Targeting Stromal Collagen in Pancreatic Cancer

描述（申请人提供）：胰腺导管腺癌（PDA）是最致命的恶性肿瘤之一。晚期PDA患者的中位生存期为6个月，5年生存率<5%。其预后不良的主要原因之一是PDA的极度耐药。耐药的一个主要机制被认为是由于PDA间质结缔组织增生导致肿瘤内间质液压力（IFP）高，导致药物渗透到肿瘤床的率低。PDA中致密的间质基质是细胞外基质（ECM）蛋白如胶原、透明质酸和SPARC（富含半胱氨酸的酸性分泌蛋白）过量产生的结果。我们的团队一直在探索不同的方法来靶向这些ECM成分，以减少基质硬度和改善药物摄取。到目前为止，我们已经取得了一些非常令人鼓舞的成果。基于我们之前的工作记录，直接从患者身上取出的肿瘤中基质SPARC增加，我们进行了一项I/II期临床研究，将白蛋白结合(nab)-紫杉醇靶向SPARC与吉西他滨联合使用。在IV期疾病完全缓解的患者中，该方案的疾病控制率为68% （CR + PR +稳定持续bbb16周）。IV期PDA患者的中位生存期为12.2个月。患者的反应与肿瘤基质中的SPARC水平密切相关，而与肿瘤细胞中的SPARC水平无关。最近，为了攻击第二种基质成分（透明质酸），我们使用聚乙二醇化的重组人透明质酸酶（PEGPH20）进行了I期临床试验。此前，牛透明质酸酶在动物模型和中试临床试验中均显示出改善药物灌注和疗效的作用。然而，进一步的临床开发受到对牛酶的免疫反应的阻碍。我们的I期研究结果表明，PEGPH20具有良好的安全性和良好的活性。我们正在进行nab-紫杉醇+吉西他滨加或不加PEGPH20的临床试验。基于上述靶向肿瘤基质的良好结果，在本应用中，我们建议靶向ECM基质的主要成分胶原。我们的假设是，减少基质胶原会导致PDA的“基质塌陷”，从而降低IFP，增强化疗药物对肿瘤组织的渗透，从而提高药物疗效和患者生存率。我们试图通过以下具体目的提出的临床前研究来验证这一假设：目的1：研究Rho激酶（ROCK）抑制剂或halofuginone对胰星状细胞（PSC）失活的影响，以破坏胶原动力学并改善PDA中的药物灌注和摄取；目的2：探讨抑制胶原合成/分泌的药物改善PDA肿瘤灌注和化疗药物摄取的能力；目的3：评估胶原靶向药物联合吉西他滨或吉西他滨+ nab-紫杉醇或其他有临床前景的方案对我们团队开发的患者原发性异种移植物和PDA的KPC小鼠模型的疗效。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies. The median survival for patients with advanced PDA is 6 months and 5-year survival rate is <5%. One of main reasons for such poor prognosis is the extreme treatment resistance of PDA. One major mechanism for that resistance is thought to be the low rate of drug penetration into the tumor bed, caused by the high intratumor interstitial fluid pressure (IFP) as a result of the stromal desmoplasia in PDA. The dense stromal matrix in PDA is a result of the overproduction of extracellular matrix (ECM) proteins such as collagens, hyaluronan, and SPARC (secreted protein acidic and rich in cysteine). Our team has been exploring different approaches to target these ECM components to reduce stromal stiffness and improve drug uptake. So far we have had some very encouraging results. Based on our prior work documenting that stromal SPARC is increased in tumors taken directly from patients we performed a Phase I/II clinical study of the combination of the albumin-bound (nab)-paclitaxel targeting SPARC added to gemcitabine. That regimen has given a documented disease control rate of 68% (CR + PR + stable for >16 weeks) in patients with stage IV disease with some complete remission. The median survival of patients with stage IV PDA was 12.2 months. The patients' response correlated very well with the level of SPARC in their tumor stroma but not in tumor cells. Most recently, to attack a second stromal component (hyaluronan) we performed a Phase I clinical trial with the pegylated human recombinant hyaluronidase (PEGPH20). Previously bovine hyaluronidase was shown to improve drug perfusion and efficacy in both animal models and pilot clinical trials. However, further clinica development was hampered by the immunological response to the bovine enzyme. Results from our Phase I study demonstrated a good safety profile and promising activity for PEGPH20. We are working on additional clinical trials of nab-paclitaxel + gemcitabine with or without PEGPH20. Based on the above promising results of targeting tumor stroma, in this application we propose to target collagen, the major component of ECM matrix. Our hypothesis is that reducing stromal collagen will result in "stromal collapse" in PDA which will in turn decrease IFP and enhance the penetration of chemotherapeutics into tumor tissues and consequently improve drug efficacy and patient survival. We seek to test this hypothesis by performing preclinical studies proposed in the following specific aims: Aim 1: to investigate the effect of pancreatic stellate cell (PSC) inactivation either by Rho kinase (ROCK) inhibitors or by halofuginone to disrupt collagen dynamics and improve drug perfusion and uptake in PDA; Aim 2: to investigate the ability of agents that inhibit collagen synthesis/secretion to improve tumor perfusion and uptake of chemotherapeutic agents in PDA; Aim 3: to evaluate the efficacy of combination treatment of a collagen targeted agent plus gemcitabine or gemcitabine + nab-paclitaxel or other clinically promising regimens both against patient primary xenografts developed by our team and the KPC mouse model for PDA.