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: 8685204
• 负责人: GABRIELA CHIOSIS
• 金额: $ 55.06万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685204
• 关键词: Adverse effects; Affect; Apoptosis; Applications Grants; Automobile Driving; Biological Assay; Biological Markers; Biology; Biopsy Specimen; Cancer Patient; Cell Line; Cell Survival; Characteristics; Chemicals; Client; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Companions; Complex; Data; Development; Diagnostic; 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; Learning; Letters; Life; Liquid substance; Malignant Neoplasms; Marketing; Measures; Medical; Memorial Sloan-Kettering Cancer Center; Minority; Molecular; Molecular Chaperones; Nature; New Agents; Normal Cell; Oncogene Proteins; Oncogenic; Outcome; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Population; Population Study; Positron-Emission Tomography; Pre-Clinical Model; Primary Neoplasm; Proteins; Proto-Oncogene Proteins c-akt; Radiochemistry; Radiolabeled; Reading; Reporting; Research Personnel; Role; Sampling; Selection for Treatments; Signal Pathway; Solid; Solid Neoplasm; Solutions; Technology; Testing; Therapeutic; Time; Transplantation; Treatment Efficacy; Tumor Burden; United States National Institutes of Health; Validation; addiction; base; cancer cell; chemotherapy; clinical decision-making; effective therapy; established cell line; follow-up; improved; in vivo; inhibitor/antagonist; leukemia; malignant breast neoplasm; mouse model; neoplastic cell; news; novel therapeutics; oncology; patient population; preference; prospective; protein folding; public health relevance; radiotracer; research clinical testing; response; statistics; tool; tumor; tumor addiction; tumor xenograft; 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：HSP90患者选择的诊断测定 - 未满足的医疗需求：如今，制药公司通常不足以将药物推向市场。监管机构和保险公司还要求公司开发测试，以指出哪些患者更有可能从药物中受益，从而使其他患者免于不必要的副作用和费用。 FDA于2011年7月向该行业发布了有关伴侣诊断测定法的指导，其中包括偏爱与药物同时准备批准的测试。对于临床研究中的近20个HSP90抑制剂或即将进行临床评估，这一点尤其重要，在该评估中，指出了TH患者人群尤其难以捉摸。对于HSP90抑制剂，患者的选择目前是基于HSP90依赖性的肿瘤蛋白（即HER2和MUTALK）的存在，但是对于大多数肿瘤而言，HSP90脱生的OnCo-Client蛋白（S）难以识别。为了预测个体患者的反应能力，需要以肿瘤的方式定义HSP90的癌蛋白客户群，然后了解伴侣蛋白 - 客户 - 客户群的构成和功能，以及它们所在的分子网络涉及，一个令人生畏的技术挑战。 假设：我们在这里提出了一种简单的替代方法：我们建议在每个肿瘤中测量肿瘤驱动HSP90顾客的网络，而是在每个肿瘤中测量hsp90种的丰度，即“致癌HSP90”，允许存在异常肿瘤的存在 - 驾驶客户。虽然肿瘤沉迷于HSP90-共蛋白网络上的生存，但这些蛋白质依赖于“致癌HSP90”以进行功能和稳定性。这种共生的相互依赖性表明，肿瘤对HSP90癌蛋白的成瘾等于成瘾与“致癌HSP90”。测量后者的丰度是第一个的读出，因此是HSP90治疗富集的潜在生物标志物。 方法：但是如何测量这种“致癌HSP90”物种？它的丰度并不是仅由HSP90表达来决定的，但是某些HSP90抑制剂，例如Chiisoiss Lab开发的PU-H71，目前正在MSKCC和NCI临床中心进行临床评估，特别是与这种“致癌HSP90”物种相互作用。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。的确，我们既创建了荧光灯又创建了PU-H71的放射性标记版本，我们将其优化用于流式细胞仪（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）。这些工具专门与“致癌HSP90”相互作用，并为临床中的HSP90物种定量提供了一种手段。 在这里，我们建议（a）进行探索性分析，以验证“致癌性HSP90”物种作为HSP90抑制剂治疗的患者选择的生物标志物，并且（b）证明了两种化学工具，PU-FITC和124i-Pu--- H71，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）在液体和实体瘤的体外临床前模型中确定所提出的生物标志物预测将对HSP90抑制剂（Guzman和Chiosis）做出反应的癌症子集的能力。 （2）确定在体内液体和实体瘤的临床前模型中，是否通过液体肿瘤中的PU-FITC标记和124i-PU-H71摄取和在实体瘤中保留的“致癌性HSP90”，是否可以预测抗肿瘤活性（Guzman，Lewis和Chiosis）。 （3）在临床中对拟议生物标志物进行探索性研究（Dunphy，Lewis，Guzman，Chiosis，与临床同事Gerecitano（第1阶段，PI），Modi和Hudis（乳腺癌，第2阶段），Roboz，Roboz，Tallman（Tallman（Tallman））（ AML，第1,2阶段PIS）和Larson（核医学）。 肿瘤敏感性与生物标志物谱的探索性相关性分析一旦在大型临床研究中得到验证，最终将为肿瘤对HSP90抑制剂的预测反应提供一种测定。最终目标是提供一种手段，通过分析使用液体癌中的PU-FITC和PET PU-FITC测量的“致癌HSP90”的存在和丰度，通常通过分析“致癌HSP90”的存在和丰度来提供一种方法。在实体瘤中使用124i-PU-H71放射性成像。 意义：据我们所知，这些是首次报道的非侵入性伴侣诊断技术，具有潜在的HSP90治疗中患者选择的预测能力。在描述的两种形式中，该测定提出了针对液体癌和实体瘤的解决方案。由于这些测定法从未在临床医生提供之前提供数据，因此他们承诺有助于加速癌症中HSP90抑制剂的发展，并用HSP90靶向的药物为临床决策提供信息。因此，他们可以以个性化的，特定于患者的方式彻底改变HSP90抑制剂的临床发展和使用。