Targeting RAF and VEGF Signaling in Thyroid Cancer

描述（由申请人提供）：甲状腺癌的发病率每年在美国以所有癌症中第二快的速度增加。虽然甲状腺癌的总体预后很好，但对于远处转移的患者没有有效的治疗方法。编码BRAF的基因中的激活突变，以及涉及BRAF上游调节因子的突变和遗传重排，包括RET/PTC重排和RAS的激活突变，发生在约50%的所有高分化甲状腺癌中。这些癌基因甚至在长期存在的甲状腺癌中继续表达，并且人类肿瘤的细胞信号传导特性已经证实了它们的持续生物活性。总之，这些数据支持RAF激酶抑制剂对传统疗法无反应的甲状腺癌患者具有潜在治疗益处的概念。与这些数据一致，1例转移性甲状腺癌患者在1期研究中对RAF激酶抑制剂（BAY 43-9006; NSC 724772）表现出部分缓解。我们的中心最近被选为协调中心，为一个多中心发起的，NCI申办的2期临床试验，这种药物的转移性甲状腺癌。到目前为止，还没有使用甲状腺癌细胞系或动物模型对该药物进行体外或非人体内研究。由于该药物还抑制甲状腺癌中涉及的其他几种受体酪氨酸激酶，包括VEGF和PDGF受体，我们认为这些推论研究对于确定该药物在甲状腺癌中的药效学作用以及预测哪些乳头状甲状腺癌患者将从其使用中获得最大益处至关重要。因此，目前的资助申请的目标是寻求相关的支持，以确定基于肿瘤基因型的这种药物的反应预测因子，并将细胞信号传导和血管生成标记物表达与临床反应和新型非侵入性成像技术相关联。

DESCRIPTION (provided by applicant): The incidence of thyroid cancer is increasing yearly in the United States at the second fastest rate of all cancers. Although the overall prognosis from thyroid cancer is excellent, no effective therapies exist for patients with distant metastases. Activating mutation in the gene encoding BRAF, and mutations and genetic rearrangements involving upstream regulators of BRAF, including RET/PTC rearrangements and activation mutations of RAS occur in approximately 50% of all well-differentiated thyroid cancers. These oncogenes continue to be expressed in even long-standing thyroid cancers and cell signaling properties of human tumors have confirmed their continued biological activity. Taken together, these data support the concept that RAF kinase inhibitors have potential therapeutic benefit for patients with thyroid cancers that do not respond to traditional therapies. Consistent with these data, one patient with metastatic thyroid cancer demonstrated a partial response to a RAF kinase inhibitor (BAY 43-9006; NSC 724772) in a phase 1 study. Our center was recently selected to be the coordinating center for an investigator-initiated, NCI-sponsored multicenter phase 2 trial of this agent for metastatic thyroid cancer. To date, there are no in vitro or nonhuman in vivo studies of this agent using thyroid cancer cell lines or animal models. As this agent also inhibits several other receptor tyrosine kinases involved in thyroid cancer, including VEGF and PDGF receptors, we believe that these corollary studies are critical in defining the pharmacodynamic effects of this agent in thyroid cancer, and in predicting which papillary thyroid cancer patients would derive greatest benefit from its use. Therefore, the goal of the current grant application is to seek support for correlates to determine predictors of response to this agent based on tumor genotype, and to correlate cell signaling and angiogenic marker expression with clinical response and with novel non-invasive imaging techniques.