Targeting Transforming Growth Factor-beta in Metastatic Breast Cancer

描述（由申请人提供）：转化生长因子-？？(TGF?)通过抑制细胞周期进程、诱导分化和凋亡以及维持基因组完整性来控制组织稳态。其次，TGF？通过诱导上皮细胞向间充质细胞转化（EMT）以及通过以时间和空间有限的方式增加细胞运动性和侵袭性来协调对组织损伤的反应并介导修复。当肿瘤逃避TGF？的稳态功能，许多转移性乳腺癌似乎已经增选了组织修复功能，以增强其侵袭性/转移性表型。我们的核心假设是，一个特定的肿瘤细胞是否能够在一个特定的外来微环境中成功地建立转移，将取决于TGF？信号在肿瘤细胞以及对TGF β？在第二位点的宿主细胞上。使用Kang博士开发的转移性乳腺癌的独特模型，具体目标1将确定TGF？？途径抑制剂是转移类型的函数。具体目标2将确定乳腺癌细胞系成功建立转移的能力是否主要依赖于TGF β？作用于乳腺癌细胞本身（所谓的细胞自主效应），而特异性目的3将决定TGF β 1的作用。对宿主细胞的作用。最后，作为两大类TGF？由于乳腺癌通路拮抗剂（作为配体陷阱和化学激酶抑制剂的大分子）具有独特的生物学和药理学特性，具体目标4将解决这些差异是否以及如何影响其在转移性乳腺癌中的治疗效果的问题。因此，本项目的总体目标是双重的：（1）第一个是解剖TGF？。TGF？Smad信号在假定的转移性乳腺癌细胞和不同次级部位的转移性小生境之间复杂的共生关系中发挥作用。(2)第二个是更多的翻译目标，评估不同类别的TGF？？正在开发用于临床使用的通路拮抗剂，目的是为未来临床试验的设计提供信息。这些研究将对乳腺癌患者的健康产生重大影响。这是女性中最常见的癌症，占女性癌症死亡人数的第二位。由于大多数这些妇女死于转移，阐明乳腺癌转移的基本机制和开发新的靶向药物来治疗或预防转移可能会对患有这种疾病的妇女的结果产生重大影响。

DESCRIPTION (provided by applicant): Transforming Growth Factor-??(TGF?) controls tissue homeostasis by inhibiting cell cycle progression, inducing differentiation and apoptosis, and maintaining genomic integrity. Secondly, TGF??orchestrates the response to tissue injury and mediates repair by inducing epithelial to mesenchymal transition (EMT), and by increasing cell motility and -invasiveness in a time- and space-limited manner. While tumors escape from TGF?'s homeostatic function early on in their development, many metastatic breast cancers appear to have co-opted the tissue repair function to enhance their invasive/metastatic phenotype. Our core hypothesis is that whether or not a particular tumor cell is capable of successfully establishing a metastasis within a particular foreign microenvironment will depend on TGF¿?signaling in the tumor cell as well as on the effects of TGF??on the host cells at the secondary site. Using a unique model of metastatic breast cancer developed by Dr. Kang, Specific Aim 1 will determine whether or not the anti-metastatic efficacy of TGF??pathway inhibitors is a function of the type of metastasis. Specific Aim 2 will determine whether the ability of mammary carcinoma cell lines to successfully establish metastases is predominantly dependent on TGF??actions on the mammary carcinoma cells themselves (so called cell autonomous effects), while Specific Aim 3 will determine the role of TGF??actions on host cells in this process. Finally, as the two major classes of TGF??pathway antagonists (macromolecules that act as ligand traps and chemical kinase inhibitors) have distinct biological and pharmacological properties, Specific Aim 4 will address the question whether and how these differences affect their therapeutic efficacy in metastatic breast cancer. Thus, the global goal of this project is two-fold: (1) The first is the fundamental one of dissecting the roles of TGF??and TGF?/Smad signaling play in the complex symbiotic relationship between a putative metastatic breast cancer cell and the metastatic niche at different secondary sites. (2) The second is the more translational goal of assessing the relative therapeutic merits of the different classes of TGF??pathway antagonists that are being developed for clinical use, with the intent of informing the design of future clinical trials. The proposed studies will have major implications for the health of patients with breast cancer. This is the most common cancer in women, and accounts for the second to highest number of cancer deaths in women. As most of these women die of metastases, elucidating the fundamental mechanisms of breast cancer metastasis and developing novel targeted agents to either treat or prevent metastasis will likely have a major impact on the outcome of women with this disease.