Description:
<jats:title>Abstract</jats:title>
<jats:p>Medulloblastoma (MB) accounts for 20% of diagnosed brain tumors in children. The Group 3 (G3) MB subtype is found to be especially malignant. Current G3 MB treatment regimens provide for 50% 5-year survival rates and are associated with severe side effects, including hearing loss and neurocognitive deficits. G3 MB is characterized by MYC overexpression, which drives elevated protein translation in tumor cells. High expression levels of PERK correlate with poor survival outcome in G3 MB, and knockdown of PERK combined with hypoxic stress induces apoptosis in MB cells. PERK is an eIF2α kinase that responds to ER stress and is one of the key mediators of unfolded protein response. When ER stress is detected, PERK phosphorylates eIF2α to shut down global translation and to initiate integrated stress response. However, there are 3 other eIF2α kinases that work alongside PERK to help cells respond to various stresses. ISRIB is in an integrated stress response inhibitor that blocks P-eIF2α attenuation by eIF2B, thus maintaining high translation levels under stress. Combining ISRIB with stress such as hypoxia induces apoptosis in MB cells. In addition, combination of ISRIB and hypoxia is correlated with increased levels of oxidative stress. Apart from restoring global translation levels, ISRIB can prevent stress granules (SGs) from being formed. High expression of SG proteins such as G3BP1 and YB1 also correlates with poor survival outcome in G3 MB patients. When SG formation is inhibited by knocking down expression of G3BP1 and G3BP2, MB cells undergo higher levels of apoptosis under vincristine induced stress. We show that preventing G3 MB cells from undergoing integrated stress response and inhibiting formation of stress granules induces higher levels of cancer cell death. Overall, combining ISRIB with conventional chemotherapy may enhance the effects of the latter, which is increasingly relevant for patients suffering from G3 MB.</jats:p>
<jats:p>Citation Format: Sofya Langman, Poul H. Sorensen. Exploring integrated stress response pathway to target MYC-amplified medulloblastoma [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 5837.</jats:p>