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

• 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
• 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

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”.

提高局部晚期癌症治愈率的一个主要障碍是我们无法取得进展

项目成果

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
• 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
• 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

A Mail Audit Independent Peer Review System for Dosimetry Verification of a Small Animal Irradiator.

• DOI: 10.1667/rr15220.1
• 发表时间: 2020-04
• 期刊: Radiation research
• 影响因子: 3.4
• 作者: Gronberg MP;Tailor RC;Smith SA;Kry SF;Followill DS;Stojadinovic S;Niedzielski JS;Lindsay PE;Krishnan S;Aguirre F;Fujimoto TN;Taniguchi CM;Howell RM
• 通讯作者: Howell RM