Protein prenylation, oncogenesis and novel therapeutics

描述（由申请人提供）：我们研究的一个主要目标是描述蛋白质异戊二烯化在促进Ras和Rhc gtpase介导的肿瘤发生中的作用。从这些研究中，出现了三个主要主题。首先，Ras和Rho GTPase功能的异常激活在人类肿瘤发生的许多方面起着重要作用。其次，虽然最初认为，类异戊二烯类脂质修饰蛋白只是作为疏水的、非特异性的膜靶向脂质“胶”，但我们现在认识到，异戊二烯化与其他序列元件和脂质修饰一起，决定了动态膜相互作用的复杂光谱，使原本高度相关的gtp酶具有显著不同的生物学作用。第三，由于Ras和Rho GTPase膜的结合和功能严重依赖于类异戊二烯修饰，因此药物抑制蛋白质烯酰化可能是治疗癌症的有效途径。催化Ras和Rho gtpase异戊二烯化的酶抑制剂已被开发为新的靶向治疗方法。特别是，修饰Ras蛋白的法尼基转移酶（FTase）抑制剂（FTIs）在临床前模型中显示出显著的抗肿瘤活性，目前正在进行II-III期临床评估。令人惊讶的是，现在人们认为FTIs的抗肿瘤活性不是由于Ras抑制。相反，fti的关键靶点被认为是其他fti酶底物。确定这些关键的FTI靶点对于FTI的成功临床开发至关重要。从这三个主题出发，我们提出了四个具体目标。首先，我们将定义Cdc42相关蛋白的c端序列Wrch-1和Wrch-2/Chp决定Cdc42的膜结合和功能多样性的新机制。出乎意料的是，这两种Rho gtpase都不是FTase或GGTase I酶的底物，后者使其他Ras和Rho gtpase异丙烯化。其次，我们将确定FTIs是否靶向最近通过mTOR/S6激酶途径激活的与肿瘤发生有关的法酰化GTPase Rheb。第三，我们将确定FTI介导的法酰化ras相关肿瘤抑制蛋白NOEY2/ARHI和Rig/Di-Ras的丢失是否定义了FTI治疗的潜在有害后果。最后，我们将确定参与促进肿瘤细胞侵袭和转移的PRL蛋白酪氨酸磷酸酶是否是FTI抗肿瘤活性的重要靶点。

DESCRIPTION (provided by applicant): A major goal of our research has been the delineation of the role of protein isoprenylation in facilitating Ras and Rhc GTPase-mediated oncogenesis. From these studies, three major themes have emerged. First, the aberrant activation of Ras and Rho GTPase function contributes significantly to many facets of human oncogenesis. Second, while it was initially believed that isoprenoid lipid modification of proteins served simply as hydrophobic, nonspecific membrane-targeting lipid "glues", we now appreciate that isoprenylation, together with other sequence elements and lipid modifications, dictate a complex spectrum of dynamic membrane interactions that endow otherwise highly related GTPases with strikingly divergent biological roles. Third, since Ras and Rho GTPase membrane association and function are critically dependent on isoprenoid modification, pharmacologic inhibition of protein prenylation may be an effective approach for cancer treatment. Inhibitors of the enzymes that catalyze the isoprenylation of Ras and Rho GTPases have been developed as novel, target-based therapies. In particular, inhibitors (FTIs) of the enzyme farnesyl transferase (FTase) that modifies Ras proteins have shown remarkable anti-tumor activity in preclinical models and are currently under phase II-III clinical evaluation. Surprisingly, it is now accepted that the anti-tumor activity of FTIs is not due to Ras inhibition. Instead, the critical targets of FTIs are thought to be other FTase substrates. Defining these critical FTI targets will be crucial for the successful clinical development of FTIs. We propose four specific aims that extend from these three themes. First, we will define the novel mechanism by which the C-terminal sequences of the Cdc42-related proteins, Wrch-1 and Wrch-2/Chp, dictate membrane association and functional diversity from Cdc42. Unexpectedly, these two Rho GTPases are not substrates for either the FTase or GGTase I enzyme that isoprenylates the other Ras and Rho GTPases. Second, we will determine whether the farnesylated GTPase Rheb, recently implicated in oncogenesis by activation of the mTOR/S6 kinase pathway, is targeted by FTIs. Third, we will determine whether FTI-mediated loss of the farnesylated, Ras-related tumor suppressor proteins NOEY2/ARHI and Rig/Di-Ras define a potentially deleterious consequence of FTI therapy. Finally, we will determine whether the PRL protein tyrosine phosphatases, involved in promoting tumor cell invasion and metastasis, are important targets of FTI antitumor activity.