Combined treatment with paxalisib and mirdametinib significantly extends survival of SJ-DIPGX37-bearing mice.

Combined treatment with paxalisib and mirdametinib significantly extends survival of SJ-DIPGX37-bearing mice.



ARTICLE
Patient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma (pHGG).
Nature Communications - Published 2 July 2021.

https://www.nature.com/articles/s41467-021-24168-8.pdf

Discussion
Among available inhibitors of PI3K/mTOR and MEK, we selected paxalisib and mirdametinib, respectively,for in vivo studies because of their ability to traverse the blood–brain barrier. In vivo testing with these drugs induced dramatic inhibition of pathway activity in both PDOXs with differential tumor responses consistent with in vitro studies. SJ-DIPGX7 showed relative resistance to MEK inhibition and a more moderate impact of combined PI3K/mTOR inhibition compared with the more responsive SJ-DIPGX37, where the drug combination drove greater cytotoxic and cytostatic responses and extended survival of mice carrying intracranial tumors. Additional in vivo studies would be needed to determine if the in vitro screening results are predictive of response in all cases. Identifying reliable biomarkers to accurately predict response from biopsy samples will likely require a significantly larger collection models. Pharmacokinetic (PK) analyses showed no substantial drug–drug interaction changing drug exposures, so the enhanced effects are likely to represent the result of combined pathway inhibition. However, levels of mirdametinib used to effectively block signaling in our study were significantly higher than those observed in humans following exposure at the current clinical dosing of 4 mg twice daily. Given the compelling survival advantage and observed in vivo toxicity, there is a rationale to consider local delivery of PI3K/mTOR and MEK inhibitors to these tumors to avoid systemic toxicities and reach the necessary levels of drug activity.It is promising that the majority of compounds screened in our study showed substantially greater efficacy across all of the tumor models tested when compared to temozolomide, which is still frequently used in treating pHGG.

Onesurfed, thank you for posting the article, and yes paxalisib in combination with mirdametinib significantly extends survival of SJ-DIPGX37-bearing mice.
Dr Matt Dun's DIPG study using the combination of paxalisib with ONC-201 in humans, is presently being reviewed before publication. - EUREKA !

Kazia new clinical trial, PNOC022, will employ an adaptive trial design to test several therapies in different combinations and in different subsets of patients. In addition to paxalisib, the other therapies involved will initially include ONC201, manufactured by Oncoceutics, Inc, and panobinostat, manufactured by SecuraBio, Inc. The study is expected to open initially in the United States and will then expand to other countries during CY2021

Regards.