Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis

by Selleckchem | Nov 03 2023

Medulloblastoma is the most common malignant pediatric brain tumor. Amplification of c-MYC is a hallmark of a subset of poor-prognosis medulloblastoma. MYC upregulates glutamine metabolism across many types of cancer. We modified the naturally occurring glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) by adding 2 promoeities to increase its lipophilicity and brain penetration creating the prodrug isopropyl 6-diazo-5-oxo-2-(((phenyl (pivaloyloxy) methoxy) - carbonyl) amino) hexanoate, termed JHU395. This prodrug was shown to have a 10-fold improved CSF-to-plasma ratio and brain-to-plasma ratio relative to DON. We hypothesized that JHU395 would have superior cell penetration compared with DON and would effectively and more potently kill MYC-expressing medulloblastoma. JHU395 treatment caused decreased growth and increased apoptosis in multiple human high-MYC medulloblastoma cell lines at lower concentrations than DON. Parenteral administration of JHU395 in Nu/Nu mice led to the accumulation of micromolar concentrations of DON in brain. Treatment of mice bearing orthotopic xenografts of human MYC-amplified medulloblastoma with JHU395 increased median survival from 26 to 45 days compared with vehicle control mice (p < 0.001 by log-rank test). These data provide preclinical justification for the ongoing development and testing of brain-targeted DON prodrugs for use in medulloblastoma.

Comments:

The passage you provided describes a study conducted on medulloblastoma, which is a common malignant brain tumor found in pediatric patients. In a subset of medulloblastoma cases, the amplification of a gene called c-MYC is observed, and this is associated with a poor prognosis.

The researchers in this study aimed to develop a more effective treatment for MYC-expressing medulloblastoma by targeting glutamine metabolism. Glutamine is an important nutrient for cancer cells, and MYC has been found to upregulate glutamine metabolism in various types of cancer.

To target glutamine metabolism in medulloblastoma, the researchers modified a naturally occurring compound called 6-diazo-5-oxo-l-norleucine (DON). They added two groups to DON to increase its lipophilicity (ability to dissolve in fats) and brain penetration. This modified compound, called JHU395, was designed as a prodrug, which means it is converted into its active form inside the body.

The researchers hypothesized that JHU395 would have better cell penetration and would effectively kill MYC-expressing medulloblastoma cells compared to DON. They tested this hypothesis by treating human high-MYC medulloblastoma cell lines with JHU395 and comparing the results to treatment with DON.

The results of the study showed that JHU395 treatment resulted in decreased tumor growth and increased apoptosis (cell death) in the MYC-expressing medulloblastoma cell lines. Importantly, JHU395 demonstrated greater potency than DON, as it achieved these effects at lower concentrations.

To assess the effectiveness of JHU395 in a living organism, the researchers administered the prodrug to mice with MYC-amplified medulloblastoma tumors. They found that JHU395 was able to accumulate in the brain at micromolar concentrations after parenteral administration. The treatment with JHU395 significantly increased the median survival of the mice compared to the control group that received no treatment.

Based on these preclinical findings, the researchers concluded that brain-targeted DON prodrugs, such as JHU395, hold promise for the development of improved treatments for medulloblastoma. Further development and testing of these prodrugs are warranted to assess their potential clinical application for patients with medulloblastoma.