Biomarkers for predicting response to Hsp90 therapy

用于预测 Hsp90 治疗反应的生物标志物

• 批准号: 9265308
• 负责人: GABRIELA CHIOSIS
• 金额: $ 57.22万
• 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: 2013-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265308
• 关键词: Adverse effects; Affect; Apoptosis; Applications Grants; Automobile Driving; Biochemical; Biological Assay; Biological Markers; Biology; Biopsy Specimen; Cancer Patient; Cell Line; Cell Survival; Characteristics; Chemicals; Client; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Complex; Data; Development; Discipline of Nuclear Medicine; ERBB2 gene; Enrollment; Failure; Flow Cytometry; Fluorescein-5-isothiocyanate; Future; Goals; Hand; Hematopoietic Neoplasms; Housekeeping; Human; Image; In Vitro; Individual; Induction of Apoptosis; Industry; Insurance Carriers; Iodine; Label; Letters; Liquid substance; Malignant Neoplasms; Measures; Medical; Memorial Sloan-Kettering Cancer Center; Minority; Modernization; Molecular; Molecular Chaperones; Nature; New Agents; Normal Cell; Oncogenic; Oncoproteins; Outcome; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I/II Trial; Population; Positron-Emission Tomography; Pre-Clinical Model; Primary Neoplasm; Proteins; Proto-Oncogene Proteins c-akt; Radiochemistry; Radiolabeled; Reporting; Role; Sampling; Selection for Treatments; Signal Pathway; Solid; Solid Neoplasm; Statistical Data Interpretation; Technology; Testing; Therapeutic; Therapy trial; Time; Transplantation; Treatment Efficacy; Tumor Burden; United States National Institutes of Health; Validation; addiction; base; biomarker development; biomarker-driven; cancer cell; chemotherapy; clinical decision-making; clinical development; companion diagnostics; diagnostic assay; effective therapy; established cell line; follow-up; improved; in vivo; individual patient; inhibitor/antagonist; leukemia; malignant breast neoplasm; mouse model; neoplastic cell; news; novel therapeutics; oncology; patient biomarkers; patient population; potential biomarker; predicting response; predictive marker; preference; prospective; protein folding; public health relevance; radiotracer; research clinical testing; response; response biomarker; statistics; study population; targeted agent; tool; translational scientist; tumor; tumor addiction; uptake; validation studies

DESCRIPTION (provided by applicant): Background: Diagnostic assay for Hsp90 patient selection -an unmet medical need: These days it is often not enough for pharmaceutical companies to bring a drug to market. Regulators and insurers are also requiring companies to develop tests to pinpoint which patients are more likely to benefit from the drug, thereby sparing other patients from needless side effects and expense. The FDA issued guidance to the industry on companion diagnostic assays in July 2011, including its preference for having the test ready for approval at the same time as the drug. This is especially important for the almost 20 Hsp90 inhibitors in clinical studies or about to enter clinical evaluation, where pinpointing th patient population has been especially elusive. For Hsp90 inhibitors, patient selection is currently based on the presence of an Hsp90-dependent oncoclient protein (i.e. HER2 and mutALK), but for most tumors the Hsp90-adicted onco-client protein(s) that drive transformation are difficult to identify. To predict an individual patient's responsiveness, one would need to define, in a tumor-by-tumor manner, the Hsp90's oncoprotein clientele and then understand the make-up and function of chaperone-client complexes, together with the molecular networks in which they are involved, a daunting technical challenge. Hypothesis: We propose here a simple alternative: instead of measuring the network of tumor-driving Hsp90 clientele, we propose to measure in each tumor the abundance of an Hsp90 species, the "oncogenic Hsp90", that allows for the existence of the aberrant tumor-driving clientele. While the tumor becomes addicted to survival on a network of Hsp90-oncoproteins, these proteins become dependent on "oncogenic Hsp90" for functioning and stability. This symbiotic interdependence suggests that addiction of tumors to Hsp90 oncoproteins equals addiction to "oncogenic Hsp90". Measuring the abundance of the latter is a read-out of the first, and therefore a potential biomarker for Hsp90 therapy enrichment. Approach: But how to measure this "oncogenic Hsp90" species? Its abundance is not dictated by Hsp90 expression alone, however certain Hsp90 inhibitors, such as PU-H71 developed by the Chiosis lab and currently in clinical evaluation at MSKCC and the NCI Clinical Center, specifically interact with this "oncogenic Hsp90" species. Labeled derivatives of PU-H71 therefore can be used as tools to measure its presence and its abundance. Indeed, we have created both a fluorescent and a radiolabeled version of PU-H71 that we optimized for use in flow cytometry (for liquid tumors) or positron emission tomography (PET) imaging (for solid tumors), respectively. These tools interact specifically with the "oncogenic Hsp90" and provide a means for the quantification of this Hsp90 species in clinic. Here we propose to (a) conduct exploratory analyses towards validation of the "oncogenic Hsp90"species as a biomarker for patient selection on Hsp90 inhibitor therapy and (b) demonstrate the use of the two chemical tools, PU-FITC and 124I-PU-H71, to non-invasively measure the presence and abundance of this biomarker. Specifically, we plan: (1) To determine in in vitro preclinical models of liquid and solid tumors the ability of the proposed biomarker to predict the subset of cancers that will respond to Hsp90 inhibitors (Guzman and Chiosis). (2) To determine in in vivo pre-clinical models of liquid and solid tumors whether the "oncogenic Hsp90", as measured by PU-FITC labeling in liquid tumors and by 124I-PU-H71 uptake and retention in solid tumors, predicts for anti-tumor activity (Guzman, Lewis and Chiosis). (3) To conduct an exploratory study of the proposed biomarker in clinic (Dunphy, Lewis, Guzman, Chiosis in collaboration with clinical colleagues Gerecitano (Phase 1, PI), Modi and Hudis (breast cancer, Phase 2), Roboz, Tallman (AML, Phase 1,2 PIs) and Larson (nuclear medicine)). This exploratory correlation analysis of tumor sensitivity vs biomarker profile, once validated in follow- up large clinical studies, will ultimately provide an assay for predictive response of tumors to Hsp90 inhibitors. The ultimate goal is to provide a means by which patient selection for future Hsp90 inhibitor treatment would be routinely performed by analysis of the presence and abundance of the "oncogenic Hsp90" as measured by multiparameter flow cytometry using PU-FITC in liquid cancers and by PET using 124I-PU-H71 radiotracer imaging in solid tumors. Significance: To our knowledge, these are the first reported non-invasive companion diagnostic technologies with potential predictive power for patient selection in Hsp90 therapy. In the two described forms, the assay proposes a solution for both liquid cancers and solid tumors. Because the assays offer data never- before available to clinicians, they promise to help accelerate the development of Hsp90 inhibitors in cancers and to inform clinical decision-making with Hsp90-targeted agents. They could therefore, revolutionize the clinical development and the use of Hsp90 inhibitors in an individualized, patient-specific manner.

描述（由申请人提供）：背景：用于Hsp 90患者选择的诊断测定-未满足的医疗需求：如今，制药公司将药物推向市场往往是不够的。监管机构和保险公司还要求公司开发测试，以确定哪些患者更有可能从药物中受益，从而使其他患者免受不必要的副作用和费用。FDA于2011年7月向该行业发布了关于伴随诊断测定的指导，包括其倾向于在药物批准的同时准备测试。这对于近20种正在进行临床研究或即将进入临床评价的Hsp 90抑制剂尤其重要，其中精确定位患者群体尤其难以实现。对于Hsp 90抑制剂，患者选择目前基于Hsp 90依赖性癌客户蛋白（即HER 2和mutALK）的存在，但对于大多数肿瘤，驱动转化的Hsp 90依赖性癌客户蛋白难以鉴定。为了预测个体患者的反应性，需要以逐个肿瘤的方式定义Hsp 90的癌蛋白客户端，然后了解伴侣-客户端复合物的组成和功能，以及它们所涉及的分子网络，这是一项艰巨的技术挑战。 假设：我们在这里提出了一个简单的替代方案：而不是测量网络的肿瘤驱动Hsp 90的客户端，我们建议在每个肿瘤中的Hsp 90物种，“致癌Hsp 90”，允许存在的异常肿瘤驱动的客户端的丰度测量。虽然肿瘤变得依赖于Hsp 90-癌蛋白网络的生存，但这些蛋白质变得依赖于“致癌Hsp 90”的功能和稳定性。这种共生的相互依赖性表明肿瘤对Hsp 90癌蛋白的成瘾等于对“致癌Hsp 90”的成瘾。测量后者的丰度是第一个的读数，因此是Hsp 90治疗富集的潜在生物标志物。 方法：但是如何测量这种“致癌的Hsp 90”物种？它的丰度并不取决于单独的Hsp 90表达，然而某些Hsp 90抑制剂，如由Chiosis实验室开发的PU-H71，目前在MSKCC和NCI临床中心进行临床评估，与这种“致癌Hsp 90”物种特异性相互作用。因此，PU-H71的标记衍生物可以用作测量其存在和丰度的工具。事实上，我们已经创建了PU-H71的荧光和放射性标记版本，我们分别优化用于流式细胞术（用于液体肿瘤）或正电子发射断层扫描（PET）成像（用于实体肿瘤）。这些工具与“致癌Hsp 90”特异性相互作用，并提供了在临床上定量该Hsp 90种类的手段。 在这里，我们建议（a）进行探索性分析，以验证“致癌Hsp 90“物种作为Hsp 90抑制剂治疗患者选择的生物标志物，和（B）证明使用两种化学工具，PU-FITC和124 I-PU-H71，以非侵入性测量该生物标志物的存在和丰度。 具体而言，我们计划：（1）在液体和实体肿瘤的体外临床前模型中确定所提出的生物标志物预测将响应于Hsp 90抑制剂的癌症子集的能力（Guzman和Chiosis）。(2)在液体肿瘤和实体肿瘤的体内临床前模型中，通过液体肿瘤中的PU-FITC标记和通过实体肿瘤中的124 I-PU-H71摄取和保留测量的“致癌Hsp 90”是否预测抗肿瘤活性（Guzman，刘易斯和Chiosis）。(3)在临床上对拟定的生物标志物进行探索性研究（Dunphy、刘易斯、Guzman、Chiosis与临床同事Gerecitano（I期，PI）、Modi和Hudis（乳腺癌，II期）、Roboz、Tallman（AML，I期，II期PI）和Larson（核医学）合作）。 一旦在后续大型临床研究中验证，这种肿瘤敏感性与生物标志物谱的探索性相关性分析将最终提供肿瘤对Hsp 90抑制剂的预测反应的测定。最终目标是提供一种方法，通过该方法，通过分析“致癌性Hsp 90”的存在和丰度来常规地进行未来Hsp 90抑制剂治疗的患者选择，所述“致癌性Hsp 90”的存在和丰度通过多参数流式细胞术使用PU-FITC在液体癌中测量，并且通过PET使用124 I-PU-H71放射性示踪剂成像在实体瘤中测量。 重要性：据我们所知，这些是第一次报道的非侵入性伴随诊断技术，具有潜在的预测能力，用于Hsp 90治疗中的患者选择。在两种描述的形式中，该测定提出了用于液体癌和实体瘤的解决方案。由于这些检测方法提供了临床医生从未获得过的数据，它们有望帮助加速癌症中Hsp 90抑制剂的开发，并为Hsp 90靶向药物的临床决策提供信息。因此，他们可以以个性化，患者特异性的方式彻底改变Hsp 90抑制剂的临床开发和使用。

项目成果

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