State of the Art of Pharmacological Activators of p53 in Ocular Malignancies

Abstract

The pivotal role of p53 in the regulation of a vast array of cellular functions has been the subject of extensive research. The biological activity of p53 is not strictly limited to cell cycle arrest but also includes the regulation of homeostasis, DNA repair, apoptosis, and senescence. Thus, mutations in the p53 gene with loss of function represent one of the major mechanisms for cancer development. As expected, due to its key role, p53 is expressed throughout the human body including the eye. Specifically, altered p53 signaling pathways have been implicated in the development of conjunctival and corneal tumors, retinoblastoma, uveal melanoma, and intraocular melanoma. As non-selective cancer chemotherapies as well as ionizing radiation can be associated with either poor efficacy or dose-limiting toxicities in the eye, reconstitution of the p53 signaling pathway currently represents an attractive target for cancer therapy. The present review discusses the role of p53 in the pathogenesis of these ocular tumors and outlines the various pharmacological activators of p53 that are currently under investigation for the treatment of ocular malignancies.

CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells

“…p53 mutations are very rare, and MDM4 is overexpressed in UM [ 6 , 11 ]. Therefore, we hypothesized that, similar to its effects in retinoblastoma, CEP-1347 may also effectively suppress MDM4, which is a functional p53 inhibitor.…”

“…Recent studies have focused on the development and clinical testing of novel p53-activating small molecules for AML, multiple myeloma, and other hematological malignancies [ 44 ]. Alrizomadlin (APG-115), a small-molecule inhibitor that selectively targets the p53-MDM2 interaction, has been approved by the US FDA and exhibited preliminary antitumor activity in UM [ 6 ]. Additional information on the safety and antitumor effects of these MDM2 inhibitors in UM patients may facilitate the translation of combinations of CEP-1347 and MDM2 inhibitors into the treatment of UM.…”

“…However, advanced cases do not respond to local therapy, and due to the lack of effective chemotherapy, large lesions, lesions with vitreous seeds, and lesions with optic nerve involvement require enucleation of the eye [ 4 ]. Moreover, approximately 50% of UM patients develop distant metastases in the liver and other organs via the bloodstream, resulting in a poor prognosis [ 3 , 5 , 6 ]. Metastatic UM is often resistant to chemotherapy [ 7 ], and immune checkpoint inhibitors, such as PD-1 antibodies, have limited effects [ 8 , 9 , 10 ].…”

“…TP53 , a tumor suppressor gene that encodes the p53 protein, is frequently mutated in human cancers. However, unlike other human cancers, the p53 mutation is relatively rare in UM [ 6 , 11 ]. Instead, the function of wild-type p53 in UM is often inactivated by negative regulators of p53, such as murine double minute 2 (MDM2) and MDM4 (MDMX).…”

Retinal Alterations Predict Early Prodromal Signs of Neurodegenerative Disease

“…Vascular pathology is another key feature of the eye in AD patients, as well as in other ocular vascular diseases (i.e., diabetic retinopathy, retinal and macular edema, retinal vein occlusion), where the vascular damage alters nutrient supply and the Aβ clearance, further promoting retinal degeneration [3,[166][167][168][169][170]. Further studies of postmortem retinas have identified the deposition of Aβ aggregates and NFTs in ganglion cells, amacrine cells, horizontal cells, and Müller cells of the inner and outer plexiform layers, which correlate with the cortical cerebral pathology burdens, demonstrating the relationship between ocular-brain pathology and cognitive impairment [57][58][59][60].…”