AGING AS A SELECTIVE PRESSURE THAT DRIVES TUMOR PROGRESSION

衰老是驱动肿瘤进展的选择性压力

• 批准号: 10245907
• 负责人: Ana da silva Gomes
• 金额: $ 148.23万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245907
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Biological Aging; Cancer Patient; Cells; Clinical Trials; Data; Diabetes Mellitus; Disease; Evolution; FDA approved; FarGo; Genotype; Healthcare Systems; Human; Immunotherapy; Incidence; Infrastructure; Knowledge; Lead; Malignant Neoplasms; Maps; Metabolic; Mutagens; Neoplasm Metastasis; Older Population; Organism; Outcome; Patients; Phenotype; Play; Population; Primary Neoplasm; Process; Prognosis; Risk; Risk Factors; Role; Sampling; Serum; Therapeutic; Therapeutic Intervention; Time; Tissues; age effect; age group; age related; aged; anti-cancer; anticancer research; anticancer treatment; cancer cell; cancer diagnosis; cancer therapy; design; guided inquiry; human old age (65+); malignant phenotype; neglect; neoplastic cell; new therapeutic target; novel therapeutic intervention; pre-clinical research; pressure; response; single cell technology; tumor microenvironment; tumor progression; virtual

PROJECT SUMMARY Aging is the major risk factor for cancer incidence, with more than 60% of cancer diagnoses occurring in those aged 65 and above. In addition, anecdotal observations indicate that age affects prognosis and outcome. Yet, very little experimental data dissect the connection of aging, cancer progression and sensitivity to anti-cancer therapies. In fact, the vast majority of preclinical research that guide the discovery of novel therapeutic targets and clinical trials that lead to anti-cancer treatments approved by the FDA neglect to account for the age of the average patient. This lack of understanding of how aging plays a role in cancer is especially troubling considering that the number of new cancer cases is on the rise globally, a fact that is tied to the increase in the proportion of the older population in the world. Biologically the aging process affects the function of every cell in an organism suggesting that a cancer developing in an aged host is a different disease than a cancer developing in a young one. Using human serum samples, I recently demonstrated that tumor progression and metastasis formation occur, at least in part, as a manifestation of global metabolic deregulation of the aged host. This supports the idea that the role of aging in cancer goes far beyond increased exposure time to mutagens and puts the aging process at the center stage coordinating the different aspects required for the evolution of malignant phenotypes. Therefore, in order to effectively treat cancer, we must look beyond the current framework which neglects the role of the cancer patient’s age. Here, we propose that the aged host tumor microenvironment exerts distinct Darwinian pressures that combined with the decline of the host anti-cancer defenses define how tumor cells evolve within the primary tumor, progress into metastatic disease and respond to anti-cancer therapies. Employing a combination of cutting-edge bulk and single cell technologies we expect to systematically delineate how aging affects the phenotypes and genotypes of cancer cells as well as to characterize the effects of the aging process on the composition and interactions of the different components of the tumor microenvironment. Finally, we will directly evaluate if old age affects the response to FDA-approved chemotherapeutic regiments and immunotherapies, and evaluate if strategies known to rejuvenate old tissues can affect the response to these therapeutic interventions. Through these studies, we aim to build the knowledge infrastructure required to design therapeutic strategies that account for the reprogramming that occurs with aging.

项目概要 老龄化是癌症发病的主要危险因素，超过 60% 的癌症诊断发生在老龄化人群 65岁及以上。此外，轶事观察表明年龄影响预后和结果。然而， 很少有实验数据剖析衰老、癌症进展和抗癌敏感性之间的联系 疗法。事实上，绝大多数指导新治疗靶点发现的临床前研究 导致 FDA 批准的抗癌治疗的临床试验忽视了患者的年龄 普通病人。考虑到对衰老如何在癌症中发挥作用缺乏了解尤其令人不安 全球新发癌症病例数正在上升，这一事实与癌症患者比例的增加有关 世界上老年人口。从生物学角度来看，衰老过程会影响有机体中每个细胞的功能 表明老年宿主中发生的癌症与年轻宿主中发生的癌症是不同的疾病 一。我最近使用人类血清样本证明了肿瘤进展和转移形成 发生，至少部分是作为老年宿主整体代谢失调的表现。这支持 认为衰老在癌症中的作用远远超出了暴露于诱变剂的时间的增加，并且使衰老 处于中心阶段的过程，协调恶性表型进化所需的不同方面。 因此，为了有效治疗癌症，我们必须超越目前忽视癌症治疗的框架。 癌症患者年龄的作用。在这里，我们提出衰老的宿主肿瘤微环境发挥着独特的作用 达尔文压力与宿主抗癌防御能力的下降相结合，决定了肿瘤细胞如何 在原发肿瘤内进化，进展为转移性疾病并对抗癌治疗产生反应。 采用尖端散装和单细胞技术的组合，我们希望系统地描绘 衰老如何影响癌细胞的表型和基因型，以及表征衰老的影响 衰老过程对肿瘤微环境不同成分的组成和相互作用的影响。 最后，我们将直接评估老年是否影响 FDA 批准的化疗方案的反应 和免疫疗法，并评估已知的使旧组织恢复活力的策略是否可以影响对这些疗法的反应 治疗干预。通过这些研究，我们的目标是建立设计所需的知识基础设施 解释随衰老而发生的重编程的治疗策略。