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:8024962
- 负责人:
- 金额:$ 60.88万
- 依托单位:
- 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 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAngiogenesis InhibitorsBlood VesselsBreast Cancer ModelCholineClinicalClinical TrialsCombined Modality TherapyComplexContrast MediaCytokine ReceptorsDeath RateDetectionDevelopmentDiseaseDisease ProgressionDrug CarriersDrug Delivery SystemsDrug FormulationsERBB2 geneEarly DiagnosisEarly treatmentEncapsulatedFunctional ImagingGoalsGrantHypoxiaImageLigandsLiposomesMagnetic Resonance ImagingMalignant NeoplasmsMeasuresMetabolicMethodsModelingMolecularMolecular TargetMonitorMonoclonal AntibodiesNIH Program AnnouncementsNuclearOralOutcomePaclitaxelPatientsPharmaceutical PreparationsPharmacotherapyPhysiologicalPositron-Emission TomographyProgression-Free SurvivalsPropertyPublic HealthRadiolabeledReceptor Protein-Tyrosine KinasesRenal Cell CarcinomaReporterResistanceSignal PathwaySiteTherapeuticToxic effectTreatment outcomeVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth Factor Receptor-2Vascular PermeabilitiesVascular blood supplyaggressive therapyangiogenesisbevacizumabcombination cancer therapycontrolled releasecytotoxicdesigndrug developmenthumanized antibodyimaging modalityimaging probeimprovedinhibitor/antagonistmalignant breast neoplasmmolecular imagingnanonanocarriernew technologynovelnovel strategiesoptical imagingoutcome forecastpre-clinicalradiotracerresponseresponse markersmall moleculespectroscopic imagingtargeted deliverytreatment responsetumortumor growthtumor 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.
PUBLIC HEALTH RELEVANCE: In this project we will develop a novel platform for targeted image-guided delivery of a cytotoxic component of combination antiangiogenic therapy. Novel technology will provide optimized delivery of the drug to the tumor and noninvasive detection of the response early in the treatment. Implementation of the novel image-guided drug delivery system can have significant impact for public health by improving the treatment outcome and minimizing systemic toxicity of the combination chemo- and antiangiogenic therapy.
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。
公共健康相关性:在这个项目中,我们将开发一个新颖的平台,用于联合抗血管生成疗法的细胞毒性成分的靶向图像引导递送。新技术将优化药物向肿瘤的输送,并在治疗早期对反应进行无创检测。新型图像引导药物输送系统的实施可以通过改善治疗结果并最大限度地减少化疗和抗血管生成联合治疗的全身毒性,对公众健康产生重大影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Dmitri Artemov其他文献
Dmitri Artemov的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Dmitri Artemov', 18)}}的其他基金
HER2-pretargeting image-guided therapy of breast cancer
HER2 预靶向图像引导乳腺癌治疗
- 批准号:
9893831 - 财政年份:2017
- 资助金额:
$ 60.88万 - 项目类别:
HER2-pretargeting image-guided therapy of breast cancer
HER2 预靶向图像引导乳腺癌治疗
- 批准号:
9301787 - 财政年份:2017
- 资助金额:
$ 60.88万 - 项目类别:
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:
8516472 - 财政年份:2011
- 资助金额:
$ 60.88万 - 项目类别:
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:
8338806 - 财政年份:2011
- 资助金额:
$ 60.88万 - 项目类别:
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:
8915639 - 财政年份:2011
- 资助金额:
$ 60.88万 - 项目类别:
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 - 财政年份:2011
- 资助金额:
$ 60.88万 - 项目类别:
Activated nano-sized MR contrast agents for imaging of tumor proteolytic activity
用于肿瘤蛋白水解活性成像的活化纳米级磁共振造影剂
- 批准号:
7822825 - 财政年份:2009
- 资助金额:
$ 60.88万 - 项目类别:
Activated nano-sized MR contrast agents for imaging of tumor proteolytic activity
用于肿瘤蛋白水解活性成像的活化纳米级磁共振造影剂
- 批准号:
7739994 - 财政年份:2009
- 资助金额:
$ 60.88万 - 项目类别:
MR Pharmacoangiography-Vascular Modulation of Delivery
MR 药物血管造影-输送的血管调节
- 批准号:
7477382 - 财政年份:2007
- 资助金额:
$ 60.88万 - 项目类别:
MR Imaging of Endothelial Progenitor Cells in Prostate Cancer
前列腺癌内皮祖细胞的 MR 成像
- 批准号:
7268162 - 财政年份:2006
- 资助金额:
$ 60.88万 - 项目类别:
相似国自然基金
基于lncRNA NONHSAT042241/hnRNP D/β-catenin轴探讨雷公藤衍生物(LLDT-8)对类风湿关节炎滑膜成纤维细胞功能影响及机制研究
- 批准号:82304988
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
针刺手法和参数对针刺效应启动的影响及其机制
- 批准号:82305416
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
二仙汤影响肾上腺皮质-髓质激素分泌及调控下丘脑温度感受器以缓解“天癸竭”潮热的研究
- 批准号:82374307
- 批准年份:2023
- 资助金额:48 万元
- 项目类别:面上项目
固定翼海空跨域航行器出水稳定性与流体动力载荷影响机制
- 批准号:52371327
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
经济制裁对跨国企业海外研发网络建构的影响:基于被制裁企业的视角
- 批准号:72302155
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Extracellular Matrix Impacts Angiogenesis and Growth Plate Repair
细胞外基质影响血管生成和生长板修复
- 批准号:
10668056 - 财政年份:2023
- 资助金额:
$ 60.88万 - 项目类别:
PBRM1 bromodomain missense mutations in ccRCC vascular signaling
ccRCC 血管信号传导中的 PBRM1 溴结构域错义突变
- 批准号:
10604440 - 财政年份:2023
- 资助金额:
$ 60.88万 - 项目类别:
Antiangiogenic Therapy to Reduce Bleeding and Improve Health-Related Quality of Life in Hereditary Hemorrhagic Telangiectasia
抗血管生成疗法可减少遗传性出血性毛细血管扩张症的出血并改善健康相关的生活质量
- 批准号:
10448102 - 财政年份:2022
- 资助金额:
$ 60.88万 - 项目类别:
Sexual dimorphism in antigen-independent angiogenesis inhibition of IgG1 antibodies
IgG1 抗体的抗原非依赖性血管生成抑制中的性别二态性
- 批准号:
10705615 - 财政年份:2022
- 资助金额:
$ 60.88万 - 项目类别: