Abstract
Temozolomide (TMZ) is currently the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM). However, the inherent heterogeneity of GBM often results in suboptimal outcomes, particularly due to varying degrees of resistance to TMZ. Over the past several decades, O-methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair pathway has been extensively investigated as a target to overcome TMZ resistance. Nonetheless, the combination of small molecule covalent MGMT inhibitors with TMZ and other chemotherapeutic agents has frequently led to adverse clinical effects. Recently, additional mechanisms contributing to TMZ resistance have been identified, including epidermal growth factor receptor (EGFR) mutations, overactivation of intracellular signalling pathways, energy metabolism reprogramming or survival autophagy, and changes in tumor microenvironment (TME). These findings suggest that novel therapeutic strategies targeting these mechanisms hold promise for overcoming TMZ resistance in GBM patients. In this review, we summarize the latest advancements in understanding the mechanisms underlying intrinsic and acquired TMZ resistance. Additionally, we compile various small-molecule compounds with potential to mitigate chemoresistance in GBM. These mechanism-based compounds may enhance the sensitivity of GBM to TMZ and related chemotherapeutic agents, thereby improving overall survival rates in clinical practice.
Overview
- The study focuses on the mechanisms underlying intrinsic and acquired resistance to Temozolomide (TMZ) in glioblastoma multiforme (GBM) patients. The hypothesis being tested is that novel therapeutic strategies targeting these mechanisms hold promise for overcoming TMZ resistance in GBM patients. The methodology used for the experiment includes a review of the literature on TMZ resistance mechanisms and the compilation of various small-molecule compounds with potential to mitigate chemoresistance in GBM. The primary objective of the study is to provide a comprehensive overview of the latest advancements in understanding the mechanisms underlying TMZ resistance and to identify potential therapeutic strategies for overcoming this resistance in GBM patients.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions detailed in the literature on TMZ resistance mechanisms. The results show that TMZ resistance in GBM is often due to multiple mechanisms, including MGMT-mediated DNA repair pathway, EGFR mutations, overactivation of intracellular signalling pathways, energy metabolism reprogramming or survival autophagy, and changes in tumor microenvironment (TME). The study identifies various small-molecule compounds with potential to mitigate chemoresistance in GBM, such as O6-benzylguanine (OBG), temozolomide-potentiating agents (TPAs), and autophagy inhibitors. The key findings of the study suggest that novel therapeutic strategies targeting these mechanisms hold promise for overcoming TMZ resistance in GBM patients.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The identification of multiple mechanisms contributing to TMZ resistance in GBM suggests that a combination of targeted therapies may be more effective than single-agent chemotherapy. The study also highlights the potential of small-molecule compounds to mitigate chemoresistance in GBM, which could lead to improved overall survival rates in clinical practice. Future research directions could focus on developing combination therapies targeting multiple mechanisms of TMZ resistance, as well as exploring the use of these compounds in combination with other chemotherapeutic agents. Additionally, further studies are needed to evaluate the safety and efficacy of these compounds in clinical trials.