Targeting tumor architecture as a novel therapeutic strategy for pancreatic cancer

靶向肿瘤结构作为胰腺癌的新型治疗策略

• 批准号: 10559502
• 负责人: Matteo Ligorio
• 金额: $ 45.99万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559502
• 关键词: Adult; Aftercare; Architecture; Behavior; Biological; Biological Markers; CRISPR screen; Cells; Chemoresistance; Clinical Trials; Color; Core Biopsy; Disease Progression; Engineering; Evolution; Extracellular Matrix; Fibronectins; Gland; Goals; Homeostasis; Human; Imaging Techniques; Immunotherapy; Impairment; Individual; Knowledge; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Methodology; Methods; Mus; Names; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phenotype; Prognosis; Proliferating; Property; Publishing; Refractory; Reporter; Research Support; Resolution; Role; STAT3 gene; Shapes; Solid Neoplasm; Structure; Survival Rate; System; Testing; Time; Tissues; Tumor Tissue; Work; cancer cell; chemotherapy; genome-wide; human tissue; improved; in vivo imaging; in vivo two-photon imaging; innovation; insight; mouse model; novel marker; novel therapeutic intervention; novel therapeutics; pancreatic cancer patients; preclinical study; predicting response; predictive marker; preservation; prognostic value; programs; refractory cancer; research study; response; subcutaneous; synergism; targeted treatment; time use; treatment response; tumor; tumor behavior; tumor progression; two photon microscopy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemorefractory cancers among solid tumors. Even with the most effective chemotherapy (i.e., FOLFIRINOX), only 30% of PDAC patients respond. Therefore, identifying novel therapies is an urgent and unmet need in the PDAC field. One of the emerging strategies for treating these patients is targeting tumor architecture. The rationale of these therapies is to target tissue-specific properties, either in the stroma or in the tumor compartment, to disrupt tumor tissue homeostasis during disease progression or in response to treatment (chemotherapies). The majority of the previous studies have focused on targeting the stroma compartment (cellular or extracellular matrix portion), leaving the tumor compartment (e.g., tumor tissue-specific properties) a relatively unexplored territory. The goal of this proposal is to fill this knowledge gap by identifying tissue-specific properties in the tumor compartment to impair disease progression and to overcome PDAC chemoresistance. The rationale and feasibility of our proposed research studies are supported by our recent published work (Ligorio et al., Cell, 2019), in which we showed the existence of 8 different types of tumor glands, based on their internal composition of cells, with distinct proliferation (PRO) and metastatic (EMT) capabilities. Moreover, we found that tumor glands can be considered discrete functional “units” with distinct levels of aggressiveness and different chemorefractory behaviors. Therefore, our overarching hypothesis is that tissue-specific properties exist that govern tumor architecture by regulating the formation, internal structure, and evolution of tumor glands during disease progression and under treatment. To test this central hypothesis, we have recently developed (i) a method that allows us to characterize the cell identity (i.e., different PRO and EMT phenotypes) while preserving architectural information within human tissue, and (ii) an ad hoc mouse model to study tumor gland-forming ability using a time-course in vivo imaging technique (i.e., two-photon microscopy). By integrating these two methodologies, we (a) will clarify the functional behavior of tumor glands as a consequence of their internal structure (AIM.1), (b) will target an aggressive subpopulation of cancer cells to impair tissue homeostasis (AIM.2), and (c) will define the role of tumor architecture in PDAC chemoresistance and as a potential novel biomarker to predict the response to FOLFIRINOX chemotherapy (AIM.3). The proposed study will uncover new mechanisms (i.e., tumor tissue-specific properties) that drive tumor progression and PDAC chemoresistance with the ultimate intent (i) to find novel therapeutic avenues for PDAC patients, (ii) to define the role of tumor architecture in PDAC chemoresistance, and (iii) discover new FOLFIRINOX-predictive biomarkers to improve the dismal prognosis of PDAC patients.

胰腺导管腺癌（PDAC）是实体瘤中最难治的癌症之一。 即使使用最有效的化疗（即，FOLFIRINOX），只有30%的PDAC患者有反应。因此，我们认为， 在PDAC领域，鉴定新的治疗方法是一个迫切的和未满足的需要。一个新兴的战略， 治疗这些患者的方法是靶向肿瘤结构。这些疗法的基本原理是靶向组织特异性 在疾病期间，基质或肿瘤隔室中破坏肿瘤组织稳态的特性 进展或对治疗（化疗）的反应。以前的大多数研究都集中在 靶向基质区室（细胞或细胞外基质部分），留下肿瘤区室（例如， 肿瘤组织特异性）是一个相对未开发的领域。 这项提案的目标是通过识别肿瘤中的组织特异性来填补这一知识空白 在某些实施方案中，PDAC可以通过调节隔室以损害疾病进展和克服PDAC化学抗性来实现。了理论基础和 我们提出的研究的可行性得到了我们最近发表的工作的支持（Ligorio等人，细胞， 2019），其中我们根据其内部组成显示了8种不同类型的肿瘤腺体的存在 具有不同的增殖（PRO）和转移（EMT）能力。此外，我们发现肿瘤腺体 可以被认为是具有不同侵袭性水平和不同化学抗性的离散功能“单元”， 行为。因此，我们的总体假设是，存在组织特异性属性， 通过调节肿瘤腺体的形成、内部结构和演变， 疾病进展并正在接受治疗。 为了验证这一中心假设，我们最近开发了（i）一种方法，使我们能够表征细胞 身份（即，不同的PRO和EMT表型）同时保留人体组织内的结构信息， 和（ii）使用时间过程体内成像研究肿瘤腺体形成能力的特设小鼠模型 技术（即，双光子显微术）。通过整合这两种方法，我们（a）将澄清功能 肿瘤腺体的行为作为其内部结构的结果（AIM.1），（B）将靶向侵袭性肿瘤细胞。 （c）将定义肿瘤细胞亚群的作用，以损害组织稳态（AIM.2），以及（d）将定义肿瘤细胞亚群的作用， PDAC化疗耐药性的结构，并作为一种潜在的新的生物标志物，以预测对 FOLFIRINOX化疗（AIM.3）。 这项研究将揭示新的机制（即，肿瘤组织特异性）， 最终目的是（i）找到PDAC的新治疗途径 患者，（ii）定义肿瘤结构在PDAC化疗耐药性中的作用，以及（iii）发现新的 FOLFIRINOX预测生物标志物改善PDAC患者的不良预后