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R 01申请是建立在MPI教授Jason刘易斯和Michael Evans博士与基础科学和临床研究人员密切合作的最新工作基础上的。基于令人回味的初步数据，中心假设是新型放射性示踪剂89 Zr标记的转铁蛋白（89 Zr-Tf）将成为前列腺癌分期和管理的非侵入性工具。这种放射性示踪剂与其同时代的放射性示踪剂（18F-FDG、18F-FACBC、ProstascintTM）的区别在于，它系统地靶向肿瘤相关蛋白（转铁蛋白受体[TFRC]），该蛋白的表达和生物活性与MYC或PI 3 K的病理激活直接相关，MYC或PI 3 K是与前列腺癌的发病机制密切相关的两种癌基因。为了解决我们的假设，已经提出了三个具体目标：具体目标1（SA 1）旨在确定89 Zr-Tf可以测量赋予肿瘤对JQ 1（表观遗传蛋白BRD 4（和MYC）的抑制剂）的反应所需的MYC信号传导的变化;具体目标2（SA 2）旨在表明89 Zr-Tf可以测量前列腺癌中的异常PI 3 K信号传导并监测肿瘤对靶向治疗的反应;具体目标3（SA 3）建议在新诊断的前列腺癌中进行89 Zr-Tf的首次人体研究（0期），以启动更大的临床项目来评估89 Zr-T在人体中的许多潜在应用。通过为其开发调用明确的生物学任务（即TFRC与MYC或PI 3 K之间的直接功能关系），89 Zr-Tf的应用超出了对总体肿瘤性质的检测，以测量通过两个重要致癌途径的信号传导程度。此外，89 Zr-Tf的特殊药代动力学将其与其他临床验证的靶向转铁蛋白受体（67 Ga-柠檬酸盐）的技术区分开来。这些考虑因素直接影响了该提案的影响，因为我们恭敬地提出，我们可以回答至少三个与癌症诊断中的基本重要主题相关的问题：（1）89 Zr-Tf的基础摄取是否定量区分具有MYC和/或PI 3 K信号传导的病理性活化的肿瘤（预后生物标志物的开发），（2）治疗后89 Zr-Tf摄取的变化是否测量靶抑制（药物药效学和临床试验终点），（3）89 Zr-Tf能更清楚地区分新诊断前列腺癌的肿瘤形态和扩散（准确的分期和治疗计划）。如果成功的话，这种PET试剂可能会导致放射性示踪剂开发策略以及人类前列腺癌诊断和管理的重大范式转变。

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.