Genoscience Pharma, 13006 Marseille, France.
Department of Medical Oncology, Paris Saint-Joseph Hospital Group, 75014 Paris, France.
Cells. 2023 Jun 23;12(13):1702. doi: 10.3390/cells12131702.
Autophagy is a highly conserved and natural degradation process that helps maintain cell homeostasis through the elimination of old, worn, and defective cellular components, ensuring proper cell energy intake. The degradative pathway constitutes a protective barrier against diverse human diseases including cancer. Autophagy basal level has been reported to be completely dysregulated during the entire oncogenic process. Autophagy influences not only cancer initiation, development, and maintenance but also regulates cancer response to therapy. Currently, autophagy inhibitor candidates mainly target the early autophagy process without any successful preclinical/clinical development. Lessons learned from autophagy pharmaceutical manipulation as a curative option progressively help to improve drug design and to encounter new targets of interest. Combinatorial strategies with autophagy modulators are supported by abundant evidence, especially dealing with immune checkpoint inhibitors, for which encouraging preclinical results have been recently published. GNS561, a PPT1 inhibitor, is a promising autophagy modulator as it has started a phase 2 clinical trial in liver cancer indication, combined with atezolizumab and bevacizumab, an assessment without precedent in the field. This approach paves a new road, leading to the resurgence of anticancer autophagy inhibitors as an attractive therapeutic target in cancer.
自噬是一种高度保守的自然降解过程，通过清除衰老、磨损和功能失调的细胞成分来帮助维持细胞内环境的稳定，确保适当的细胞能量摄入。该降解途径构成了一道保护屏障，可以预防多种人类疾病，包括癌症。自噬的基础水平在整个致癌过程中被报道完全失调。自噬不仅影响癌症的发生、发展和维持，还调节癌症对治疗的反应。目前，自噬抑制剂候选物主要针对早期自噬过程，但没有任何成功的临床前/临床开发。从自噬药物干预作为一种治疗选择中吸取的经验教训，逐渐有助于改进药物设计并发现新的有价值的靶点。自噬调节剂的组合策略有大量证据支持，特别是在免疫检查点抑制剂方面，最近已经发表了令人鼓舞的临床前结果。GNS561 是一种 PPT1 抑制剂，作为一种有前途的自噬调节剂，已经开始在肝癌适应症的 2 期临床试验中与阿替利珠单抗和贝伐珠单抗联合使用，这在该领域是前所未有的评估。这种方法开辟了一条新路，使抗癌自噬抑制剂作为癌症治疗的一个有吸引力的治疗靶点重新受到关注。
