jk184 and Neoplasms

Topics: Antineoplastic Agents; Drug Discovery; Hedgehog Proteins; Humans; Neoplasms; Signal Transduction; Transcription Factors; Zinc Finger Protein GLI1

Chimeric antigen receptor (CAR) T cells and immune checkpoint blockades (ICBs) have made remarkable breakthroughs in cancer treatment, but the efficacy is still limited for solid tumors due to tumor antigen heterogeneity and the tumor immune microenvironment. The restrained treatment efficacy prompted us to seek new potential therapeutic methods.. In this study, we conducted a small molecule compound library screen in a human BC cell line to identify whether certain drugs contribute to CAR T cell killing. Signaling pathways of tumor cells and T cells affected by the screened drugs were predicted via RNA sequencing. Among them, the antitumor activities of JK184 in combination with CAR T cells or ICBs were evaluated in vitro and in vivo.. We selected three small molecule drugs from a compound library, among which JK184 directly induces tumor cell apoptosis by inhibiting the Hedgehog signaling pathway, modulates B7-H3 CAR T cells to an effector memory phenotype, and promotes B7-H3 CAR T cells cytokine secretion in vitro. In addition, our data suggested that JK184 exerts antitumor activities and strongly synergizes with B7-H3 CAR T cells or ICBs in vivo. Mechanistically, JK184 enhances B7-H3 CAR T cells infiltrating in xenograft mouse models. Moreover, JK184 combined with ICB markedly reshaped the tumor immune microenvironment by increasing effector T cells infiltration and inflammation cytokine secretion, inhibiting the recruitment of MDSCs and the transition of M2-type macrophages in an immunocompetent mouse model.. These data show that JK184 may be a potential adjutant in combination with CAR T cells or ICB therapy.

Topics: Animals; Cell Line, Tumor; Cytokines; Drug Evaluation, Preclinical; Early Detection of Cancer; Hedgehog Proteins; Humans; Immunotherapy; Immunotherapy, Adoptive; Mice; Neoplasms; Tumor Microenvironment; Xenograft Model Antitumor Assays

JK184 can specially inhibit Gli in the Hedgehog (Hh) pathway, which showed great promise for cancer therapeutics. For developing aqueous formulation and improving anti-tumor activity of JK184, we prepared JK184 encapsulated MPEG-PCL micelles by the solid dispersion method without using surfactants or toxic organic solvents. The cytotoxicity and cellular uptake of JK184 micelles were both increased compared with the free drug. JK184 micelles induced more apoptosis and blocked proliferation of Panc-1 and BxPC-3 tumor cells. In addition, JK184 micelles exerted a sustained in vitro release behavior and had a stronger inhibitory effect on proliferation, migration and invasion of HUVECs than free JK184. Furthermore, JK184 micelles had stronger tumor growth inhibiting effects in subcutaneous Panc-1 and BxPC-3 tumor models. Histological analysis showed that JK184 micelles improved anti-tumor activity by inducing more apoptosis, decreasing microvessel density and reducing expression of CD31, Ki67, and VEGF in tumor tissues. JK184 micelles showed a stronger inhibition of Gli expression in Hh signaling, which played an important role in pancreatic carcinoma. Furthermore, circulation time of JK184 in blood was prolonged after entrapment in polymeric micelles. Our results suggested that JK184 micelles are a promising drug candidate for treating pancreatic tumors with a highly inhibitory effect on Hh activity.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Biocompatible Materials; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromatography, High Pressure Liquid; Drug Delivery Systems; Female; Hedgehog Proteins; Heterocyclic Compounds, 2-Ring; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Nude; Micelles; Nanomedicine; Neoplasm Transplantation; Neoplasms; Polymers; Signal Transduction; Thiazoles; Transgenes; Zebrafish