Uveal melanoma, or MU, is a rare and fatal eye cancer, and the death rate has not increased for 40 years. Half of melanomas spread to other organs in the body, causing death within a year. New treatments to preserve vision and prevent death are therefore urgently needed.
Now, a preclinical study by researchers at the University of Alabama, Birmingham and Emory University, Atlanta, offers hope – a small-molecule inhibitor has been identified that dampens potent drivers of this disease. tumor. In mouse models, the inhibitor, KCN1, severely limited primary disease in the eye and spread of metastatic tumor to the liver, and the animals survived longer with no obvious side effects.
Thus, this class of inhibitory compounds shows promise, although the research co-leads – Erwin Van Meir, Ph.D., professor of neurosurgery at UAB, and Hans Grossniklaus, MD, MBA, professor of ophthalmic pathology at Emory – – say the drug still needs to be optimized before clinical use.
“Overall”, they wrote in the article published in the newspaper Oncogene, “Our preclinical studies support the further translation of the arylsulfonamide KCN1 scaffold into a novel treatment for patients with metastatic uveal melanoma.” The uvea is the pigmented layer of the eye.
Prior to this study, it was known that: 1) a hypoxia gene signature, indicating low oxygen levels in the tumor, is associated with a poor prognosis and high metastasis rate in uveal melanoma; 2) the hypoxia-inducible transcription factor, or HIF, activates a large number of gene products with critical roles in cancer growth and metastasis; and 3) for UM specifically, HIF promotes tumor progression by regulating proliferation, migration, invasion and adhesion of tumor cells, as well as promoting the growth of blood vessels to nourish the tumor.
Little was known about the role of HIF in directing pro-invasive extracellular matrix remodeling in MU. Changes in the extracellular matrix, including increased collagen deposition and reorganization of collagen fibers outside the cell, are known to promote cancer progression and tumor cell invasion. The extracellular matrix is the non-cellular component of all tissue that provides a physical scaffold for cells and has other biochemical roles.
Hypoxia promotes collagen deposition, in part because HIF increases the production of two gene products, P4HA1 and P4HA2, which are part of an enzyme complex that adds hydroxyl residues to prolines in procollagen. Procollagen is a precursor protein in the complex maturation process that collagen undergoes.
In their study, Van Meir, Grossniklaus and their colleagues decided to evaluate the expression of the P4HA1 / 2 genes in relation to the prognosis of patients with MU and to determine whether the inhibition of the expression of P4HA1 / 2 induced by hypoxia in a preclinical model of metastatic MU would produce therapeutic effects. advantage.
They found that P4HA1 and P4HA2 were induced by hypoxia in human UM cell lines, and this induction was reduced by KCN1. Comparison of 46 patients with non-metastatic MU and 46 with metastatic MU showed that P4HA1 / 2 was significantly overexpressed in patients with metastatic disease. In addition, expression of P4HA1 / 2 was correlated with poor overall survival in patients with MU. This suggests that P4HA1 and P4HA2 may serve as prognostic markers in MU, and that they may be important for malignant disease progression and patient survival.
The researchers then turned to preclinical animal models of UM. They have shown that KCN1 is abundantly absorbed in the liver and eyes after intraperitoneal injection, and that it attenuates tumor growth and disease burden at the primary site of the eye, as well as the reduction of distant metastases. in the liver. KCN1 also increased survival in three different models that test the growth of human MU after injection into the uvea of mice. The inhibitor was more effective in reducing metastasis when given early.
At the molecular level, treatment with KCN1 to inhibit hypoxic induction of P4HA1 / 2 decreased amino acid hydroxylation of proline in procollagen. It also caused the cleavage of collagen and disorganized the structure of collagen VI, a mature structural component of the extracellular matrix. These changes in collagen were correlated with a reduction in tumor cell invasion.
“Our study,” concluded Van Meir and Grossniklaus, “suggests that KCN1 has desirable properties as a metastasis suppressor: it is well tolerated, has excellent distribution in the eye and liver, and is therefore ideally suited for treat metastatic MU. “
Reference: Kaluz S, Zhang Q, Kuranaga Y, et al. Targeting expression of HIF-activated collagen prolyl 4-hydroxylase disrupts collagen deposition and blocks the growth of primary and metastatic uveal melanoma. Oncogene. 2021: 1-10. do I: 10.1038 / s41388-021-01919-x
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