A team of researchers at the University of Michigan Health Rogel Cancer Center has designed a molecule that impairs signaling mediated by two key drivers of cancer therapy resistance.
The design and preclinical evaluation of the inhibitor, MTX-531 was published in Nature Cancer.
Researchers, led by Judith Sebolt-Leopold, Ph.D., discovered MTX-531, a kinase inhibitor with the ability to selectively block both epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-OH kinase (PI3K).
Sebolt-Leopold is research professor of radiology and pharmacology at Michigan Medicine and co-leader of Rogel’s developmental therapeutics programme.
The researcher said: “By dual targeting of EGFR and PI3K, MTX-531 acts to shut down the escape mechanisms that tumours use to resist treatment.
“In certain cancers, such as head and neck squamous cell carcinomas, each of these kinases are known to mediate resistance to inhibition of the other.”
The study shows that, in mouse models, MTX-531 led to tumour regressions in multiple head and neck cancer models and was well tolerated.
Furthermore, MTX-531, in combination with drugs targeting the RAS pathway, was shown to be highly effective against KRAS-mutated gastrointestinal tumours originating in the colon or pancreas.
Other PI3K inhibitors are associated with hyperglycemia, which can be severe enough that treatment must be stopped.
MTX-531 does not lead to this side effect, indicating it could become a less-toxic treatment option.
The innovative design of MTX-531 was achieved through a computational chemistry approach, led by Sebolt-Leopold and Christopher Whitehead, Ph.D., a former member of the Leopold laboratory team, and currently chief operating officer of MEKanistic Therapeutics, Inc.
Advanced development activities are underway to support the clinical evaluation of MTX-531.
Researchers are hopeful that these studies will ultimately lead to initiation of clinical trials in patients.
