Targeting Stromal Collagen in Pancreatic Cancer

靶向胰腺癌中的基质胶原

• 批准号: 9262171
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262171
• 关键词: Adverse effects; Albumins; Animal Model; Beds; 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; Immune response; 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; Survival Rate; Testing; Tissues; Transgenic Mice; Translating; Tumor Tissue; United States; Work; Xenograft procedure; base; cancer cell; cancer stem cell; chemotherapeutic agent; clinical development; conventional therapy; disorder control; drug efficacy; efficacy testing; experimental study; gemcitabine; improved; inhibitor/antagonist; mouse model; neoplastic cell; outcome forecast; overexpression; phase 1 study; phase I trial; phase III trial; preclinical study; pressure; public health relevance; resistance mechanism; response; rho; stellate cell; targeted agent; targeted treatment; therapy resistant; 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(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年生存率为5%。PDA对治疗的极端抗药性是导致预后不良的主要原因之一。这种耐药性的一个主要机制被认为是药物对肿瘤床的低渗透率，这是由于PDA的间质间质结缔组织增生导致的高肿瘤间质液体压(IFP)所致。PDA中致密的间质是细胞外基质(ECM)蛋白过度产生的结果，如胶原蛋白、透明质酸和SPARC(酸性和富含半胱氨酸的分泌蛋白)。我们的团队一直在探索不同的方法来靶向这些ECM成分，以减少间质僵硬和提高药物摄取。到目前为止，我们已经取得了一些非常令人鼓舞的结果。根据我们先前的工作，直接取自患者的肿瘤间质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。该方案记录的疾病控制率为68%(CR+PR+稳定&GT；16周)，在一些完全缓解的IV期患者中。IV期PDA患者的中位生存期为12.2个月。患者的反应与肿瘤间质中SPARC的水平有很好的相关性，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)，我们对聚乙二醇化的人重组透明质酸酶(PEGPH20)进行了I期临床试验。此前，牛透明质酸酶在动物模型和试点临床试验中都被证明可以改善药物灌注量和疗效。然而，对牛酶的免疫反应阻碍了临床的进一步发展。我们第一阶段研究的结果表明，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的额外临床试验。基于上述靶向肿瘤间质的有希望的结果，在这一应用中，我们建议靶向ECM基质的主要成分-胶原。我们的假设是，减少间质胶原会导致PDA的间质塌陷，进而降低IFP，增强化疗药物对肿瘤组织的渗透，从而改善药物疗效和患者生存。我们试图通过执行以下特定目标的临床前研究来验证这一假说：目的1：研究Rho激酶(ROCK)抑制剂或常青藤酮灭活胰腺星状细胞(PSC)是否能够扰乱胶原动力学，改善PDA的药物灌注量和摄取量；目的2：研究抑制胶原合成/分泌的药物能否改善PDA中肿瘤的灌注量和化疗药物的摄取量；目的3：评价胶原靶向制剂联合吉西他滨或吉西他滨+NAB-紫杉醇或其他临床有希望的方案对PDA患者原发异种移植瘤的疗效。

项目成果

RNA Interference to Knock Down Gene Expression.

• DOI: 10.1007/978-1-4939-7471-9_16
• 发表时间: 2018
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Han H

Parallel Accumulation of Tumor Hyaluronan, Collagen, and Other Drivers of Tumor Progression.

• DOI: 10.1158/1078-0432.ccr-17-3284
• 发表时间: 2018-10-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Li X;Shepard HM;Cowell JA;Zhao C;Osgood RJ;Rosengren S;Blouw B;Garrovillo SA;Pagel MD;Whatcott CJ;Han H;Von Hoff DD;Taverna DM;LaBarre MJ;Maneval DC;Thompson CB
• 通讯作者: Thompson CB