Abstract 5932: Immunomodulatory and anticancer effects of cyclical gemcitabine/nab-paclitaxel with continuous dosing of tinodasertib (AUM001) in preclinical KPC model

Abstract

Abstract Background: PDAC has a poor 5-year survival outcome, and its aggressiveness limits the treatment efficacy. This is often driven by dysregulated mRNA translation of pro-tumorigenic genes that contribute to the proliferative and metastatic nature of PDAC. Synergizing chemotherapy with inhibition of oncogenic mRNA translation via MNK-coupled phosphorylation of eIF4E could potentially be viable. To support this hypothesis, we combined AUM001, a MNK inhibitor, with gemcitabine (GEM)-nab-paclitaxel (nPTX) with the aim of modulating tumor growth kinetics and maintaining it in a stable state. Methods: PDAC KPC cells were subcutaneously inoculated into BL6 mice and randomized to five treatment groups. Chemotherapy involved administering GEM-nPTX intraperitoneally on days 1, 4, and 8. AUM001 was given orally daily for 8 days for both mono- and combination therapies and was further administered for an additional 3 weeks in continuous dosing group. IHC staining for Ki67, MVD, and stromal markers was conducted on FFPE sections as well as Western blot analysis of tumor tissues. Apoptosis was assessed using Annexin V. Immune profiling were evaluated by flow cytometric assay and GeoMx spatial transcriptomics analysis. Results: The administration of GEM-nPTX and AUM001 (GPA) or GEM-nPTX alone (GP) led to an average 38% reduction in net tumor growth with no observed toxicity. Notably, continuous dosing of AUM001 (GPAc) following the cessation of chemotherapy exhibited a 45% decrease in net tumor growth (P=0.056) when compared to GPA. EIF4E phosphorylation and Myc expression were markedly inhibited in GPAc with lower recovery rate for MVD as compared to the GPA group at EOO (P < 0.05). A higher fraction of apoptotic cells was detected in the GPAc group at EOO than GPA group in reference to GP group (P=NS). GPA also resulted in a lower frequency of NK cells which was partially lifted in GPAc during observation phase. Macrophages which are known to have a pro-tumor role initially increased in frequency upon addition of AUM during chemotherapy, but subsequently decreased during observation. These modulations in infiltrating immune cells correlated with the differential expression of several immune related genes in the tumor associated CD45+ immune cells, revealed by the GeoMx analysis. Conclusions: This study showed that sustained administration of AUM001 alongside cyclical GEM-nPTX is well-tolerated with good anti-tumor outcomes. Additionally, the maintenance of AUM001 may enhance the decrease in pro-oncogenic protein expression and remodel the tumor immune microenvironment. In conclusion, continuous dosing of AUM001 following the cessation of chemotherapy could stabilize the tumor state, potentiating its application in clinical settings as maintenance therapy for PDAC. Citation Format: Wai Fook Leong, Sze Sing Lee, Jyue Yuan Lim, Siwen Sylvialin Chen, Fara Faye Desacola Regis, Romana Vidergar, Subhra K. Biswas, Balram Chowbay. Immunomodulatory and anticancer effects of cyclical gemcitabine/nab-paclitaxel with continuous dosing of tinodasertib (AUM001) in preclinical KPC model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5932.