Abstract B13: Reprogramming glioblastoma multiforme cells to neurons by protein kinase inhibitors

Abstract

Abstract Reprogramming healthy somatic cells into pluripotent stem (iPS) cells with defined factors has been intensively investigated. However, reprogramming cancer cells has fallen much behind. Direct reversion of cancers into normal tissues is an ideal strategy for cancer treatment. Recent reports have showed that defined factors can induce reprogramming of cancer cells into iPS cells, supporting this notion. Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. Despite multimodal therapy, the outcome for patients with GBM is still poor, with a median survival of just 14.2 months. Therefore, developing novel therapeutic strategy is an emergent task. The tumor suppressor p53 is considered today the most important tumor suppressor protein in humans and it suppresses both reprogramming and oncogenic transformation. p53 inactivation or mutations are the most common in GBM, and this p53 deficient GBM subgroup is currently the most difficult to treat, typically associated with rapid local recurrence after treatment. p53 mutations result in loss-of-function, gain-of-function, and dominant-negative mutational effects for p53. Thus, different p53 mutants may have various effects on reprogramming, promoting or inhibiting GBM reprogramming. Furthermore, p53 activity is often inactivated in GBM with wild-type p53 that may also affect reprogramming. We have demonstrated that the depletion of p53 reprograms human somatic cells into neurons by regulation of a set of transcription factors (Nature Communications, 2014; Cell Reports, 2014, International Journal of Stem Cell Research & Therapy, 2016). Integration-free reprogramming cancer cells would be safer and preferable for clinical use. Along those lines, we screened a protein kinase inhibitor library and found that the kinase inhibitors can substitute for all transcription factors and convert human p53-deficient GBM cells into “normal” neurons (functional neurons). In vitro and in vivo tumorigenesis assays showed that induced neurons lose tumorigenicity. Moreover, the inhibitor reprogramming prevents GBM local recurrence in mice. Currently these inhibitors are used as anti-tumor drugs in patients, so this reprogramming strategy has significant potential to move rapidly toward clinical trials. Note: This abstract was not presented at the conference. Citation Format: Jie Yuan, Fan Zhang, Meng You, Qin Yang. Reprogramming glioblastoma multiforme cells to neurons by protein kinase inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B13.