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

• 批准号: 8704890
• 负责人: Dmitri Artemov
• 金额: $ 55.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704890
• 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; 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; controlled release; cytotoxic; design; drug development; humanized antibody; imaging modality; imaging probe; improved; inhibitor/antagonist; malignant breast neoplasm; molecular imaging; nano; nanocarrier; new technology; novel; novel strategies; optical imaging; outcome forecast; pre-clinical; radiotracer; response; response marker; small molecule; spectroscopic imaging; targeted delivery; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression

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）： 癌症抗血管生成疗法 (AAT) 的早期承诺和希望已经成熟，人们更加现实地认识到肿瘤微环境 (TME) 的变化会导致混杂效应，使包含 ATT 成分的联合疗法的结果复杂化。由于早期发现，乳腺癌的死亡率在过去十年中有所下降，但许多患者仍然复发转移性疾病，预后不良。紫杉醇和抗血管生成药物的组合是治疗侵袭性乳腺癌的一种有吸引力的新策略。在一项针对 HER2 阴性转移性乳腺癌的研究中，紫杉醇与抗 VEGF 人源化抗体贝伐珠单抗的联合治疗显示，无进展生存期从 6 个月延长至 12 个月。然而，尽管最初有临床获益，但大多数患者最终会出现疾病进展。肿瘤对这种治疗形式产生耐药性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，从而导致药物输送减少。另一个原因是AAT可能诱导肿瘤缺氧，进一步增加肿瘤的侵袭性和侵袭性。酪氨酸激酶受体的小分子抑制剂代表了一种更有效的方法，因为它们抑制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。帕唑帕尼是一种新型多激酶抑制剂，是最有前途的AAT药物之一，最近被批准用于晚期肾细胞癌，目前正在进行多种肿瘤类型联合治疗的临床试验。帕唑帕尼具有较低的全身毒性，可作为口服制剂使用。在这项研究中，我们将开发成像方法，用于指导使用帕唑帕尼和新型图像引导靶向紫杉醇纳米载体的临床前原位乳腺癌模型的联合治疗。该药物输送平台将能够通过无创 MRI 监测封装成分在目标部位的输送和释放，并且还将增强紫杉醇在肿瘤中的分布，从而改善治疗反应并最大限度地减少毒性。先进的分子和功能成像相结合，将用于表征治疗引起的肿瘤脉管系统和 TME 的变化，并确定有助于治疗反应或随后癌症进展的机制。