Mechanism of Acquired Resistance to VEGF-R Antagonists in RCC

描述(申请人提供)：肾细胞癌(RCC)领域的关键进展之一是酪氨酸激酶抑制剂(TKIs)的开发和批准，索拉非尼和舒尼替尼。虽然这些抑制血管内皮生长因子(VEGF)驱动的血管生成的药物具有令人印象深刻的临床活性，但这些药物的反应有限，在5-12个月内产生耐药性。对这类药物的耐药性的产生可能伴随着疾病的加速，这可能会否定该疗法的大部分潜在价值。 我们发现，在肾癌的小鼠模型中，对索拉非尼和舒尼替尼治疗的耐药性伴随着干扰素γ(IFNG)信号的丢失，并且正如动脉自旋标记磁共振成像所看到的那样，耐药性发生在新的血管生成的环境中。此外，我们发现有证据表明，对VEGFR TKI治疗的耐药性是可逆的，因为当耐药肿瘤重新植入幼稚宿主体内时，它们会再次对治疗产生反应。 我们的建议概述了IFNG在VEGFR TKIs耐药中的作用研究，以进一步了解耐药的生物学。我们的假设是，失去IFNG信号足以导致耐药性，恢复一个或多个IFNG调节的趋化因子可能会阻止或推迟对索拉非尼或舒尼替尼治疗的耐药性。了解这些耐药机制的进展可以极大地提高转移性肾癌患者的治疗选择。 公共卫生相关性：肾细胞癌(RCC)对血管内皮生长因子受体(VEGFR)抑制剂的反应表现出一段疾病稳定期。然而，这种反应不可避免地伴随着对治疗的耐药性的发展。我们已经发现，在对VEGFR抑制剂产生耐药性时，干扰素伽马信号的丢失。这项提案试图证实这一发现，并将其推广到开发治疗肾癌的新方法。

DESCRIPTION (provided by applicant): One of the key advances in the field of renal ell cancer (RCC) is the development and approval of the tyrosine kinase inhibitors (TKIs), sorafenib and sunitinib. While these inhibitors of vascular endothelial growth factor (VEGF) driven angiogenesis have impressive clinical activity, the response to these agents is finite with resistance developing within 5-12 months. Development of resistance to such agents possibly with accompanying disease acceleration might negate much of the potential value of the therapy. We have found, in a mouse model of RCC, that resistance to sorafenib and sunitinib therapy is accompanied by a loss in interferon gamma (IFNg) signaling and that resistance occurs in the setting of renewed angiogenesis as seen by Arterial Spin Labeling Magnetic Resonance Imaging. In addition, we have found evidence that resistance to VEGFR TKI therapy is reversible as resistant tumors respond to therapy again when they are reimplanted into naive hosts. Our proposal outlines the study of the role of IFNg in resistance to VEGFR TKIs to further understand the biology of resistance. Our hypothesis is that loss of IFNg signaling is sufficient to lead to resistance and that restoration of one or more of the IFNg regulated chemokines may prevent or delay resistance to treatment with sorafenib or sunitinib. Advances in the understanding of these mechanisms of resistance could greatly enhance the therapeutic options for patients with metastatic RCC. PUBLIC HEALTH RELEVANCE: Renal cell carcinoma (RCC) exhibits a period of disease stabilization in response to inhibitors of vascular endothelial growth factor receptor (VEGFR). However, this response is inevitably ensued by the development of resistance to therapy. We have identified a loss in interferon gamma signaling at the time of resistance to VEGFR inhibitors. This proposal seeks to confirm this finding and extend it to develop new treatments for RCC.