Post-doctoral Fellowship Grant Awarded to Ryan Duchatel

We face many major challenges in the development of treatment approaches that increase the survival of DIPG/DMG patients. Two of the most vexing of these are i) therapies that penetrate the brain’s highly protective blood-brain barrier (BBB) in sufficient quantitates to show an anti-DIPG effect in vivo, and ii) therapies that are selective for DIPG cells without causing systemic toxicities. Given traditional cytotoxic chemotherapies do not pass through the BBB, our best hope of achieving long-term survival is if we can develop treatment modalities that combine and amplify the benefits of standard-of-care radiotherapy (RT), and then exploit the unique biology of DIPG as a consolidation strategy.

Seeking to address these key areas of unmet need, my research has focused on optimizing the BBB penetrant therapy ‘paxalisib’, for the treatment of DIPG. Over the last four years, we have discovered that the cellular targets of paxalisib, i.e., the PI3K-pathway (PIK3CA, mTOR) are critical for DIPG cell survival. However, clinically, it has proven difficult to elucidate the full benefit of paxalisib due to numerous systemic and cellular responses that combine to reduce its efficacy. But thanks to the work of our laboratory, we now know what these rescue mechanisms are, and how to target them to drive a potent and sustained anti-DIPG response.

This Fellowship will enable the preclinical optimization of strategies using paxalisib as a backbone to inform the established adaptive clinical trial PNOC022 (NCT05009992), currently testing radiotherapy in combination with paxalisib and ONC201. Our team is responsible for the preclinical and case study results that underpins this international clinical trial. Specifically, this Fellowship will optimize the use of paxalisib in combination with RT by taking into consideration the effects of corticosteroids, optimize therapies that modulate insulin feedback driven by systemic PI3K-inhbition, and develop consolidation strategies that simultaneously target DIPG-specific escape mechanisms following partial PI3K-
pathway inhibition.