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率和死亡率的主要原因。新颖的治疗剂 迫切需要。在过去的资金周期中，TGFBETA信号被证明会增加乳腺癌细胞 用衰减的TGFBETA信号传导的骨化因子，PTH-RP和乳腺癌细胞的产生显示为 在体内导致骨转移较少。 TGFBETA已显示可通过主要作用来增强转移癌转移 以旁分泌方式。骨头是人体最大的TGFBETA来源，从癌症中释放出过多的TGFBETA 乳腺癌细胞转移到骨骼后的细胞和骨基质已被证明会引起骨质水解 通过PTHRP病变。但是，TGFBETA导致PTH-RP表达增加的机制，以及是否是否 TGFBETA拮抗剂在临床上可以在预防和治疗乳腺癌介导的骨骼方面有用 转移仍然相对尚未探索。因此，我们的具体目标1将确定TGFBETA调节Gli2表达以检验GLI2介导TGFBETA诱导的PTH-RP表达和骨溶解的假设的机制。我们的初步研究还表明，全身施用TGFBETA I型受体（RL）激酶抑制剂显着抑制了体内人类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TGFBETA拮抗剂在抑制乳腺癌引起的骨转移的比较疗效，以检验TGFBETA拮抗剂可能具有治疗骨骨转移的临床实用性的假设。由于已经证明自分泌TGFBETA信号传导的废除可以促进原发性肿瘤的生长，因此必须解决TGFBETA拮抗剂的系统性给药是否还将促进具有TGFBETA的自分泌性肿瘤抑制活性的乳腺乳腺细胞的肿瘤性。因此，我们的具体目标3将检验以下假设：针对TGFBETA粘合剂的拮抗剂的不同模式或RL激酶抑制剂可能会被利用以抑制过度旁分泌TGFBETA引起的肿瘤进展，同时保留自乳蛋白蛋白抑制性TGFBETA的肿瘤活性。 我们的长期目标是阐明分子 驱动骨转移和骨溶解并最终发展安全，有效的TGFBETA拮抗剂的机制 作为预防和治疗乳腺癌引起的骨转移的新型药物。