Image-guided combination therapy: noninvasive assessment of delivery and response

图像引导联合治疗：递送和反应的无创评估

基本信息

批准号：
8915639
负责人：
Dmitri Artemov
金额：
$ 56.28万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915639
关键词：
Address Affect Angiogenesis Inhibitors Blood Vessels Breast Cancer Model Choline Clinical Clinical Trials Combined Modality Therapy Complex Contrast Media Cytokine Receptors Death Rate Detection Development Disease Disease Progression Drug Carriers Drug Delivery Systems Drug Formulations ERBB2 gene Early Diagnosis Early treatment Encapsulated Functional Imaging Goals Grant Hypoxia Image Ligands Liposomes Magnetic Resonance Imaging Malignant Neoplasms Measures Metabolic Metastatic breast cancer Methods Modeling Molecular Molecular Target Monitor Monoclonal Antibodies NIH Program Announcements Nuclear Oral Outcome Paclitaxel Patients Pharmaceutical Preparations Pharmacotherapy Physiological Positron-Emission Tomography Progression-Free Survivals Property Public Health Radiolabeled Receptor Protein-Tyrosine Kinases Renal Cell Carcinoma Reporter Resistance Signal Pathway Site Therapeutic Toxic effect Treatment outcome Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Vascular Permeabilities Vascular blood supply aggressive therapy angiogenesis bevacizumab combination cancer therapy contrast enhanced controlled release cytotoxic design drug development humanized antibody image guided imaging modality imaging probe improved inhibitor/antagonist malignant breast neoplasm molecular imaging nano nanocarrier new technology non-invasive imaging novel novel strategies optical imaging outcome forecast pre-clinical quantitative imaging radiotracer response response marker small molecule spectroscopic imaging targeted delivery targeted imaging treatment response tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): The early promise and hope for antiangiogenic therapy (AAT) in cancer has matured to a more realistic understanding that changes in the tumor microenvironment (TME) result in confounding effects that complicate outcome of combination therapy that includes an ATT component. Because of earlier detection, death rates from breast cancer have decreased over the last decade, but many patients still recur with metastatic disease with poor prognosis. A combination of paclitaxel and antiangiogenic agents is an attractive novel strategy in therapy of aggressive breast cancer. In a study of HER2-negative metastatic breast cancer a combination of paclitaxel with an anti-VEGF humanized antibody, bevacizumab, showed a doubling in progression free survival from 6 to 12 months. However, despite an initial clinical benefit, most patients ultimately develop disease progression. Potential mechanisms of tumor resistance to this form of therapy may include activation of alternative signaling pathways, and interference of AAT with the vascular supply that can result in reduced drug delivery. Another reason is possible induction of tumor hypoxia by AAT that further increases tumor aggressiveness and invasiveness. Small molecule inhibitors of tyrosine- kinase receptors represent a more potent approach as they inhibit functions of multiple cytokine receptors and have better delivery properties compared to monoclonal antibodies (mAb). A new multikinase inhibitor, pazopanib, is one of the promising AAT drugs and has been recently approved for advanced renal cell carcinoma and is currently in clinical trials for combination therapy of multiple tumor types. Pazopanib has low systemic toxicity and is available as oral formulation. In this study we will develop imaging methods for guidance of combination therapy in preclinical orthotopic breast cancer models using pazopanib and novel image-guided targeted paclitaxel nanocarriers. This drug delivery platform will enable noninvasive MRI monitoring of the delivery and release of the encapsulated components at the target site and will also enhance distribution of paclitaxel in the tumor thus improving treatment response and minimizing toxicity. A combination of advanced molecular and functional imaging will be used to characterized changes in tumor vasculature and TME induced by the therapy and to identify mechanisms that can contribute to treatment response or subsequent cancer progression.

描述（由申请人提供）：癌症中抗血管生成治疗（AAT）的早期希望和希望已经成熟到更现实的理解，即肿瘤微环境（TME）的变化会导致混淆作用，使组合疗法的结果复杂化，包括ATT成分。由于较早的检测，在过去的十年中，乳腺癌的死亡率降低了，但是许多患者仍然患有转移性疾病，预后不良。紫杉醇和抗血管生成剂的结合是侵袭性乳腺癌治疗的一种有吸引力的新型策略。在一项针对HER2阴性转移性乳腺癌的研究中，紫杉醇与抗VEGF人源化抗体贝伐单抗的结合显示，无进展生存率从6到12个月增加了一倍。但是，尽管有最初的临床益处，但大多数患者最终会发展疾病的进展。肿瘤对这种形式治疗的潜在机制可能包括激活替代信号通路，以及AAT干扰血管供应，这可能导致药物递送减少。另一个原因是AAT可能会诱导肿瘤缺氧，从而进一步提高肿瘤侵袭性和侵入性。酪氨酸 - 激酶受体的小分子抑制剂是一种更有效的方法，因为它们抑制了多种细胞因子受体的功能，并且与单克隆抗体（MAB）相比具有更好的递送特性。一种新的多次抑制剂Pazopanib是一种有前途的AAT药物之一，最近已被批准用于晚期肾细胞癌，目前正在临床试验进行多种肿瘤类型的联合治疗。 Pazopanib的全身毒性低，可作为口服配方可用。在这项研究中，我们将使用pazopanib和新型的图像引导的靶向紫杉醇纳米载体来开发临床前矫正乳腺癌模型中联合治疗指导的成像方法。该药物输送平台将对目标部位的封装成分的输送和释放进行无创的MRI监测，并将增强紫杉醇在肿瘤中的分布，从而改善治疗反应并最大程度地减少毒性。晚期分子和功能成像的组合将用于表征疗法诱导的肿瘤脉管系统的变化和TME的变化，并确定可以有助于治疗反应或随后的癌症进展的机制。