Tracking the Mechanisms of Adaptation to Autophagy Inhibition

追踪自噬抑制的适应机制

• 批准号: 10685861
• 负责人: Christina G Towers
• 金额: $ 171万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685861
• 关键词: Autophagocytosis; Biological Markers; Biological Models; Cancer Biology; Cancer Model; Cancer Patient; Cells; Cellular biology; Combined Modality Therapy; Complex; DNA Sequence Alteration; Dependence; Development; Drug resistance; Epigenetic Process; Event; Genetic; Genetic Transcription; Goals; Homeostasis; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mutation; Natural regeneration; Nutrient; Organelles; Patient Selection; Patients; Population; Process; Recycling; Resistance; Signal Transduction; Stress; Therapeutic; Work; anti-cancer therapeutic; cancer cell; epigenome; improved; inhibition of autophagy; metabolic abnormality assessment; metabolome; neoplastic cell; novel; patient biomarkers; prevent; resistance mechanism; response; therapy resistant; tool; transcriptome

SUMMARY Acquired resistance to anti-cancer therapeutics has proven to be one of the largest hurdles in cancer cell biology because cancer cells have the remarkable ability to adapt to diverse conditions. For example, when essential metabolic processes are blocked, some cancer cells die, but subsets of cells can survive and acquire resistance. The organelle recycling process, autophagy, provides an excellent paradigm to study metabolic adaptations in cancer. Many cancer cells are addicted to autophagy to maintain homeostasis and regenerate nutrients, but previous work highlighted the ability of rare cells to rapidly adapt and acquire new dependencies on alternate metabolic pathways. Rapid and transient adaptations to stress that manifest in the metabolome, epigenome and transcriptome have been understudied. This proposal suggests that resistance mechanisms are more complex than just pre-existing genetic differences between heterogeneous tumor cells, but instead include rapid signaling events, broad stress and metabolic responses, epigenetic changes, and the acquisition of new genetic mutations. How and when each of these factors contribute to resistance remains unknown. Many studies analyze adapted populations after they have undergone selection. The approach taken here is different: these studies aim to observe the process of selection and adaptation in action. The proposed projects will develop a set of novel tools and model systems to track the dynamic interactions of rapid signaling, stress and metabolic responses, along with transcriptional changes, epigenetic changes, and genetic alterations – all with temporal precision. Despite decades of studies on therapeutic resistance, fundamental questions remain. For example, it is critical to determine whether: A) cancer cells undergo a change in state and adapt in response to a treatment, or B) a treatment simply selects for a pre-existing state that is heterogenous and already resistant. It is critical to differentiate the dynamics between these two models to determine whether a given resistance mechanism should be targeted as a combination therapy (a consequence of Model A), or instead used as a biomarker for patient selection (a consequence of Model B). Some patients respond remarkably well to autophagy inhibition and the field is desperate for both biomarkers associated with these patients to improve patient selection, and for ways to prevent therapy resistance. To this end, these studies will facilitate the development of better autophagy-targeting cancer therapeutics. Moreover, understanding the temporally dynamic contributions of different kinds of adaptations will generate new models of cancer cell drug resistance, beyond those that model autophagy modulation.

总结 对抗癌疗法的获得性耐药性已被证明是治疗癌症的最大障碍之一。 癌细胞生物学，因为癌细胞具有非凡的适应多样性的能力 条件例如，当基本代谢过程被阻断时，一些癌细胞死亡， 但细胞亚群可以存活并获得抵抗力。细胞器的循环过程， 自噬，提供了一个很好的范例，研究癌症的代谢适应。许多 癌细胞依赖自噬来维持体内平衡和再生营养， 以前的工作强调了稀有细胞快速适应和获得新依赖性的能力 替代代谢途径对压力的快速和短暂的适应表现在 代谢组学、表观基因组学和转录组学研究不足。 这一提议表明，耐药机制比预先存在的机制更为复杂。 异质性肿瘤细胞之间的遗传差异，而是包括快速信号传导， 事件，广泛的压力和代谢反应，表观遗传变化，以及新的 基因突变这些因素中的每一个是如何以及何时促成耐药性的， 未知许多研究分析了经过选择后的适应种群。的 这里采取的方法是不同的：这些研究旨在观察选择的过程， 适应在行动。拟议的项目将开发一套新颖的工具和模型系统 追踪快速信号、压力和代谢反应的动态相互作用，沿着 转录变化，表观遗传变化和遗传改变-所有这些都具有时间精度。 尽管对治疗耐药性进行了数十年的研究，但基本问题仍然存在。为 例如，关键是要确定：A）癌细胞是否经历了状态的变化并适应 响应于治疗，或者B）治疗简单地选择预先存在的状态， 异质性和已经耐药。区分这两者之间的动态至关重要 模型，以确定是否应将给定的耐药机制作为一种组合 治疗（模型A的结果），或替代地用作患者选择的生物标志物（a 模型B的结果）。一些患者对自噬抑制反应非常好， 该领域迫切需要与这些患者相关的两种生物标志物来改善患者的 选择，以及防止治疗耐药性的方法。为此，这些研究将促进 开发更好的自噬靶向癌症疗法。此外，了解 不同种类的适应的时间动态贡献将产生新的模型， 癌细胞耐药性，超越那些模型自噬调节。