Enhancing Chemoradiation Efficacy through Unbiased Drug Discovery Approaches

通过公正的药物发现方法提高放化疗的疗效

基本信息

批准号：
10223893
负责人：
Sunil Krishnan
金额：
$ 59.63万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-05 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223893
关键词：
Amino Acids Animal Model Animals Biological Assay Biological Markers Cancer Therapy Evaluation Program Carboplatin Cell Death Cell Line Cells Clinic Clinical Clinical Research Clinical Treatment Clinical Trials Combined Modality Therapy DNA Damage DNA Repair Data Development Dose Drug Targeting Drug resistance Evaluation Failure Fractionated radiotherapy Future Generations Genetic Genetically Engineered Mouse Gold Heterogeneity Human Cell Line Image Immune Immunocompetent Immunotherapeutic agent In Vitro Lead Locally Advanced Malignant Neoplasm Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Modeling Molecular Molecular Target Mouse Cell Line Mus Non-Small-Cell Lung Carcinoma Paclitaxel Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Pre-Clinical Model Process Property Protein Array Protein Array Analysis Proteins Proteome Proteomics Radiation Radiation Tolerance Radiation therapy Reactive Oxygen Species Reproducibility Resistance Signal Pathway Stable Isotope Labeling System Testing Toxic effect Translations Treatment Efficacy Treatment outcome Validation Xenograft procedure base cancer cell cancer type capecitabine chemoradiation chemotherapy clinical translation clinically relevant dosimetry drug discovery drug distribution efficacy study fractionated radiation high throughput screening improved improved outcome in silico in vitro Assay in vivo in vivo Model in vivo evaluation insight molecular drug target molecular targeted therapies neoplastic cell novel pancreatic cancer cells pancreatic ductal adenocarcinoma cell patient derived xenograft model personalized medicine pharmacokinetics and pharmacodynamics phosphoproteomics pre-clinical preclinical study radiation effect resistance mechanism response standard of care targeted agent targeted treatment therapeutic evaluation tool treatment response tumor tumor heterogeneity tumor xenograft validation studies

项目摘要

A major barrier to improving cure rates in locally advanced cancers is our inability to make progress beyond what chemoradiation (CRT) can currently deliver. Combination strategies using molecular targeted therapies with CRT hold promise for improving outcomes further. While many drugs could enhance the effects of radiation alone, we have discovered that the effects are quite unpredictable when drugs are combined with chemotherapy and radiotherapy. The successful translation of adding molecular targeted agents to CRT would require an understanding of the molecular pathways that enable the cancer cell to survive under conditions of CRT. Inhibiting these pathways with molecular targeted drugs will be synergistic with CRT in the cancer-specific context. Using a set of molecular targeted drugs from the CTEP portfolio as an initial starting point, we will investigate two hard-to-treat cancer types treated with CRT, non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). We will identify drugs that could synergize with radiation and CRT using a high throughput clonogenic survival screen that we have developed on validated cancer lines and then test the most clinically promising combinations of agents to multiple cell lines with varying genetic backgrounds, first in vitro and then further validated using 2 in vivo models: a panel of patient-derived xenografts (PDXs) and orthotopic tumor models using syngeneic tumors, all done in combination with clinically-relevant chemotherapies. The pharmacokinetic and pharmacodynamic properties of these drugs with chemotherapy in animals and tumors will be assessed in order to determine the optimal sequencing approach with conventionally fractionated radiotherapy. Since we have discovered that chemotherapy significantly alters the response of cancer cells to radiation and targeted drugs, we will also evaluate the molecular mechanisms that explain the response to CRT, and identify potential factors that may influence this response using 4 major approaches. In the first more classic approach, we will assess DNA damage repair pathways and reactive oxygen species generation when targeted agents are combined with radiation or CRT. Second, we will use reverse phase protein arrays (RPPA) to assess the functional proteome to determine pathways that may be altered with molecular targeted drugs in the setting of RT or CRT. In the third approach, we will use Stable Isotope Labeling with Amino Acids (SILAC) to assess global proteomic and phosphoproteomic changes that occur with radiation and CRT treatment, and how these pathways could be altered with specific molecular targeted therapies. Lastly, we will use Imaging Mass Spectrometry to analyze drug distribution within the various tumor models and assess how the pharmacodynamic heterogeneity impacts CRT responsiveness. Our proposal will not only identify the most promising drugs that could best be combined with CRT in NSCLC and PDAC, but we will have identified molecular and tumor factors that confer drug resistance which will enable future development of novel targeted strategies to enhance CRT or appropriately select patient for personalized therapy. Our approach will generate the high quality preclinical data and novel insights to fulfill the overall FOA objective, which is “to accelerate the pace at which combined modality treatments with greater efficacy are identified and incorporated into standard practices for treatments”.

提高本地高级癌症治疗率的主要障碍是我们无法取得超越的进步当前可以交付化学辐射（CRT）。使用CRT使用分子靶向疗法的组合策略坚持进一步改善结果的希望。虽然许多药物可以单独增强辐射的影响，但我们已经发现，当药物与化学疗法和化学疗法和放疗。将分子靶向剂添加到CRT的成功翻译将需要了解使癌细胞在CRT条件下生存的分子途径。用分子靶向药物抑制这些途径将与癌症特异性的CRT协同作用语境。将CTEP投资组合中的一组分子靶向药物作为初始起点，我们将研究两种用CRT，非小细胞肺癌（NSCLC）和胰腺治疗的难以治疗的癌症类型导管腺癌（PDAC）。我们将确定可以使用高辐射和CRT协同作用的药物我们已经在经过验证的癌症线上开发的吞吐量克隆生存屏幕，然后测试最多临床上有望与具有不同遗传背景的多个细胞系的临床有望的组合，首先是体外然后使用2种体内模型进一步验证：一组患者衍生的特征（PDXS）和原位肿瘤模型使用合烯肿瘤，全部与临床上相关的化学疗法结合完成。这这些药物在动物和肿瘤中使用化学疗法的药代动力学和药效学特性将进行评估以确定最佳的测序方法，并以常规分级为单位放疗。由于我们发现化疗显着改变了癌细胞对辐射和靶向药物，我们还将评估解释对CRT反应的分子机制并确定可能使用4种主要方法影响这一响应的潜在因素。在第一个经典方法，我们将评估目标时DNA损伤修复途径和活性氧的产生代理与辐射或CRT结合。其次，我们将使用反相蛋白阵列（RPPA）评估在情况下可以用分子靶向药物改变途径的功能蛋白质组 RT或CRT。在第三种方法中，我们将使用稳定的同位素标记与氨基酸（SILAC）评估辐射和CRT处理发生的全局蛋白质组学和磷酸化蛋白质组学变化，以及如何可以使用特定的分子靶向疗法来改变途径。最后，我们将使用成像质量光谱法分析各种肿瘤模型中的药物分布并评估如何药物动态异质性会影响CRT反应性。我们的建议不仅会确定最多的在NSCLC和PDAC中最好与CRT结合的有希望的药物，但我们将确定会议耐药性的分子和肿瘤因素将使未来的新颖目标发展增强CRT或适当选择患者进行个性化治疗的策略。我们的方法将产生高质量的临床前数据和新颖的见解以实现整体FOA目标，这是“加速鉴定并纳入标准的效率，结合效率更高的模态处理的步伐治疗实践”。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Simple oligonucleotide-based multiplexing of single-cell chromatin accessibility.

DOI：
10.1016/j.molcel.2021.09.026
发表时间：
2021-10-21
期刊：
Molecular cell
影响因子：
16
作者：
Wang K;Xiao Z;Yan Y;Ye R;Hu M;Bai S;Sei E;Qiao Y;Chen H;Lim B;Lin SH;Navin NE
通讯作者：
Navin NE

Severe lymphopenia during neoadjuvant chemoradiation for esophageal cancer: A propensity matched analysis of the relative risk of proton versus photon-based radiation therapy.

DOI：
10.1016/j.radonc.2017.11.028
发表时间：
2018-07
期刊：
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
影响因子：
0
作者：
Shiraishi Y;Fang P;Xu C;Song J;Krishnan S;Koay EJ;Mehran RJ;Hofstetter WL;Blum-Murphy M;Ajani JA;Komaki R;Minsky B;Mohan R;Hsu CC;Hobbs BP;Lin SH
通讯作者：
Lin SH

High-Content Clonogenic Survival Screen to Identify Chemoradiation Sensitizers.

高内涵克隆生存筛选，用于鉴定放化疗增敏剂。

DOI：
10.1016/j.ijrobp.2021.07.1712
发表时间：
2021
期刊：
International journal of radiation oncology, biology, physics
影响因子：
0
作者：
Ye,Rui;Qiao,Yawei;Singh,PankajK;Wang,Yifan;He,Jianzhong;Li,Nan;Krishnan,Sunil;Lin,StevenH
通讯作者：
Lin,StevenH

Outcomes of Stereotactic Body Radiotherapy for T1-T2N0 Small Cell Carcinoma According to Addition of Chemotherapy and Prophylactic Cranial Irradiation: A Multicenter Analysis.

DOI：
10.1016/j.cllc.2017.03.009
发表时间：
2017-11
期刊：
Clinical lung cancer
影响因子：
3.6
作者：
Verma V;Simone CB 2nd;Allen PK;Lin SH
通讯作者：
Lin SH

Moving Beyond the Standard of Care: Accelerate Testing of Radiation-Drug Combinations.

DOI：
10.1016/j.ijrobp.2021.08.018
发表时间：
2021-12-01
期刊：
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
影响因子：
7
作者：
Lin, Steven H.;Willers, Henning;Krishnan, Sunil;Sarkaria, Jann N.;Baumann, Michael;Lawrence, Theodore S.
通讯作者：
Lawrence, Theodore S.