KCN1 Suppresses Metastatic Uveal Melanoma, in Mice

Article: Melanoma of the eye: preclinical tests show path toward treatment
Source: University of Alabama at Birmingham, via ScienceDaily  and NEI
Published: July 14, 2021

Uveal melanoma (UM) is a type of cancer of the vascular, pigmented middle layer of the eye, the uvea. Though rare among cancers, uveal melanoma is the most prevalent primary intraocular malignancy in adults and can be both vision- and life-threatening as the cancer metastasizes to other tissues of the body. Researchers have identified an inhibitory molecule, arylsulfonamide KCN1, that dampens drivers of tumorgenesis in animal models, limiting both the primary disease in the eye and metastatic tumor dissemination to the liver. The animals treated with KCN1 also survived longer, without overt side effects. Tumor progression and metastasis in uveal melanoma is associated with hypoxia-inducible transcription factor (HIF), which turns on many gene products that promote cancer growth, including proliferation, migration, invasion and adhesion of tumor cells as well as angiogenesis to feed the tumor. Two of these gene products, P4HA1 and P4HA2, promote collagen deposition in the extracellular matrix, which in turn reorganizes the extracellular matrix in a way that aids cancer progression and tumor cell invasion. Comparison of 46 patients with non-metastatic UM and 46 with metastatic UM showed that P4HA1 and P4HA2 were significantly overexpressed in patients with metastatic disease, and furthermore correlated with poor survival outcomes in UM patients, suggesting that P4HA1 and P4HA2 could serve as prognostic markers in UM. When tested in human UM cell lines, the researchers found that P4HA1 and P4HA2 were induced by hypoxia, and this induction was reduced by KCN1. In animal models injected (intraperitoneally) with KCN1, the molecule was abundantly taken up in the liver and in the eyes. KCN1 dampened tumor growth in the eye and reduced metastases in the liver, especially when administered early. Although the study suggests that “KCN1 has desirable properties as a suppressor of metastasis: It is well tolerated, has excellent distribution to the eye and the liver, and is thus ideally suited for treating metastatic UM," the researchers also caution that the drug needs further optimization before clinical use.

Personal commentary: A direct quote from my notes regarding hypoxia-inducible transcription factor HIF-1, from August 20, 2018: "Toward the end of the lecture, we learned about some of the nonstandard amino acids. Of note in particular was hydroxylproline, which is an important component of collagen, which in turn is an important component of both skin and corneas. Hydroxylproline also acts as an oxygen sensor. In the presence of oxygen, prolyl hydroxylase adds hydroxyl to proline residues on transcription factor Hif-1, tagging it for ubiquitination. (HIF = hypoxia-induced factor.) In hypoxia, proline is not hydroxylated, and angiogenesis follows. Relevant to hypoxia-induced hyperemia and vascular-related retinal diseases!!!"

My rating of this study: ⭐⭐

Kaluz S, Zhang Q, Kuranaga Y, et al. "Targeting HIF-activated collagen prolyl 4-hydroxylase expression disrupts collagen deposition and blocks primary and metastatic uveal melanoma growth." Oncogene.  3 July 2021. https://doi.org/10.1038/s41388-021-01919-x