Biomarkers for predicting response to Hsp90 therapy

用于预测 Hsp90 治疗反应的生物标志物

基本信息

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
项目类别：
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

项目摘要

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，制药公司将药物推向市场通常是不够的。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该药物中受益，从而使其他患者免受不必要的副作用和费用。 FDA 于 2011 年 7 月向行业发布了伴随诊断检测指南，其中包括优先考虑将检测与药物同时准备好进行批准。这对于临床研究中或即将进入临床评估的近 20 种 Hsp90 抑制剂尤其重要，因为在临床评估中精确定位患者群体尤其难以捉摸。对于 Hsp90 抑制剂，患者选择目前基于 Hsp90 依赖性癌客户蛋白（即 HER2 和 mutALK）的存在，但对于大多数肿瘤来说，驱动转化的 Hsp90 依赖性癌客户蛋白很难识别。为了预测个体患者的反应性，需要以逐个肿瘤的方式定义 Hsp90 的癌蛋白客户，然后了解伴侣-客户复合物的组成和功能，以及它们所在的分子网络涉及一项艰巨的技术挑战。假设：我们在这里提出一个简单的替代方案：我们不测量肿瘤驱动的 Hsp90 客户网络，而是测量每个肿瘤中 Hsp90 物种（“致癌 Hsp90”）的丰度，它允许异常肿瘤的存在- 吸引客户。当肿瘤变得依赖于 Hsp90 癌蛋白网络上的生存时，这些蛋白的功能和稳定性变得依赖于“致癌 Hsp90”。这种共生相互依赖表明肿瘤对 Hsp90 癌蛋白的成瘾等同于对“致癌 Hsp90”的成瘾。测量后者的丰度是对前者的读数，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”物种呢？它的丰度不仅仅由 Hsp90 表达决定，然而某些 Hsp90 抑制剂，例如 Chiosis 实验室开发的 PU-H71，目前正在 MSKCC 和 NCI 临床中心进行临床评估，与这种“致癌 Hsp90”物种特异性相互作用。因此，PU-H71 的标记衍生物可用作测量其存在及其丰度的工具。事实上，我们已经创建了 PU-H71 的荧光和放射性标记版本，我们对其进行了优化，分别用于流式细胞术（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 Hsp90”特异性相互作用，并提供了一种在临床上量化该 Hsp90 物种的方法。在这里，我们建议（a）进行探索性分析，以验证“致癌 Hsp90”物种作为 Hsp90 抑制剂治疗患者选择的生物标志物，以及（b）展示两种化学工具 PU-FITC 和 124I-PU-的使用H71，以非侵入性方式测量该生物标志物的存在和丰度。具体来说，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对 Hsp90 抑制剂（Guzman 和 Chiosis）产生反应的癌症子集的能力。 (2) 确定液体和实体肿瘤的体内临床前模型，通过液体肿瘤中的 PU-FITC 标记和实体肿瘤中的 124I-PU-H71 摄取和保留测量的“致癌 Hsp90”是否可以预测抗肿瘤活性（Guzman、Lewis 和 Chiosis）。 (3) 在临床中对拟议的生物标志物进行探索性研究（Dunphy、Lewis、Guzman、Chiosis 与临床同事 Gerecitano（第 1 期，PI）、Modi 和 Hudis（乳腺癌，第 2 期）、Roboz、Tallman（ AML，1,2 期 PI）和拉森（核医学））。这种肿瘤敏感性与生物标志物谱的探索性相关性分析一旦在后续大型临床研究中得到验证，将最终提供一种肿瘤对 Hsp90 抑制剂的预测反应的测定方法。最终目标是提供一种方法，通过对液体癌症中使用 PU-FITC 的多参数流式细胞术和 PET 测量的“致癌 Hsp90”的存在和丰度进行分析，对患者进行未来 Hsp90 抑制剂治疗的常规选择在实体瘤中使用 124I-PU-H71 放射性示踪剂成像。意义：据我们所知，这些是首次报道的非侵入性伴随诊断技术，对 Hsp90 治疗中的患者选择具有潜在的预测能力。在所描述的两种形式中，该测定提出了针对液体癌和实体瘤的解决方案。由于这些检测方法为临床医生提供了前所未有的数据，因此它们有望帮助加速癌症中 Hsp90 抑制剂的开发，并为 Hsp90 靶向药物的临床决策提供信息。因此，他们可以以个体化、针对患者的方式彻底改变 Hsp90 抑制剂的临床开发和使用。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of FDG-PET scans in staging, response assessment, and follow-up care for non-small cell lung cancer.

FDG-PET 扫描在非小细胞肺癌分期、疗效评估和后续护理中的作用。

DOI：
发表时间：
2012
期刊：
影响因子：
0
作者：
Cuaron, John;Dunphy, Mark;Rimner, Andreas
通讯作者：
Rimner, Andreas

Prognostic Value of Preradiotherapy (18)F-FDG PET/CT Volumetrics in Limited-Stage Small-Cell Lung Cancer.

放疗前 (18)F-FDG PET/CT 容量测定对局限期小细胞肺癌的预后价值。

DOI：
发表时间：
2016-05
期刊：
影响因子：
3.6
作者：
Ong, Leonard T;Dunphy, Mark;Foster, Amanda;Woo, Kaitlin M;Zhang, Zhigang;Perez, Carmen A;Pietanza, Catherine M;Rosenzweig, Kenneth E;Gelblum, Daphna Y;Rimner, Andreas;Wu, Abraham J
通讯作者：
Wu, Abraham J

Value of second-opinion review of outside institution PET-CT examinations.

外部机构 PET-CT 检查的第二意见审查的价值。

DOI：
发表时间：
2017-04
期刊：
影响因子：
1.5
作者：
Ulaner, Gary A;Mannelli, Lorenzo;Dunphy, Mark
通讯作者：
Dunphy, Mark

Synthesis and evaluation of (18)F-labeled ATP competitive inhibitors of topoisomerase II as probes for imaging topoisomerase II expression.

(18)F 标记的拓扑异构酶 II ATP 竞争性抑制剂的合成和评估，作为拓扑异构酶 II 表达成像探针。

DOI：
发表时间：
2014-10-30
期刊：
影响因子：
6.7
作者：
Daumar, Pierre;Zeglis, Brian M;Ramos, Nicholas;Divilov, Vadim;Sevak, Kuntal Kumar;Pillarsetty, NagaVaraKishore;Lewis, Jason S
通讯作者：
Lewis, Jason S

Adaptive Neoadjuvant Chemotherapy Guided by (18)F-FDG PET in Resectable Non-Small Cell Lung Cancers: The NEOSCAN Trial.

(18)F-FDG PET 引导的适应性新辅助化疗治疗可切除的非小细胞肺癌：NEOSCAN 试验。