Simultaneous Imaging of Tumor and Host Cells in the Microenvironment

微环境中肿瘤和宿主细胞的同步成像

• 批准号: 10549299
• 负责人: Megan Suzanne Michie
• 金额: $ 3.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549299
• 关键词: Adverse event; Affect; Affinity; Aftercare; Annexins; Antibodies; Atlas of Cancer Mortality in the United States; Binding; Bispecific Antibodies; Breast Cancer Cell; Breast Cancer Detection; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer gene; Breast Cancer therapy; Cancer Biology; Cancer Detection; Cancer Etiology; Cancerous; Cause of Death; Cells; Cessation of life; Circulation; Clinical; Detection; Diagnosis; Disease; Disease Outcome; Drug Kinetics; Dyes; ERBB2 gene; Equilibrium; Exhibits; Fibroblasts; Fluorescence; Foundations; Goals; Histologic; Image; Image Enhancement; Immune; Immunotherapeutic agent; Intervention; Lesion; Ligands; Localized Disease; Malignant Neoplasms; Maps; Measures; Metastatic breast cancer; Methods; Microscopic; Molecular; Molecular Probes; Molecular Target; Monitor; Mus; Near-infrared optical imaging; Neoplasm Metastasis; Optics; Outcome; Patient-Focused Outcomes; Patients; Penetration; Peptides; Pharmaceutical Preparations; Phosphorylation; Population; Prediction of Response to Therapy; Process; Prognosis; Property; Quality of life; Recurrence; Recurrent disease; Recurrent tumor; Regional Disease; Reporting; Research; Residual Neoplasm; Residual state; Signal Transduction; Specificity; Stromal Cells; Survival Rate; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Treatment outcome; Tumor Biology; Tumor Tissue; Tumor Volume; Woman; Work; cancer biomarkers; cancer cell; cancer imaging; cancer therapy; cell type; chemotherapy; design; detection method; detection sensitivity; effective therapy; fibroblast-activating factor; fluorescence lifetime imaging; fluorophore; imaging agent; imaging modality; imaging platform; imaging probe; improved; in vivo; in vivo fluorescence; malignant breast neoplasm; microscopic imaging; molecular imaging; mortality; mouse model; neoplastic cell; novel; optical imaging; optimal treatments; overtreatment; personalized medicine; pre-clinical; prognostic; prognostic indicator; side effect; small molecule; standard of care; targeted agent; targeted biomarker; targeted imaging; targeted treatment; trait; treatment planning; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment

Proposal Summary/Abstract While there have been significant advances in the detection and treatment of breast cancer, mortality due to metastatic disease recurrence remains unacceptably high and a leading cause of death. Furthermore, chemotherapies with intolerable side effects remain the standard of care for metastatic breast cancer patients, which is highly detrimental to quality of life. Advances in molecular targeting cancer imaging offer a window into underlying tumor biology and support the use of individualized targeted therapies that can spare patients over- treatment with harsh chemotherapies. However, most molecular imaging probes typically target either cancer cells or, more recently, a single cell type in the tumor microenvironment. These approaches are inherently limited in the information they can provide. Optimal treatment planning relies on a complete picture of disease state, including microscopic regions of residual disease and understanding the potential for recurrence based on a lesion’s specific molecular traits. As such, the goal of this proposal is to provide the foundation for a clinically useful means to image and understand disease status before, during, and after treatment of primary breast cancer and metastatic disease. We postulate that molecular imaging of both the microenvironment and cancer cells simultaneously will provide more complete detection of diseased regions and an understanding of dynamic changes in tumor microenvironment that are needed to support personalized therapy. We propose: (Aim1) A bispecific strategy targeting both breast cancer cells and cancer-associated fibroblasts in the tumor microenvironment to enhance tumor detection. (Aim 2) Differentially targeting cancer cells and cancer-associated fibroblasts with near-infrared molecular probes with similar spectral properties but different fluorescent lifetime values to extract tumor-stroma ratio noninvasively, which is a prognostic indicator in breast cancer. This non-invasive method of determining the relative abundance of malignant cells and cancer- associated fibroblasts will be compared with the traditional histologic determination of tumor-stroma ratio. At the completion of this study, we expect to have established a signal amplification method to detect small cancerous lesions and a non-invasive approach to map cancer-stromal ratio to understand how the dynamic changes in the tumor microenvironment affect cancer biology.

提案摘要/摘要 虽然在乳腺癌的检测和治疗方面已经取得了重大进展，但由于乳腺癌而导致的死亡率仍然很高。 转移性疾病的复发仍然高得不可接受，并且是死亡的主要原因。此外，委员会认为， 具有不可忍受的副作用的化疗仍然是转移性乳腺癌患者的标准治疗， 这对生活质量非常有害。分子靶向癌症成像的进展提供了一个窗口， 潜在的肿瘤生物学，并支持使用个性化的靶向治疗，可以节省患者超过- 用严厉的化疗来治疗。然而，大多数分子成像探针通常靶向癌症， 细胞或最近的肿瘤微环境中的单一细胞类型。这些方法本质上是 他们能提供的信息有限。 最佳的治疗计划依赖于疾病状态的完整图像，包括微观区域， 残留疾病和了解潜在的复发病变的基础上的具体分子性状。 因此，本提案的目标是为临床上有用的成像和 了解原发性乳腺癌和转移性疾病治疗前、治疗中和治疗后的疾病状态。 我们假设同时对微环境和癌细胞进行分子成像将提供 更完整地检测病变区域并了解肿瘤的动态变化 需要支持个性化治疗的微环境。 我们提出：（Aim 1）靶向乳腺癌细胞和癌症相关成纤维细胞的双特异性策略 在肿瘤微环境中增强肿瘤检测。(Aim 2）差异靶向癌细胞， 癌症相关成纤维细胞与近红外分子探针具有相似的光谱特性，但不同 非侵入性提取肿瘤-间质比率的荧光寿命值，这是乳腺癌的预后指标 癌这种确定恶性细胞和癌症相对丰度的非侵入性方法- 将相关的成纤维细胞与传统的肿瘤-间质比率的组织学测定进行比较。 在完成这项研究后，我们期望已经建立了一种信号放大方法来检测小的 癌性病变和一种非侵入性的方法来绘制癌症-间质比率，以了解动态 肿瘤微环境的变化影响癌症生物学。