Simultaneous Imaging of Tumor and Host Cells in the Microenvironment

建议书摘要/摘要 虽然在乳腺癌的检测和治疗方面取得了重大进展，但由于 转移性疾病的复发率仍然高得令人无法接受，是导致死亡的主要原因。此外， 副作用无法忍受的化疗仍然是转移性乳腺癌患者的标准护理， 这对生活质量是非常有害的。分子靶向肿瘤成像的进展为我们提供了一扇窗 基础肿瘤生物学，并支持使用个体化靶向治疗，使患者不必- 用严酷的化疗进行治疗。然而，大多数分子成像探针通常针对的是其中一种癌症 肿瘤微环境中的细胞或最近的一种单一细胞类型。这些方法本身就是 他们所能提供的信息有限。 最佳治疗计划依赖于疾病状态的完整图景，包括 根据病变的特定分子特征，了解残留疾病和复发的可能性。 因此，这项建议的目标是为临床上有用的手段提供基础，以形象和 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况。 我们假设同时对微环境和癌细胞进行分子成像将提供 更全面地检测病变区域并了解肿瘤的动态变化 支持个性化治疗所需的微环境。 我们提出：(Aim1)针对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对肿瘤的检测。(目标2)差异化靶向癌细胞和 具有相似光谱性质但不同光谱性质的近红外分子探针的肿瘤相关成纤维细胞 无创提取乳腺肿瘤间质比作为预后指标的荧光寿命值 癌症。这种非侵入性的方法可以确定恶性细胞和癌症的相对丰度- 相关的成纤维细胞将与传统的组织学肿瘤间质比测定方法进行比较。 在这项研究完成后，我们希望建立一种信号放大方法来检测微小的 癌症病变和非侵入性方法绘制癌症-间质比图以了解动态 肿瘤微环境的变化影响肿瘤生物学。

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.