Targeting Stromal Collagen in Pancreatic Cancer

靶向胰腺癌中的基质胶原

• 批准号: 8827288
• 负责人: Haiyong Han
• 金额: $ 38.67万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-19 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827288
• 关键词: Adverse effects; Albumins; Animal Model; Beds; Binding; Cancer Patient; Cattle; Cessation of life; Clinical; Clinical Research; Clinical Trials; Colchicine; Collagen; Cysteine; DNA; Deposition; Desmoplastic; Development; Diffusion; Disease; Disease remission; Enzymes; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Fibrosis; Genes; Genetically Engineered Mouse; Growth; Halofuginone; Health; Hepatic Stellate Cell; Human; Hyaluronan; Hyaluronidase; Intercellular Fluid; Lead; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediator of activation protein; Microtubules; Modeling; Molecular; Mus; Paclitaxel; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Penetration; Perfusion; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phosphotransferases; Play; Plicamycin; Production; Proteins; ROCK1 gene; Recombinants; Regimen; Resistance; Rho-associated kinase; Role; Safety; Signal Transduction; Sp1 Transcription Factor; Staging; Survival Rate; Testing; Tissues; Transgenic Mice; Translating; Tumor Tissue; United States; Work; Xenograft procedure; base; cancer cell; cancer stem cell; chemotherapeutic agent; conventional therapy; disorder control; drug efficacy; efficacy testing; gemcitabine; improved; inhibitor/antagonist; mouse model; neoplastic cell; outcome forecast; overexpression; phase 1 study; phase I trial; phase III trial; preclinical study; pressure; research study; resistance mechanism; response; rho; stellate cell; targeted treatment; tumor; uptake

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.

描述（由申请人提供）：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%。预后不良的主要原因之一是PDA的极端治疗耐药性。 这种耐药性的一个主要机制被认为是药物渗透到肿瘤床的速度较低，这是由于 PDA 中基质结缔组织增生导致的高肿瘤内间质液压力 (IFP) 造成的。 PDA 中致密的基质基质是细胞外基质 (ECM) 蛋白过量产生的结果，例如胶原蛋白、透明质酸和 SPARC（富含半胱氨酸的酸性分泌蛋白）。 我们的团队一直在探索针对这些 ECM 成分的不同方法，以降低基质硬度并提高药物吸收。 到目前为止，我们已经取得了一些非常令人鼓舞的成果。 根据我们之前的工作记录，直接取自患者的肿瘤中基质 SPARC 增加，我们进行了一项 I/II 期临床研究，将靶向 SPARC 的白蛋白结合 (nab)-紫杉醇添加到吉西他滨。 据记录，该方案对 IV 期疾病患者的疾病控制率为 68%（CR + PR + 稳定>16 周），并有部分完全缓解。 IV期PDA患者的中位生存期为12.2个月。 患者的反应与其肿瘤基质中的 SPARC 水平密切相关，但与肿瘤细胞中的 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人重组透明质酸酶（PEGPH20）进行了 I 期临床试验。 此前，在动物模型和预临床试验中，牛透明质酸酶被证明可以改善药物灌注和疗效。 然而，牛酶的免疫反应阻碍了进一步的临床开发。 我们的第一阶段研究结果表明 PEGPH20 具有良好的安全性和有前景的活性。 我们正在开展白蛋白结合型紫杉醇 + 吉西他滨（有或没有 PEGPH20）的其他临床试验。 基于上述靶向肿瘤基质的有希望的结果，在本申请中，我们建议靶向胶原蛋白，ECM基质的主要成分。 我们的假设是，减少基质胶原蛋白将导致 PDA 中的“基质塌陷”，从而降低 IFP 并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。我们试图通过进行以下具体目标中提出的临床前研究来检验这一假设： 目标 1：研究 Rho 激酶 (ROCK) 抑制剂或卤常酮灭活胰腺星状细胞 (PSC) 对破坏胶原动力学并改善 PDA 中药物灌注和摄取的影响；目标2：研究抑制胶原蛋白合成/分泌的药物改善PDA中肿瘤灌注和化疗药物摄取的能力；目标 3：评估胶原蛋白靶向药物加吉西他滨或吉西他滨 + 白蛋白结合型紫杉醇或其他临床上有前景的方案联合治疗对我们团队开发的患者原发异种移植物和 PDA 的 KPC 小鼠模型的疗效。