Stromal depletion for pancreatic cancer therapy

胰腺癌治疗中的基质耗竭

基本信息

批准号：
8900034
负责人：
Warren Foltz
金额：
$ 12.31万
依托单位：
UNIVERSITY OF BRITISH COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8900034
关键词：
Abraxane Albumins Apoptosis Binding Biological Markers Biopsy Blood Chemical Analysis Body Weight Breast Cancer Cell Breast Cancer Model Cells Characteristics Clinical Collagen Connective Tissue Data Dose Drug Delivery Systems Drug Exposure Drug Formulations Drug Kinetics Drug Targeting Drug toxicity Exhibits Extracellular Matrix Fibrosis Flow Cytometry Goals Growth Factor Health Histology Human Hypoxia Imaging Techniques Imaging technology Injection of therapeutic agent Intercellular Fluid Investigation Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of pancreas Measurement Measures Mitosis Modality Modeling Monitor Mus Names Neoplasm Metastasis Normal tissue morphology Paclitaxel Pancreas Patients Penetration Peptide Hydrolases Perfusion Permeability Pharmaceutical Preparations Pharmacodynamics Phase I/II Trial Phase III Clinical Trials Physicians Primary Neoplasm Role SCID Mice Saline Stromal Cells Stromal Neoplasm Supporting Cell Taxane Compound Techniques Therapeutic Therapeutic Agents Time Tissues Toxic effect Treatment Efficacy Unresectable Visceral Xenograft Model Xenograft procedure blood perfusion cancer care cancer cell cancer therapy chemotherapy comparative efficacy docetaxel drug testing gemcitabine human disease imaging modality improved innovation mouse model nanoparticle neoplastic cell non-invasive imaging palliation pancreatic neoplasm preclinical evaluation pressure response standard of care taxane therapeutic target treatment planning treatment response tumor tumor growth tumor progression tumor xenograft uptake

项目摘要

DESCRIPTION (provided by applicant): This project is focused on developing an innovative treatment modality for pancreatic cancer, which is one of the most lethal human malignancies. This treatment modality consists of two components: an innovative drug with enhanced efficacy, and imaging techniques that can non-invasively monitor treatment responses to assist physicians adjusting the therapeutic plan accordingly. We will evaluate the efficacy of the agent and the sensitivity of the imaging methods in multiple primary tumor models in mice. It has been recognized that a pancreatic tumor contains not only malignant cells but also supporting cells and connective tissues, which are referred to as stroma collectively. Stroma is known to promote cancer progression and spread, and has been identified as a therapeutic target to enhance pancreatic cancer therapy. Unfortunately, the progress of developing a stroma-targeted drug has been limited, and almost all of the testing drugs have failed in early human trials. The recent encouraging data with Abraxane (a taxane drug with an improved formulation) in human patients suggest that taxanes can be an effective stromal depleting agent to enhance pancreatic cancer treatment if the drug delivery efficiency is improved. We have thus created an innovative formulation for docetaxel (named Cellax), which selectively accumulate in tumors for sustained drug release and prolonged efficacy. In a mouse pancreatic tumor model, Cellax depleted most of the stroma and eventually eliminated the pancreatic tumors. We plan to further evaluate Cellax in 5 human primary tumor models that better represent the human disease, and also to investigate if the existing MRI techniques can monitor therapeutic response after Cellax therapy. 1. Evaluate Cellax in 5 primary models of pancreatic cancer. We will compare the efficacy of Cellax for inhibiting stroma and tumor growth compared to native docetaxel and Abraxane. The toxicity of these drugs will also be compared. We will also compare these treatments for their intratumoral drug delivery and effects on tumor cells and stromal cells separately to determine their mode-of-action and whether Cellax exhibits improved antitumor efficacy via enhanced anti-stromal activity. 2. Investigate if MRI techniques can monitor therapeutic response of Cellax. We will investigate if existing MRI techniques (magnetization transfer MRI and dynamic contrast enhanced MRI) can sensitively monitor tumor stromal depletion and tumor vascularity changes after Cellax therapy in 2 selected primary models of pancreatic cancer. If successful, these immediately translatable MR techniques will enable clinical monitoring of the response of stromal depletion therapy and timely adjustment of the treatment plan. The overall goal is to create an enhanced treatment modality to improve pancreatic cancer care.

描述（由申请人提供）：该项目的重点是为胰腺癌开发创新的治疗方式，胰腺癌是最致命的人类恶性肿瘤之一。这种治疗方式由两个组成部分组成：一种具有增强功效的创新药物，以及可以非侵入性监测治疗反应的成像技术，以帮助医生相应地调整治疗计划。我们将评估剂的功效和成像方法在小鼠多种原发性肿瘤模型中的敏感性。人们已经认识到，胰腺肿瘤不仅包含恶性细胞，还包含支撑细胞和结缔组织，共同称为基质。众所周知，基质可以促进癌症的进展和扩散，并被确定为增强胰腺癌治疗的治疗靶标。不幸的是，开发靶向基质的药物的进展受到限制，几乎所有的测试药物在早期的人类试验中都失败了。在人类患者中使用Abraxane（一种具有改善配方的紫杉烷药物）的最新鼓励数据表明，如果提高药物递送效率，则可以是一种有效的基质耗尽剂，以增强胰腺癌治疗。因此，我们为多西他赛（名为Cellax）创建了一种创新的配方，该配方在肿瘤中有选择地积累，以持续释放药物并延长疗效。在小鼠胰腺肿瘤模型中，Cellax耗尽了大部分基质，并最终消除了胰腺肿瘤。我们计划进一步评估5种人类原发性肿瘤模型，这些模型更好地代表人类疾病，并研究现有的MRI技术是否可以在Cellax治疗后监测治疗反应。 1。评估5个主要模型的胰腺癌模型。我们将比较与天然多西他赛和阿布沙烷相比，将细胞纳克斯抑制基质和肿瘤生长的疗效。这些药物的毒性也将被比较。我们还将比较这些治疗方法的肿瘤内药物递送以及对肿瘤细胞和基质细胞的影响，以确定其行动方式，以及通过增强的抗块状活性通过增强的抗肿瘤功效提高了抗肿瘤功效。 2。研究MRI技术是否可以监测细胞的治疗反应。我们将研究现有的MRI技术（磁化转移MRI和动态对比度增强的MRI）是否可以敏感地监测2种选定的胰腺癌主要模型的Cellax治疗后肿瘤基质耗竭和肿瘤血管变化。如果成功，这些可立即转换的MR技术将能够临床监测基质耗竭疗法的反应并及时调整治疗计划。总体目标是创建增强的治疗方式，以改善胰腺癌护理。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle.

DOI：
10.1016/j.jconrel.2015.03.023
发表时间：
2015-05-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Ernsting MJ;Hoang B;Lohse I;Undzys E;Cao P;Do T;Gill B;Pintilie M;Hedley D;Li SD
通讯作者：
Li SD

Docetaxel-carboxymethylcellulose nanoparticles display enhanced anti-tumor activity in murine models of castration-resistant prostate cancer.

DOI：
10.1016/j.ijpharm.2014.05.021
发表时间：
2014-08-25
期刊：
INTERNATIONAL JOURNAL OF PHARMACEUTICS
影响因子：
5.8
作者：
Hoang, Bryan;Ernsting, Mark J.;Murakami, Mami;Undzys, Elijus;Li, Shyh-Dar
通讯作者：
Li, Shyh-Dar

Modifying the tumor microenvironment using nanoparticle therapeutics.

DOI：
10.1002/wnan.1406
发表时间：
2016-11
期刊：
WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY
影响因子：
8.6
作者：
Roy, Aniruddha;Li, Shyh-Dar
通讯作者：
Li, Shyh-Dar

Docetaxel-carboxymethylcellulose nanoparticles target cells via a SPARC and albumin dependent mechanism.

DOI：
10.1016/j.biomaterials.2015.04.032
发表时间：
2015-08
期刊：
BIOMATERIALS
影响因子：
14
作者：
Hoang, Bryan;Ernsting, Mark J.;Roy, Aniruddha;Murakami, Mami;Undzys, Elijus;Li, Shyh-Dar
通讯作者：
Li, Shyh-Dar

Recent progress in the development of polysaccharide conjugates of docetaxel and paclitaxel.

DOI：
10.1002/wnan.1264
发表时间：
2014-07
期刊：
WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY
影响因子：
8.6
作者：
Roy, Aniruddha;Bhattacharyya, Mousumi;Ernsting, Mark J.;May, Jonathan P.;Li, Shyh-Dar
通讯作者：
Li, Shyh-Dar