Overcoming stromal barriers to therapeutics in pancreas cancer

克服胰腺癌治疗的基质障碍

• 批准号: 8699699
• 负责人: Sunil R Hingorani
• 金额: $ 49.41万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699699
• 关键词: Aneuploidy; Animal Model; Beds; Birth; Cancer Etiology; Cells; Cessation of life; Chemicals; Chromosomal Instability; Collagen; Convection; Country; Cytotoxic Chemotherapy; Cytotoxic agent; Desmoplastic; Development; Diffusion; Disease; Disease Progression; Disease Resistance; Ductal; Elements; Environment; Enzymes; Epithelial; Epithelial Cells; Erinaceidae; Exhibits; Extracellular Matrix; Extracellular Matrix Degradation; Fibroblasts; Genetic Engineering; Genetically Engineered Mouse; Glycosaminoglycans; Hormonal; Hormones; Hyaluronidase; Hypoxia; Immunosuppressive Agents; Incidence; Intercellular Fluid; Intervention; Invaded; Investigation; Label; Lesion; Life; Liquid substance; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Methods; Molecular; Neoplasms; Oncogenic; Outcome; Pancreatic Ductal Adenocarcinoma; Patients; Perfusion; Pharmaceutical Preparations; Proteoglycan; Radiation therapy; Reaction; Recombinants; Relaxin; Resected; Resistance; Safety; Signal Pathway; Signal Transduction; Sonic Hedgehog Pathway; Staging; Stromal Cells; Testing; Therapeutic; Tissues; Treatment Efficacy; angiogenesis; arm; base; cancer cell; chemotherapeutic agent; clinically significant; collagenase; combat; density; efficacy testing; gemcitabine; hypoxia inducible factor 1; improved; inhibitor/antagonist; killings; macrophage; mortality; mouse model; novel; pancreatic neoplasm; paracrine; pressure; programs; response; small molecule; smoothened signaling pathway; treatment strategy; tumor; tumor progression

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDA) is an unusually lethal disease with the highest 1-year and 5- year mortality rates of any cancer. An inability to detect the disease early together with multiple mechanisms of intrinsic resistance to chemical and radiotherapies contribute to the extreme lethality of PDA. Compounding the challenge in developing effective targeted therapies against pancreas cancer is the high degree of both numerical (aneuploidy) and structural (non-reciprocal translocations) chromosomal instability. The robust fibroinflammatory response, or desmoplasia, that accompanies and chronicles disease progression presents additional challenges to treating the disease, while also providing novel potential targets and approaches to combating PDA. We have recently characterized a number of critical elements of the desmoplastic reaction in pancreas cancer and the mechanisms by which these components promote and sustain nascent neoplasms. These components include tumor- associated macrophages, stromal fibroblasts and multiple types of immunosuppressive cells that invade and surround precursor ductal lesions from the earliest stages of preinvasive disease; a dense stromal collagen and proteoglycan matrix that appears to suppress angiogenesis and compromise tumor vascularity; and extremely high intratumoral fluid pressures. Thus, the delivery, diffusion and convection of small molecules are all critically limited by the stromal environment and together these various factors conspire to create a sanctuary for pancreas cancer progression. In this proposal, we will investigate first the ability of distinct interventions to disrupt the stromal matrix and improve perfusion in pancreas cancer to enhance the delivery and efficacy of chemotherapeutic agents. We will also test the ability of combining strategies directed against the stromal and epithelial compartments to make a clinically significant impact against this lethal disease.

描述（由申请人提供）：胰腺导管腺癌 (PDA) 是一种异常致命的疾病，其 1 年和 5 年死亡率是所有癌症中最高的。无法及早发现这种疾病，加上对化学和放射治疗的多种内在抵抗机制，导致了 PDA 的极端致命性。染色体数值（非整倍体）和结构（非相互易位）的高度不稳定性使得开发针对胰腺癌的有效靶向疗法面临更大的挑战。伴随并记录疾病进展的强烈纤维炎症反应或结缔组织形成，为治疗该疾病提出了额外的挑战，同时也提供了对抗 PDA 的新的潜在靶标和方法。我们最近描述了胰腺癌促纤维增生反应的许多关键要素以及这些成分促进和维持新生肿瘤的机制。这些成分包括肿瘤相关巨噬细胞、基质成纤维细胞和多种类型的免疫抑制细胞，它们从侵袭前疾病的最早阶段侵入并围绕前体导管病变；致密的基质胶原蛋白和蛋白聚糖基质似乎可以抑制血管生成并损害肿瘤血管分布；以及极高的瘤内流体压力。因此，小分子的递送、扩散和对流都受到基质环境的严重限制，这些不同的因素共同为胰腺癌的进展创造了庇护所。在本提案中，我们将首先研究不同干预措施破坏基质基质并改善胰腺癌灌注的能力，以增强化疗药物的输送和疗效。我们还将测试针对基质和上皮区室的组合策略的能力，以对这种致命疾病产生临床显着影响。