, in a KITexpressing uveal melanoma cell line, stimulation led toMAPK pathway activation only (65). Inhibition of KIT,using both imatinibmesylate, a small molecule inhibitor ofseveral receptor tyrosine kinases, including ABL (c-abloncogene 1), KIT, and PDGFR, as well as siRNA techniques,leads to a reduction in proliferation of uveal melanoma celllines expressing the target. This effect was not observed inKIT negative cell lines or in normal uveal melanocytes (63,65, 66). Treatment with imatinib abrogates both the MAPKand PI3K/AKT pathways in normal uveal melanocytes. InKIT expressing uveal melanoma, treatment with imatinibdecreased the SCF-induced MAPK activation and resultedin decreased invasion by uveal cell melanoma lines asdetermined by penetration through a Matrigel-coatedmembrane (65). Interestingly, inhibition of MEK in theuveal melanoma cell line using UO126 decreased SCF-induced cell proliferation by 92% to 98%, but AKT inhibi-tion had no significant effect, suggesting that the prolif-erative effects of the SCF/KIT autocrine loop in uvealmelanoma likely funnel primarily through the MAPK path-way (66).

There are currently several clinical trials investigatingvarious KIT inhibitors, including imatinib, nilotinib, anddasatinib, in patients with advanced melanoma (Table 1).Despite promising preclinical data, results observed inpatients with uveal melanoma treated on these studies

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have been underwhelming (67). In a phase II study ofimatinib in 13 patients with uveal melanoma metastatic tothe liver, 1 patient achieved stable disease for 5 months;however, no objective responses were observed (68). In aphase II study of sunitinib, a tyrosine kinase inhibitor ofc-kit, PDGFR, VEGF receptor, and fms-related tyrosinekinase 3 (FLT-3), of 18 evaluable patients with advanceduveal melanoma, 1 patient achieved a partial response and12 achieved stable disease (69). The median overall andPFS durations were 8.2 months and 4.0 months, respec-tively. Because the lack of the response observed in thesestudies might reflect treatment of patients with absent orvery low KIT expression, Hoffman and colleagues hypothe-sized that more consistent responses might be achieved in apatient population with high tumor expression levels;however, in another study of 12 patients with metastaticuveal melanoma characterized by high KIT expression byimmunohistochemistry treated with imatinib, no signifi-cant responses were observed (70).The results observed in these clinical trials are disap-

pointing but consistent with what has been observed intrials of KIT inhibition in cutaneousmelanoma. The "onco-gene addiction" hypothesis is based upon the hypothesisthat tumorigenesis is dependent upon dysregulation of agene or gene product. Protein expression is not indicative ofsuch dysregulation in all cases and cannot be reliably usedto guide drug development. Indeed, no difference in sur-vival is observed between patients with uveal melanomacharacterized by high KIT expression and those with diseasecharacterized by low KIT expression (63). Rather thansimple expression, activation of KIT via a mutation oramplification may be required to connote sensitivity toKIT inhibition as has been observed in tumors such asgastrointestinal stromal tumors and, more recently, inmelanoma (71). Although such alterations have beenassociated with melanomas arising from acral, mucosal,and chronically sun-damaged surfaces (72, 73), thus far, noactivating mutations have been identified in primary uvealmelanoma samples (63, 64, 70).IGF-1R as a therapeutic target. The IGF signaling path-

way is implicated in both MAPK and PI3K signaling andappears to play a role in cell–cell adhesion as well as tumorinvasiveness (74, 75). IGF-1 binds IGF-1R, leading toactivation of the intrinsic receptor tyrosine kinase activityand phosphorylation of insulin receptor substrate (IRS).IGF-1R is expressed on primary uveal melanomas (76).Although melanoma cells do not secrete or express IGF-1(76), this ligand is produced by the liver, the predominantmetastatic site in uveal melanoma. It has been shown thatinhibition of IGF-1R in uveal melanoma cell lines results indecreased proliferation (77, 78), and the IGF-1 signalingaxis is implicated, not only in proliferation of uveal mel-anoma cells, but also in their metastatic potential (79, 80).In a study of 36 patients with uveal melanoma, 10 of 18

patients (56%) who died of advanced disease bore tumorswith high IGF-1R expression. In contrast, only 5 of 18patients (28%) who survived more than 15 years followingprimary surgical enucleation had tumors with high levels of

IGR-1R expression (77). This association between IGF-1Rexpression and melanoma-specific mortality was also sug-gested in a subsequent study of 132 patients with uvealmelanoma, in which 24 of 42 patients (57%) with highexpression of IGF-1R died of metastatic disease, whereasonly 31 of 90 patients (34%) succumbed to metastaticuveal melanoma (80).

Treatmentofuvealmelanomacell lineswithPPP,a specificinhibitor of IGF-1R, results in decreased IGF-1R expression,decreased IGF-1R phosphorylation, decreased downstreamMAPK and PI3K signaling, and a 60% to 90%decrease in cellsurvival (81,82).PPPhasa lower IC50 inuvealmelanomacelllines when compared with cisplatin, 5-fluorouracil, anddoxorubicin, and has variable synergistic effects when usedwith chemotherapy. In vivo xenograft studies using a uvealmelanoma cell line in severe combined immunodeficient(SCID) mice showed that intraperitoneal, intravitreal, andoral treatment with PPP leads to tumor regression, decreasedliver micrometastases, decreased IGF-1R phosphorylation,decreased PI3K and MAPK signaling, decreased MMP-2expression, and increased apoptosis in tumor cells (81,83). Interestingly, xenografts lacking IGF-1R exhibit no suchresponse to PPP (82).

To date, there are several monoclonal antibodies andsmall molecule agents targeting IGF-1R in clinical devel-opment for advanced solid cancers. Several of these agentsare being combined with agents targeting mTOR in aneffort to overcome the feedback disinhibition observedwith mTOR blockade alone discussed above (Table 1).Whether such a therapeutic strategy will be effective inuveal melanoma will be addressed in an upcoming phase IIstudy of IMC-A12, the anti-IGF-1R monoclonal antibody,in patients with this disease (Table 2).

IGF-1 as a therapeutic target. An alternative strategy todirectly targeting IGF-1R for the inhibition of the IGFpathway is suppression of the ligand, IGF-1. Basal serumIGF-1 levels have been associated with locally advanceddisease as well as the development of liver metastases (84).

Octreotide is a somatostatin analogue that binds primar-ily to somatostatin receptor subtype sst2 and has beenshown to suppress IGF-1 plasma levels in patients withsolid tumors (85, 86). Octreotide has been further shownto decrease tyrosine phosphorylation levels of p85, thePI3K regulatory subunit, leading to dephosphorylationof phosphoinositide-dependent kinase 1 (PDK1) andAKT, without affecting PTEN, total PDK1 levels, or totalAKT levels (87–89). Pasireotide (SOM230) is a novel,multireceptor, somatostatin analogue that binds withnanomolar affinity to somatostatin receptor subtypessst1, sst2, sst3, and sst5, and potently suppresses growthhormone (GH) IGF-1, and adrenocorticotropin secretion(90). Pasireotide has been shown to significantly suppressIGF-1 plasma levels to a greater extent than that achievedwith octreotide. Administration of pasireotide in dosages of1 and 10 mg/kg/h to male Lewis rats significantly decreasedplasma IGF-1 levels by 68% and 98%, respectively, onday 2 of therapy (91–93). This suppression was achievedprimarily via the reduction of pituitary GH secretion,

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although peripheral inhibitory effects of pasireotide onIGF-1 action have been shown as well (94).

In addition to affecting IGF-1 plasma levels, both octreo-tide and pasireotide may have direct effects upon uvealmelanoma cells, as somatostatin receptors are known to beexpressed on melanoma cells. One study showed that 96%of cutaneous melanomas tested expressed the somatostatinreceptor sst1, 83% expressed sst2, 61% expressed sst3, 57%expressed sst4, and 9% expressed sst5 (95). Of 25 clinicaluveal melanoma samples tested, all showed expression ofsst2, 7 (28%) expressed sst3, and 14 (56%) expressed sst5(96). Interestingly, octreotide or vapreotide showed dose-dependent inhibitory effects on cell proliferation in 3 uvealmelanoma cell lines (OMM2.3, OCM3, andMel270) tested(96).

The combination of the mTOR inhibitor RAD001 withpasireotide is being tested in an ongoing phase I trial, andthe recommended phase II dose has been identified. Aphase II study of this combination testing the hypothesisthat mTOR inhibition in combination with inhibition ofthe IGF-1R pathway is an effective therapy for uveal mel-anoma is ongoing (Table 2).

c-MET as a therapeutic target. The c-MET proto-onco-gene encodes a tyrosine kinase receptor responsible forbiological functions as diverse as cell motility, proliferation,and survival (97–100). Hepatocyte growth factor/scatterfactor (HGF) is a plasminogen-like protein that acts as theendogenous ligand for this receptor, binding of which leadsto autophosphorylation of tyrosine residues within thereceptor’s activation loop,activationofkinaseandphosphor-ylation of additional tyrosine residues adjacent to the car-boxyl terminus, which form a docking site for intracellularadaptors of downstream signaling (97, 100, 101). Signalingin this pathway is primarily mediated by Grb2, PI3K Src,Gab1, STAT3, PLCg , Shc, Shp2, and Shp1 (100).

HGF acts as a mitogen to melanocytes, and c-MET over-expression correlates with the invasive growth phase ofmelanoma (102). Melanoma cells, but not melanocytes,express HGF, leading to a potential autocrine positivefeedback loop in the development of melanoma (102).Although uveal melanomas overexpress c-MET, activatingmutations or genetic amplifications of c-MET do notappear to play a significant role in this disease (103).Hendrix and colleagues first reported in 1998 the expres-sion of c-MET by the more invasive interconverted pheno-type of uveal melanoma cell lines, and subsequentlyshowed a mitogenic response to HGF by c-Met expressingcells, but not by those who failed to express c-Met (104).Cell migration capacity appears to be enhanced by HGF viaactivation of phospho-AKT and the downregulation of thecell adhesion molecules e-cadherin and beta-catenin in adose-dependent fashion (105). Both c-MET inhibition andAKT inhibition independently inhibited the downregula-tion of adhesion molecules by HGF and completely abol-ished the migration of these 2 cell lines, suggesting thatactivation of p-AKT via the HGF/c-MET axis is involved inHCF-induced uveal melanoma cell migration (105, 106).c-MET blockade using the small molecule SU11274

significantly inhibited both cell proliferation and migra-tion in all uveal melanoma cell lines tested (103).

HGF and its receptor tyrosine kinase c-Met play essentialroles in the processes of liver embryogenesis and in hepaticregeneration following injury in the adult state, emphasiz-ing their role as bothmorphogen andmitogen for this organ(98, 106). Because uveal melanoma metastases preferen-tially involve the liver, the question arises as to whetherlocal factorswithin the hepatic environment such asHGForIGF-1 are responsible for the dominant pattern of metas-tases seenat this site, andwhether inhibitionof this pathwaycould decrease the risk of developing metastatic disease(107). In a series of 60 patients with resected uveal mela-noma, higher levels of c-MET expression were associatedwith a significantly higher risk of death from metastaticdisease (79); however, another series of 132 patients withuvealmelanoma showed that, whereas expressionof both c-MET and IGF-1R was predictive of poor prognosis in uni-variate analysis, the presence of c-MET alone was not pre-dictive for decreased overall survival (108).

Work further exploring the role of c-MET in the patho-genesis of uveal melanoma is ongoing. Although there isgreat interest in targeting the HGF/c-MET pathway for thetreatment of this disease, with a number of relevant agentscurrently in clinical development (Table 1), the efficacy ofthis strategy remains to be determined.

Emerging insights into the biology of advanced uvealmelanoma. As discussed in the Introduction section, priorstudies indicate that uveal melanomas segregate into 2tumor classes based upon microarray gene expressionprofiles. Class I tumors have low rates of metastasis,whereas class II tumors are more aggressive and associatedwith a higher rate of death frommetastatic disease (12–15).Harbour and colleagues interrogated a sample of 31 class IIuveal melanomametastatic samples and identified an 84%incidence of somatic mutations in the ubiquitin carboxy-terminal hydrolase breast cancer 1, early onset (BRCA1)-associated protein-1 (BAP1; ref. 109), a component of theubiquitin proteasome system that has been implicated incancers such as lung, breast, and renal cell carcinoma (110–113). BAP1 is a deubiquinating enzyme that interacts withthe breast cancer susceptibility gene, BRCA1, via its RINGfinger domain, but does not appear to function as adeubiquinator of BRCA (114, 115). Unlike other membersof the ubiquitin carboxyl hydrolase family, BAP1 possessesa large C-terminal domain which is predicted to coordinatethe selective association with potential substrates or reg-ulatory components (116). BAP1 participates in the assem-bly of multiprotein complexes containing numeroustranscription factors and cofactors, and activates transcrip-tion in an enzymatic-activity–dependent manner, therebyregulating the expression of a variety of genes involved invarious cellular processes (117).

Mutations, deletions, and rearrangements of BAP1 onchromosome 3p21.3 have been detected in lung and lungcancer cell lines, and in sporadic breast tumors (114, 118).Depletion of BAP1 resulted in an altered expression of 249genes, including key mediators of cell-cycle progression,

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DNA replication and repair, cell metabolism, survival, andapoptosis (117). BAP1 has tumor suppressor activity bothin vitro and in vivo (119, 120). Expression of wild-type BAP1significantly abolished tumorigenicity of a human non–small cell lung cancer cell line in nude mice, whereasexpression of mutant BAP1 that lacks either deubiquitinat-ing activity or nuclear localization did not suppress tumor-igenicity, implying that both deubiquinating activity andnuclear localization are necessary for the tumor-suppres-sive activity (119). Suppression of BAP1 by RNA interfer-ence has also been shown to inhibit cellular proliferation(120–122).Microarray analysis comparing 92.1 uveal melanoma

cells characterized by a wild-type BAP1 transfected witheither control or BAP1 siRNA indicated that the geneexpression profile of the BAP1 siRNA–treated cells shiftedtoward a class II tumor profile versus the class I profileobserved in the control-treated cells, indicating a domi-nant role for BAP1 in the regulation of expression of thesegenes (109). mRNA levels of CDH1 and c-Kit wereincreased, whereas those for ROBO1, a neural crest dif-ferentiation gene, and the melanocyte differentiationgenes CTNNb1, EDNRB, and SOX10 were downregulated.More work is required to elucidate the molecular mechan-isms governing the function of BAP1 in uveal melanoma

and to assess potential treatment strategies derived fromthese studies.

SummaryBecause there are no effective systemic therapies for uveal

melanoma, prognosis after the development of metastaticdisease remains dismal. Recent studies have brought tolight several key signaling cascades that are implicated inthe development and progression of uveal melanoma,some of which serve as potential therapeutic targets. It isbecoming increasingly clear that, like many cancers, uvealmelanomas comprise a heterogenous group of diseases,each with distinct molecular features. Each molecular sub-type may have unique clinical characteristics and mayrespond best to a specific therapeutic strategy. The identi-fication of effective therapies for uveal melanoma willdepend upon our ability to develop clinical trials with thispossibility in mind.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Received November 29, 2010; revised February 4, 2011; acceptedFebruary 7, 2011; published OnlineFirst March 28, 2011.

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