Interferon-beta inhibits the expansion of cancer stem-cells

干扰素-β 抑制癌症干细胞的增殖

• 批准号: 9099008
• 负责人: MARK W. JACKSON
• 金额: $ 17.24万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-20 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099008
• 关键词: 4T1; Address; Adverse effects; Apoptosis; Biological Assay; Breast Epithelial Cells; Cancer Patient; Cancer Survivor; Cause of Death; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Data; Dose; Dose-Limiting; Gene Targeting; Generations; Genetic Transcription; Goals; Heterogeneity; High Dose Chemotherapy; Human; Immune Cell Activation; Immune system; Immunocompetent; Immunocompromised Host; In Vitro; Interferon-beta; Interferons; Link; Malignant Neoplasms; Mediating; Modeling; Mus; Patients; Play; Population; Proliferating; Recurrence; Recurrent tumor; Reporting; Resistance; Role; Seeds; Signal Pathway; Signal Transduction; Testing; Transcriptional Activation; Transforming Growth Factor beta; United States; Work; Xenograft procedure; angiogenesis; cancer cell; cancer stem cell; cancer therapy; chemotherapy; cytokine; effective therapy; genetic element; improved; in vivo; innovation; interferon-stimulated gene factor 3; killings; member; mortality; mouse model; neoplastic cell; novel; novel therapeutics; prevent; public health relevance; response; small hairpin RNA; small molecule inhibitor; standard of care; stem cell population; success; therapy resistant; treatment response; tumor; tumor growth; tumor microenvironment

 DESCRIPTION (provided by applicant): There will be an estimated 585,720 deaths due to cancer in the United States this year resulting from tumors that regrow after therapy. Most patients suffering from cancer respond initially to treatment resulting in shrinking tumors. In some cases, tumors are completely eliminated or tumor shrinkage is maintained resulting in an effective cure for the patient. However, many tumors will eventually switch from shrinkage to regrowth resulting in tumors that are resistant to therapy. The initial response to treatment results from successful killing of bulk tumor cells, but a subset of tumor cells, the cancer stem cells (CSC), are not sensitive to current therapies. In fact, treatment often causes the expansion of CSC populations through TGFβ signaling. The expansion of surviving CSC seeds the regrowth of tumors that are resistant to therapy. Identifying new therapies that inhibit CSC expansion would prevent the regrowth of resistant tumors significantly improving the number of effective cures following cancer treatment. An innovative model was used to identify factors that could inhibit the expansion of CSC driven by TGFβ signaling following treatment. IFNβ, an important factor in immune system responses, was shown to prevent the expansion of CSC driven by TGFβ. Therefore, we hypothesize that IFNβ inhibits TGFβ signaling and will prevent the regrowth of resistant tumors following treatment. Two aims have been developed to test this hypothesis. Aim 1 will determine: (1) how IFNβ suppresses TGFβ signaling; and (2) which components of IFNβ signaling are required to suppress the TGFβ signaling. Aim 2 will determine: (1) the optimal dosing for IFNβ to inhibit tumor regrowth; (2) the direct effects of IFβ that inhibit tumor regrowth; and (3) the effect of IFNβ on the immune system that inhibits tumor regrowth. IFNβ has been used alone to treat cancer, because at high doses it inhibits tumor growth. Unfortunately, IFNβ use in humans is limited by side effects at the high doses required to treat tumors. Our data suggests that IFNβ may prevent tumor regrowth at much lower doses. Therefore, we suggest using lower doses of IFNβ in combination with current therapies to inhibit tumor regrowth. Our short-term goal is to demonstrate that adding IFNβ to current treatments for cancer will result in less regrowth of treated tumors in mouse models. Our long-term goal would be to use IFNβ as a combination therapy in human cancers to prevent tumor regrowth and reduce patient death. Since IFNβ is already used in humans, it will be easier to have it tested as a combination therapy at lower doses. Successful completion of this proposal would provide a new treatment to prevent the regrowth of therapy-resistant tumors that cause the majority of patient deaths due to cancer.

 描述（由申请人提供）：预计今年美国将有 585,720 人因治疗后肿瘤再生而导致癌症死亡。大多数癌症患者最初对治疗有反应，导致肿瘤缩小。在某些情况下，肿瘤被完全消除或肿瘤缩小得以维持，从而有效治愈患者。然而，许多肿瘤最终会从缩小转变为再生，导致肿瘤对治疗产生抗性。对治疗的最初反应是成功杀死大量肿瘤细胞的结果，但肿瘤细胞的一个子集，即癌症干细胞（CSC），对当前的疗法不敏感。事实上，治疗常常通过 TGFβ 信号传导导致 CSC 群体的扩张。存活的癌症干细胞的扩张导致了对治疗有抵抗力的肿瘤的再生。确定抑制 CSC 扩张的新疗法将防止耐药肿瘤的再生长，从而显着提高癌症治疗后有效治愈的数量。使用创新模型来确定治疗后可抑制由 TGFβ 信号传导驱动的 CSC 扩张的因素。 IFNβ 是免疫系统反应的重要因素，已被证明可以阻止 TGFβ 驱动的 CSC 扩张。因此，我们假设 IFNβ 抑制 TGFβ 信号传导，并防止治疗后耐药肿瘤的再生。已经制定了两个目标来检验这一假设。目标 1 将确定：(1) IFNβ 如何抑制 TGFβ 信号传导； (2) IFNβ 信号传导的哪些成分需要抑制 TGFβ 信号传导。目标 2 将确定：（1）抑制肿瘤再生的 IFNβ 最佳剂量； (2) IFβ抑制肿瘤再生的直接作用； (3) IFNβ对免疫系统的作用，抑制肿瘤的再生。 IFNβ 已单独用于治疗癌症，因为高剂量时它会抑制肿瘤生长。不幸的是，IFNβ在人类中的使用受到治疗肿瘤所需高剂量的副作用的限制。我们的数据表明，IFNβ 可以在低得多的剂量下阻止肿瘤再生。因此，我们建议使用较低剂量的 IFNβ 与当前疗法相结合来抑制肿瘤再生。我们的短期目标是证明，在当前的癌症治疗中添加 IFNβ 将导致小鼠模型中治疗肿瘤的再生减少。我们的长期目标是使用 IFNβ 作为人类癌症的联合疗法，以防止肿瘤再生并减少患者死亡。由于 IFNβ 已用于人类，因此更容易对其进行测试： 较低剂量的联合治疗。该提案的成功完成将提供一种新的治疗方法，以防止耐药性肿瘤的再生长，这种肿瘤导致大多数患者因癌症死亡。