Overcoming stromal barriers to therapeutics in pancreas cancer

描述（由申请方提供）：胰腺导管腺癌（PDA）是一种异常致命的疾病，在所有癌症中1年和5年死亡率最高。不能早期发现疾病以及对化学和放射疗法的内在抗性的多种机制导致PDA的极端致命性。开发针对胰腺癌的有效靶向疗法的挑战是染色体数目（非整倍性）和结构（非相互易位）的高度不稳定性。伴随和记录疾病进展的强烈的纤维炎症反应或结缔组织增生对治疗疾病提出了额外的挑战，同时也提供了对抗PDA的新的潜在靶点和方法。我们最近的特点是一些关键要素的促结缔组织增生反应在胰腺癌和机制，这些成分促进和维持新生肿瘤。这些成分包括肿瘤相关的巨噬细胞、基质成纤维细胞和多种类型的免疫抑制细胞，它们从浸润前疾病的最早阶段侵入并包围前体导管病变;致密的基质胶原和蛋白聚糖基质，其似乎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格限制，这些各种因素共同为胰腺癌进展创造了一个避难所。在这个提议中，我们将首先研究不同干预措施破坏胰腺癌基质和改善灌注的能力，以增强化疗药物的递送和疗效。我们还将测试针对基质和上皮隔室的组合策略对这种致命疾病产生临床显著影响的能力。

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.