Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas
Stefan R. Sweha, Chan Chung, Siva Kumar Natarajan, Pooja Panwalkar, Matthew Pun, Amer Ghali, Jill Bayliss, Drew Pratt, Anand Shankar, Visweswaran Ravikumar, Arvind Rao, Marcin Cieślik, Kari Wilder-Romans, Andrew J. Scott, Daniel Wahl, Selin Jessa, Claudia L. Kleinman, Nada Jabado, Alan Mackay, Chris Jones, Daniel Martínez, Mariarita Santi, Alexander R. Judkins, Viveka Nand Yadav, Tingting Qin, Timothy N. Phoenix, Carl Koschmann, Suzanne J. Baker, Arul M. Chinnaiyan, Sriram Venneti
Abstract
) locus to drive increased LIF abundance and secretion by H3.3G34R/V cells. LIF activated signal transducer and activator of transcription 3 (STAT3) signaling in an autocrine/paracrine manner to promote survival of H3.3G34R/V glioma cells. Moreover, immunohistochemistry and single-cell RNA sequencing from H3.3G34R/V patient tumors revealed high STAT3 protein and RNA expression, respectively, in tumor cells with both inter- and intratumor heterogeneity. We targeted STAT3 using a blood-brain barrier–penetrable small-molecule inhibitor, WP1066, currently in clinical trials for adult gliomas. WP1066 treatment resulted in H3.3G34R/V tumor cell toxicity in vitro and tumor suppression in preclinical mouse models established with KNS42 cells, SJ-HGGx42-c cells, or in utero electroporation techniques. Our studies identify the LIF/STAT3 pathway as a key epigenetically driven and druggable vulnerability in H3.3G34R/V gliomas. This finding could inform development of targeted, combination therapies for these lethal brain tumors.