Abstract 5666: Akos: A novel CAF-targeted therapy to reprogramming the tumor microenvironment to reverse metastatic traits in all solid tumors

Abstract Introduction: Metastasis is responsible for approximately 90% of cancer-related deaths, yet current therapies fail to effectively address this critical challenge. The tumor microenvironment (TME), particularly carcinoma-associated fibroblasts (CAFs), plays a pivotal role in metastatic progression by driving extracellular matrix (ECM) remodeling, epithelial-to-mesenchymal transition (EMT), and immune evasion. Within metastatic CAFs (mCAFs), we identified a key protein that regulates these processes and developed Akos, a small molecule that selectively inhibits this protein, reprogramming the TME to disrupt the metastatic cascade. This study evaluates the preclinical efficacy, specificity, and safety of Akos across multiple solid tumor models. Materials and Methods: Primary stromal cell cultures were obtained from needle biopsies of primary tumors from patients with advanced/metastatic cancer (mCAFs), non-metastatic cancer (CAFs), and non-cancerous patients (BAFs). Protein expression was validated through gene profiling, immunohistochemistry, and western blot. In vitro assays were conducted to assess Akos’ ability to inhibit mCAF-mediated tumor cell invasion, proliferation, and EMT marker expression. In vivo xenograft models of prostate, breast, colorectal, and pancreatic cancers were utilized to evaluate Akos’ effects on tumor growth, weight, and metastatic spread. A spontaneous metastasis assay, replicating the full metastatic cascade, was employed to evaluate its anti-metastatic potential. Toxicology and pharmacokinetic studies were conducted to assess systemic safety and drug stability. Results: Akos demonstrated significant in vitro efficacy, inhibiting mCAF-driven tumor cell invasion and proliferation while reducing EMT marker expression. In in vivo xenograft models, Akos reduced tumor volume by 50-fold and tumor weight by 30-fold compared to untreated controls. In the spontaneous metastasis assay, Akos completely blocked 100% of metastatic foci across all tested models. Toxicology studies confirmed Akos’ safety profile, with no significant off-target effects observed, while pharmacokinetics showed stable systemic exposure. Discussion: These findings position Akos as a promising therapeutic candidate for targeting the TME to address the unmet need in metastatic cancer treatment. By inhibiting a key protein in mCAFs, Akos effectively disrupts the processes driving metastatic progression, offering a novel approach to halting the spread of cancer. The observed efficacy across multiple tumor types, combined with its favorable safety profile, supports further clinical investigation of Akos as a first-in-class therapeutic for metastatic solid tumors. These results underscore the potential of targeting the TME to improve patient outcomes and advance the standard of care in oncology. Citation Format: Javier Cerda-Infante, Benjamin Prieto, Valentina Cerda, Muriel Nuñez. Akos: A novel CAF-targeted therapy to reprogramming the tumor microenvironment to reverse metastatic traits in all solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5666.