Table 2.

Selected agents prioritized for drug discovery.

Systemic administrationa
Compound	Mechanism of action	Known and mechanism-related effects
Brefeldin-A	Antimicrobial; ATPase inhibitor	• Macrocyclic lactone • Exerts transcytosis inhibition resulting in impaired transcription • Induces caspase-mediated cell death independent of p53 status in several human tumor cell lines; also inhibits VEGF secretion[88, 89] • Safe in cultured rat photoreceptors[90]
JTC-801	Nociceptin receptor (NOP) antagonist	• Cytotoxic against NCI-60 human cancer cell panel and panel of human xenograft including ortothopic and metastatic tumors[91] • Effects mediated by pH-dependent cell death[91] • Induces apoptosis mediated by PI3K-AKT[92] • Inhibits invasion and migration[92]
Omaveloxolone	Nuclear factor erythroid 2-related factor (Nrf2) activator	• Antioxidant inflammation modulator (AIM); reduces oxidative stress and inflammation • Antitumor activity may also involve inhibition of NF-κB, decreased cyclin D1 levels, increased p21, and JNK phosphorylation[93] • Inhibits growth of several tumor cell lines • Well tolerated in adult patients with advanced solid tumors after oral administration[93] • Protects against oxidative stress-induced damage in retinal pigmented epithelium (RPE) cells[94]
(−)Parthenolide	NF-κB/ histone deacetylase dual inhibitor	• Sesquiterpene • Causes downstream PI3K/AKT pathway inhibition, reducing cell proliferation and inducing apoptosis in glioblastoma as well as several adult tumor cells[95] • Apoptosis induction may be mediated by generation of reactive oxygen species (ROS)[95] • Combination with the plant-derived compound okadaic acid increased oxidative stress that led to apoptosis in Y79 retinoblastoma cells mediated by PTEN[96]
Local administration b
YM155	Survivin inhibitor	• Inhibits transcription and expression of survivin, a member of the inhibitor of apoptosis family that also regulates mitosis, DNA damage repair and autophagy[97, 98] • Survivin overexpression is associated with poor prognosis and chemoresistance in other cancers, in which its inhibition slows tumor growth in preclinical models[97, 98] • Survivin is overexpressed in retinoblastoma tumors and retinoblastoma cell cultures[83, 99] • Suppressing survivin expression reduces Y79 cell growth and migration potential, and slows tumor growth in a xenograft model[100] • Low toxicity, no ocular toxicity[101, 102] • Poorly penetrates the BBB[103] •Antitumor effects are time dependent, requiring careful attention to treatment schedule [102]
ABT-737	BH3 mimetic inhibitor	• Inhibits anti-apoptotic B-cell lymphoma-2 (Bcl-2) and Bcl-xL proteins, resulting in apoptosis[104, 105] Promotes apoptosis in commercial WERIRB1 cells; relatively nontoxic to normal human photoreceptor cells[84] • Ineffective against Y79 cells, which do not express Bax and thus, not likely to be proapoptotic inall retinoblastomas •Navitoclax, a related compound, induces apoptosis in Y79 cells; the triple combination of this agent with topotecan and RAD51 inhibitor showed synergistic effects in vitro and in vivo[106] • Related Bcl-2 inhibitor obatoclax caused neurologic symptoms in patients in clinical trials, calling for evaluation of these adverse events after ocular administration of this agent[107, 108] • Local administration recommended because of severe thrombocytopenia reported in humans with navitoclax, probably resulting from on-target BclxL inhibition[109]
BIX01294 and UNC0631	G9a/ G9a-like protein (GLP)	• G9a and GLP are histone methyltransferases and specifically methylate the non-histone target p53 at lysine 373, leading to its inactivation[110, 111]
	inhibitor	• G9a is aberrantly regulated in multiple tumors[110] • No evidence of methyltransferase dysregulation in retinoblastoma to date
Ispinesib, ARQ621, and SB743921	Kinesin spindle protein (KSP) inhibitor	• Part of a promising family of antimitotic compounds that may circumvent current limitations of the antimitotic taxanes such as neurotoxicity and resistance • Overexpression of kinesin spindle (KIF) proteins, in particular KIF14, has been associated with tumor growth and poor prognosis in several cancers, but its role in tumor development and progression is still unclear[112] • These agents also inhibit Eg5, have shown cytotoxic activity against preclinical models, and have been evaluated human Phase I/II clinical studies in other cancers[113, 114] • KIF14 overexpression is among the most frequent aberrations in retinoblastoma, observed in almost 50% of cases[115]. • Overexpression of KIF14 in a transgenic model of retinoblastoma promoted tumor formation and enhanced tumor burden[116]
NH125	Eukaryotic elongation factor 2 (eEF-2) inhibitor	•Eukaryotic elongation factor-2 kinase (eEF2K) inactivates eEF2, limiting protein synthesis under stress[117] • Activation of eEF2K has been detected in cells under stress such as nutrient deficiency and promotes cell survival by inhibiting apoptosis[117] • eEF2K overexpression in some adult tumors has been associated with tumor growth and poor patient survival[117, 118] • This agent has cytotoxic activity and causes apoptosis in several adult tumor cell lines[119]
NSC 319726	p53 reactivator	•Cytotoxic in cells and mouse tumor models carrying the TP53R175H mutation, one of the most frequent TP53 mutations that causes gain-of-function by impairing Zn binding dependence for DNA binding [120] • Functions as a zinc ionophore, delivering the metal ion to the mutant p53 and restoring wildtype conformation[120] • Increases intracellular reactive oxygen species by this transcriptional activation of p53-R175H[121] • Other mechanism for cytotoxicity in wild-type p53 cells involve binding to copper and boost of intracellular reactive oxygen species resulting in cell growth arrest[122].
BAY 11–7085	NF-κB (nuclear factor κB) α (IκBα) inhibitor	• NF-kB transcription factors are associated with tumor growth and survival in addition to key function in innate immunity[123] • In retinoblastoma, NF-kB is overexpressed compared with normal retin[124] • Inhibition of NF-kB induces in vitro retinoblastoma cell apoptosis and sensitizes cells to doxorubicin [125]
SBI-0640756	Eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) inhibitor	• EIF4G1 is a key component of the eIF4F protein complex that mediates initiation of mRNA translation • Several tumor cell lines overexpress EIF4G1 mRNA[126] • Exerts anti-proliferative effects in human melanoma cell lines[127]
Stattic	Signal transducer and activator of transcription 3 (STAT3) inhibitor	• STAT3 is a transcription factor that regulates cell cycle progression, survival, and inflammation[128]. STAT3 is constitutively activated in several human cancers and hyperphosphorylation has been associated with aggressiveness and immune evasion[129] •STAT3 is upregulated in retinoblastoma; STAT3 knockdown inhibits Y79 cell proliferation and suppresses tumor growth in vivo[130] • Non-toxic in RPE cells[131]

^aAble to cross the blood-brain or blood-ocular barriers and not associated with serious adverse events

^bCannot penetrate the blood-brain or blood-ocular barriers, or evidence that they can is not available; not associated with serious adverse events.