NOVEL SMALL MOLECULE INHIBITION OF DDR2 TO PREVENT BREAST CANCER METASTASIS

 描述(申请人提供)：预防或治疗乳腺癌转移的一个主要挑战是了解肿瘤如何对调节其侵袭/迁移能力的环境信号做出反应，然后开发有选择的治疗策略来消除这些过程。我们已经确定了一条新的通路(细胞表面受体酪氨酸激酶盘状结构域受体2(DDR2))，它在乳腺癌细胞中被激活，并被肿瘤环境信号(纤维性胶原)激活，这对乳腺癌的转移是至关重要的。DDR2存在于70%的人类浸润性乳腺肿瘤细胞上，包括所有临床亚型和侵袭性DCIS。重要的是，DDR2在正常乳腺上皮中不表达。我们现在已经发现了一组与DDR2胞外区(ECD)相互作用的有效和选择性的新小分子，它们可以抑制DDR2与I型胶原的结合和激活。当表达DDR2的浸润性人乳腺癌细胞株用这些分子处理时，DDR2的激活、细胞增殖和肿瘤细胞的侵袭被抑制。 我们推测，RTK，DDR2，是治疗乳腺癌转移的新靶点，并且针对DDR2 ECD的新型抑制剂将在预防和/或治疗乳腺癌转移中发挥作用。为了验证这两个假设，我们首先要确定肿瘤中哪些表达DDR2的细胞(上皮和(或)间质)对DDR2‘S在调节乳腺癌转移中的作用以及如何发挥作用至关重要。然后确定我们的新小分子如何在肿瘤细胞和癌症相关成纤维细胞(CAF)中抑制DDR2介导的细胞信号和细胞功能，以及这些分子是否与DDR2的TK抑制剂协同作用(AIM 2)。通过解算含有抑制剂和配体的络合物中DDR2的ECD的晶体结构，确定这些新分子抑制DDR2活化的分子基础(目标3)。最后，在目标4中，我们将确定这些新的DDR2抑制剂是否能阻止体内已经建立的转移的乳腺癌转移的发展和消退。

 DESCRIPTION (provided by applicant): A major challenge to the prevention or treatment of breast cancer metastasis is to understand how tumors respond to environmental signals that regulate their invasive/migratory capacity and then develop selective therapeutic strategies to abrogate these processes. We have identified a novel pathway (the cell surface receptor tyrosine kinase discoidin domain receptor 2 (DDR2)) turned on in breast cancer cells and activated by tumor environmental signals (fibrillar collagen) that is critical for breast cancer metastasis. DDR2 is present on 70% of human invasive breast tumor cells including all clinical subtypes and also invasive DCIS. Importantly DDR2 is not expressed by normal breast epithelia. We have now identified a group of potent and selective novel small molecules that interact with the extracellular domain (ECD) of DDR2 to inhibit DDR2 binding to, and activation by collagen I. When invasive human breast cancer cell lines that express DDR2 are treated with these molecules the activation of DDR2, cell proliferation, and tumor cell invasion are inhibited. We hypothesize that the RTK, DDR2, is a new target for the treatment of breast cancer metastasis and that novel inhibitors targeting the ECD of DDR2 to prevent its activation will be effective in the prevention and, or treatment of breast cancer metastasis. To test these two hypothesis we shall first determine which DDR2 expressing cells within the tumor (epithelial and, or stroma) are critical for DDR2's action in the regulation of breast cancer metastasis and how. Then determine how our novel small molecules inhibit cellular signaling and cellular functions mediated by DDR2 in tumor cells and cancer associated fibroblasts (CAFs), and whether these molecules synergizes with TK inhibitors of DDR2 (Aim 2). Determine the molecular basis for inhibition of DDR2 activation by these novel molecules by solving the crystal structure of the ECD of DDR2 in a complex with inhibitor and ligand (Aim 3). Finally in Aim 4 we will determine if these novel inhibitors of DDR2 block breast cancer metastasis development and regression of already established metastases in vivo.