Abstract CT165: Modifying the tumor microenvironment in gastric and gastroesophageal junction adenocarcinoma using a cGMP-phosphodiesterase inhibitor
Abstract
The current standard approach for locoregional gastric and gastroesophageal junction adenocarcinoma (GAC) includes perioperative chemoimmunotherapy with 5-florouracil, oxaliplatin, docetaxel, and durvalumab (FLOT-D). However, FLOT-D shows limited efficacy with suboptimal response rates, high recurrence risk, and unproven long-term outcomes, highlighting an unmet need for new targets. Our murine preclinical studies identified a subset of Schlafen4 (SLFN4) expressing myeloid derived suppressor cells (MDSCs) that correlate with metaplasia. These SLFN4+-MDSCs are programmed death-ligand1 (PD-L1) positive and display a strong type I interferon inducible transcriptional program and potent T cell suppressor activity. Sildenafil suppressed SLFN4+-MDSCs, restored T cell function, and reduced metaplasia, supporting a therapeutic potential for cGMP-dependent phosphodiesterase (PDE) inhibition. Here we present the results of a first in human, proof of principle, window of opportunity, clinical trial, designed to modify GAC tumor microenvironment (TME) marked by inhibiting cGMP-PDEs and SLFN12L+-MDSCs.
Using single-cell RNA sequencing, we examined tissues from stage I-III GAC patients (n=10) enrolled in this phase II, single arm study (NCT05709574). The patients received tadalafil (20mg) for 14 days, followed by combined tadalafil and FLOT for 8 weeks. Gastric tissue and fluids (blood and urine) were collected i) before treatment, ii) after 14 days of tadalafil, and iii) after 8 weeks of…
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