Treatment of Metastatic Choroidal Melanoma

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Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and is derived most frequently from choroidal melanocytes.[1] It has a strong tendency to metastasize to the liver and other organs including the lung, bones, skin, lymph nodes, and brain.[2][3] Metastasis is rapidly progressive and fatal. Typically, UM is initially asymptomatic, which is an important barrier to early treatment.

Despite technological advances and newer targeted therapies, no established, effective treatments are known in advanced stages. Current management strategies depend on the location and size of the tumor, degree of metastasis, and the patient’s goals. This article summarizes the treatment strategies in metastatic UM.

Contents

Goals of Treatment of Uveal Melanoma

The treatment of UM is to achieve the following goals:[4]

  • Prevention of metastasis
  • Prevention of removing the eye
  • Preservation of useful vision in the affected eye

General Biology of Uveal Melanoma

Molecular Pathways

Disruptions in various molecular pathways have been reported in UM, including the MAPK, PI3K/Akt, and YAP1 pathways.

Mutations in G alpha (Gα) protein subunits, such as Gαq (GNAQ) and Gα11 (GNA11) are common and believed to be early events in the pathogenesis of UM.[5] Under normal circumstances, these Gα protein subunits are activated when an external signal stimulates its associated G-protein coupled receptor (GPCR). The external stimulus is transduced through the GPCR and Gα protein subunits to intracellular signaling pathways. Various pathways are regulated by GNAQ and GNA11 as discussed below.

Growth factors excite receptor tyrosine kinases (RTKs) that activate Gα proteins, such as GNAQ. GNAQ stimulates phospholipase C-β (PLCβ), which upregulates production of second messengers diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 then increases intracellular calcium, stimulating various calcium-driven pathways and protein kinase C (PKC).[6] PKC subsequently activates the mitogen-activated protein kinase (MAPK) signal transduction pathway that ultimately stimulates cellular growth and proliferation through activating various serine/threonine-specific protein kinases including RAS, RAF, MEK, and ERK.[7]

 In UM, mutations in GNAQ and GNA11 result in the constitutive activation of the MAPK signal transduction pathway. The constitutively active GNAQ and GNA11 results in increased MEK activity and cellular proliferation. In contrast to UM, BRAF mutations are common in cutaneous melanoma but are rare in UM.[8]

RTKs also stimulate Gα proteins that activate the phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) signaling pathways.[9][10][11] PI3K phosphorylates phosphatidyl inositol-4,5-bisphosphate (PIP2), generating phosphatidyl inositol-3,4,5-triphosphate (PIP3) that activates Akt, stimulating the mammalian target of rapamycin (mTOR) to stimulate cellular growth and proliferation. The activity of PI3K is opposed by PTEN, a major tumor suppressor that dephosphorylates PIP3.[12] In UM, overactivation of PI3K/Akt has been observed due to hemizygous deletions of PTEN and activating mutations to RTKs, such as c-kit, that are implicated in activating the MAPK and PI3K/Akt pathways.[13]

Stimulation of GNAQ and GNA11 are also involved with the activation of transcriptional co-activator Yes-associated protein 1 (YAP1), an important component of the Hippo signaling pathway through the Trio-Rho/Rac signaling circuit, which controls the size of organs in mammals. This pathway, which operates independently from the MAPK and PI3K/Akt pathway, is also dependent on the activity of Gα proteins and has been shown to be upregulated in activating mutations of GNAQ.[14]

Mutations in other components of the Gα signaling pathway such as phospholipase C β4 (PLCB4) and cysteinyl leukotriene receptor 2 (CYSLTR2) are also implicated in the UM.[15][16]

Cell Cycle Disruptions

Healthy melanocytes produce Bcl-2, an antiapoptotic factor that is important in inhibiting apoptosis. However, mutations in the major tumor suppressor genes retinoblastoma (Rb) and p53 (TP53) can allow melanocytes to enter the cell cycle and proliferate.[17] Alterations in upstream mediators, such as cyclin D1, which phosphorylates Rb and inactivates its tumor suppressor function, allows cells to enter the cell cycle. Further upstream epigenetic modifications, such as methylation of the CDK2NA gene promoter region, impairs the production of p16, which exerts an important inhibition of Cyclin D1, of Rb, and cell cycle initiation.[18] Increased MDM2, a key inhibitor of p53 that causes cellular proliferation, has also been observed in UM.[19]

Cytogenetic Changes

Changes in cytogenetics have been associated with invasion and metastasis, including monosomy 3, trisomy 8, and loss of chromosome 6q. The BRCA-associated protein-1 (BAP1), a deubiquitinating enzyme, is involved in regulating the cell cycle, cellular differentiation, and DNA repair.[20] The loss of inactivating tumor suppressor genes such as BAP1 on chromosome 3p21.1 is postulated to be associated with metastasis in UM.[21][22][23]

In contrast, mutations associated with disomy 3 (EIF1AX and SF3B1) are associated with low-grade UM and a better prognosis.[24][25] Other genes predictive of metastatic UM include CDH1, ECM1, FXR1, HTR2B, ID2, LMCD1, LTA4H, MTUS1, RAB31, ROBO1, and SATB1.[26][27]

Through gene expression profiling (GEP) of UM, three different prognostic classes of disease have been delineated.[23]  

Class Metastatic Risk 5-year metastatic risk Associated genes
Class 1A Low 2% EIF1AX, SF3B1
Class 1B Intermediate 21% EIF1AX, SF3B1, CDH1/RAB31
Class 2 High 72% BAP1

A GEP test for UM prognostication (DecisionDx®-UM) has been developed.[23]

The cancer-testis antigen PRAME (preferentially expressed antigen in melanoma) is a biomarker for increased metastatic risk in Class 1 and Class 2 UMs.[28][29] It is an independent prognostic biomarker for metastasis in UM.[30][31][32]

Class 5-year metastasis rate
Class 1PRAME- 0%
Class 1PRAME+ 38%
Class 2 71%

Data from[32]

Cellular Adhesion Molecules

Disruptions in cellular adhesion molecules are implicated in the mechanism of metastasis in many cancer types through mediating detachment of cells from the primary tumor and attachment of disseminated cells to components of the extracellular matrix or the vascular endothelium. UMs express various integrins and attachment molecules, including a1b1, a2b2, a3b1, a5b1, avb3, intercellular adhesion molecule-1 (ICAM-1), neural cell adhesion molecule, and vascular cell adhesion molecule-1. Loss of expression of ICAM-1, in particular, is associated with an increased risk of metastasis.[33][34]

Matrix Metalloproteins

Matrix metalloproteins (MMPs) are zinc-dependent endopeptidases that degrade extracellular matrix and are important components in the invasion and metastasis of UM. In UM, increased expression of MMP-2 and MMP-9 have been observed as well as expression of MMP inhibitors such as tissue inhibitor of metalloproteases (TIMP-2). Inappropriate activation or inhibition of MMPs are associated with tumor progression.[35][36]

Local Therapy to the Eye

Invasive Therapy

Enucleation

Enucleation was previously the standard treatment for UM. However, the Zimmerman-McLean-Foster Hypothesis theorized that elevated intraocular pressure could facilitate dissemination of malignant cells through the vortex veins into systemic circulation.[37] The benefits of enucleation were evaluated in the Collaborative Ocular Melanoma Study (COMS), where no long-term survival differences were observed in patients treated with enucleation or iodine-125 (125I) brachytherapy.[38] UM can therefore be managed conservatively except when the eye is rendered painful or when vision is not salvageable. This occurs in large and extensive melanomas or melanomas with associated retinal detachment or vitreous hemorrhage.[39] 

Local resection

Many indications for resection exist, including:[40]

  • Iridociliary tumors of indeterminate pathology with suspicious features.
  • Iridociliary tumors with rapid growth.
  • Situations where plaque brachytherapy or proton beam radiotherapy are not available.
  • Thick ciliary body and choroidal tumors that require dangerously high radiation dosages.


Two surgical resection techniques exist: “Exoresection” and “endoresection”

  • Exoresection (transscleral resection via partial lamellar sclerouvectomy (PLSU)). Exoresection is more appropriate for anteriorly located tumors.50 Adjunctive plaque radiotherapy or proton beam radiotherapy can be done after exoresection.
  • Endoresection (transretinal resection via pars plana vitrectomy). Endoresection is more suitable for posterior tumors but carries increased surgical risks. One such theoretical risk is intraoperative dissemination of tumor cells that can lead to recurrence. The use of neoadjuvant irradiation to destroy tumor cells prior to endoresection has been controversial.[41][42]


Conservative Therapy

Photodynamic Therapy

Photodynamic Therapy (PDT) involves intravenous administration of a photosensitive dye (a photosensitizer) that pools within the tumor vasculature and generates toxic reactive oxidative species when activated by a specific wavelength of light. These chemotoxic reactive oxidative species cause endothelial changes and subsequent thrombosis of the tumor. The use of PDT with verteporfin, a second-generation photosensitizer, has shown short-term tumor control while circumventing the risks of radiation retinopathy in small melanomas, but long-term tumor control rates are lower.[43][44][45] 

Transpupillary thermotherapy

Transpupillary thermotherapy (TTT) ablates tumor cells using focused thermal energy. TTT is not considered a primary treatment of small UMs due to high recurrence rates. Presently, it is used for residual or recurrent disease following other primary treatments.[46] It is not recommended in cases of melanoma with multiple high-risk features, such as visual changes, subretinal fluid, or close proximity to the optic disc.[47]

Ionizing radiation

Radiotherapy induces DNA damage, causing tumor cell death and proliferation arrest. Plaque brachytherapy, charged-particle therapy including proton beam radiotherapy, and stereotactic radiosurgery are all means of delivering localized radiation therapy to the eye. The goal of radiotherapy is to destroy the tumor while preserving vision and minimizing complications. Complications of radiation therapy include cataract formation, retinal and choroidal vasculopathy, and optic neuropathy. In addition, the irradiated tumor may become ischemic, resulting in macular edema, serous retinal detachment, retinal ischemia, rubeosis, and neovascular glaucoma.[48]

Plaque brachytherapy

Plaque brachytherapy involves suturing a radioactive plaque to the sclera to deliver focal radiation to the tumor. The most commonly used radioisotopes include iodine-125 (125I), ruthenium-106 (106Ru), and Palladium-103 (103Pd). 125I emits gamma radiation, which penetrates deeper into tumors, but increases toxicity to the eye. Ruthenium emits beta radiation, which may result in less toxicity to surrounding structures.[49] Intraocular radiation toxicity includes optic nerve atrophy and maculopathy.[50]

Proton beam therapy

Proton beam therapy (PBT) applies focused radiation to a targeted area. It is used in medium- to large-sized tumors or for tumors in regions inaccessible to plaque brachytherapy such as the optic disc and fovea. The physical properties of the proton beam limits collateral damage to surrounding structures due to the Bragg peak, where the most destructive ionizing radiation occurs immediately before the location particles stop travelling. This allows precise delivery of ionizing radiation.[47] PBT is a well-established treatment option but is not easily accessible for many centers.[50]

Stereotactic radiosurgery

Stereotactic radiosurgery, such as gamma(γ) knife and CyberKnife®, utilizes high-dose γ radiation delivered over a small, well-defined 3-dimensional area with minimal exposure to surrounding tissue. Its high precision makes this approach is useful for tumors near the macula and optic disc. Additionally, stereotactic radiosurgery is noninvasive and requires only one procedure, unlike plaque brachytherapy which necessitates two separate, invasive operations. One study found that stereotactic radiosurgery is effective in posterior UM while allowing for good visual outcomes.[51] Similarly, the CyberKnife® robotic radiosurgery system additionally can accurately track tumors, thereby precisely delivering repeated radiation to a focused area.[52]  

Novel approaches

Tissue factor

Tissue factor is a transmembrane cytokine receptor expressed on sub-endothelial tissues that binds to factor VII and initiates the extrinsic coagulation cascade. It is upregulated in UM and postulated to contribute to tumor angiogenesis, growth, and metastasis.[53] Treatment with ICON-1, a human immunoconjugate (ICON) fusion protein that is composed of the Fc domain of the human IgG and a structurally modified human factor VII, is under investigation in a phase I trial in patients with UM (NCT02771340).[54] 

Therapeutic nanoparticles

Human papillomavirus (HPV) induces tumor growth through heparan sulfate modifications found on cancerous cells. Currently under investigation, intravitreal AU-011 is a novel photosensitive recombinant papillomavirus-like particle (VLP) that binds to the atypically expressed heparan sulfate and destroys cancer cells when activated by a 690 nm wavelength of light without affecting healthy tissue (NCT03052127).[55] Early data demonstrates reduction in tumor thickness and preservation of vision.[56]

Locoregional treatments of liver metastasis

Resection of metastatic nodules

In colon and other types of cancers, hepatectomy is the best prognosis-maximizing strategy in patients with liver-limited metastasis.[57] However, hepatectomy in UM patients offers limited response and is rarely indicated as most present with multiple liver metastases involving both liver lobes.[58]

Hepatic intra-arterial chemotherapy

Metastases are disseminated through and perfused by the hepatic artery. Through hepatic intra-arterial (HIA) chemotherapy, medication is delivered through an indwelling hepatic artery catheter, directly to metastatic liver cells to chemotherapy. Metastatic hepatic cells are thus exposed to maximum medication levels while minimizing toxicity of unaffected hepatic tissue supplied by the portal veins. In a phase III open label randomized trial, HIA-administered fotemustine yielded a statistically significant increase in PFS (4.5 months) compared to patients treated intravenously (3.5 months), but no improvement to OS was observed in either group.[59][60] HIA administration of melphalan, an alkylating nitrogen mustard, has also been used safely in patients with metastatic UM.[61][62] The efficacy of other HAI regimens, including the combination of cisplatin, vinblastine, and dacarbazine, is comparable to other HAI regimens.[63] 

Intra-arterial hepatic chemoembolization

Hepatic transarterial chemoembolization (TACE) combines hepatic artery embolization with chemotherapy infusion. Hepatic artery embolization deprives metastatic cells significant perfusion, causing tumor ischemia. Additionally, direct administration of medication maximizes tumor exposure to chemotherapy while minimizing systemic chemotherapy-related toxicity.[64] Various chemotherapeutic medications have been used to embolize the hepatic artery to treat metastatic UM, including cisplatin, thiotepa, and lipiodol.[65][66] Another study concluded that the efficacy of TACE with BCNU (1,3-bis[2-chloroethyl]-1-nitrosuourea) is superior to conventional systemic chemotherapy.[67][68]

Trans-arterial hepatic immunoembolization

Immunoembolization involves hepatic artery embolization using immune-stimulating agents such as granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) rather than chemotherapeutic agents, as in chemoembolization. GM-CSF is a glycoprotein produced by T-cells that simulates immune cells such as macrophages and dendritic cells. Therefore, in addition to inducing tumor ischemia, immunoembolization may also attract and stimulate immune cells, facilitate antigen uptake, and enhance systemic immunity against tumor cells.[69] A double-blinded, randomized, phase II study reported an OS of 21.5 months and elevated interleukin (IL)-6 and IL-8 levels in 52 patients with UM and hepatic metastases who received GM-CSF. The authors concluded that the robust inflammatory responses delayed progression of extrahepatic systemic metastases.[70]

Selective Internal Radiation Therapy

Selective internal radiation therapy (SIRT), also referred to as microsphere radioembolization or transarterial radioembolization (TARE), involves inserting variously sized radioactive microspheres into the hepatic artery, thereby occluding and depriving metastatic tissue from perfusion. These microspheres also deliver localized 90yttrium (90Y), a high-energy, pure β-emitter, to hepatic tumors, unlike whole-liver doses in external beam radiation therapy that can cause fatal radiation hepatitis.[71][72] Various clinical trials have found that 90Y resin microspheres are a safe and effective salvage therapy for patients with limited pretreatment burden hepatic metastases or unresectable liver metastases from UM.[73][74] A clinical trial investigating radioactive 90Y microspheres (SIR-Sphere®) in UM with hepatic metastasis is ongoing (NCT01473004).  

Drug-eluting beads

Drug-eluting bead microspheres are designed to occlude vessels and expose metastatic tumors to localized, controlled, and sustained dosages of chemotherapeutic medications. Doxorubicin- and irinotecan-eluting beads have demonstrated efficacy in the treatment metastatic UM.[75][76][77][78]

Isolated hepatic perfusion

Isolated hepatic perfusion (IHP) is a procedure where hepatic blood flow is segregated from the systemic vasculature through cannulation and clamping of the hepatic artery and inferior vena cava and joining this circulation to an extracorporeal circuit. Having a distinct circulation, highly potent chemotherapies can be administered specifically to the liver while bypassing systemic circulation, thereby reducing undesirable systemic effects.[79] However, this surgical procedure is complex and extensive, thereby limiting its availability. It is also associated with considerable morbidity and mortality due to veno-occlusive disease and hepatotoxicity. The role of IHP in metastatic liver UM is being studied in the randomized multicenter phase III SCANDIUM trial (NCT01785316).[80]

Systemic therapy

Conventional chemotherapy

Systemic chemotherapy is reserved for metastatic UM although there is currently no standard therapy for metastatic UM. Effective treatments for metastatic cutaneous melanoma are generally ineffective in metastatic uveal melanoma. Various chemotherapeutic agents have been evaluated, including dacarbazine, temozolomide, treosulfan, and fotemustine. 

Dacarbazine

Dacarbazine chemotherapy is ineffective with a response rate below 1% and no improvement in survival.[81] Another clinical trial assessing bleomycin, vincristine, lomustine, and dacarbazine (BOLD regimen) with interferon-a2, demonstrated 20 of 24 (83%) patients exhibiting disease progression while two (8.3%) remained stable with a PFS of 1.9 months and OS of 10.6 months.[82] In addition, liver metastases from UM had a lower response rate (10%) than metastases from cutaneous melanoma (33%) when patients are treated with the “Dartmouth combination” (dacarbazine, carmustine, cisplatin, and tamoxifen).[83] Higher response rates and median survival have been reported with chemotherapy administration directly into the hepatic artery in a highly selected group of patients.[84]

Temozolomide

Temozolomide, a triazene analog of dacarbazine, is a cytotoxic alkylating agent that has demonstrated minimal efficacy in metastatic UM. A phase II trial of temozolomide in 14 enrolled patients with metastatic UM, demonstrated no complete or partial responses and only 2 patients were able to achieve stable disease. The investigators concluded that temozolomide is not effective in the treatment of metastatic UM.[85] A recent phase II trial of bevacizumab and temozolomide as first-line treatment in patients with metastatic UM revealed a 6-month PFR (progression free rate) of 23%.[86]

Treosulfan

Treosulfan, a bifunctional sulfonate alkylating cytotoxic agent, has poor efficacy against metastatic UM. A phase II study of cisplatin, gemcitabine, and treosulfan reported no response in 17 patients with a median PFS and OS of 7 months and 7.7 months, respectively.[87] A prospective phase II clinical trial of dacarbazine and treosulfan for metastatic UM revealed no responses with a PFS of 12 weeks and median OS of 30 weeks.[88]

Fotemustine

The safety and efficacy of IV fotemustine was evaluated in 25 patients with metastatic UM. In one study, 9 patients were found to have stable disease with a median survival duration of 13.9 months and  a 1-year survival rate of 60%.[89]

Adjuvant Therapies

Adjuvant therapy is additional treatment that follows a primary treatment modality, such as surgical resection followed by chemotherapy or radiotherapy. This approach to treat metastatic UM has been evaluated in numerous studies, but at present, no effective adjuvant therapy decreases the risk of metastasis or improves OS.[90][91] No survival difference was found in patients treated with adjuvant dacarbazine or bacilli Calmette-Guérin (BCG).[92][93] The phase III randomized multicenter FOTEADJ trial evaluating adjuvant IV fotemustine for UM was terminated early due to futility; there were no differences in the 3-year metastasis-free survival and OS between the two groups.[94] Treatment with systemic adjuvant interferon (IFN) in various nonrandomized clinical trials also did not improve survival in patients with UM.[95][96][97] Adjuvant crizotinib, a tyrosine kinase inhibitor (TKI), demonstrated positive results but minimally impacted tumor size.[98] A clinical trial investigating crizotinib in high-risk UM following definitive therapy is ongoing (NCT02223819). Treatment with adjuvant sunitinib, a TKI that inhibits c-Kit, VEGFR1, VEGFR2, IGFR1, and PDGFRb, in a retrospective study in patients with confirmed monosomy 3 and 8q and large tumor size (T3 or T4) and/or DecisionDx-UM Class 2 (high-grade) UM demonstrated encouraging results.[99] A randomized phase II clinical trial of adjuvant sunitinib versus valproic acid for high-grade UM is currently underway (NCT02068586).

Targeted therapies

Mutations in GNAQ or GNA11 are common in UM, resulting in constitutive activation of the MAPK and PI3K/Akt pathways. Therapies directed against downstream effectors such as MEK, Akt, and protein kinase C are being investigated.[91]

MAPK, PI3K/Akt, KIT

c-Kit and c-Met are both RTKs that are implicated in angiogenesis, metastasis, cell motility, cell growth, and inhibition of apoptosis in metastatic UM. They are associated with an increased risk of hepatic tumor proliferation and differentiation due to hepatocyte growth factor/scatter factor (HGF/SF), which are produced in high quantities in the liver. Thus, targeting the interaction between RTKs and HGF/SF has been an area of interest for the treatment of metastatic UM.[100][101]

Crizotinib

Crizotinib is a TKI that has demonstrated prevention of metastasis in an animal metastatic UM model.[102] Inhibition of c-Met, EGFR, and IGFR1 inhibits proliferation of uveal UM cells. A phase II clinical trial of crizotinib for high-risk UM is currently underway (NCT02223819).

Sunitinib malate

The efficacy of sunitinib malate, a nonselective c-Kit inhibitor, with dacarbazine has been studied in the randomized multicenter phase II SUAVE clinical trial in 74 patients with metastatic UM. However, PFS and OS were not improved with sunitinib as an overall response rate of 0% and 8% were observed in the sunitinib and dacarbazine arms and it was concluded that sunitinib did not provide clinical benefit in patients with metastatic UM.[103]

Cabozatinib

Cabozatinib (XL184), an oral RTK inhibitor that inhibits c-Met and VEGFR2, has been shown to inhibit HGF-induced migration and invasion of melanoma cells.[104] A randomized phase II discontinuation trial of 23 patients treated with cabozatinib for metastatic UM revealed a median OS of 12.6 months and a median PFS of 4.8 months, suggesting some clinical benefit in patients with metastatic UM.[105]

Sorafenib

The efficacy of sorafenib (BAY439006), an oral multikinase inhibitor that impairs tumor growth by acting on both tumor and tumor vasculature cells, was found to be clinically positive in the phase II STREAM clinical trial (median survival = 14.8 months, median PFS = 5.5 months (placebo median PFS = 1.9 months, p = 0.0079)).[106]

Selumetinib

Selumetinib (AZD6244, ARRY-142886) is a highly selective MEK1/2 inhibitor that has been used in combination therapy but has not demonstrated positive results. In a randomized, open-label phase II clinical trial, selumetinib versus chemotherapy (temozolomide or dacarbazine) did not improve overall survival.[107] Furthermore, in the randomized, phase III, double-blinded SUMIT clinical trial, selumetinib with dacarbazine did not significantly improve PFS.[108]

Trametinib

Trametinib (GSK1120212) is a reversible selective, allosteric inhibitor of MEK1/MEK2 activation and kinase activity that demonstrated no objective responses and a median PFS of 1.8 months in a multicenter phase 1 clinical trial in 16 patients with primary UM.[109] A randomized phase II clinical trial of trametinib with or without the Akt inhibitor GSK2141795 is currently in progress (NCT01979523).

Binimetinib

Binimetinib (MEK162, ARRY-162, ARRY-438162) is a MEK inhibitor that is currently being studied in a phase Ib/II clinical trial in patients with UM (NCT01801358).

Imatinib mesylate

Imatinib mesylate is an inhibitor of the RTK of c-kit, bcr-abl, and PDGFR. A phase II multicenter single-arm clinical trial investigating the efficacy of imatinib in 25 patients with c-kit-positive metastatic UM did not improve PFS.[110] 

Ulixertinib

A phase II study of ulixertinib (BVD-523), an ERK1/2 inhibitor, is currently underway in patients with metastatic UM (NCT03417739).

PKC inhibition

PKC, an upstream activator of the MAPK pathway, is a potential target in the treatment of UM. Sotrastaurin (AEB071) has been shown to exert antitumor activity in UM cell lines with GNAQ mutations through selectively inhibiting growth by targeting the PKC/ERK1/2 and PKC/NF-kB pathways.[111] The synergistic antitumor effects of sotrastaurin with BYL719, a selective PI3Ka inhibitor, has been shown in UM cell lines harboring GNAQ and GNA11 mutations.[112] A phase I clinical trial on the efficacy and safety of sotrastaurin (NCT01430416) and combination of AEB071 with BYL719 (NCT02273219) is currently ongoing. Another PKC inhibitor, LXS196, is being studied in a phase I clinical trial (NCT02601378).

Apoptosis

Oblimersen, a bcl-2 anti-sense oligonucleotide, interrupts the Bcl-2/Bcl-XL interactions with pro-death proteins (Bim), leading to Bax translocation, cytochrome c release, and subsequent apoptosis. This medication has demonstrated efficacy against advanced cutaneous melanoma. An open label phase II of combination oblimersen, paclitaxel, and carboplatin is currently underway (NCT01200342).

Proteasome inhibitors

Bortezomib is a tripeptide that inhibits the activity of proteasomes by binding to the catalytic site of the 26S proteasome and has demonstrated efficacy against multiple myeloma in the SUMMIT, CREST, and APEX trials.[113][114][115] It can induce a proapoptotic state by reducing antiapoptotic proteins such as Bcl-2 while stabilizing proapoptotic proteins such as p53 and Bcl-2 associated X protein (BAX).[116] In phase II trials, bortezomib has been observed to enhance the sensitivity of melanoma cells to various chemotherapeutics, rather than directly destroying cancer cells.[117] An open label phase II study of bortezomib, paclitaxel, and carboplatin is currently underway (NCT00288041)).  

Chaperonin inhibitors

Chaperone proteins, or chaperonins, play important roles in protein folding and suppression of protein aggregation. Disruptions of chaperone proteins may allow for toxic accumulations of atypically folded proteins. These abnormal proteins are then tagged and cleared through the ubiquitin-proteasome pathway. Heat-shock protein 90 (Hsp90) is a molecular chaperone protein that interacts with RTKs and components of the MAPK and PI3K/Akt pathway.[118] Ganetespib (STA-9090) is a second-generation Hsp90 inhibitor that has been shown to produce significant cytotoxicity and antitumor activity against various hematological and solid tumor cell lines. In a phase II trial of ganetespib in 17 patients with metastatic UM, only one partial response, four stable disease, 11 progressive disease, and 1 withdrawal were observed.[119]

Invasion and metastasis

Adhesion molecules

Vitaxin, a humanized monoclonal antibody that binds to avb3, triggers an antibody-dependent cellular cytotoxic reaction and blocks tumor growth. Volociximab, an a5b1 anti-integrin monoclonal antibody is also being evaluated in patients with metastatic melanoma. This treatment has not been evaluated in patients with UM and its efficacy remains unknown.[91]

Matrix metalloproteins

A clinical study by the National Cancer Institute of Canada Clinical Trials Group found that the MMP inhibitor, marimastat (BB-2516), only exhibits limited activity in patients with metastatic malignant melanoma. However, no such trial has yet been performed in patients with metastatic UM.[91]

Angiogenesis

FGF-2

Lenalidomide, a derivative of thalidomide, exhibits antiangiogenic effects directed against fibroblast growth factor 2 (FGF2). However, no significant responses were observed in a phase II randomized clinical trial that evaluated the efficacy and safety of low-dose (5 mg) versus high-dose (25 mg) oral lenalidomide in 16 evaluable patients with metastatic UM.[120]

VEGF

Bevacizumab, an anti-VEGF monoclonal antibody that targets all isoforms of vascular endothelial growth factor (VEGF), has not demonstrated significant survival benefit.[121]

Aflibercept (VEGF Trap) is a soluble decoy fusion protein derived from the VEGFR that selectively inhibits VEGF and has demonstrated efficacy in both cutaneous and UM in a multicenter phase II clinical trial. Of the 41 enrolled patients, 9 of the patients had primary UM. Despite an observed response rate of 0%, a median PFS of 5.7 months was obtained with an OS of 19 months.[122]

Sorafenib, as mentioned above, has anti-neovascular activity due to inhibition of the RTK of VEGFR).

A clinical trial assessing the efficacy of AZD2171 (cediranib), an inhibitor of the VEGFR RTK, is underway (NCT00243061).

Immunotherapy

Immunotherapy refers to the use of the host immune system to treat cancer. Various immunotherapies exist for cancer, including cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either stimulate cells or block immune checkpoint pathways.[123] An antitumor immune response can be generated through the production of cytokines.

CTLA4

The eye is an immune-privileged site and can be responsive to T-cell based therapy.[124] A promising target for cutaneous melanoma is the cytotoxic T lymphocyte-associated protein 4 (CTLA4). Ipilimumab (humanized anticytotoxic T-lymphocyte antigen-4 monoclonal (anti-CTLA4) antibody) has been shown to improve OS in patients with advanced cutaneous melanoma. However, in a trial investigating ipilimumab for metastatic UM, no objective responses were observed but ended with 3 of 13 (23%) patients achieving stable disease. In the Spanish Melanoma Group (GEM) study, a median OS of 9.8 months was obtained after receiving ipilimumab 10 mg/kg every 3 weeks for 4 doses followed by a maintenance dose every 12 weeks. One of 13 (7.7%) treatment-naïve patients achieved a partial response and six (46.2%) attained stable disease.[125] Ipilimumab was found to have very limited activity against metastatic UM in the phase II Dermatologic Cooperative Oncology Group (DeCOG) study.[126] Another study investigating ipilimumab plus dacarbazine for metastatic UM revealed promising result.[127]

 An open-label, multicenter phase 2 study on the efficacy of fully humanized anti-CTLA4 monoclonal antibody, tremelimumab, was terminated due to the initial poor response.[128]

PD-1/PD-L1 Pathway

UM can avoid immune surveillance through the production of indoleamine-pyrrole-2,3-dioxygenase (IDO) and the programmed death-ligand 1 (PD-L1). PD-L1 is expressed on the cell surface of some UM cells and binds to the programmed death receptor-1 (PD-1) on T-lymphocytes. This interaction results in the inhibition of T cell proliferation and activity in peripheral tissues.[128] Nivolimumab and pembrolizumab are two anti-PD-1 receptor antibodies that have shown efficacy against advanced cutaneous melanoma. However, treatment of metastatic UM with pembrolizumab, nivolumab, or atezolizumab, yielded poor PFS and OS results in a clinical trial.[129] A multicenter phase II clinical trial of pembrolizumab in patients with advanced UM is in progress (NCT02359851).

Novel therapies

IMCgp100

High densities of CD3+ T cells in tumor microenvironments have been correlated with longer survival in many solid cancers. However, the T cell response to cancer antigens is typically poor as tumor cells can deactivate cancer-reactive T cells. To improve the T-lymphocyte response to cancer antigens, immune mobilizing monoclonal T cell receptors (TCRs) against cancer (ImmTAC) have been developed. ImmTAC molecules are bispecific biologics that are composed of a monoclonal high-affinity T cell receptor (mTCR) fused to an anti-CD3 single-chain antibody fragment (scFv). The mTCR presents the cancer-associated or cancer-specific antigen of interest and the scFv engages polyclonal T cells, thus activating cytotoxic T cells to destroy tumor cells.[130] IMCgp100, a specific ImmTAC that targets the gp100-derived peptide in complex with HLA-A*201 on the surface of melanoma cells, has been evaluated in patients with metastatic UM in a phase I study. Encouraging OS and PFS data were found and the medication was well tolerated (NCT02570308).[131][132] IMCgp100 versus investigator’s choice of dacarbazine, pembrolizumab, or ipilimumab in treatment-naïve patients with metastatic UM was recently initiated (NCT03070392).[91] 

Tumor infiltrating lymphocytes

A subset of tumor infiltrating lymphocytes (TILs) demonstrated robust activity against UM.[133] In an attempt to determine if transfer of such reactive TILs could induce tumor regression, a phase II study was conducted (NCT01814046) in 21 patients with metastatic UM treated with lympho-depleting chemotherapy (cyclophosphamide, fludarabine) followed by a single infusion of autologous TILs and high-dose interleukin-2 (IL-2).[134] Of the 20 evaluable patients, 7 (35%) had objective tumor regression (6 partial responses, 1 complete response).

Glembatumumab vedotin

Glembatumumab vedotin (CDX-011) is an antibody-drug conjugate that is directed against glycoprotein NMB (GPNMB), a transmembrane protein found in various tumors, including UM, that is conjugated via a cathepsin B-sensitive valine-citrulline linkage to the cytotoxic agent monomethyl auristatin E (MMAE). CDX-011 IgG2 component binds to the GPNMB antigen, which is expressed on 86% of UMs. The entire conjugate is taken into the target cell via endocytosis. The antibody-drug conjugate is mobilized through endosomes or lysosomes where the drug is eventually released through cleavage of the valine-citrulline linkages, allowing dispersion of the cytotoxic MMAE at the target tissue.[135][136] Results from a single metastatic UM trial (NCT02363283) revealed that out of the 31 enrolled and evaluable patients, 61% disease control rate, despite a low objective response rate of 6%. In addition, 17/31 (55%) patients achieved stable disease.[136]

PRAME

Various studies have found that PRAME-specific CD8+ T cells could recognize and lyse PRAME-positive malignant cells. As a potential therapeutic target, clinical trials evaluating PRAME-TCR (T cell receptor) gene therapy are currently underway for patients with various cancers that could eventually be evaluated in advanced UM as well.[29] 

Epigenetics

Histone Deacetylase

UM has been studied extensively at the epigenetic level.[137][138] Histone deacetylase (HDAC) regulates transcription of various transcriptional factors involved in tumor initiation and progression through deacetylation of histones, thus modifying the structure of DNA and chromatin. HDAC inhibitors induce cell-cycle arrest through increasing overall histone acetylation, which increases activity of transcriptional factors and transcription of tumor-suppressor genes.[139] HDAC inhibitors include valproic acid, trichostatin A, panobinostat (LBH-589), vorinostat, suberoylanilide hydroxamic acid (SAHA), depsipeptide, tenovin-6, JSL-1, MC1568, and MC1575.[140][141] In a multicenter phase II clinical trial of vorinostat in advanced UM, the investigators concluded that vorinostat did not yield a beneficial response.[142] 

BET inhibitors

Bromodomains are important amino acid domains of transcription factor complexes that serve key functions in epigenetic modifications.[143] Bromodomain and extra-terminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT) share a similar structure and BRD4, in particular, has been implicated in various cancers.[144][145] BRD4 stimulates the positive transcription elongation factor (P-TEFb) complex, and upregulates expression of growth promoting genes such as c-Myc, which is important in the pathogenesis of UM.[146] JQ1, a BRD4 competitive inhibitor, has shown cytotoxicity in UM mouse models with GNAQ and GNA11 mutations.[147][148] Similarly, PLX51107, a novel BRD4 inhibitor, has demonstrated high cytotoxic activity in UM cell lines at nanomolar concentrations.[149] A recent phase 1 study of mivebresib (ABBV-075), a pan-BET inhibitor, in 10 patients with UM achieved an OS of 7.4 (95% CI: 0.9-3.6) and PFS of 2.0 months (95% CI: 1.8 – 11.0).[150]

Conclusions

UM is the most common primary intraocular malignancy. Enucleation is most commonly used for large tumors and radiotherapy for select tumors. Adjuvant therapy and systemic therapy has not demonstrated efficacy in decreasing the risk of metastasis and improving outcomes. Existing systemic treatments used for cutaneous melanoma are not effective against UM. Metastasis occurs most frequently to the liver via hematogenous spread. Locoregional treatment of liver metastases can be offered with variable efficacy. There is no consensus on follow-up, but annual history and physical examinations under an ophthalmologist or oncologist are recommended.

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