CD44 Antagonists in Targeted and Combinational Therapy for Glioblastoma

描述(申请人提供)：多形性胶质母细胞瘤(GBM)预后极差。因此，迫切需要确定其靶向可以消除GBM细胞和/或敏化GBM对细胞毒和靶向药物的反应的分子。CD44是透明质酸(HA)的主要细胞表面受体，也是癌症干细胞标记物，并与癌症进展有关。然而，对于CD44在GBM进展中的作用，对GBM细胞对化疗和靶向治疗的反应，以及介导CD44促肿瘤作用的主要下游信号通路，人们知之甚少。我们发现CD44在恶性胶质瘤中上调，它的缺失阻碍了GBM的生长，并在体内使GBM细胞对细胞毒药物敏感。我们首先证明了CD44拮抗剂在小鼠模型中显示出强大的抗GBM效果，并且CD44在哺乳动物河马信号通路的上游发挥作用。此外，CD44还通过抑制河马通路中MST1/2和Lats1/2的激活来促进GBM细胞对活性氧和细胞毒剂诱导的应激和凋亡的抵抗。我们还发现CD44增强了ErbB和c-Met受体酪氨酸激酶(RTKs)的生长信号。基于这些结果，我们假设CD44拮抗剂通过增强Hippo信号通路的激活和抑制ErbB/c-Met RTK产生的生长信号来抑制GBM细胞的存活，从而抑制GBM的进展和对化疗和靶向治疗的敏感性。我们进一步假设CD44是GBM治疗的主要靶点，在GBM小鼠模型中，CD44拮抗剂单独和/或与erbB和c-Met RTK的化疗药物和药理抑制剂联合使用是有效的。提出了三个具体目标。目的1建立CD44拮抗剂，一种可溶性的CD44-Fc融合蛋白，在体内显示抗胶质瘤活性，增敏GBM对化疗和靶向治疗的反应。目的2确定CD44拮抗剂在体内的化学增敏作用是通过促进Hippo信号通路的激活而实现的。最后，目的3是确定hsCD44-Fc融合蛋白至少部分通过抑制erbB和c-Met RTK的活性来实现其抗胶质瘤作用和增敏GBM对靶向治疗的反应。拟议的实验结果将确立CD44作为GBM的主要治疗靶点，并证明新开发的CD44拮抗剂在临床前GBM模型中作为单一药物和/或与化疗和其他靶向治疗相结合的有效治疗效果。这些结果可能会为未来的GBM患者带来更好的临床结果和更持久的临床益处。因此，这项建议具有很高的生物学和临床相关性和意义，并具有翻译潜力。

DESCRIPTION (provided by applicant): The prognosis for glioblastoma multiforme (GBM) is extremely poor. Identification of molecules whose targeting may eliminate GBM cells and/or sensitize GBM responses to cytotoxic and targeted agents is therefore urgently needed. CD44 is a major cell surface receptor for hyaluronan (HA) and a cancer stem cell marker, and has been implicated in cancer progression. However, little is known about its contributions to GBM progression and to the responses of GBM cells to chemo- and targeted therapies and about the major downstream signaling pathway that mediates the pro-tumor effect of CD44. We show that CD44 is up regulated in malignant gliomas and that its depletion blocks GBM growth and sensitizes GBM cells to cytotoxic drugs in vivo. We first demonstrate that CD44 antagonists display potent anti-GBM efficacy in mouse models and that CD44 functions upstream of mammalian Hippo signaling pathway. Furthermore, CD44 promotes GBM cell resistance to reactive oxygen species- and cytotoxic agent-induced stress and apoptosis by attenuating activation of the Hippo pathway kinases MST1/2 and Lats1/2. We also show that CD44 enhances the growth signals derived from ErbB and c-Met receptor tyrosine kinases (RTKs). Based on these results, we hypothesize that CD44 antagonists inhibit GBM progression and sensitize GBM responses to chemo- and targeted therapies by inhibiting GBM cell survival through enhancing activation of the Hippo signaling pathway and inhibiting the growth signals derived from ErbB/c-Met RTKs. We further hypothesize that CD44 is a prime target for GBM therapy and its antagonists are efficacious when used as single agents and/or combination with chemotherapeutic agents and pharmacological inhibitors of erbB and c-Met RTKs in the GBM mouse models. Three specific aims are proposed. Aim 1 is to establish that CD44 antagonists, a variety of soluble CD44-Fc fusion proteins, display anti- glioma activity, sensitize GBM response to chemo- and targeted therapies in vivo. Aim 2 is to establish that the chemosensitizing effect of CD44 antagonists in vivo is achieved by enhancing activation of Hippo signaling pathway. Finally, aim 3 is to establish that hsCD44-Fc fusion proteins achieve their anti-glioma effect and sensitize GBM response to the targeted therapies, at least partially, through inhibiting activities of erbB and c-Met RTKs. The results from proposed experiments will establish CD44 as a prime therapeutic target for GBM and demonstrate potent therapeutic efficacies of the newly developed CD44 antagonists as single agents and/or in combinations with chemo- and other targeted therapies in preclinical GBM models. These results may lead to better clinical outcome and longer lasting clinical benefit for GBM patients in the future. Therefore, this proposal has high biological and clinical relevance and significance, and translational potential.