Actually I think we have here very significant research here. An easier version to read, at the bottom.
Research comes not only from people at Dana Farber, but Memorial Sloan Kettering and Weill Cornell.
When the results are released from the paxalisib study in GBM AGILE - they must be taken in context of this research, from Weill Cornell and these highly credentialed other researchers here.
Post release of results, dealings with the FDA, will/should be driven by GBM AGILE - in the context that paxalisib in GBM AGILE is a sub optimal study. Its very clear that is the case now - GBM AGILE results are far from a BE ALL, END ALL situation. If you doubt what I have just said - slowly read and understand what is being said here, at the bottom.
-------- "These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in glioblastoma"
Hyperglycaemia is the medical term for a high blood sugar (glucose) level. It's a common problem for people with diabete
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It is suggested, there is modest complexity - in GBM patients moving to an insulin reduced diet and metformin / paxalisib combination....in future treatment for GBM. FDA have spoken about a willingness to use logic in any future drug approval situations - given the limited other treatments in this deadly disease.
Much focus will turn to the Weill Cornell combination results - which can very much compliment what comes out of GBM AGILE.
Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma
Evan K Noch, Laura N Palma, Isaiah Yim, Nayah Bullen, Yuqing Qiu, Hiranmayi Ravichandran, Junbum Kim, Andre Rendeiro, Melissa B Davis, Olivier Elemento, David J Pisapia, Kevin Zhai, H Carl LeKaye, Jason A Koutcher, Patrick Y Wen, Keith L Ligon, Lewis C Cantley Neuro-Oncology, noad117, https://doi.org/10.1093/neuonc/noad117
Published:
03 July 2023 Abstract
Background
Insulin feedback is a critical mechanism responsible for poor clinical efficacy of PI3K inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma. We investigated combination anti-hyperglycemic therapy in a mouse model of glioblastoma and evaluated the association of glycemic control in clinical trial data from patients with glioblastoma.
Methods
The effect of the anti-hyperglycemic regimens metformin and the ketogenic diet were evaluated in combination with PI3K inhibition in patient-derived glioblastoma cells and an orthotopic glioblastoma mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent glioblastoma.
Results
We found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves treatment efficacy in an orthotopic glioblastoma xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with glioblastoma. We also found that PI3K inhibition increased insulin receptor activation and T cell and microglia abundance in tumor tissue from these patients.
Conclusion
Reducing insulin feedback improves the efficacy of PI3K inhibition in glioblastoma in mice, and hyperglycemia worsens progression-free survival in patients with glioblastoma treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in glioblastoma and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in glioblastoma patients.
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