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: 8842513
• 负责人: Michael John Evans
• 金额: $ 5.2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842513
• 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; Label; Lesion; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Memorial Sloan-Kettering Cancer Center; Molecular; 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; Technology; Therapeutic; Therapeutic Intervention; Transferrin; Transferrin Receptor; Translations; Up-Regulation; Validation; Work; base; cancer cell; design; drug development; in vivo imaging; inhibitor/antagonist; innovation; man; molecular imaging; mouse model; novel; oncology; pre-clinical; professor; programs; prostate cancer model; public health relevance; radiotracer; research clinical testing; response; tool; treatment planning; treatment response; tumor; uptake; 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; Label; Lesion; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Memorial Sloan-Kettering Cancer Center; Molecular; 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; Technology; Therapeutic; Therapeutic Intervention; Transferrin; Transferrin Receptor; Translations; Up-Regulation; Validation; Work; base; cancer cell; design; drug development; in vivo imaging; inhibitor/antagonist; innovation; man; molecular imaging; mouse model; novel; oncology; pre-clinical; professor; programs; prostate cancer model; public health relevance; radiotracer; research clinical testing; response; 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）：纪念斯隆 - 凯特林癌症中心的R01申请是建立在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的最新工作的。基于回忆性的初步数据，中心假设是新型的放射性示意剂89ZR标记的转铁蛋白（89ZR-TF）将是用于分期和管理前列腺癌的非侵入性工具。区别这种放射性示例与同时代人（18F-FDG，18F-FACBC，ProstaScIntTM）的区别在于，它系统地靶向肿瘤相关的蛋白（转铁蛋白受体[TFRC]），其表达和生物活性直接与Myc或Pi3k-Two的病理性激活直接相关。为了解决我们的假设，已经提出了三个具体目标；特定的目标1（SA1）打算确定89ZR-TF可以测量对肿瘤反应对JQ1的反应（表观遗传蛋白BRD4（和MYC）的抑制剂）所需的MYC信号的变化；具体目标2（SA2）打算表明，89ZR-TF可以在前列腺癌中测量异常的PI3K信号传导，并监测肿瘤对靶向疗法的反应；并且，特定的目标3（SA3）建议在新诊断的前列腺癌中进行89ZR-TF的首次人类研究（第0阶段），以启动更大的临床计划，以评估MAN中89ZR-T的许多潜在应用。该提案的创新源自89ZR-TF的原始设计。通过为其发育援引明确的生物学任务（即TFRC与MYC或PI3K之间的直接功能关系），应用89ZR-TF的应用超出了检测到毛肿瘤特性的检测，以测量通过两个重要的致癌途径来测量信号传导的程度。此外，89ZR-TF的特殊药代动力学显然将其与针对转铁蛋白受体（67GA-CITRATE）的其他经过临床验证的技术区分开。 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 （药物药物动力学和临床试验终点）和（3）可以更清楚地区分新诊断的前列腺癌（准确的分期和治疗计划）中的肿瘤形态和传播。如果成功，该宠物代理可能会引起放射性示意剂开发策略的范式转移，并诊断和管理人类中的前列腺癌。