P10.22.B COMBINATION OF ARTS MIMETICS WITH AUTOPHAGY INHIBITORS AS A NOVEL THERAPEUTIC STRATEGY TO OVERCOME APOPTOSIS RESISTANCE IN GLIOBLASTOMA

• DOI: 10.1093/neuonc/noad137.220
• Publication Date: 2023-09-08T16:03:21Z
• Authors: H Kuzmychova; E Martell; V Yathindranath; H Senthil; E Kaul; D Miller; S K Singh; T Sharif
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

Abstract BACKGROUND Glioblastoma (GBM) is the most common malignant brain tumour in adults. The current standard of care for GBM patients consists maximal surgical resection followed by chemotherapy and radiation. Despite such an aggressive treatment approach, average 5-year survival rate approximately 5%. One main reasons poor therapy response resistance to programmed cell death, otherwise known as apoptosis. mechanisms behind apoptosis relies on upregulation inhibitor proteins (IAPs) which are hinder pro-apoptotic allow under abnormal conditions severe DNA damage. However, there natural IAP antagonists ARTS capable stimulating death promoting degradation IAPs. To harness function antagonists, small peptide mimetics have been developed. This project investigates efficacy utilizing a novel strategy overcome treatment. MATERIAL AND METHODS study utilizes patient-derived cells with exogenous gain-of-function (GOF) overexpression introduce full-length protein well pharmacological evaluate following promotion activity. We also employ orthotopic xenograft mouse model test combinatorial strategies vivo, where we used nanoparticle drug delivery system ensure across blood-brain barrier (BBB). RESULTS found that were highly resistant ARTS-induced Further molecular investigation unveiled role autophagy mechanism. A combination GOF or mimetic peptides inhibitors mitigated ARTS-mediated drastically decreased proliferation. was further tested model, demonstrated successful through BBB via lipid carriers. Animals treated Spautin-1 significantly prolonged survival, confirming therapeutic potential approach CONCLUSION Altogether, these findings uncover previously unknown regulation provide evidence IAP-antagonist can be effective against tumours. work supported Health Sciences Centre Foundation (HSCF).