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（由申请方提供）：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%。PDA的极端治疗抵抗性是其预后不良的主要原因之一。 耐药的一个主要机制被认为是药物渗透到肿瘤床中的速率低，这是由PDA中的间质结缔组织增生导致的高肿瘤间质液压力（IFP）引起的。 PDA中致密的基质基质是细胞外基质（ECM）蛋白如胶原、透明质酸和β-半胱氨酸（分泌的酸性蛋白和富含半胱氨酸）过度产生的结果。 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。 基于我们先前的工作记录了直接取自患者的肿瘤中基质细胞增加，我们进行了将白蛋白结合（nab）-紫杉醇靶向紫杉醇添加至吉西他滨的组合的I/II期临床研究。 该方案已在IV期疾病患者中提供了68%的有记录的疾病控制率（CR + PR +稳定>16周），并有一些完全缓解。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间质中而不是肿瘤细胞中的β-内酰胺酶水平非常相关。 最近，为了攻击第二基质成分（透明质酸），我们用聚乙二醇化的人重组透明质酸酶（PEGPH 20）进行了I期临床试验。 此前，牛透明质酸酶在动物模型和初步临床试验中均被证明可以改善药物灌注和功效。 然而，对牛酶的免疫反应阻碍了进一步的临床开发。 我们的I期研究结果表明，PEGPH 20具有良好的安全性和有希望的活性。 我们正在进行nab-紫杉醇+吉西他滨（有或没有PEGPH 20）的其他临床试验。 基于靶向肿瘤基质的上述有希望的结果，在本申请中，我们提出靶向胶原，ECM基质的主要成分。 我们的假设是，减少基质胶原将导致PDA中的“基质塌陷”，这将反过来减少IFP并增强化疗药物向肿瘤组织中的渗透，从而提高药物疗效和患者存活率。我们试图通过进行临床前研究来验证这一假设，这些研究提出了以下具体目标：目标1：研究Rho激酶（ROCK）抑制剂或常山酮对胰腺星状细胞（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;目标2：研究抑制胶原合成/分泌的试剂改善PDA中肿瘤灌注和化疗剂摄取的能力;目的3：评价胶原靶向剂加吉西他滨或吉西他滨+nab-紫杉醇或其他临床上有前景的方案对我们团队开发的患者原发性异种移植物和KPC PDA小鼠模型的联合治疗的疗效。