Targeting Transforming Growth Factor-beta in Metastatic Breast Cancer

描述（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、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质转化（EMT），以及在有限的时间和空间内增加细胞的运动性和侵袭性，协调对组织损伤的反应和介导修复。肿瘤逃避TGF？许多转移性乳腺癌似乎在其发展早期就采用了组织修复功能来增强其侵袭性/转移性表型。我们的核心假设是，特定肿瘤细胞是否能够在特定的外源微环境中成功建立转移将取决于TGF¿？肿瘤细胞中的信号通路以及对TGF?？在次要位点的宿主细胞上。使用Kang博士开发的一种独特的转移性乳腺癌模型，Specific Aim 1将确定TGF?？途径抑制剂是一种功能类型的转移。特异性Aim 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？作用于乳腺癌细胞本身（即所谓的细胞自主效应），而特异性Aim 3将决定TGF?？在这个过程中对宿主细胞的作用。最后，作为TGF?？途径拮抗剂（作为配体陷阱和化学激酶抑制剂的大分子）具有不同的生物学和药理学特性，Specific Aim 4将解决这些差异是否以及如何影响转移性乳腺癌的治疗效果的问题。因此，本项目的总体目标是双重的：(1)首先是剖析TGF?？TGF ?/Smad信号在假定的转移性乳腺癌细胞与不同继发部位的转移生态位之间的复杂共生关系中发挥作用。(2)二是更具有翻译性的目的，评估不同类别TGF??的相对治疗优势。正在开发用于临床使用的途径拮抗剂，目的是为未来临床试验的设计提供信息。拟议的研究将对乳腺癌患者的健康产生重大影响。这是妇女中最常见的癌症，也是妇女癌症死亡人数第二高的癌症。由于这些女性大多死于转移，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女性的预后产生重大影响。

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.