Interferon-beta inhibits the expansion of cancer stem-cells

 描述（由申请人提供）：估计今年美国将有585，720人死于治疗后重新生长的肿瘤引起的癌症。大多数患有癌症的患者最初对治疗有反应，导致肿瘤缩小。在某些情况下，肿瘤被完全消除或维持肿瘤缩小，从而有效治愈患者。然而，许多肿瘤最终会从收缩转变为再生长，导致肿瘤对治疗产生抗性。对治疗的最初反应是由于成功杀死大量肿瘤细胞，但肿瘤细胞的一个子集，癌症干细胞（CSC），对目前的治疗不敏感。事实上，治疗通常通过TGFβ信号传导引起CSC群体的扩增。存活的CSC的扩增为对治疗有抗性的肿瘤的再生长播下种子。确定抑制CSC扩增的新疗法将防止耐药肿瘤的再生长，显着提高癌症治疗后有效治愈的数量。使用创新模型来鉴定可以抑制治疗后由TGFβ信号传导驱动的CSC扩增的因素。IFNβ是免疫系统应答中的重要因子，显示出可阻止由TGFβ驱动的CSC的扩增。因此，我们假设IFNβ抑制TGFβ信号传导，并将阻止治疗后耐药肿瘤的再生长。为了检验这一假设，人们提出了两个目标。目的1将确定：（1）IFNβ如何抑制TGFβ信号传导;以及（2）抑制TGF β信号传导需要IFNβ信号传导的哪些组分。目标2将确定：（1）IFNβ抑制肿瘤再生长的最佳剂量;（2）IFN β抑制肿瘤再生长的直接作用;（3）IFNβ对免疫系统抑制肿瘤再生长的作用。IFNβ已经单独用于治疗癌症，因为在高剂量下它抑制肿瘤生长。不幸的是，IFNβ在人类中的使用受到治疗肿瘤所需的高剂量副作用的限制。我们的数据表明，IFNβ可以在低得多的剂量下防止肿瘤再生长。因此，我们建议使用较低剂量的IFNβ与目前的治疗相结合，以抑制肿瘤的再生长。我们的短期目标是证明在目前的癌症治疗中加入IFNβ将导致小鼠模型中治疗肿瘤的再生长减少。我们的长期目标是使用IFNβ作为人类癌症的联合治疗，以防止肿瘤再生并减少患者死亡。由于IFNβ已经用于人类，因此将其测试为 低剂量的联合治疗这项提案的成功完成将提供一种新的治疗方法，以防止导致大多数患者死于癌症的耐药肿瘤的再生长。

 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.