TGFB Antagonists & Breast Cancer-Induced Bone Metastasis

TGFB拮抗剂

• 批准号: 7028459
• 负责人: LUZHE SUN
• 金额: $ 19.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028459
• 关键词: angiogenesis; athymic mouse; biological signal transduction; bone disorder; breast neoplasms; genetic regulation; genetic transcription; green fluorescent proteins; host neoplasm interaction; kinase inhibitor; metastasis; molecular oncology; neoplasm /cancer blood supply; neoplastic cell; neoplastic growth; parathyroid hormone related protein; pathologic bone resorption; tissue /cell culture; transcription factor; transforming growth factors; tumor promoters

Bone metastasis is the major cause of morbidity and mortality in breast cancer patients. Novel therapeutic agents are urgently needed. During the past funding cycle, TGFbeta signaling was shown to increase breast cancer cell production of the osteolytic factor, PTH-rP, and breast cancer cells with attenuated TGFbeta signaling were shown to cause fewer bone metastases in vivo. TGFbeta has been shown to enhance carcinoma metastasis by acting mainly in a paracrine fashion. Bone is the body's largest source of TGFbeta, and excessive TGFbeta released from cancer cells and bone matrix after breast cancer cells metastasize to the bone has been shown to cause osteolytic lesions via PTHrP. However, the mechanism by which TGFbeta causes increased PTH-rP expression, and whether TGFbeta antagonists can be useful clinically in the prevention and treatment of breast cancer-mediated bone metastasis are still relatively unexplored. As such, our Specific Aim 1 will determine the mechanism by which TGFbeta regulates Gli2 expression to test the hypothesis that Gli2 mediates TGFbeta-induced PTH-rP expression and osteolysis. Our preliminary studies also showed that systemic administration of a TGFbeta type I receptor (Rl) kinase inhibitor significantly inhibited bone metastasis of human breast cancer cells in vivo. Our Specific Aim 2 will thus determine the comparative efficacy of different types of TGFbeta antagonists in inhibiting breast cancer-induced bone metastasis to test the hypothesis that TGFbeta antagonists may have clinical utilities for the treatment of osteolytic bone metastasis. Since abrogation of autocrine TGFbeta signaling has been shown to promote primary tumor growth, it is essential to address whether systemic administration of TGFbeta antagonists will also promote tumorigenicity of premalignant breast cells that possess the autocrine tumor-suppressive activity of TGFbeta. Therefore, our Specific Aim 3 will test the hypothesis that different modes of antagonism against TGFbeta signaling with TGFbeta binders or Rl kinase inhibitors may be exploited to inhibit tumor progression due to excessive paracrine TGFbeta activity while preserving the tumor-suppressive activity of autocrine TGFbeta. Our long-term goals are to elucidate the molecular mechanisms that drive bone metastasis and osteolysis and to ultimately develop safe, effective TGFbeta antagonists as novel agents for the prevention and treatment of breast cancer-induced bone metastasis.

骨转移是乳腺癌患者发病和死亡的主要原因。新型治疗剂 是迫切需要的。在过去的资助周期中，TGFbeta 信号传导被证明可以增加乳腺癌细胞 溶骨因子、PTH-rP 的产生和 TGFbeta 信号减弱的乳腺癌细胞被证明 导致体内骨转移较少。 TGFbeta 已被证明可通过主要作用来增强癌症转移 以旁分泌的方式。骨骼是人体最大的 TGFbeta 来源，癌症会释放过量的 TGFbeta 乳腺癌细胞转移到骨后的细胞和骨基质已被证明会引起溶骨 通过 PTHrP 产生的损伤。然而，TGFbeta 引起 PTH-rP 表达增加的机制以及是否 TGFβ拮抗剂在临床上可用于预防和治疗乳腺癌介导的骨 转移仍相对未被探索。因此，我们的具体目标 1 将确定 TGFbeta 调节 Gli2 表达的机制，以检验 Gli2 介导 TGFbeta 诱导的 PTH-rP 表达和骨溶解的假设。我们的初步研究还表明，全身施用TGFbeta I型受体（R1）激酶抑制剂可显着抑制体内人乳腺癌细胞的骨转移。因此，我们的具体目标2将确定不同类型的TGFβ拮抗剂在抑制乳腺癌诱导的骨转移方面的比较功效，以检验TGFβ拮抗剂可能具有治疗溶骨性骨转移的临床实用性的假设。由于自分泌 TGFbeta 信号传导的废除已被证明可促进原发性肿瘤生长，因此有必要解决 TGFbeta 拮抗剂的全身给药是否也会促进具有 TGFbeta 自分泌肿瘤抑制活性的癌前乳腺细胞的致瘤性。因此，我们的具体目标 3 将测试以下假设：可以利用 TGFbeta 结合剂或 Rl 激酶抑制剂对 TGFbeta 信号传导的不同拮抗模式来抑制由于过度旁分泌 TGFbeta 活性而导致的肿瘤进展，同时保留自分泌 TGFbeta 的肿瘤抑制活性。 我们的长期目标是阐明分子 驱动骨转移和骨质溶解的机制，并最终开发出安全、有效的 TGFβ 拮抗剂 作为预防和治疗乳腺癌引起的骨转移的新药。