Role of necrosis in the evolution of highly metastatic and chemo-resistant breast cancers

坏死在高度转移性和化疗耐药性乳腺癌演变中的作用

• 批准号: 10736486
• 负责人: Kevin Jon Cheung
• 金额: $ 64.2万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736486
• 关键词: Adjuvant; Adjuvant Therapy; Aftercare; Aggressive behavior; Aneuploidy; Angiopoietins; Animal Model; Antineoplastic Agents; Benefits and Risks; Biological Availability; Biological Models; Blood; Blood Vessels; Blood flow; Blood specimen; Breast Cancer Cell; Breast Cancer Detection; Breast Cancer Patient; Breast Cancer therapy; Breast cancer metastasis; Cell Death; Cells; Cessation of life; Chemoresistance; Clinical; Complex; DNA analysis; Data; Development; Diagnosis; Disease; Dissection; Distant; Drug Delivery Systems; Drug resistance; Ecosystem; Epidemiologist; Evolution; Family; Generations; Genes; Genome; Genomics; Hand; Heterogeneity; Histologic; Human; Hypoxia; Impairment; Individual; Malignant Neoplasms; Mammary Neoplasms; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Modeling; Molecular; Mus; Mutate; Mutation; Necrosis; Necrosis Induction; Neoadjuvant Therapy; Neoplasm Metastasis; Nutrient; Organ; Outcome; Oxygen; Patients; Penetration; Perfusion; Pharmaceutical Preparations; Phenotype; Population Study; Prevention; Primary Neoplasm; Prognostic Marker; Protein Secretion; Rattus; Recurrence; Recurrent Malignant Neoplasm; Residual Cancers; Resistance; Risk; Risk Factors; Risk Reduction; Role; Sampling; Source; Testing; Therapeutic; Tissue Sample; Tissues; Toxic effect; Tumor-Derived; Woman; Work; aggressive therapy; barrier to testing; cancer recurrence; cancer subtypes; cancer therapy; chemotherapy; clinical prognostic; cohort; driving force; drug development; genomic signature; improved; innovation; knock-down; liquid biopsy; malignant breast neoplasm; member; molecular marker; mouse model; neoplastic cell; patient derived xenograft model; population based; prevent; prognostic; prognostication; programs; response; risk prediction; synergism; therapeutic development; therapy development; therapy resistant; trait; tumor; tumor DNA; tumor growth; tumor heterogeneity

High-grade, fast-growing breast cancers often display necrosis, usually within the tumor interior, where perfusion, nutrients, and oxygen are limited. Recent studies indicate that necrosis is not just an indicator of aggressive disease, but also a regulator of the aggressive phenotype, by impairing cancer drug delivery, promoting genomic evolution, and instigating metastasis to distant organs. However, we currently lack an understanding of the molecular mechanisms regulating necrosis development and consequently, there are no therapies to prevent the development of necrosis and its downstream effects on tumor aggression. For this application, we have developed animal models that enable the robust dissection of the tumor-host ecosystem in the necrotic interior. Our studies reveal that a secreted protein, angiopoietin-like 7 (Angptl7), is produced by tumor cells adjacent to the necrotic core and is a regulator of tumor core vasculature development. Importantly, when Angptl7 is suppressed genetically, tumor necrosis, tumor growth, and metastatic dissemination are each drastically reduced. Thus, necrosis development is not inevitable but rather is preventable by Angptl7 suppression. In the proposed work, we will combine studies using innovative animal models and breast cancer patient blood and tissue samples to test the hypothesis that the development of necrosis is a driving force for the evolution of highly metastatic and drug-resistant breast tumor cells. In Aim 1, we will use mouse models to test the hypothesis that Angptl7-induced necrosis limits delivery of chemotherapeutics to the tumor core, and that Angptl7 suppression synergizes with neoadjuvant chemotherapeutics to improve drug delivery and improve tumor killing. In Aim 2, we will use tissue from a large population-based cohort of early-stage breast cancer patients to determine how dilated blood vessels, an indicator of Angptl7-induced necrosis, influences risk of local and distant metastatic dissemination to predict benefit from adjuvant therapy. In Aim 3, we will apply genomic sequencing and circulating tumor DNA analysis in an innovative rat model for liquid biopsy studies to define the genomic signatures associated with Angptl7-induced necrosis. We will then determine the prognostic impact of a circulating tumor DNA signature of necrosis in human clinical samples. This work will define necrosis development as an engine for tumor diversification and aggression, and the clinical contexts both in early stage and metastatic settings where necrosis prevention could benetits patients with breast cancer and tumor types.

高级别、快速生长的乳腺癌通常显示坏死，通常在肿瘤内部， 灌注、营养和氧气有限。最近的研究表明，坏死不是 它不仅是侵袭性疾病的指标，也是侵袭性表型的调节因子， 削弱癌症药物递送，促进基因组进化，并促使转移到远处 机关然而，我们目前缺乏对调节坏死的分子机制的理解， 因此，没有治疗方法来防止坏死的发展及其 对肿瘤侵袭的下游影响。对于这个应用，我们已经开发了动物模型， 能够在坏死的内部稳健地解剖肿瘤宿主生态系统。我们的研究 揭示了一种分泌的蛋白质，血管生成素样7（Angptl7），由邻近的肿瘤细胞产生， 并且是肿瘤核心脉管系统发育的调节剂。重要的是 Angptl7在遗传上受到抑制，肿瘤坏死、肿瘤生长和转移性播散受到抑制。 每一个都大幅减少。因此，坏死的发展并非不可避免，而是可以通过以下措施预防的 Angptl7抑制。在拟议的工作中，我们将使用创新的动物模型进行联合收割机研究 和乳腺癌患者的血液和组织样本，以测试的假设， 坏死是高转移和耐药乳腺肿瘤演变的驱动力 细胞在目的1中，我们将使用小鼠模型来检验以下假设：Angptl7诱导的坏死 限制了化疗剂向肿瘤核心的递送，并且Angptl7抑制协同 与新辅助化疗剂一起使用以改善药物递送并改善肿瘤杀伤。在目标2中， 将使用来自大量早期乳腺癌患者群体的组织， 确定扩张的血管（Angptl7诱导的坏死的指标）如何影响血管炎的风险。 局部和远处转移性播散，以预测辅助治疗的获益。在目标3中，我们 将在一个创新的大鼠模型中应用基因组测序和循环肿瘤DNA分析， 液体活检研究以确定与Angptl7诱导的坏死相关的基因组特征。 然后，我们将确定循环肿瘤坏死DNA特征对预后的影响。 人类临床样品。这项工作将确定坏死发展为肿瘤的引擎 多样化和侵略性，以及早期和转移性的临床背景 坏死预防可以使乳腺癌和肿瘤类型患者受益的环境。