Annotating Oncogene Status in Prostate Cancer with Zr-89-transferrin PET

描述(由申请人提供)：纪念斯隆-凯特琳癌症中心的这份R01申请是基于MPIS教授Jason Lewis和Michael Evans博士与基础科学和临床研究人员密切合作最近开展的工作。根据初步数据，中心假设是新型放射性示踪剂89Zr标记的转铁蛋白(89Zr-Tf)将成为前列腺癌分期和治疗的非侵入性工具。这种放射性示踪剂与它的同代物(18F-FDG，18F-FACBC，ProstascintTM)的不同之处在于，它系统地靶向一种肿瘤相关蛋白(转铁蛋白受体[TFRC])，其表达和生物活性直接与MYC或PI3K-两个与前列腺癌发病密切相关的癌基因的病理激活有关。为了解决我们的假设，已经提出了三个特定目标；特定目标1(SA1)打算建立89Zr-Tf可以测量89Zr-Tf在肿瘤对表观遗传蛋白BRD4(和MYC)的抑制剂JQ1的反应中所需的MYC信号的变化；特定目标2(SA2)打算表明89Zr-Tf可以测量前列腺癌中异常的PI3K信号并监测肿瘤对靶向治疗的反应；以及特定目标3(SA3)建议在新诊断的前列腺癌中进行89Zr-Tf的首次人体研究(0期)，以启动一个更大的临床计划来评估89Zr-T在人类中的许多潜在应用。本方案的创新之处来自于89Zr-Tf的原始设计。通过调用其发展的明确的生物学授权(即TFRC和MYC或PI3K之间的直接功能关系)，89Zr-Tf的应用超越了对肉眼肿瘤属性的检测，扩展到通过两个重要的致癌途径测量信号的程度。此外，89Zr-Tf的特殊药代动力学明显区别于其他临床验证的针对转铁蛋白受体(67Ga-柠檬酸盐)的技术。这些考虑因素直接影响到该建议的效果，因为我们谨此提出，我们至少可以回答三个与癌症诊断中基本重要的主题相关的问题：(1)89Zr-Tf的基础摄取是否能定量区分具有病理性激活的MYC和/或PI3K信号的肿瘤(预后生物标记物的开发)，(2)治疗后89Zr-Tf摄取测量靶点的变化(药物药效学和临床试验终点)，以及(3)89Zr-Tf能否更清晰地区分新诊断前列腺癌中的肿瘤地形和播散(准确的分期和治疗计划)。如果成功，这种PET试剂可能会在放射性示踪剂开发策略以及人类前列腺癌的诊断和治疗方面引起重大的范式转变。

DESCRIPTION (provided by applicant): This R01 application from Memorial Sloan-Kettering Cancer Center is founded on recent work spearheaded by the MPIs Professor Jason Lewis and Dr. Michael Evans in close collaboration with basic science and clinical investigators. Based on the evocative preliminary data, the central hypothesis is that the novel radiotracer 89Zr- labeled transferrin (89Zr-Tf) will be a non-invasive tool for the staging and management of prostate cancer. What distinguishes this radiotracer from its contemporaries (18F-FDG, 18F-FACBC, ProstascintTM) is that it systematically targets a tumor associated protein (the transferrin receptor [TFRC]) whose expression and bioactivity is directly linked to the pathological activation of MYC or PI3K-two oncogenes deeply relevant to the pathogenesis of prostate cancer. To address our hypothesis three Specific Aims have been proposed; Specific Aim 1 (SA1) intends to establish that 89Zr-Tf can measure the changes in MYC signaling required to confer a tumor response to JQ1, an inhibitor of the epigenetic protein BRD4 (and MYC); Specific Aim 2 (SA2) intends to show that 89Zr-Tf can measure aberrant PI3K signaling in prostate cancer and monitor tumor response to targeted therapies; and, Specific Aim 3 (SA3) proposes to conduct first-in-human studies (Phase 0) of 89Zr-Tf in newly diagnosed prostate cancer to initiate a larger clinical program to evaluate the many potential applications for 89Zr-T in man. The innovation of this proposal derives from the original design of 89Zr-Tf. By invoking a clear biological mandate for its development (i.e. the straightforward functional relationship between TFRC and MYC or PI3K), the application of 89Zr-Tf extends beyond the detection of a gross tumor property to measuring the degree of signaling through two important oncogenic pathways. Moreover, the exceptional pharmacokinetics of 89Zr-Tf clearly distinguishes it from other clinically validated technologies targeting the transferrin receptor (67Ga-citrate). These considerations directly influence the impact of the proposal, as we respectfully submit that we may answer at least three questions related to fundamentally important themes in cancer diagnostics: (1) does the basal uptake of 89Zr-Tf quantitatively distinguish tumors bearing pathological activation of MYC and/or PI3K signaling (prognostic biomarker development), (2) do post-therapy changes in 89Zr-Tf uptake measure target inhibition (drug pharmaco- dynamics and clinical trial endpoints), and (3) can 89Zr-Tf more clearly distinguish tumor topography and dissemination in newly diagnosed prostate cancer (accurate staging and treatment planning). If successful this PET agent could cause a significant paradigm shift in radiotracer development strategies and the diagnosis and management of prostate cancer in man.