| Popis: |
Diffuse intrinsic pontine glioma (DIPG) is a rare and lethal pediatric brain tumor arising in?the?midline structures of the brain, namely the pons and thalamus. Surgery is not an option for these patients, and, to date, no chemotherapy has significantly improved survival. While radiation therapy provides some benefit, the average survival remains dismal, with patients succumbing to disease within a year post diagnosis. Thus, there is a critical need to develop new therapeutic strategies to improve the outcome for patients and their families. One approach which has elicited a robust and durable response?in several solid and liquid cancers is immune checkpoint inhibition. Immune checkpoint inhibitors harness the immune system to promote tumor cell clearance and have been most beneficial in tumors which display immune cell infiltration prior to treatment.?Although many tumors, including DIPG, display limited immune cell infiltration, recent studies in other solid tumors have identified small molecule inhibitors that increase immune cell infiltration and activity. In this study, we evaluate the potential of using small molecule inhibitors to improve response to immune checkpoint inhibitor treatment?in a mouse model of DIPG. Analysis of selected small molecule inhibitors reveals differential sensitivity of mouse DIPG cell lines, nominating candidates which may increase immune cell infiltration and recognition of tumor cells. An?in vivo?study of a cyclin dependent kinase 4/6 inhibitor combined with immune checkpoint inhibitor demonstrates the feasibility of these types of studies in our mDIPG models and reveals increased immune cell recruitment related to immune check point inhibition. |
