Overcoming stromal barriers to therapeutics in pancreas cancer

描述(申请人提供)：胰腺导管腺癌(PDA)是一种罕见的致命疾病，在所有癌症中，1年和5年死亡率最高。无法及早发现疾病，加上对化疗和放射治疗的内在抵抗的多种机制，导致了PDA的极端致命性。在开发针对胰腺癌的有效靶向治疗方面的挑战是数字(非整倍体)和结构(非相互易位)染色体高度不稳定。伴随和记录疾病进展的强大的纤维炎性反应或结缔组织增生给疾病的治疗带来了额外的挑战，同时也为抗击PDA提供了新的潜在靶点和方法。我们最近描述了胰腺癌中促结缔组织增生反应的一些关键因素，以及这些因素促进和维持新生肿瘤的机制。这些成分包括肿瘤相关的巨噬细胞、间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早期阶段就入侵和包围前驱导管病变；致密的间质胶原和蛋白多糖基质，似乎抑制了血管生成，损害了肿瘤的血管；以及极高的肿瘤内液体压力。因此，小分子的传递、扩散和对流都受到间质环境的严重限制，这些不同的因素共同创造了胰腺癌进展的避难所。在这项提案中，我们将首先研究不同干预措施破坏胰腺癌间质基质和改善胰腺癌血流灌注的能力，以增强化疗药物的输送和疗效。我们还将测试针对间质和上皮室的联合策略的能力，以对这种致命疾病产生临床上的重大影响。

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.