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

使用 Zr-89-转铁蛋白 PET 注释前列腺癌中的癌基因状态

• 批准号: 9040777
• 负责人: Michael John Evans
• 金额: $ 63.13万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9040777
• 关键词: Address; Adenocarcinoma; Animals; Antineoplastic Agents; Avidity; Basic Science; Biological; Biological Markers; Biology; Cancer Biology; Cancer Diagnostics; Cell Surface Proteins; Cellular biology; Citrates; Clinical; Clinical Investigator; Clinical Trials; Clinical assessments; Collaborations; Communities; Community Clinical Oncology Program; Data; Deformity; Detection; Development; Diagnosis; Diagnostic; Disease; Drug Kinetics; Epigenetic Process; Event; Genetically Engineered Mouse; Goals; Histopathology; Human; Image; Imaging Device; In Transferrin; Investigational Therapies; Label; Lesion; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Memorial Sloan-Kettering Cancer Center; Molecular Abnormality; Monitor; Newly Diagnosed; Oncogenes; Oncogenic; Outcome; PTEN gene; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Positioning Attribute; Positron-Emission Tomography; Prognostic Marker; Property; Prostate Adenocarcinoma; Proteins; Publishing; Radical Prostatectomy; Radiochemistry; Radiopharmaceuticals; Reference Standards; Resistance; Role; Signal Pathway; Signal Transduction; Specimen; Staging; TFRC gene; Technology; Therapeutic Intervention; Transferrin; Translations; Up-Regulation; Validation; Work; base; biomarker development; cancer cell; design; drug development; imaging biomarker; in vivo imaging; inhibitor/antagonist; innovation; man; molecular imaging; mouse model; non-invasive imaging; novel; oncology; pharmacodynamic biomarker; pre-clinical; professor; programs; prostate cancer model; public health relevance; radiotracer; research clinical testing; response; targeted agent; targeted treatment; tool; treatment planning; treatment response; tumor; uptake

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.

描述（由申请人提供）：Memorial Sloan-Kettering 癌症中心的 R01 申请是在 MPI 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的基础上建立的。基于令人回味的初步数据，中心假设是新型放射性示踪剂 89Zr 标记的转铁蛋白 (89Zr-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同类产品（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 PI3K 的病理激活直接相关-与前列腺癌发病机制密切相关的两种癌基因。为了解决我们的假设，提出了三个具体目标；具体目标 1 (SA1) 旨在确定 89Zr-Tf 可以测量 MYC 信号传导的变化，从而赋予肿瘤对 JQ1（表观遗传蛋白 BRD4（和 MYC）的抑制剂）的反应；具体目标 2 (SA2) 旨在证明 89Zr-Tf 可以测量前列腺癌中的异常 PI3K 信号传导并监测肿瘤对靶向治疗的反应；具体目标 3 (SA3) 提议在新诊断的前列腺癌中开展 89Zr-Tf 的首次人体研究（第 0 阶段），以启动更大规模的临床计划，以评估 89Zr-T 在人类中的许多潜在应用。该方案的创新源于89Zr-Tf的原创设计。通过为其开发提供明确的生物学指令（即 TFRC 和 MYC 或 PI3K 之间的直接功能关系），89Zr-Tf 的应用超越了大体肿瘤特性的检测，扩展到测量通过两个重要致癌途径的信号传导程度。此外，89Zr-Tf 卓越的药代动力学使其明显区别于其他针对转铁蛋白受体（67Ga-柠檬酸盐）的临床验证技术。这些考虑因素直接影响该提案的影响，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基本重要主题相关的问题：(1) 89Zr-Tf 的基础摄取是否可以定量区分具有 MYC 病理激活的肿瘤和/或 PI3K 信号传导（预后生物标志物开发），(2) 治疗后 89Zr-Tf 摄取的变化测量目标抑制（药物药效动力学和临床试验） (3) 89Zr-Tf 可以更清楚地区分新诊断的前列腺癌中的肿瘤形态和扩散（准确的分期和治疗计划）。如果成功，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的诊断和治疗发生重大范式转变。