CHA1: A New Combinatorial Therapy That Reciprocally Regulates Wnt and JAK/STAT/Interferon Signaling to Re-program Breast Tumors and the Tumor-Resident Landscape

作者：Mariam K. Alamoudi, Mollie E. Chipman, Francesca Deieso-Frechette, Ahlam Mukhtar Bogis, Roaya S. Alqurashi, Kaiqi Li, Rui Zhang, Maricel Castañer, George Triafallou, Christopher G. Herbosa, Corinne Carland, AJ. Jaehoon Lee, Kyle Gillani, K. Eric Paulson, Amy S. Yee · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2022 · DOI：10.1101/2022.03.25.485706 · 研究领域：Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis、Cancer Mechanisms and Therapy

ABSTRACT Triple negative breast cancers (TNBC) pose exceptional challenges with fatal brain metastases as a clear and unmet need. Immune checkpoint inhibitors (ICIs) are promising therapeutic strategies, but most TNBC are resistant, or “cold” tumors, due to lack of tumor-resident immune engagement. No FDA-approved therapies exist which promote a “cold-to-hot” transition or induce the important biomarker PD-L1, often used for ICI clinical decision-making. Maximal ICI susceptibility, or a full “cold-to-hot” transition, requires reciprocal Wnt signaling inhibition and Jak/STAT/interferon signaling activation. We report a new compound combination (CHA1) that fits the above criteria. CHA1 is comprised of EGCG (epigallocatechin-3-gallate; green-tea compound) and decitabine (DNA-methyltransferase (DNMT1) inhibitor; 5’deaza-cytidine; FDA-approved for hematologic malignancies). We used immune-compromised and syngeneic TNBC pre-clinical models to investigate tumor-intrinsic and tumor-resident T-cell effects, respectively. All results required CHA1 (but not EGCG or decitabine alone) and utilized attainable human dose equivalences with manageable safety profiles. CHA1 triggered efficient Wnt signaling inhibition by elevating Wnt pathway inhibitors (HBP1 and SFRP1) and traversed the blood-brain barrier to reduce both tumor and brain metastatic growth. Transcriptomic and expression analyses revealed that CHA1 treatment effectuated a robust tumor-intrinsic JAK/STAT/IFN response 1) to induce...