Abstract 5416: Positioning the NQO1-bioactivatable drug isobutyl-deoxynyboquinone in diffuse intrinsic pontine glioma (DIPG): an exceptional therapeutic opportunity in pediatric brain tumor

Abstract Purpose: Diffuse Intrinsic Pontine Glioma (DIPG), is a very aggressive pediatric cancer with poor overall survival and no effective treatment. Despite numerous clinical trials, the overall survival remains at 9 months after diagnosis and only radiotherapy has shown a relative efficacy. Therefore, it is primordial to increase our understanding of the biology of DIPG tumors, as well as finding new healthcare strategies to tackle this pediatric disease. Recently, we discovered that NQO1, a stress-related protein, was overexpressed in 3 out of 6 DIPG patient-derived cell lines, as well as in half of the primary tissues. Interestingly, NQO1 overexpression can be targeted by substrates that induce an excessive oxidative stress into the cells that finally push them to apoptosis, while normal surrounding tissues with basal expression of NQO1 would be keep safe. Experimental procedure: This discovery prompted us to test in in vitro and in vivo assays a promising drug named isobutyl-deoxynyboquinone (IB-DNQ): a NQO1 bioactivatable substrate. We first tested the drug response of the 6 cell lines before testing it on orthotopic xenograft mouse models. We also investigated by which mechanism NQO1 is regulated in DIPG. Finally, we performed experiments in order to decipher by which mechanism NQO1 is regulated in DIPG. Results: We saw that NQO1 overexpressing cells are very sensitive to the drug, compared to the cell lines with normal expression. Moreover, we started to validate the use of IB-DNQ in vivo using a DIPG cell line treated or not (mock) with IB-DNQ and also a NQO1-knockdown model in orthotopic xenograft mice models, confirming that IB-DNQ crosses the blood brain barrier and increases the overall survival. NQO1 increased expression in DIPG is surprisingly not due to a NRF2-mediated transcriptional regulation as we did not observe a correlation between NQO1 transcript abundance and protein expression in DIPG cell lines, indicating that NRF2 pathway could not be implicated, but translational or post-translational regulation could be operating. We performed a polysome profiling of 4 patient-derived cell lines, a protein stability assay and a large scale proteome for the 6 cell lines (pending results). Conclusion: Our preliminary results, including drug efficacy, are very encouraging for the development of this new therapeutic in DIPG. This discovery represents a promising opportunity to tackle this devastating disease and a new hope for the patients and their families. Citation Format: Maxime Henri Janin, Vanessa Ortiz Barahona, Pere Llinas Arias, Carolina De La Torre, Angel Montero Carcaboso, Andres Morales La Madrid, Paul Hergenrother, Manel Esteller. Positioning the NQO1-bioactivatable drug isobutyl-deoxynyboquinone in diffuse intrinsic pontine glioma (DIPG): an exceptional therapeutic opportunity in pediatric brain tumor [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5416.