Abstract 4571: Combination of FOLFIRI (5-FU, Leucovorin, and Irinotecan) and ProAgio on colon cancer growth and metastasis

Abstract Background/Objective: One of the common mechanisms of resistance of solid tumors, including colon cancers, is activation of integrins on endothelial cells (ECs) and cancer-associated fibroblasts (CAFs). ProAgio is a small molecule developed to target integrin alpha V beta 3 (αvβ3), located on surface of abnormal ECs and CAFs. ProAgio enhances apoptosis and inhibits angiogenesis via targeting αvβ3. The aim of the current study is to evaluate the ProAgio combination with FOLFIRI on the immune profile and tumor growth of colon cancer. Material and Methods: Female BALB/CJ and male NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice were acquired from the Jackson Laboratory, and experiments were performed under the approval of The University of Alabama at Birmingham-Institutional Animal Care and Use Committee. For orthotropic tumor efficacy studies, BALB/CJ mice were injected with 2×105 CT-26 wild type and CT26.CL25 cells in 30ul 1:1 Matrigel Matrix and PBS into the Cecum. PDX (10mg) was orthotopically implanted into the NSG mice cecum. At Day five, mice were divided into four treatment groups: including 1) sterile water (vehicle), 2) ProAgio (15mg/kg; IP; once daily for nine days), 3) FOLFIRI (5-FU: 30mg/kg; Leucovorin 50mg/kg; Irinotecan; 20mg/kg - once every three days intraperitoneal) or 4) combination of ProAgio and FOLFIRI. The study completed on day 15, tumor weight was noted, and tumors were processed for histology and flow cytometry. Results: ProAgio plus FOLFIRI significantly (p<0.001) reduced tumor weight in both models compared to individual treatments and vehicles. Combination-treated mice showed a significant (p<0.001) reduction in T-cell exhaustion (CD8+ T cells that are positive for PD-1, TIM-3, and CTLA-4). Analysis of the myeloid compartment showed a significant (p<0.001) increase in the M1 macrophages that express F4/80 as well as CD86, MHC-II and a decrease in the M2 macrophage in the mice treated with ProAgio plus FOLFIRI. The combination therapy exhibited a significant (p<0.001) increase in the dendritic cell infiltration into the tumor microenvironment. Histology analysis showed that ProAgio treatment reduced the incidence of organ site metastasis (disseminated and locoregional spread) such as liver, pancreas, and diaphragm. Conclusion: Our study offers encouraging observations that ProAgio plus FOLFIRI can suppress colon cancer growth and metastasis by inhibiting αvβ3 preclinically and may provide a novel therapeutic combination for the management of colon cancers. Citation Format: Purnachandra Nagaraju Ganji, Jeremy B. Foote, Madhu Sudhana Saddala, Falguni Mishra, Sujith Sarvesh, Midhun Malla, Ashiq Masood, Zhi-Ren Liu, Bassel F. El-Rayes. Combination of FOLFIRI (5-FU, Leucovorin, and Irinotecan) and ProAgio on colon cancer growth and metastasis [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 4571.