A new drug might help successfully treat mesothelioma, one of the deadliest cancers, according to results from cell culture and mouse xenograft models of the disease. The drug, HXR9, blocks receptors in the HOX family.1
Though rare, mesothelioma diagnosis has a poor prognosis, with median survival at 12 months after diagnosis. Asbestos exposure is the most frequent cause of the disease.
HOX genes are a family of homeotic genes that regulate the body plan in a developing embryo. Until now, it had been unknown whether they had a role in the development and progression of mesothelioma.
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This study, published in BMC Cancer, used 3 different mesothelioma-derived cell lines to examine whether HOX genes are involved in the disease’s characteristic resistance to a process called apoptosis. Apoptosis is akin to ‘cell suicide’ and can eliminate deregulated cells. HOX genes were significantly deregulated in mesothelioma, as measured by gene expression with RT-QPCR.
Researchers then administered HXR9, a protein that blocks HOX receptors, to the 3 mesothelioma-derived cell cultures and measured apoptosis. HXR9 treatment caused apoptosis in all 3 cell lines. Cell line sensitivity to HXR9 correlated with the amount of expression of HOX genes.
“Both the immune system and nearby healthy cells send signals instructing damaged and unhealthy cells to undergo apoptosis, which is like programmed ‘cell suicide’. But cancer cells have developed a wide range of strategies to ignore these instructions,” said Richard Morgan, PhD, professor of molecular oncology and director of the Institute of Cancer Therapeutics at the University of Bradford, Bradford, United Kingdom, and first author of the study.
“There’s a range of drugs which try to force apoptosis in different cancers, but this is the first one to work in mesothelioma.”
In a mouse xenograft model of mesothelioma, HXR9 treatment prevented growth of tumors. With these results, researchers then examined the expression of specific HOX genes from mesothelioma tumor samples from patients. Five patients were female, and 16 were male. They observed that patients with the shortest overall survival, less than 6 months, had the highest expression of HOXB4 (P = .0166).
“We’ve effectively knocked out a key defense mechanism in this cancer through targeting the HOX genes,” stated Morgan.
“We examined the amount of HOXB4 protein in tumors of 21 mesothelioma patients and compared it with their length of survival. There was a clear link: the more HOXB4 we found, the shorter time the patient survived, so we may also have found a way to predict which patients have the most aggressive form of this cancer,” explained Morgan.
REFERENCE
1. Morgan R, Simpson G, Gray S, et al. HOX transcription factors are potential targets and markers in malignant mesothelioma [published online ahead of print February 11, 2016]. BMC Cancer. doi:10.1186/s12885-016-2106-7.
