Therapeutic Implications of the Emerging Molecular Biology of … · 2011. 3. 25. · Therapeutic...

Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma

Mrinali Patel MD1, Elizabeth Smyth MD1, Paul B. Chapman MD,1 Jedd D. Wolchok MD

PhD,1 Gary K Schwartz, MD1, David H Abramson, MD2, Richard D Carvajal, MD1

Departments of Medicine1 and Surgery2, Memorial Sloan-Kettering Cancer Center, New

York, NY, USA

**Mrinali Patel MD and Elizabeth Smyth MD contributed equally to this manuscript.

Corresponding Author:

Richard D. Carvajal, MD

1275 York Avenue

New York, NY 10065

Tel: 212-639-5096

Fax: 212-717-3342

Email: [email protected]

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Statement of Translational Relevance

Uveal melanoma is a unique clinical and molecular subtype of melanoma that has no

known effective therapy in the metastatic setting. Significant advances in our

understanding of the biology of this disease, combined with the growing availability of

agents which can be used to rationally target these findings, have led to the

development of a number of clinical trials testing various treatment strategies for

advanced disease. Herein, we present an overview of the current knowledge of the

molecular biology of uveal melanoma, with particular attention paid to tumor specific

aberrations which can be exploited for therapeutic benefit. We discuss the pathogenic

roles of GNAQ/11, PTEN, IGF/IGF1R, MET, BAP1, and other key molecules, review

potential therapeutic strategies, and review the next generation of recently initiated

clinical trials for the treatment of advanced uveal melanoma.




Abstract

Uveal melanoma represents the most common primary intraocular malignancy in adults.

Although uveal and cutaneous melanoma both arise from melanocytes, uveal

melanoma is clinically and biologically 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/11, PTEN, IGF/IGF1R, MET, BAP1, 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.




Introduction

Although uveal melanoma represents only 5% of all melanomas, this disease is the

most common primary intraocular malignancy of the adult eye, affecting six individuals

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 prognosis, 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 two tumor

classes by risk of metastasis (12-15). Class I tumors appear to have a low-risk of

metastasis while class II tumors are more aggressive, correspond with monosomy in

chromosome 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

chemotherapy, hepatic embolization, metastastectomy, and others, have been used to

treat patients with metastatic uveal melanoma. However, a recent meta-analysis

demonstrated no compelling evidence that these interventions confer any survival

benefit (23). Although a recently completed phase III trial which randomized 93 patients

with hepatic metastases from uveal (n = 82) or cutaneous (n = 11) melanoma to

percutaneous hepatic perfusion with melphalan to standard of care met its primary

endpoint of hepatic progression-free survival, 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 melanoma,




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 demonstrated a 22% five

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 underwent

complete surgical metastatectomy. Factors relating to improved outcomes included

female gender, age younger than sixty, longer time from treatment for the primary uveal

melanoma to the development of metastases, surgical resection of metastases, and

lung or soft tissue as sole site of metastasis.

Given these unsatisfactory outcomes, there is a compelling need for novel and effective

therapeutic strategies for the management of metastatic uveal melanoma. As current

treatment for localized disease often leads to visual loss, whether due to enucleation or

the local effects of radiation within the eye, the identification of active pharmacologic

agents may obviate the necessity for these locally destructive therapies. Innovation in

pharmacotherapy depends largely upon elucidating the molecular mechanisms

underlying uveal melanoma pathogenesis. 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

recent developments in our understanding of the pathogenesis of uveal melanoma, as

well as the associated potential therapeutic implications.

I. MAPK Pathway

Eighty-six percent of primary uveal melanoma tissue exhibits activation of the mitogen-

activated protein kinase (MAPK) pathway (25). In this signaling pathway, ligand binding

to cell surface tyrosine kinase receptors leads to exchange of GDP for GTP on Ras.

Activated in its GTP-bound state, Ras activates Raf, which subsequently activates

MAPK/extracellular signal-related kinase kinase (MEK). MEK phosphorylates and

activates extracellular signal-related kinase (ERK), which dimerizes and translocates to




the nucleus, where it mediates cell proliferation, survival, differentiation, and apoptosis.

Preclinical studies demonstrate that inhibition of the MAPK pathway in uveal melanoma

cell lines results in decreased cell proliferation (26, 27), suggesting that several key

molecules in this pathway, including BRAF, GNAQ/11, and MEK, may serve as potential

therapeutic targets.

BRAF as a Therapeutic Target. Cutaneous and uveal melanomas differ in many

ways, including pattern of spread and responsiveness to chemotherapy; however, given

their common melanocytic origin and the significantly larger body of knowledge about

cutaneous melanoma, observations made in cutaneous melanoma have served to

guide investigation into the molecular biology of uveal melanoma. BRAF has been

shown to be of great significance in cutaneous melanoma, with up to 62% of cases

harboring activating mutations in BRAF (28). Ninety-five percent of such cases result in

a V600E mutation which involves a valine to glutamic acid substitution at position 600.

Based upon these findings in cutaneous melanoma, several groups have investigated

the mutational status of BRAF in primary uveal melanomas (29-32), as well as in liver

metastases of uveal melanoma (25). These studies have been overwhelmingly

negative, with only one case harboring a BRAF V600E mutation (30). Several groups,

however, have posited that uveal melanoma exhibits significant intra-tumoral

heterogeneity and that conventional PCR techniques are insufficiently sensitive to

identify BRAF mutations that may be present in a small subset of cells within a tumor.

Using nested PCR and pyrophosphorylysis-activated polymerization techniques, these

groups demonstrated that subsets of tumor tissue, but not the entire tumor, harbor a

BRAF mutation (33, 34). This observation, in part, may explain the identification of

several uveal melanoma cell lines that harbor a BRAF mutation (29, 33, 35-37).

Interestingly, Calipel et al. demonstrated that uveal melanoma cell lines exhibit similar

MAPK pathway activation and proliferation regardless of BRAF mutational status,

indicating that other mechanisms of MAPK pathway activation are present in uveal

melanoma (35).




Preclinical studies have demonstrated that sorafenib, a small molecule inhibitor of the

Raf family of kinases, PDGFR-β, VEGFR-2 and -3, and KIT, inhibits MAPK signaling

and decreases proliferation, even in BRAF wild-type cell lines. Interestingly, studies of

PLX4270, an inhibitor with relative selectivity for V600E BRAF, in uveal melanoma cell

lines demonstrated that only the BRAF mutant lines exhibited decreased cell viability

with therapy, while no effect was observed in the wild-type cells (unpublished data).

This is consistent with recent data indicating that effective RAF inhibition in BRAF wild-

type cells may activate rather than inhibit MAPK pathway signaling (38-40), and that,

although both BRAF mutant and wild-type uveal melanomas may require MAPK

signaling for growth, inhibition of this pathway likely has different consequences

depending upon the genetic background 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 in

melanoma (Table 1). Several of these have enrolled patients with uveal melanoma, and

one trial of the combination of carboplatin, paclitaxel, and sorafenib is specifically

enrolling patients with ocular melanoma. The ongoing phase I study of XL281 in

patients with advanced solid tumors included 1 patient with uveal melanoma who

achieved a confirmed partial response lasting 4 months (41). It will be critical to

carefully assess any clinical benefit observed in patients treated on these trials in

relationship to tumor mutational status to optimally assess the role and future of BRAF

inhibition as a therapeutic strategy for the treatment of uveal melanoma.

GNAQ/11 as Therapeutic Targets. Despite the absence of BRAF mutations, 86% of

primary uveal melanomas exhibit activation of the MAPK pathway as evidenced by

activation of phospho-ERK.(26-32) In cutaneous melanoma, MAPK pathway activation

has also shown to be mediated by mutations in NRAS (42); however, these mutations

have not been found in uveal melanoma (29). Thus, while uveal melanoma, like

cutaneous melanoma, is characterized by MAPK activation, the mechanism of MAPK

activation differs between these two unique subtypes of melanoma.




Recent studies have identified G-proteins as potential drivers of MAPK activation in

uveal melanoma. Genetic screens have demonstrated that 46% to 53% of uveal

melanoma exhibit mutations in GNAQ (26, 43-45). These mutations are not associated

with clinical, pathological, immunohistochemical, or genetic factors associated with

advanced uveal melanoma, indicating that this alteration may represent an early event

in disease pathogenesis (43). Recent data suggest that over half of uveal melanomas

lacking a mutation in GNAQ exhibit a mutation in GNA11 (44). GNAQ is a q class G-

protein α-subunit. G proteins are a family of heterotrimeric proteins (Gαβγ) coupled to

cell surface, seven-transmembrane spanning receptors. Upon ligand binding to these

receptors, the GDP bound to the Gα subunit of Gαβγ is exchanged for GTP, resulting in

a conformational change and the subsequent dissociation of the Gα from the Gβγ

subunits. These two subunits are then able to regulate various second messengers.

Gα activation is terminated by a GTPase intrinsic to the Gα subunit. The q class Gα

(Gqα) mediates its activity through stimulation of phospholipase Cβ, which cleaves

phosphatidylinositol 4,5-bisphosphate (PIP2) to inosol triphosphate (IP3) and diacyl

glycerol (DAG). DAG goes on to activate protein kinase C, which ultimately activates

downstream pathways including the MAPK signaling pathway.

Van Raamsdonk et al. demonstrated that transfection of GNAQ Q209L in human

melanocytes results in anchorage-independent growth, with cells able to grow in the

absence of the DAG analog 12-O-tetradeconoyl phorbol-13-acetate, presumably due to

high levels of DAG production by constitutively activated phospholipase Cβ. GNAQ

Q290L transfected melanocytes have increased ERK activation, as compared to

melanocytes with wild-type GNAQ. Interestingly, small interfering RNA (siRNA)

targeting Gnaq normalizes phospho-ERK levels, increases the number of resting cells,

decreases cell number, and decreases anchorage-independent growth. Injection of

nude mice with melanocytes harboring GNAQ Q209L, but not wild-type GNAQ

melanocytes, leads to the development of pigmented tumors at the injection site (26).

GNA11 has similarly been validated as an oncogene that results in MAPK activation,

comparable to that achieved with GNAQ (44).




The somatic GNAQ exon 5 Q209L and Q209P mutations most commonly identified lead

to a glutamine to lysine and glutamine to proline substitution, respectively, at position

209, which lies in the Ras-like domain of GNAQ. The GNA11 exon 5 mutation most

commonly observed results in a Q209L substitution that is analogous to the Q209L

substitution observed in GNAQ. Mutations at this site cause loss of the intrinsic

GTPase activity, similar to that seen in Ras family members (46). Since Gα inactivation

is mediated by this intrinsic GTPase, such mutations lead to constitutive Gα activation

and downstream signaling. Exon 4 mutations in GNAQ and GNA11 have also been

identified in 4.8% of uveal melanomas that lead to alterations at arginine 183 (R183)

(44). In all but one of the tumors tested, exon 5 Q209 and exon 4 R183 mutations were

mutually exclusive. Interestingly, tumors characterized by these mutations display

distinct biologic activity. Injection of GNA11 Q209L transfected melanoma cells in

immunocompromised mice produced rapidly growing tumors at all injection sites,

whereas injection of R183C transfected cells produced tumor growth at only one half of

injection sites with a longer latent period. Furthermore, while all mice injected with the

GNA11 Q209L variant developed visceral metastases, this was not observed with

melan-a cells transfected with GNAQ Q209L, supporting the hypothesis that GNA11

Q209 mutations are more oncogenic than the GNAQ Q209 variant. Indeed, a recent

study demonstrated an inverse relationship of the frequency of GNAQ mutations and

GNA11 mutations when comparing blue nevi, uveal melanoma, and uveal melanoma

metastases. While GNA11 mutations were observed in 7% of blue nevi, 32% of uveal

melanoma, and 57% of uveal melanoma metastases, GNAQ mutations were present in

55% of blue nevi, 45% of uveal melanoma and 22% of uveal melanoma metastases.

This also suggests that mutations in GNA11 connote a greater risk of distant metastasis

in uveal melanoma than GNAQ mutations.

Thus, in vitro and in vivo studies support the hypothesis that GNAQ/11 mutations result

in MAPK activation and play an essential role in the development of uveal melanomas.

There is currently significant interest in investigating inhibition of the GNAQ/11 pathway

for the treatment of uveal melanoma; however, whether inhibition of this pathway will be

an effective strategy is yet to be determined. Importantly, it is also not known whether




pathway inhibition at the level of GNAQ/11 or further downstream will be optimal.

Currently, there are no clinically available specific inhibitors of GNAQ/11, phospholipase

Cβ or the various PKC isoforms with which to investigate these critical questions.

MEK as a Therapeutic Target. An alternative therapeutic strategy for these patients

is the targeting, not of GNAQ/11, but rather of the downstream effector MEK. Treatment

of uveal melanoma cell lines bearing GNAQ mutations with U0126, a small molecule

inhibitor of MEK, leads to a decrease in phospho-ERK and cell number, a loss of

anchorage-independent growth, and an increase in the sub-G0/G1 subpopulation.

Moreover, in these cell lines, U0126 results in lower cell numbers than siRNA-mediated

knockdown of GNAQ, suggesting that targeting the downstream target MEK may be

more effective than inhibiting GNAQ itself (26). Additional in vitro studies indicate that

uveal melanoma cell lines bearing the GNAQ Q209L mutation are sensitive to MEK

inhibition with AZD6244, another potent, selective, orally-available, and non-ATP

competitive small molecule inhibitor of MEK1/2 (47). MEK inhibition in these cells is

associated with decreased signaling through both the MAPK and PI3K pathways, as

demonstrated by inhibition of phospho-ERK and phospho-AKT. Although these effects

are not observed in cells wild-type for GNAQ or BRAF, transfection of GNAQ wild-type

cell lines resistant to AZD6244 with GNAQ Q209L leads to the induction of sensitivity to

AZD6244 in terms of both ERK inhibition and decreased proliferation.

We have observed clinical efficacy of MEK inhibition in subset analysis of patients with

metastatic uveal melanoma treated with AZD6244 on 3 completed trials (48-50). On a

randomized phase II study of AZD6244 versus temozolomide for patients with

melanoma, of the 20 patients with uveal melanoma, 17 received AZD6244 during the

study: 7 received AZD6244 upfront while 10 received AZD6244 following progression

on temozolomide (49). The progression-free survival (PFS) hazard ratio (HR) was 0.76

(80% CI, 0.38 - 1.53) in favor of AZD6244, with a median PFS of 50 days for those

randomized to temozolomide (80%CI = 43 days, 83 days; 12 events/13 patients) and

114 days for those randomized to AZD6244 (80%CI = 70 days, 202 days; 5 events/7

patients). Insufficient numbers of patients have been treated thus far with AZD6244 to




conclude a benefit over chemotherapy and to assess whether GNAQ/11 status is

predictive of response; however, these questions are currently being assessed in a

randomized phase II trial of temozolomide versus AZD6244 in patients with advanced

uveal melanoma, with patients stratified by GNAQ/11 mutational status (Table 2). This

study is powered to test the hypothesis that AZD6244 will decrease the 4 month

progression rate by 40% when compared with temozolomide in the GNAQ/11 mutant

patient population who are temozolomide/DTIC naive. This study will also assess the

efficacy of AZD6244 in temozolomide/DTIC naive patients regardless of genetic

background, as well as patients with tumor characterized by a GNAQ/11 mutation who

have previously been treated with temozolomide/DTIC.

II. PI3K/Akt Pathway

Phosphoinositide 3-kinase (PI3K) signaling is also implicated in uveal melanoma. PI3K

is activated by G-protein coupled receptors and by receptor tyrosine kinases. Upon

activation, PI3K catalyzes the conversion of phosphatidylinisotol (3,4)-bisphosphate

(PIP2) to phosphatidylinositol(3,4,5)-triphosphate (PIP3). PIP3 mediates translocation

of Akt (also known as protein kinase B) to the cell membrane, where it is activated. Akt

mediates several key proliferation and cell survival pathways. PI3K signaling is

antagonized by phosphatase and tensin homolog (PTEN), a protein that stimulates

conversion of PIP3 to PIP2, and, thus, decreases Akt activation.

A relative decrease in PTEN expression in aggressive primary uveal melanomas

compared with less aggressive tumors was previously reported, with either decreased

or complete loss of PTEN expression as measured by immunohistochemistry observed

in 58.7% of cases evaluated (51). Loss of PTEN was associated with a less favorable

profile for patients presenting with primary uveal melanoma, where patients with a total

loss of PTEN have a median survival of 60 months compared with more than 120

months for patients with normal or nearly normal PTEN expression.

PI3K and Akt as Therapeutic Targets. Several uveal melanoma cell lines exhibit PI3K

activation (51-53). A few of these cell lines exhibit submicroscopic chromosomal




deletions leading to loss of expression of PTEN, representing one mechanism of

pathway activation (51). Inhibition of PI3K with LY294002 in uveal melanoma cell lines

results in decreased proliferation that is observed even in cell lines harboring a BRAF

mutation (53, 54). While LY294002 and the related nonreversible PI3K inhibitor

Wortmannin have limited clinical utility due to their poor solubility and high toxicity, more

tolerable PI3K inhibitors such as XL147 are currently undergoing clinical investigation.

In addition, inhibition of the PI3K/Akt pathway at the level of Akt is currently being

investigated with agents such as perifosine, GSK2141795, GSK690693, and MK2206

now in clinical trials (Table 1).

mTOR as a Therapeutic Target. Mammalian target of rapamycin (mTOR) is a

downstream effector of the PI3K pathway that stimulates cell proliferation through

translational control of cell cycle progression regulators. There exist two structurally

and functionally distinct mTOR complexes: mTORC1 (mTOR complex 1, rapamycin

sensitive) and mTORC2 (mTOR complex 2 rapamycin insensitive) (55). mTORC 1 is

activated mainly via the PI3K pathway through AKT and the tuberous sclerosis complex

(56). Activated AKT phosphorylates TSC2, which leads to dissociation of the

TSC1/TSC2 complex, thus inhibiting the ability of TSC2 to act as a GTPase activating

protein. This allows Rheb, a small G-protein, to remain in a GTP-bound state and

activate mTORC1. AKT can also activate mTORC1 by PRAS40 phosphorylation,

thereby relieving the PRAS40-mediated inhibition of mTORC1 (57, 58).

Several mTOR inhibitors, including everolimus and temsirolimus, are being evaluated in

clinical trials for melanoma, and a new class of compounds targeting both TORC1/2 is

also under investigation for advanced cancers (Table 1). No significant single agent

activity has thus far been demonstrated in melanoma (59). Of significant clinical

relevance, treatment of uveal melanoma cell lines with the mTOR inhibitor rapamycin at

levels that inhibit downstream mTOR signaling by 100% results in only 9% to 21%

inhibition of cell proliferation (53). This phenomenon is explained, in part, by the finding

that mTOR inhibition induces Akt activation through loss of the mTOR pathway-

dependent inhibition of insulin-like growth factor-1 receptor (IGF-1R) signaling




(discussed in greater detail below) (60, 61). IGF-1R blockade abrogates mTOR

inhibition-mediated Akt activation and confers sensitivity to mTOR inhibition in cancer

cells (60). Thus, IGF-1R-medated feedback activation of PI3K signaling appears to

confer resistance to mTOR inhibitors, and mTOR inhibition alone is likely insufficient for

the successful treatment of uveal melanoma. Interestingly, it has been demonstrated

that activation of Akt due to mTOR blockade can be inhibited in vitro by pretreatment

with an IGF-1R antibody (61, 62), suggesting that combination therapy targeting both

mTOR and the IGF-1R pathway may produce more favorable results than mTOR

inhibition alone.

III. Therapeutic Targets Upstream of the MAPK and PI3K/Akt Pathways

Preclinical data demonstrate that simultaneous inhibition of both the MAPK and

PI3K/Akt pathways result in the synergistic inhibition of cell proliferation (53), suggesting

that dual-pathway inhibition may be necessary for the optimal management of uveal

melanoma. Such inhibition may be achieved by combining two or more inhibitors

targeting components of both pathways. Alternatively, as several key cell-surface

receptors activate both pathways simultaneously, effective inhibition of such receptors

may serve as an alternative therapeutic strategy.

KIT as a Therapeutic Target. A member of the platelet derived growth factor receptor

(PDGFR) family of kinases, KIT is a receptor tyrosine kinase that mediates growth

differentiation, as well as attachment, migration, and proliferation of cells. Binding of the

KIT ligand stem cell-derived factor (SCF) results in receptor dimerization and

autophosphorylation. Docking sites for several Src homology-2 signaling proteins such

as those mediating PI3K, MAPK, and JAK/STAT pathway activation are subsequently

revealed.

KIT expression has been identified in up to 87% of primary uveal melanomas by

immunohistochemistry; however, less than 40% exhibit strong staining (63-65). Uveal

melanoma cell lines as well as normal uveal melanocytes produce SCF; however, only

uveal melanoma cell lines secrete SCF, suggesting the presence of a relevant autocrine




loop in the setting of malignancy (66). Stimulation of normal uveal melanocytes with

SCF results in activation of both ERK1/2 and Akt; however, in a KIT expressing uveal

melanoma cell line, stimulation led to MAPK pathway activation only (65). Inhibition of

KIT, using both imatinib mesylate, a small molecule inhibitor of several receptor tyrosine

kinases, including ABL, KIT, and PDGFR, as well as siRNA techniques, leads to a

reduction in proliferation of uveal melanoma cell lines expressing the target. This effect

was not observed in KIT negative cell lines or in normal uveal melanocytes (63, 65, 66).

Treatment with imatinib abrogates both the MAPK and PI3K/Akt pathways in normal

uveal melanocytes. In KIT expressing uveal melanoma, treatment with imatinib

decreased the SCF-induced MAPK activation and resulted in decreased invasion by

uveal cell melanoma lines as determined by penetration through a Matrigel-coated

membrane (65). Interestingly, inhibition of MEK in the uveal melanoma cell line using

UO126 decreased SCF-induced cell proliferation by 92% to 98%, but Akt inhibition had

no significant effect, suggesting that the proliferative effects of the SCF/KIT autocrine

loop in uveal melanoma likely funnel primarily through the MAPK pathway (66).

There are currently several clinical trials investigating various KIT inhibitors, including

imatinib, nilotinib, dasatinib, and others, in patients with advanced melanoma (Table 1).

Despite promising preclinical data, results observed in patients with uveal melanoma

treated on these studies have been underwhelming (67). In a phase II study of imatinib

in 13 patients with uveal melanoma metastatic to the liver, one patient achieved stable

disease for 5 months; however, no objective responses were observed (68). In a phase

II study of sunitinib, a tyrosine kinase inhibitor of c-kit, PDGFR, vascular endothelial

growth factor (VEGF) receptor, and fms-related tyrosine kinase 3 (FLT-3), of 18

evaluable patients with advanced uveal melanoma, one patient achieved a partial

response and 12 achieved stable disease (69). The median overall and progression-

free survivals were 8.2 months and 4.0 months, respectively. As the lack of the

response observed in these studies might reflect treatment of patients with absent or

very low KIT expression, Hoffman et al. hypothesized that more consistent responses

might be achieved in a patient population with high tumor expression levels; however, in

another study of 12 patients with metastatic uveal melanoma characterized by high KIT




expression by immunohistochemistry treated with imatinib, no significant responses

were observed (70).

The results observed in these clinical trials are disappointing but consistent with what

has been observed in trials of KIT inhibition in cutaneous melanoma. The “oncogene

addiction” hypothesis is based upon the hypothesis that tumorigenesis is dependent

upon dysregulation of a gene or gene product. Protein expression is not indicative of

such dysregulation in all cases and cannot be reliably used to guide drug development.

Indeed, no difference in survival is observed between patients with uveal melanoma

characterized by high KIT expression and those with disease characterized by low KIT

expression (63). Rather than simple expression, activation of KIT via a mutation or

amplification in may be required to connote sensitivity to KIT inhibition as has been

observed in tumors such as gastrointestinal stromal tumors and, more recently, in

melanoma (71). While such alterations have been associated with melanomas arising

from acral, mucosal, and chronically sun-damaged surfaces (72, 73), thus far, no

activating mutations have been identified in primary uveal melanoma samples (63, 64,

70).

IGF-1R as a Therapeutic Target. The insulin-like growth factor (IGF) signaling

pathway is implicated in both MAPK and PI3K signaling and appears to play a role in

cell-cell adhesion as well as tumor invasiveness (74, 75). IGF-1 binds IGF-1R, leading

to activation of the intrinsic receptor tyrosine kinase activity and 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 predominant metastatic site in uveal melanoma. It has been

demonstrated that inhibition of IGF-1R in uveal melanoma cell lines results in decreased

proliferation (77, 78), and the IGF-1 signaling axis is implicated, not only in proliferation

of uveal melanoma cells, but also in their metastatic potential (79, 80).

In a study of 36 patients with uveal melanoma, ten of 18 patients (56%) who died of

advanced disease bore tumors with high IGF-1R expression. In contrast, only five of 18




patients (28%) who survived more than fifteen years following primary surgical

enucleation had tumors with high levels of IGR-1R expression (77). This association

between IGF-IR expression and melanoma-specific mortality was also suggested in a

subsequent study of 132 patients with uveal melanoma, where 24 of 42 patients (57%)

with high expression of IGF-1R died of metastatic disease, while only 31 of 90 patients

(34%) succumbed to metastatic uveal melanoma (80).

Treatment of uveal melanoma cell lines with picropodophyllin (PPP), a specific inhibitor

of IGF-1R, results in decreased IGF-1R expression, decreased IGF-1R phosphorylation,

decreased downstream MAPK and PI3K signaling, and a 60% to 90% decrease in cell

survival (81, 82). PPP has a lower IC50 in uveal melanoma cell lines when compared

with cisplatin, 5-FU, and doxorubicin, and has variable synergistic effects when used

with chemotherapy. In vivo xenograft studies using a uveal melanoma cell line in SCID

mice demonstrated that intraperitoneal, intravitreal, and oral treatment with PPP leads

to tumor regression, decreased liver micrometastases, decreased IGF-1R

phosphorylation, decreased PI3K and MAPK signaling, decreased MMP-2 expression,

and increased apoptosis in tumor cells (81, 83). Interestingly, xenografts lacking IGF-

1R exhibit no such response to PPP (82).

To date, there are several monoclonal antibodies and small molecule agents targeting

IGF-1R in clinical development for advanced solid cancers. Several of these agents are

being combined with agents targeting mTOR in an effort to overcome the feedback dis-

inhibition observed with mTOR blockade alone discussed above (Table 1). Whether

such a therapeutic strategy will be effective in uveal melanoma will be addressed in an

upcoming phase II study 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 to directly targeting IGF-1R for

the inhibition of the IGF pathway is suppression of the ligand, IGF-1. Basal serum IGF-

1 levels have been associated with locally advanced disease as well as the

development of liver metastases (84).




Octreotide is a somatostatin analogue that binds primarily to somatostatin receptor

subtype sst2 and has been demonstrated to suppress IGF-I plasma levels in patients

with solid tumors (85, 86). Octreotide has been further demonstrated to decrease

tyrosine phosphorylation levels of p85, the PI3K regulatory subunit, leading to

dephosphorylation of phophosinositide-dependent kinase 1 (PDK1) and Akt, without

affecting PTEN, total PDK1 levels, or total Akt levels (87-89). Pasireotide (SOM230) is

a novel, multi-receptor, somatostatin analog that binds with nanomolar affinity to

somatostatin receptor subtypes sst1, sst2, sst3, and sst5, and potently suppresses GH,

IGF-I, and ACTH secretion (90). Pasireotide has been demonstrated to significantly

suppress IGF-I plasma levels to a greater extent than that achieved with octreotide.

Administration of pasireotide 1 µg/kg/h and 10 µg/kg/h to male Lewis rats significantly

decreased plasma IGF-1 levels by 68% and 98%, respectively, on day 2 of therapy (91-

93). This suppression is achieved primarily via the reduction of pituitary GH secretion,

although peripheral inhibitory effects of pasireotide on IGF-I action has been

demonstrated as well (94).

In addition to affecting IGF-1 plasma levels, both octreotide and pasireotide may have

direct affects upon uveal melanoma cells, as somatostatin receptors are known to be

expressed on melanoma cells. One study demonstrated that 96% of cutaneous

melanomas tested expressed the somatostatin receptor sst1, 83% expressed sst2, 61%

expressed sst3, 57% expressed sst4, and 9% expressed sst5 (95). Of 25 clinical uveal

melanoma samples tested, all demonstrated expression of sst2, 7 (28%) expressed

sst3, and 14 (56%) expressed sst5 (96). Interestingly, octreotide or vapreotide

demonstrated dose dependent inhibitory effects on cell proliferation in three uveal

melanoma cell lines (OMM2.3, OCM3 and Mel270) tested (96).

The combination of the mTOR inhibitor RAD001 with pasireotide is being tested in an

on-going phase I trial, and with the recommended phase II dose has been identified. A

phase II study of this combination testing the hypothesis that mTOR inhibition in




combination with inhibition of the IGF-1R pathway is an effective therapy for uveal

melanoma is on-going (Table 2).

c-MET as a Therapeutic Target. The c-MET proto-oncogene encodes a tyrosine

kinase receptor responsible for biological functions as diverse as cell motility,

proliferation and survival (97-100). Hepatocyte growth factor/scatter factor (HGF) is a

plasminogen-like protein which acts as the endogenous ligand for this receptor, binding

of which leads to autophosphorylation of tyrosine residues within the receptor’s

activation loop, activation of kinase activity, and to phosphorylation of additional tyrosine

residues adjacent to the carboxyl terminus which form a docking site for intracellular

adaptors of downstream signaling (97, 100, 101). Signaling in this pathway is primarily

mediated by Grb2, phosphatidylinositol 3-kinase (PI3K), Src, Gab1, STAT3,

phospholipase C-gamma (PLCγ), Shc, Shp2, and Shp1 (100).

HGF acts as a mitogen to melanocytes, and c-MET overexpression correlates with the

invasive growth phase of melanoma (102). Melanoma cells, but not melanocytes,

express HGF, leading to a potential autocrine positive feedback loop in the development

of melanoma (102). Although uveal melanomas overexpress c-MET, activating

mutations or genetic amplifications of c-MET do not appear to play a significant role in

this disease (103). Hendrix et. al. first reported in 1998 the expression of c-MET by the

more invasive interconverted phenotype of uveal melanoma cell lines, and subsequently

demonstrated a motogenic response to HGF by c-Met expressing cells, but not by those

who failed to express c-Met (104). Cell migration capacity appears to be enhanced by

HGF via activation of phospho-AKT and the downregulation of the cell adhesion

molecules e-cadherin and beta-catenin in a dose dependent fashion (105). Both c-MET

inhibition and AKT inhibition independently inhibited the downregulation of adhesion

molecules by HGF and completely abolished the migration of these two cell lines,

suggesting that activation of p-AKT via the HGF/c-MET axis is involved in HCF-induced

uveal melanoma cell migration (105, 106). c-MET blockade using the small molecule

SU11274 significantly inhibited both cell proliferation and migration in all uveal

melanoma cell lines tested (103).




HGF and its receptor tyrosine kinase c-Met play essential roles in the processes of liver

embryogenesis and in hepatic regeneration following injury in the adult state,

emphasizing their role in as both morphogen and mitogen for this organ (98, 106). As

uveal melanoma metastases preferentially involve the liver, the question arises as to

whether local factors within the hepatic environment such as HGF or IGF-1 are

responsible for the dominant pattern of metastases seen at this site, and whether

inhibition of this pathway could decrease the risk of developing metastastic disease

(107). In a series of 60 patients with resected uveal melanoma, higher levels of c-MET

expression were associated with a significantly higher risk of death from metastatic

disease (79); however, another series of 132 patients with uveal melanoma

demonstrated that while expression of both c-MET and IGF-1R were predictive of poor

prognosis in univariate analysis, the presence of c-MET alone was not predictive for

decreased overall survival (108).

Work further exploring the role of c-MET in the pathogenesis of uveal melanoma is on-

going. While there is great interest in targeting the HGF/c-MET pathway for the

treatment of this disease, with a number of relevant agents currently in clinical

development (Table 1), the efficacy of this strategy remains to be determined.

IV. Emerging Insights into the Biology of Advanced Uveal Melanoma

As discussed in the introduction, prior studies indicate that uveal melanomas segregate

into two tumor classes based upon microarray gene expression profiles. Class I tumors

have low rates of metastasis, while class II tumors are more aggressive and associated

with a higher rate of death from metastatic disease (12-15). Harbour et. al. interrogated

a sample of 31 class II uveal melanoma metastatic samples and identified an 84%

incidence of somatic mutations in the ubiquitin carboxy-terminal hydrolase BRCA1

associated protein-1 (BAP1) (109), a component of the ubiquitin proteasome system

that has been implicated in cancers such as lung, breast, and renal cell carcinoma (110-

113). BAP1 is a deubiquinating enzyme (DUB) which interacts with the breast cancer

susceptibility gene, BRCA1, via its RING finger domain, but does not appear to function




as a deubiquinator of BRCA (114, 115). Unlike other members of the ubiquitin carboxyl

hydrolase family, BAP1 possesses a large C-terminal domain which is predicted to

coordinate the selective association with potential substrates or regulatory components

(116). BAP1 participates in the assembly of multiprotein complexes containing

numerous transcription factors and cofactors, and activates transcription in an

enzymatic-activity-dependent manner, thereby regulating the expression of a variety of

genes involved in various cellular processes (117).

Mutations, deletions and rearrangements of BAP1 on chromosome 3p21.3 have been

detected in lung and lung cancer cell lines, and in sporadic breast tumors (114, 118).

Depletion of BAP1 resulted in altered expression of 249 genes, including key mediators

of cell cycle progression, DNA replication and repair, cell metabolism, survival and

apoptosis (117). BAP1 has tumor suppressor activity both in vitro and in vivo (119,

120). Expression of wild-type BAP1 significantly abolished tumorigenicity of a human

non-small cell lung cancer cell line in nude mice, while expression of mutant BAP1 that

lacks either deubiquitinating activity or nuclear localization did not suppress

tumorigenicity, implying that both deubiquinating activity and nuclear localization are

necessary for the tumor suppressive activity (119). Suppression of BAP1 by RNA

interference has also been demonstrated to inhibit cellular proliferation (120-122).

Microarray analysis comparing 92.1 uveal melanoma cells characterized by a wild-type

BAP1 transfected with either control or BAP1 siRNA indicated that the gene expression

profile of the BAP1 siRNA treated cells shifted towards a class 2 tumor profile versus

the class 1 profile observed in the control treated cells, indicating a dominant role for

BAP1 in the regulation of expression of these genes (109). mRNA levels of CDH1 and

c-Kit were increased, whereas those for ROBO1, a neural crest differentiation gene, and

the melanocyte differentiation genes CTNNb1, EDNRB, and SOX10 were down-

regulated. More work is required to elucidate the molecular mechanisms governing the

function of BAP1 in uveal melanoma and to assess potential treatment strategies

derived from these studies.




Summary

As there are no effective systemic therapies for uveal melanoma, prognosis after the

development of metastatic disease remains dismal. Recent studies have brought to

light several key signaling cascades that are implicated in the development and

progression of uveal melanoma, some of which serve as potential therapeutic targets. It

is becoming increasingly clear that, like many cancers, uveal melanomas comprise a

heterogenous group of disease, each with distinct molecular features. Each molecular

subtype may have unique clinical characteristics and may respond best to a specific

therapeutic strategy. The identification of effective therapies for uveal melanoma will

depend upon our ability to develop clinical trials with this possibility in mind.




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Legend:

Figure 1. Major signaling pathways in uveal melanoma.

The MAPK, PI3K, mTOR, and IGF1-R pathways intersect significantly in uveal

melanoma pathogenesis. Briefly, stimulation of GPCR results in replacement of GDP

for GTP on the Gα subunit. Gα-GTP is the active form and mediates activation of

PLCβ, which promotes cleavage of PIP2 to IP3 and DAG. DAG goes on to activate

PKC, which stimulates the MAPK signaling pathway. MAPK signaling leads to tumor

growth and proliferation. The GNAQ Q209L mutation inactivates the intrinsic

phosphatase of the Gα protein, thus preventing hydrolysis of GTP to GDP and enabling

constitutive downstream MAPK signaling. PI3K mediates phosphorylation of PIP2 to

PIP3, and PTEN antagonizes this process. PIP3 activates Akt, which promotes tumor

growth and proliferation. Both ERK and Akt also activate the mTOR signaling pathway,

which also mediates tumor growth and proliferation. IGF-1 simulation of IGF1-R leads

to dimerization and auto-phosphorylation of the receptor, resulting in recruitment and

activation of IRS, which can then activate both the PI3K and MAPK pathways. mTOR

also exerts inhibitory effects on IGF-1R, such that mTOR blockade disinhibits IGF-1R

signaling to paradoxically promote tumor proliferation. There are numerous points at

which these pathways can be manipulated, including inhibition of IGF-1 levels with

somatostatin analogs or IGF1-R signaling by PPP, PI3K inhibition by LY294002 or

Wortmannin, mTOR inhibition by rapamycin, everolimus, or temsorilimus, or MAPK

pathway inhibition with BAY-439006, AZD6244, U0126, 17-AAG, or 17-DMAG.

Abbreviations: DAG: diacyl glycerol, EC: extracellular space, ERK: extracellular growth

factor-related kinase also known as mitogen-activated protein kinase (MAPK), GPCR:

G-protein coupled receptor, IC: intracellular space, IGF1: insulin-like growth factor-1,

IGF1-R: insulin-like growth factor-1 receptor, IP3: inosol triphosphate, IRS: insulin

receptor substrate, MEK: MAPK/extracellular signal-related kinase kinase, mTOR:

mammalian target of rapamycin, PI3K: phosphoinositide 3-kinase, PIP2:

phosphatidylinositol 4,5-bisphosphate, PIP3: phosphatidylinositol(3,4,5)-triphosphate,

PKC: protein kinase C, PLCβ: phospholipase CB, PPP: picropodophyllin, PTEN:




phosphate and tensin homolog protein, 17-AAG: 17-allylamino-17-

demethoxygeldanamycin, 17-DMAG: 17-dimethylaminoethylamino-17-demethoxy-

geldanamycin.




Table 1. Receptor tyrosine kinase inhibitors and inhibitors of the MAP kinase and PI3K/Akt pathways of interest in uveal melanoma. Signaling Pathway Target Agent Development Stage Trial Status

ClinicalTrials.gov Identifier

MAP Kinase

BRAF PLX4032 (RO5185426) Phase III trial in cutaneous melanoma Accrual completed NCT01006980

XL281 Phase I trial in solid tumors Ongoing NCT00451880 Sorafenib (BAY 43-9006) FDA approved for renal cell and hepatocellular carcinoma n/a n/a

MEK

AZD6244 (ARRY-142886) Phase II trial in uveal melanoma Ongoing NCT01143402 GSK1120212 Phase III trial in cutaneous melanoma Ongoing NCT01245062

AS703026 Phase I trial in hematologic malignancies Ongoing NCT00957580 MSC1936369B Phase I trial in solid tumors Ongoing NCT00982865

PI3K/Akt

mTOR

Rapamycin Approved for post-renal transplant immunosuppression n/a n/a Temsirolimus FDA approved for renal cell carcinoma n/a n/a

Everolimus (RAD001) Phase II with paclitaxel/carboplatin in Stage IV melanoma Ongoing NCT01014351 Ridaforolimus (AP23573) Phase I/II in advanced/refractory malignancies Accrual completed NCT00112372

TORC1/2 AZD8055 Phase I in advanced solid malignancies Ongoing NCT00973076 OSI027 Phase I in advanced solid malignancies/lymphoma Ongoing NCT00698243 INK128 Phase I in advanced solid malignancies Ongoing NCT01058707

PI3K

XL147 GDC0941 SF1126

Phase I in advanced solid tumors/lymphoma Phase I in patients with solid tumors Phase I in patients with solid tumors

Ongoing Ongoing Ongoing

NCT00486135 NCT00876109 NCT00907205

PI3K + mTOR

XL765 PF04691502

Phase I in patients with solid tumors Phase I in patients with solid tumors

Ongoing Ongoing

NCT00485719 NCT00927823

Akt

Perifosine Phase I in solid tumors/lymphoma Accrual completed NCT00389077 GSK2141795 Phase I in solid tumors/lymphoma Ongoing NCT00920257 GSK690693 Phase I in solid tumors/lymphoma Ongoing NCT00493818

MK2206 Phase I in locally advanced or metastatic solid tumors Ongoing NCT01071018

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Receptor Tyrosine Kinases

IGF-1R

IMC-A12 Phase I with temsirolimus in advanced cancers Ongoing NCT00678769 R1507 Phase I in advanced solid tumors Ongoing NCT00400361

MK0646 Phase I in advanced solid tumors Accrual completed NCT00635778 OSI-906 Phase I in advanced solid tumors Ongoing NCT00514007 BIIB022 Phase I in advanced solid tumors Ongoing NCT00555724

CP-751,871 Phase I with sunitinib in advanced solid tumors Ongoing NCT00729833 AXL1717 Phase I in advanced solid tumors Ongoing NCT01062620 AMG479 Phase I with biologics/chemo in advanced solid tumors Ongoing NCT00974896

c-Kit

Imatinib Phase II in metastatic uveal melanoma Ongoing NCT00421317 Sunitinib Phase II with cisplatin and tamoxifen in ocular melanoma Ongoing NCT00489944 Sorafenib Phase II with carboplatin/ paclitaxel in uveal melanoma Ongoing NCT00329641 Dasatinib Phase I with bevacizumab in metastatic solid tumors Ongoing NCT00792545 Nilotinib Phase II in c-kit mutated or amplified melanoma Ongoing NCT01168050

c-Met

PF-02341066 Phase I in solid tumors other than NSCLC Not yet open NCT01121588 GSK1363089 Phase I in solid tumors Accrual completed NCT00742261

XL-184 Randomized discontinuation in advanced solid tumors Ongoing NCT00940225 ARQ 197 Phase I in refractory/advanced solid tumors Ongoing NCT00609921

EMD 1204831 Phase I in advanced solid tumors Ongoing NCT01110083 PRO143966 Phase I in advanced solid tumors Accrual completed NCT01068977

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Table 2. Currently accruing clinical trials for advanced uveal melanoma. ClinicalTrials.gov

Identifier Agent Phase Sponsor/Study Lead NCT01034787 CP-675,206 II Alberta Health Services NCT00506142 Liposomal vincristine II Hana Biosciences, Inc NCT01143402 AZD6244 versus Temozolomide II Memorial Sloan-Kettering Cancer Center NCT01200342 Genasense, Carboplatin & Paclitaxel II M.D. Anderson Cancer Center NCT00738361 Paclitaxel Albumin-Stabilized Nanoparticle Formulation II Arthur G. James Cancer Hospital NCT00110123 IV versus Hepatic Arterial Infusion of Fotemustine III EORTC NCT01217398 Temozolomide & Bevacizumab II Institut Curie NCT00313508 Vaccine Therapy and Autologous Lymphocyte Infusion With or Without Fludarabine I/II H. Lee Moffitt Cancer Center NCT00471471 Multi-Epitope Peptide Vaccine I University of Pittsburgh NCT01005472 Temozolomide & Sunitinib I/II University of California, Los Angeles NCT00168870 Gemcitabine & Treosulfan versus Treosulfan II Charite University, Berlin, Germany NCT01200238 STA-9090 II Dana-Farber Cancer Institute NCT00421317 Imatinib II Centre Oscar Lambret NCT01252251 SOM230 & RAD001 II Memorial Sloan-Kettering Cancer Center

pending IMC-A12 II M.D. Anderson Cancer Center

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© 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

GG

IGF1

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Published OnlineFirst March 28, 2011.Clin Cancer Res Mrinali Patel, Elizabeth C Smyth, Paul B Chapman, et al. Uveal MelanomaTherapeutic Implications of the Emerging Molecular Biology of

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