Targeting Transforming Growth Factor-beta in Metastatic Breast Cancer

描述(申请人提供)：转化生长因子？？(转化生长因子？)通过抑制细胞周期进程、诱导分化和凋亡以及维持基因组的完整性来控制组织的动态平衡。其次，转化生长因子β1通过诱导上皮细胞向间充质细胞转化(EMT)，并以时间和空间受限的方式增加细胞的运动性和侵袭性，协调对组织损伤的反应并介导修复。虽然肿瘤在发展早期就逃脱了转化生长因子的稳态功能，但许多转移性乳腺癌似乎已经利用组织修复功能来增强其侵袭/转移表型。我们的核心假设是，特定的肿瘤细胞是否能够在特定的外来微环境中成功地建立转移，将取决于肿瘤细胞中的转化生长因子信号以及转化生长因子对次级部位宿主细胞的影响。利用Kang博士开发的一种独特的转移性乳腺癌模型，特殊目标1将确定转化生长因子途径抑制剂的抗转移效果是否与转移类型有关。特异性目标2将决定乳腺癌细胞系成功建立转移的能力是否主要取决于转化生长因子对乳腺癌细胞本身的作用(所谓的细胞自主效应)，而特异性目标3将决定转化生长因子对宿主细胞在这一过程中的作用。最后，由于两类主要的转化生长因子途径拮抗剂(充当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，特定目标4将解决这些差异是否以及如何影响它们在转移性乳腺癌中的治疗效果的问题。因此，该项目的总体目标有两个：(1)第一个目标是深入研究转化生长因子β和转化生长因子β/Smad信号在转移性乳腺癌细胞和不同次级部位转移生态位之间复杂的共生关系中所起的作用。(2)第二个更具转化性的目标是评估正在开发用于临床的不同类别的转化生长因子途径拮抗剂的相对治疗优点，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。这是女性最常见的癌症，是女性癌症死亡人数第二多的原因。由于这些妇女中的大多数死于转移，阐明乳腺癌转移的基本机制并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.