POTENTIATING BREAST CANCER THERAPIES BY TARGETING TUMOR-ASSOCIATED MACROPHAGE

描述(由申请人提供)：目前乳腺癌的治疗重点是杀死恶性细胞，但有相当数量的患者最终无法接受这些方法。这项工作的长期目标是开发一种以促癌间质为靶点的辅助疗法，作为加强现有方法的一种方式。肿瘤相关巨噬细胞(TAMs)在肿瘤微环境中被激活，通过促进血管生成和肿瘤细胞生长，并通过抑制适应性免疫反应来促进疾病进展。我们最近发现了一种能优先识别小鼠肿瘤相关巨噬细胞的多肽，但不识别静止的巨噬细胞、其他白细胞或肿瘤细胞。在这项工作中，我们将准备多价靶向构建物，将促凋亡药物输送到乳腺癌小鼠模型中的TAMS。此外，我们还将为人类TAMs开发类似的靶向多肽。这些技术将被结合在一种新的结构中，用于靶向消融人体TAM。我们的目标是将这项技术推向临床开发，并提供一种即使对激素反应迟钝或三重阴性乳腺癌患者也有效的辅助治疗。

DESCRIPTION (provided by applicant): Current treatments for breast cancer focus on the killing malignant cells but there is a substantial population of patients for whom these approaches ultimately fail. The long-term objective of this work is to develop an adjuvant therapy that targets the tumor-promoting stroma of cancer as a way to potentiate current approaches. Tumor-associated macrophages (TAMs) are activated in the tumor microenvironment and facilitate disease progression by promoting angiogenesis and tumor cell growth, and by suppressing the adaptive immune response. We have recently identified a peptide that preferentially recognizes murine tumor-associated macrophage but not resting macrophage, other leukocytes, or tumor cells. In this work, we will prepare multivalent targeting constructs to deliver pro-apoptotic agents to TAMs in a mouse model of mammary cancer. In addition, we will develop analogous targeting peptides for human TAMs. These technologies will be combined in a new construct for targeted ablation of human TAMs. Our goal is to move this technology toward clinical development and to provide an adjuvant treatment that is effective even for women with hormone-unresponsive or triple negative breast cancer.