Determinants of Response to Type 1 Insulin-Like Growth Factor Inhibition in Prost

我们已经证明，对1型胰岛素样生长因子受体(IGF-IR)的靶向治疗非常有效 在前列腺癌(CAP)的临床前模型中有效缩小肿瘤大小。从阶段来看，它也是清晰的 1人抗IGF-IR单抗(HMAb)耐受性良好。我们还表明， IGF-IR hmabs的疗效取决于肿瘤的临床分期，例如AD与A1，以及 IGF-IR信号通路的组成部分。因此，当我们继续进行临床试验时，有一个 迫切需要基础和临床前数据来指导这些试验。这项建议的假设是： 靶向IGF-IR治疗CAP的有效性取决于雄激素的状态 肿瘤的反应性和癌症中IGF-IR信号通路的完整性。这一假设 目标有以下几点： 目的1.利用人源单抗确定胰岛素样生长因子-IR靶向治疗耐药机制 A12。这个目标将使用Biospecimen Core中提供的27种独特的人类前列腺癌异种移植瘤 以及我们的临床前发现去势和抑制IGF-IR之间的显著协同作用。 目的2.分析AR对IGF-IR基因表达的功能相互作用，以此作为决定因素 对A12大写字母的回应。这一目标将明确雄激素对IGF-IR的调节机制。 目的3.确定去势加A12治疗后仍处于休眠状态的肿瘤的可能性 重新启动肿瘤生长。这一目标将确定保留的这些上限的机制和特点 经去势和IGF-IR抑制联合治疗后处于休眠状态。 目的4.确定TMPRSS2的蛋白酶活性如何影响IGF信号转导和对A12的反应。 作为与项目2的相互作用，这进一步发展了TMPRSS2切割IGFBPs-3和-5的影响。 目的5.雄激素和胰岛素样生长因子在小鼠休眠帽细胞存活和生长中的作用 骨性部位。这种与项目1的相互作用将决定IGF-IR抑制对DCs的作用。 长期目标是确定我们以IGF-IR为目标的临床试验取得成功的特征。 相关性(见说明)； IGF-IR抑制将成为前列腺癌临床治疗手段的一部分。项目3 将为这种靶向治疗的最有效的临床使用确定适当的环境。

We have shown that targeted therapy to the type 1 insulin-like growth factor receptor (IGF-IR) is very effective in decreasing tumor size in preclinical models of prostate cancer (CaP). It is also clear from phase 1 trials that human monoclonal antibodies (hmab) to the IGF-IR are well tolerated. We also show that the efficacy of IGF-IR hmabs are dependent on the clinical stage of tumor e.g. AD vs. Al and alterations in components of the IGF-IR signaling pathway. Therefore, as we proceed with.our clinical trials, there is an urgent need for basic and preclinical data to guide these trials forward. The hypothesis of this proposal is: the effectiveness of targeting the IGF-IR in treating CaP depends on the status of the androgen responsiveness of the tumor and the integrity of the IGF-IR signaling pathway in the cancer. This hypothesis is addressed by the following aims: Aim 1. Determine mechanisms of resistance to IGF-IR targeted therapy by the human monoclonal antibody A12. This aim will use the 27 unique human prostate cancer xenografts available in the Biospecimen Core as well as our preclinical finding of the significant synergy between castration and IGF-IR inhibition. Aim 2. Analysis of the functional interactions of the AR on IGF-IR gene expression as a determinant of response to A12 in CaP. This aim will define the mechanism of androgen regulation of the IGF-IR . Aim 3. Determine the potential of tumors that remain dormant following treatment with castration plus A12 to re-initiate tumor growth. This aim will define the mechanisms and characteristics of those CaP that remain dormant after combination therapy with castration and IGF-IR inhibition. Aim 4. Determine how the protease activity of TMPRSS2 influences IGF signaling and the response to A12. As an interaction with Project 2, this further develops the effects of TMPRSS2 cleavage of IGFBPs -3 and -5. Aim 5. Role of androgens and IGF in establishing the survival and growth of dormant CaP cells in an osseous site. This interaction with Project 1 will determine the role of IGF-IR inhibition on DTCs. The long term goals are to define the characteristics for our clinical trials targettting IGF-IR to succeed. RELEVANCE (See instructions); IGF-IR inhibition will become part of the clinical armementarium for tretament of prostate cancer. Project 3 will define the appropriate setting for the most efficacious clinical use of this targeted therapy.