Targeting Stromal Collagen in Pancreatic Cancer

靶向胰腺癌中的基质胶原

• 批准号: 8506704
• 负责人: Haiyong Han
• 金额: $ 40.82万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506704
• 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; 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; Phase III 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; disorder control; drug efficacy; efficacy testing; gemcitabine; improved; inhibitor/antagonist; mouse model; neoplastic cell; outcome forecast; overexpression; phase 1 study; preclinical study; pressure; public health relevance; research study; resistance mechanism; response; rho; stellate cell; 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％。预后如此不佳的主要原因之一是PDA的极端治疗能力。 该电阻的一种主要机制被认为是由于PDA中基质的脱虫质体而导致的高肿瘤内间质体压力（IFP）引起的药物渗透率低。 PDA中的致密基质基质是细胞外基质（ECM）蛋白（例如胶原蛋白，透明质酸和SPARC）（分泌的蛋白质酸性且富含半胱氨酸）的结果。 我们的团队一直在探索针对这些ECM组件的不同方法，以减少基质僵硬并改善药物摄取。 到目前为止，我们取得了一些令人鼓舞的结果。 基于我们先前的工作记录，直接从患者手中采取的肿瘤中增加了基质SPARC，我们对添加到吉西他滨添加的白蛋白结合（NAB） - 帕克列赛靶向SPARC的组合进行了I/II期临床研究。 该方案的疾病控制率为68％（CR + PR +稳定> 16周），其中IV期疾病患者有一些完全缓解。 IV期PDA患者的中位生存期为12.2个月。 患者的反应与肿瘤基质中的SPARC水平非常好，但在肿瘤细胞中却没有。 最近，为了攻击第二个基质成分（透明质酸），我们用Pegypated人重组透明质酸酶（PEGPH20）进行了I期临床试验。 以前显示牛透明质酸酶在动物模型和试验临床试验中都可以改善药物灌注和功效。 但是，对牛酶的免疫反应阻碍了进一步的临床发展。 我们阶段I研究的结果表明，PEGPH20的安全性和有希望的活动。 我们正在研究NAB-PACLITAXEL +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，在此应用中，我们建议靶向胶原蛋白，这是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”，这反过来又会减少IFP并增强化学疗法中的化学疗法渗透到肿瘤组织中，从而提高药物疗效和患者的生存率。我们试图通过在以下特定目的中进行临床前研究来检验这一假设：目标1：研究胰腺激酶（岩石）抑制剂或卤代酮以破坏胶原蛋白动力学并改善PDA的药物灌注和摄取的胰酶（岩石酶）抑制剂或卤代酮抑制剂的胰腺抑制剂（岩石酶（岩石）抑制剂）的影响；目的2：研究抑制胶原蛋白合成/分泌的药物的能力，以改善PDA中化学治疗剂的肿瘤灌注和摄取的能力； AIM 3：评估胶原蛋白靶向剂以及吉西他滨或吉西他滨 + NAB-PACLITAXEL或其他临床上有希望的方案的组合处理的功效，无论我们的团队开发的患者主要异种移植物和PDA的KPC小鼠模型。