Simultaneous Imaging of Tumor and Host Cells in the Microenvironment

提案摘要/摘要 尽管乳腺癌的检测和治疗取得了重大进展，但由于乳腺癌导致的死亡率 转移性疾病的复发率仍然高得令人无法接受，并且是死亡的主要原因。此外， 具有无法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方法， 这对生活质量非常不利。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体化的靶向治疗，可以使患者免受过度的伤害 用严厉的化疗进行治疗。然而，大多数分子成像探针通常针对任一癌症 细胞，或者最近，肿瘤微环境中的单一细胞类型。这些方法本质上是 他们能够提供的信息有限。 最佳治疗计划依赖于对疾病状态的全面了解，包括疾病的微观区域 残留疾病并根据病变的特定分子特征了解复发的可能性。 因此，该提案的目标是为临床上有用的成像和成像方法提供基础。 了解原发性乳腺癌和转移性疾病治疗前、治疗期间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 更完整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：（目标1）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肿瘤检测。 （目标 2）差异化靶向癌细胞和 具有相似光谱特性但不同的近红外分子探针与癌症相关的成纤维细胞 荧光寿命值可无创地提取肿瘤基质比率，这是乳腺癌的预后指标 癌症。这种确定恶性细胞和癌症相对丰度的非侵入性方法- 相关成纤维细胞将与肿瘤基质比率的传统组织学测定进行比较。 在这项研究完成时，我们期望建立一种信号放大方法来检测小 癌性病变和绘制癌基质比率的非侵入性方法，以了解动态变化的情况 肿瘤微环境的变化影响癌症生物学。

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.