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Hybrigenics Presents Data on Investigational Anti-Cancer Agent That May Need Companion Test

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By Turna Ray

HX 41,108, an anti-cancer agent being developed by Hybrigenics, has demonstrated in preliminary studies that it can inhibit ubiquitin-specific protease no. 7, an enzyme critical to the regulation of the tumor suppressor protein p53.

The data, while preliminary, suggests that the drug might require a companion diagnostic to establish p53 status prior to treatment, company officials said.

Researchers from Paris-based Hybrigenics and others found in a clinical trial that the small-molecule candidate can inhibit USP7, which activates functional p53 and stops the growth of p53-dependent cancer cell lines. The compound, called HBX 41,108, has "a demonstrated potential to become an innovative anti-cancer drug candidate after further chemical optimization," Hybrigenics said in a statement this week.

Researchers published their findings in Molecular Cancer Therapeutics earlier this month.

In the study, researchers used high-throughput screening to discover the impact of HBX 41,108 on USP7 deubiquitinating activity. "Kinetics data indicate an uncompetitive reversible inhibition mechanism," researchers reported in the article.

Specifically, researchers found that HBX 41,108 affected USP7-mediated p53 deubiquitination in vitro and in cells. Furthermore, "HBX 41,108 treatment stabilized p53, activated the transcription of a p53 target gene without inducing genotoxic stress, and inhibited cancer cell growth," the abstract states. "Finally, HBX 41,108 induced p53-dependent apoptosis as shown in p53 wild-type and null isogenic cancer cell lines."

Although HBX 41,108 is in the discovery stage, Hybrigenics CEO Rémi Delansorne told Pharmacogenomics Reporter that this data suggests that down the line, a companion diagnostic might be necessary to establish p53 status prior to treatment with the drug.

"The rationale of USP7 inhibition is applicable only to p53-positive tumors," Delansorne said. As a result, "the p53 status of the tumor would be an important criterion to assess, from a biopsy, for example, in addition to routine pathological characterization on microscopic slides."

According to Delansorne, if HBX 41,108 reaches commercialization, Hybrigenics would collaborate with a diagnostic company or laboratory to develop a companion test for the drug.

Roche Molecular Diagnostics has designed a companion assay for the anticancer agent Nutlins that first PCR-amplifies the p53 gene from DNA samples and then uses a sequencing microarray to determine the p53 genotype. Nutlins and the companion Dx are still in clinical trials.

Since USP7 inhibitors, such as HBX 41,108, induce p53 reactivation, "similarly to Nutlins, the p53 status of the tumour would be an important criteria to assess," Frédéric Colland, director of biological research at Hybrigenics, told Pharmacogenomics Reporter this week.

Hybrigenics could not forecast a development timeline for HBX 41,108, as the compound has yet to enter preclinical development and chemical optimization. This will "result in another molecule than HBX 41,108 as a candidate for development," Delansorne noted.

Deregulation of the ubiquitin/proteasome system has been implicated in the pathogenesis of cancer and other diseases. Ubiquitin-specific proteases are involved in the deubiquitination of protein substrates. Due to the link between USP7 and proteins such as p53 critical to oncogenic pathways, studies suggest that small-molecule inhibitors, such as HBX 41,108, may treat cancer.

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