# Targeting Sphinogsine-1-phosphate to overcome SNAI1-mediated therapy resistance in rectal cancer

> **NIH VA I01** · MICHAEL E DEBAKEY VA MEDICAL CENTER · 2021 · —

## Abstract

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. Aligned with the goals set forth
in the VA’s Blueprint for Excellence, 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. Unfortunately, TICs and SNAI1 are challenging to
target therapeutically. 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. 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 novel SK2 inhibitor ABC294640 that was developed by our program
and already tested in Phase 1 trials representing a next-generation therapeutic strategy for RC patients.
 In this grant proposal, we will (1) define the role of S1P activation in mediating SNAI1- self renewal and
the TIC phenotype, 2) determine if SNAI1-driven RT resistance is regulated by increased ceramide
metabolism, and (3) evaluate SK2 inhibition as a strategy to enhance 5FU/RT by targeting the TIC in RC
patient-derived organoid and xenograft models. By decreasing resistance to the best current therapies, this
project has the potential to provide better outcomes for the VA’s rectal cancer patients who so desperately
need improved care. The strengths of a highly translational RC-focused research program that has developed
unique patient-derived RC models are combined with our world-class sphingolipid group that has pioneered
S1P-directed thera...

## Key facts

- **NIH application ID:** 10129892
- **Project number:** 7I01CX001880-03
- **Recipient organization:** MICHAEL E DEBAKEY VA MEDICAL CENTER
- **Principal Investigator:** Ernest Ramsay Camp
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 7
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129892

## Citation

> US National Institutes of Health, RePORTER application 10129892, Targeting Sphinogsine-1-phosphate to overcome SNAI1-mediated therapy resistance in rectal cancer (7I01CX001880-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129892. Licensed CC0.

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