OVERCOMING STROMAL BARRIERS TO THERAPEUTICS IN PANCREAS CANCER

克服胰腺癌治疗的间质障碍

• 批准号: 10682621
• 负责人: Sunil R Hingorani
• 金额: $ 49.8万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682621
• 关键词: Ablation; Adhesions; Animal Model; Architecture; Behavior; Biochemical; Biology; Biophysics; Blood Vessels; CD44 Antigens; CD44 gene; Cancer Etiology; Cell Adhesion Molecules; Cells; Cessation of life; Characteristics; Chemicals; Clinical; Clinical Trials; Complex; Country; Development; Diffusion; Disease; Disease Resistance; Drug Kinetics; Drug resistance; Engineering; Epithelial Cells; Epithelium; Evolution; Fostering; Generations; Genetic; Genetic Engineering; Glean; Glycosaminoglycans; Grant; Growth; HMMR gene; Histopathology; Hyaluronan; ICAM1 gene; Immune; Immunoglobulin Class Switching; Immunologics; Immunosuppression; In Vitro; Incidence; Investigation; Knowledge; Laboratories; Learning; Liquid substance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mechanics; Mediating; Minority; Molecular; Mutate; Neoplasm Metastasis; Normal tissue morphology; Organ; Pancreatic Ductal Adenocarcinoma; Paracrine Communication; Pathogenesis; Patients; Penetration; Perfusion; Pharmaceutical Preparations; Physiology; Process; Prognosis; Property; Proteins; Proteoglycan; Reaction; Resistance; Role; Sea; Series; Signal Pathway; Signal Transduction; Surface; Syndrome; T cell response; Testing; Therapeutic; Therapeutic Agents; Water; Work; autocrine; cancer stem cell; cell type; design; effector T cell; human disease; hypoperfusion; improved; interstitial; mortality; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; pancreatic cancer cells; pancreatic cancer model; paracrine; pharmacokinetics and pharmacodynamics; pressure; prevent; programs; receptor; therapy resistant; tumor

PROJECT SUMMARY Pancreatic ductal adenocarcinomas (PDA) are unrivaled in their lethality. PDAs have the highest 1- year, 5-year, and 10-year mortalities of any cancer and are expected to become the second-leading cause of cancer-related death by 2030. An invasive PDA represents the coordinated evolution of cell- intrinsic and extrinsic processes and capabilities that subvert and repurpose the dictums of normal tissue composition, architecture, and physiology to foster unbridled growth and colonization. This new organizational entity is constructed largely at the behest of the mutated epithelial cell. The resulting PDA neo-organ contains a minority of tumor epithelial cells amidst a heterogeneous sea of non- epithelial cells; a complex interstitial stew of proteins, proteoglycans and glycosaminoglycans, together with both freely mobile and complexed water; and a paucity of vessels that otherwise resemble a normal vasculature in lacking fenestrae or interendothelial junctions, but that are collapsed under intense interstitial pressures. We have undertaken a systematic exploration of the cell autonomous and non-cell autonomous processes that drive PDA pathogenesis and resistance. We have developed genetically engineered animal models that faithfully recapitulate the clinical syndrome, metastatic behavior, histopathology and molecular features of the human disease as primary platforms to both uncover critical principles of disease biology and to rigorously test strategies to overcome them. Through such investigations we have identified unusually high concentrations of intratumoral hyaluronan (HA) as the primary culprit in the extraordinarily elevated interstitial pressures in PDA that, in turn, cause the vascular collapse and hypoperfusion characteristic of this disease. The stromal barrier to perfusion also serves as a primary mechanism of drug resistance in limiting the penetration of systemically delivered agents. We have additionally identified multiple mechanisms of immune suppression that prevent the development of an endogenous effector T cell response. Collectively, these unique aspects of stromal biology in PDA conspire to create a drug- and immune-privileged sanctuary for unimpeded growth of the pancreas cancer cell. Very recently, we have elaborated strategies to overcome critical aspects of these physical and immunological barriers to therapy revealing a perhaps unexpected degree of vulnerability once the barriers are breached. We describe a series of continuing investigations into this overarching strategy of stromal re-engineering to build upon the significant inroads made – and the important lessons learned – in the hopes of radically transforming the approach and prognosis for this formidable disease.

项目概要 胰腺导管腺癌 (PDA) 的致死率是无与伦比的 1-。 任何癌症的一年、五年和十年死亡率，预计将成为第二大癌症 到 2030 年，癌症相关死亡的原因。侵入性 PDA 代表了细胞的协调进化 颠覆和重新利用正常格言的内在和外在过程和能力 组织组成、结构和生理学，以促进不受限制的生长和定植。 组织实体主要是根据突变上皮细胞的要求构建的。 PDA 新器官包含少数肿瘤上皮细胞，位于异质的非​​肿瘤细胞海洋中。 上皮细胞；蛋白质、蛋白聚糖和糖胺聚糖的复杂间质混合物 具有自由流动和复杂的水；以及缺乏其他类似的船只 正常脉管系统缺乏窗孔或内皮间连接，但在以下情况下塌陷 我们对细胞自主和间质压力进行了系统的探索。 我们开发了驱动 PDA 发病机制和耐药性的非细胞自主过程。 基因工程动物模型忠实地再现了临床综合征、转移性 人类疾病的行为、组织病理学和分子特征作为主要平台 揭示疾病生物学的关键原理并严格测试克服这些原理的策略。 通过这样的研究，我们发现肿瘤内异常高浓度 透明质酸 (HA) 是 PDA 间质压力异常升高的罪魁祸首， 反过来，导致这种疾病特有的血管塌陷和灌注不足。 灌注屏障也是限制药物渗透的主要耐药机制。 我们还发现了多种免疫机制。 抑制，阻止内源效应 T 细胞反应的发展。 PDA 中基质生物学的这些独特方面共同创造了药物和免疫特权 最近，我们详细阐述了胰腺癌细胞无阻碍生长的避难所。 克服这些物理和免疫治疗障碍的关键方面的策略 一旦障碍被突破，就会暴露出意想不到的脆弱性。 对基质重新设计的总体战略进行一系列持续调查，以建立 所取得的重大进展以及吸取的重要经验教训，希望能从根本上解决这一问题 改变这种可怕疾病的治疗方法和预后。

项目成果

T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma.

人胰腺导管腺癌中的 T 细胞定位、激活和克隆扩增。

• 发表时间: 2017-11
• 影响因子: 10.1
• 作者: Stromnes, Ingunn M;Hulbert, Ayaka;Pierce, Robert H;Greenberg, Philip D;Hingorani, Sunil R
• 通讯作者: Hingorani, Sunil R

Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer.

缺氧触发胰腺癌中刺猬介导的肿瘤间质相互作用。

• DOI: 10.1158/0008-5472.can-11-1433
• 发表时间: 2013-06-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Spivak-Kroizman TR;Hostetter G;Posner R;Aziz M;Hu C;Demeure MJ;Von Hoff D;Hingorani SR;Palculict TB;Izzo J;Kiriakova GM;Abdelmelek M;Bartholomeusz G;James BP;Powis G
• 通讯作者: Powis G

Runx3 and Cell Fate Decisions in Pancreas Cancer.

胰腺癌中的 Runx3 和细胞命运决定。

• DOI: 10.1007/978-981-10-3233-2_21
• 发表时间: 2024-09-13
• 期刊: Advances in experimental medicine and biology
• 作者: Martin C. Whittle;S. Hingorani
• 通讯作者: S. Hingorani

T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma.

针对天然抗原设计的 T 细胞可以克服免疫和物理障碍来治疗胰腺导管腺癌。

• DOI: 10.1016/j.ccell.2015.09.022
• 发表时间: 2015-11-09
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Stromnes IM;Schmitt TM;Hulbert A;Brockenbrough JS;Nguyen H;Cuevas C;Dotson AM;Tan X;Hotes JL;Greenberg PD;Hingorani SR
• 通讯作者: Hingorani SR

Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase.

胰腺导管腺癌的间质压力由凝胶-流体相主导。

• DOI: 10.1016/j.bpj.2016.03.040
• 发表时间: 2016-05-10
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Christopher C DuFort;Kathleen E. DelGiorno;Markus A. Carlson;R. Osgood;Chunmei Zhao;Zhongdong Huang;Curtis B. Thompson;R. Connor;C. Thanos;J. Brockenbrough;Paolo P. Provenzano;G. Frost;H. M. Shepard;Sunil R. Hingorani;Sunil R. Hingorani
• 通讯作者: Sunil R. Hingorani