For over fourteen years, neoadjuvant 5-fluorouracil chemoradiation (5FU/RT) has remained the standard option for patients with rectal cancer (RC), a deadly cancer in our Veterans. Unfortunately, therapeutic resistance is evident in ~80% of these cases, increasing the chances of surgical failure, disease recurrence, and ultimately, death. These issues highlight the current lack of effective therapeutic strategies required to advance care due, in part, to the lack of clinically relevant RC research models. To address these critical barriers, our multi-disciplinary team established complimentary RC patient-derived xenograft (PDX) and organoid models as translational platforms that closely mirror the human tumor. Our project seeks to transform RC care by designing and testing novel biomarker-directed therapeutic strategies which can then be translated rapidly to clinical application using our RC PDX.
Tumor-initiating cells (TICs) with stem cell-like properties drive tumor growth and therapy failure. Our published work identified the Snail Family Transcriptional Repressor 1 (SNAI1) as a central mediator of RC self-renewal capacity and, closely related, RT resistance (3). Unfortunately, TICs and SNAI1 are challenging to therapeutically target. Together with MUSC’s world-class sphingolipid research team, we recently determined that SNAI1 decreases ceramide levels associated with increased expression of essential sphingosine-1-phosphate (S1P) pathway members including sphingosine kinase 2 (SK2).
The role of bioactive sphingolipids in promoting SNAI1-mediated therapy resistance is largely unexplored and may represent a therapeutic vulnerability. We hypothesize that SNAI1 drives dysfunction of sphingolipid metabolism by activating S1P pathways to amplify TIC self-renewal capacity and RT resistance (Fig 1). Conversely, we hypothesize that SK2 inhibition will target resistant TICs to enhance RT response, thereby improving the effectiveness and durability of 5FU/RT. We propose to evaluate the specific SK2 inhibitor ABC294640 developed by our sphingolipid program and already in clinical trials. ABC294640 represents an exciting clinic-ready novel agent for RC patients.