Online monitoring and image-guided treatment of chemoresistant micrometastases

化疗耐药微转移的在线监测和图像引导治疗

基本信息

批准号：
9148171
负责人：
Bryan Quilty Spring
金额：
$ 18.64万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-23 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9148171
关键词：
Address Adenocarcinoma Cell Antigen Targeting Binding Biological Markers Biological Models Calibration Cancer cell line Carcinomatosis Cell Culture Techniques Cell Death Cell membrane Cell surface Cells Chemosensitization Clinic Clinical Complement Complex Deposition Development Disease Disease Resistance Disseminated Malignant Neoplasm Drug Kinetics Drug resistance Ensure Epidermal Growth Factor Receptor Epithelial ovarian cancer Excision Feedback Flow Cytometry Fluorescence Goals Greater sac of peritoneum Health Image Imaging technology Immunoconjugates In Vitro Informatics Intestines Lead Left Malignant Neoplasms Membrane Methods Micrometastasis Microscopic Modality Modeling Molecular Molecular Target Monitor Morbidity - disease rate Operative Surgical Procedures Organ Outcome Ovarian Pancreatic Ductal Adenocarcinoma Patients Pelvic cavity structure Peritoneal Pharmaceutical Preparations Phototoxicity Polymerase Chain Reaction Process Protocols documentation Receptor Protein-Tyrosine Kinases Recurrence Regimen Research Residual state Resistance Resolution Reverse Transcription Salvage Therapy Series Site Source Specificity Staging Surface Antigens Testing Therapeutic Agents Therapeutic Index Time Tissues Training Translating Validation Work Xenograft Model arm base bioimaging cancer cell cancer therapy chemotherapy design dosimetry image guided imaging agent imaging biomarker imaging modality imaging probe improved in vivo microscopic imaging minimally invasive model development molecular imaging mortality mouse model neoplastic cell novel novel therapeutics optical imaging overexpression personalized cancer therapy radio-sensitizes response standard care systemic toxicity targeted imaging therapeutic target three dimensional cell culture three-dimensional modeling tool tumor uptake

Address Adenocarcinoma Cell Antigen Targeting Binding Biological Markers Biological Models Calibration Cancer cell line Carcinomatosis Cell Culture Techniques Cell Death Cell membrane Cell surface Cells Chemosensitization Clinic Clinical Complement Complex Deposition Development Disease Disease Resistance Disseminated Malignant Neoplasm Drug Kinetics Drug resistance Ensure Epidermal Growth Factor Receptor Epithelial ovarian cancer Excision Feedback Flow Cytometry Fluorescence Goals Greater sac of peritoneum Health Image Imaging technology Immunoconjugates In Vitro Informatics Intestines Lead Left Malignant Neoplasms Membrane Methods Micrometastasis Microscopic Modality Modeling Molecular Molecular Target Monitor Morbidity - disease rate Operative Surgical Procedures Organ Outcome Ovarian Pancreatic Ductal Adenocarcinoma Patients Pelvic cavity structure Peritoneal Pharmaceutical Preparations Phototoxicity Polymerase Chain Reaction Process Protocols documentation Receptor Protein-Tyrosine Kinases Recurrence Regimen Research Residual state Resistance Resolution Reverse Transcription Salvage Therapy Series Site Source Specificity Staging Surface Antigens Testing Therapeutic Agents Therapeutic Index Time Tissues Training Translating Validation Work Xenograft Model arm base bioimaging cancer cell cancer therapy chemotherapy design dosimetry image guided imaging agent imaging biomarker imaging modality imaging probe improved in vivo microscopic imaging minimally invasive model development molecular imaging mortality mouse model neoplastic cell novel novel therapeutics optical imaging overexpression personalized cancer therapy radio-sensitizes response standard care systemic toxicity targeted imaging therapeutic target three dimensional cell culture three-dimensional modeling tool tumor uptake

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项目摘要

DESCRIPTION (provided by applicant): Despite advances in cytoreductive surgery and chemotherapy, survival of metastatic epithelial ovarian cancer and pancreatic ductal adenocarcinoma remain dismal due in part to chemoresistant micrometastases undetectable by traditional imaging modalities. Both of these diseases involve peritoneal carcinomatosis, that is, extensive tumor studding of the peritoneal cavity and its resident organs. To address these "invisible" tumors, we introduce a series of cancer cell-targeted, activatable imaging and therapeutic agents integrated with cellular-resolution, multi-molecular fluorescence microendoscopy. We developed near-infrared photocytotoxic immunoconjugates (PICs) that target cell membrane molecules overexpressed by cancer cells, including the epidermal growth factor receptor, to serve as an imaging probe and combined photodynamic and anti-molecular therapeutic agent for tumor-targeted, activatable photoimmunotherapy (taPIT). The photodynamic and fluorescence components become de-quenched (activated) upon cancer cell binding, internalization and processing. This strategy overcomes off-target phototoxicity-including bowel phototoxicity-the major clinical obstacle for photoactivated treatments in complex sites such as the pelvic cavity. This proposal builds on our prior work that shows the PIC binds ovarian micrometastases with 93% sensitivity and 93% specificity in vivo, enabling accurate recognition of tumors as small as 30 �m and selective destruction of micrometastases. We propose to further develop this platform to specifically address chemoresistant micrometastases, which represent a critical niche in cancer therapy. Current clinical imaging technologies cannot resolve microscopic tumor deposits left behind by surgery and chemotherapy, and there are limited treatment options for patients with recurrent, chemoresistant tumors. We anticipate that this new paradigm for microendoscopy-guided taPIT will complement current treatment modalities for patients with advanced-stage disease and those receiving salvage therapies.

描述（由适用提供）：尽管细胞减少手术和化学疗法的进展，转移性上皮卵巢癌和胰腺导管腺癌的存活仍部分归因于化学剂微转移，但由于传统成像模态无法检测到。这两种疾病都涉及腹膜癌变，即腹膜腔及其常驻器官的广泛肿瘤研究。为了解决这些“看不见”的肿瘤，我们引入了一系列具有癌细胞靶向的，可激活的成像和与细胞分辨率的多分子荧光微观镜检查集成的治疗剂。我们开发了近红外的光毒性免疫偶联物（PICS），这些毒性分子靶向癌细胞过表达的细胞膜分子，包括表皮生长因子受体，以作为成像探针，并组合光动力学和抗分子治疗剂，用于肿瘤 - 肿瘤 - 肿瘤 - 可活动的光吸收术（Tablemumunoply）。在癌细胞结合，内在化和加工后，光动力和荧光成分被解冻（激活）。该策略克服了靶标光毒性，包括肠光毒性 - 在复杂部位（如骨盆腔）中光活化治疗的主要临床障碍。该提议建立在我们先前的工作基础上，该工作显示了PIC结合了93％敏感性和93％特异性的卵巢微转移，从而可以准确识别30 r肿瘤的肿瘤，并选择性破坏了微观。我们建议进一步开发该平台，以专门解决化学抗性微转移酶，这代表了癌症治疗中的关键利基市场。当前的临床成像技术无法解决手术和化学疗法留下的微观肿瘤沉积物，并且对于复发性化学耐药性肿瘤的患者的治疗选择有限。我们预计，这种新的微型镜检查磁带的新范式将完成晚期疾病患者和接受打捞疗法的患者的当前治疗方式。