Preclinical Development of Therapeutics in Murine Models of Lung Cancer

小鼠肺癌模型治疗方法的临床前开发

• 批准号: 10486943
• 负责人: SHYAM SHARAN
• 金额: $ 16.44万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486943
• 关键词: Adopted; Animals; Antigen Presentation; Antineoplastic Agents; Ataxia Telangiectasia; Biological; Biological Markers; Biopsy; CCR; Cancer Model; Cancer Patient; Cells; Clinical; Clinical Investigator; Clinical Management; Clinical Trials Network; Collaborations; Collection; Data; Diagnostic; Disease; Disease Progression; Disease Resistance; Drug Targeting; Drug resistance; Eligibility Determination; Engineering; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epigenetic Process; Evaluation; Evaluation Studies; Gene Amplification; Generations; Genetic Transcription; Genetically Engineered Mouse; Immune checkpoint inhibitor; Immune system; Immunocompromised Host; Intramural Research; Laboratories; Lung; Lung Neoplasms; MET gene; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Mission; Modeling; Molecular; Molecular Abnormality; Mutagenesis; Non-Small-Cell Lung Carcinoma; Oligonucleotides; Oncogenic; Operative Surgical Procedures; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Photosensitizing Agents; Platinum; Population; Recurrence; Relapse; Research Personnel; Resistance; Retinoblastoma Protein; Sampling; Series; TP53 gene; Therapeutic; Therapeutic Intervention; Topoisomerase; Tumor-infiltrating immune cells; Virus Activation; Work; anticancer research; base; biobank; cancer cell; cancer type; checkpoint inhibition; clinical predictors; clinically relevant; cohort; combinatorial; comparative; design; drug efficacy; effective therapy; efficacy evaluation; efficacy study; efficacy testing; experimental study; imaging modality; inhibitor/antagonist; lung carcinogenesis; lung small cell carcinoma; molecular imaging; mouse model; novel; outreach program; patient derived xenograft model; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; preclinical efficacy; preclinical evaluation; prevent; programmed cell death ligand 1; programs; refractory cancer; relapse patients; replication stress; response; specific biomarkers; targeted treatment; therapeutic development; therapeutic evaluation; treatment response; tumor

Lung cancer represents the most frequent form of malignancy comprising more than one-quarter of all cancer clinical cased worldwide, while concomitantly representing one of few cancer types with steadily increasing occurrence. Non-small cell lung carcinomas (NSCLC) are proven to be challenging tumor type for clinical management with frequent re-occurrence of drug resistant cancer after initial surgery/therapy and prominent metastatic potential. In addition, through CAOR collaborative outreach program to support intramural CCR investigators, we have adopted or established in-house several GEM and PDX models for the small cell lung cancer (SCLC) malignancy and employed them in several clinically impactful projects under the guidance of CCR clinical investigators. We have successfully completed an intramural collaboration aimed at efficacy testing of several photosensitizing agents in RTK-driven lung cancer models. Delivering on the mission of supporting CCR intramural research aimed at mitigating clinical impacts from lung carcinogenesis, CAPR supported the lung cancer research of CCR clinical investigator Dr. Udayan Guha by establishing a collection of PDX models using patient samples from CCR clinical trial network in lung cancer patients. CAPR has completed several correlative co-clinical experiments to interrogate molecular basis of resistant disease and identify valid avenues to prevent and treat oligo-resistant recurrent lung malignancies. In collaboration with Dr. Guha's clinical program, CAPR lung cancer modelling experts launched a broad scale effort aimed at establishing and biobanking a PDX collection of lung cancer samples isolated from clinical patients relapsed on the third generation EGFR inhibitors (specifically, osimertinib). As the key objective for subsequent application of this collection, the tumor samples have been evaluated for expression of TTF-1, CK-7, and pMET biomarkers and two efficacy studies conducted with combination of osimertinib and a cMET inhibitor. Overall, six large scale preclinical efficacy experiments have been conducted to date to investigate combinatorial potency of cMet inhibitor and osimertinib, as well as to correlate the disease response in different PDX models with MET gene amplification status (MET amplification studies were concomitantly conducted on the same patient samples in Dr. Guha's lab) and resistance mechanists suggested that can be interrogated at the diagnostic stage to justify a choice of 3rd generation EGFRi combined with cMET inhibition. Another project, in which CAPR joined efforts with Dr. Azam Ghafoor's clinical laboratory, a Rb/p53/Myc-dependent models (known as RP and RPM models) for small cell lung cancer have been established and pAdCre-based viral induction conditions for these models optimized. Preliminary work has been completed in these interesting and capacious models to examine the effect of epigenetic modulation in PD-L1 immune checkpoint inhibitor locus expression and the functional potency of the antigen presentation machinery in these SCLC models. Two GEM models - one RP and one RPM - have been comprehensively characterized by MRI imaging modality and histopathologic markers specific for the infiltrating immune system to prepare a basis for subsequent tolerability and efficacy experimentations using combined checkpoint inhibition and targeted therapeutics. In collaboration with CCR clinical investigator Dr. Anish Tomas, CAPR preclinical lung modelling program established and characterized several PDX models for SCLC based on clinical biopsies collected in patients with platinum-sensitive vs. platinum-resistant tumors. These models have been assessed for expression pf SCLC-specific biomarkers that are predictive of clinical responses to ataxia telangiectasia and Rad related (ATR) and topoisomerase-1 combined inhibition, as well as other therapeutic combinations targeting replicative stress and cancer-selective transcription that are proposed to be an effective treatment option in relapsed SCLC patients who progressed after first-line therapeutic intervention. Together with in-depth evaluation of cell population subtypes in established PDX models to explore correlation between plasticity of SCLC cancer cell ensembles and response to therapeutic intervention, these data are being currently analyzed with a foresight of designing a series of most meaningful and informative preclinical efficacy studies using these models.

肺癌是最常见的恶性肿瘤，占全世界临床癌症病例的四分之一以上，同时也是发病率稳步上升的少数癌症类型之一。非小细胞肺癌 (NSCLC) 被证明是临床治疗中具有挑战性的肿瘤类型，在初次手术/治疗后经常复发耐药性癌症，并且具有显着的转移潜力。此外，通过 CAOR 合作外展计划来支持校内 CCR 研究人员，我们已经采用或建立了内部多个针对小细胞肺癌 (SCLC) 恶性肿瘤的 GEM 和 PDX 模型，并在 CCR 的指导下将其应用于多个具有临床影响力的项目中。临床研究者。我们已经成功完成了一项校内合作，旨在测试几种光敏剂在 RTK 驱动的肺癌模型中的功效。 CAPR 履行支持旨在减轻肺癌临床影响的 CCR 校内研究的使命，通过使用来自肺癌 CCR 临床试验网络的患者样本建立一系列 PDX 模型，支持 CCR 临床研究员 Udayan Guha 博士的肺癌研究患者。 CAPR 已经完成了几项相关的临床联合实验，以探究耐药性疾病的分子基础，并确定预防和治疗寡核苷酸耐药性复发性肺部恶性肿瘤的有效途径。 CAPR 肺癌建模专家与 Guha 博士的临床项目合作，开展了一项广泛的工作，旨在建立从使用第三代 EGFR 抑制剂（特别是奥希替尼）复发的临床患者中分离出的肺癌样本 PDX 集合并进行生物库分析。作为该集合后续应用的关键目标，对肿瘤样本的 TTF-1、CK-7 和 pMET 生物标志物的表达进行了评估，并进行了两项奥西替尼与 cMET 抑制剂组合的疗效研究。总体而言，迄今为止已进行了六次大规模临床前疗效实验，以研究 cMet 抑制剂和奥希替尼的组合效力，并将不同 PDX 模型中的疾病反应与 MET 基因扩增状态相关联（MET 扩增研究同时在同一模型上进行）。 Guha 博士实验室的患者样本）和耐药机制专家建议，可以在诊断阶段进行询问，以证明选择第三代 EGFRi 与 cMET 抑制相结合的合理性。 CAPR 与 Azam Ghafoor 博士的临床实验室合作的另一个项目，建立了小细胞肺癌的 Rb/p53/Myc 依赖性模型（称为 RP 和 RPM 模型），并建立了基于 pAdCre 的病毒诱导条件。模型优化。在这些有趣且广泛的模型中已经完成了初步工作，以检查表观遗传调节对 PD-L1 免疫检查点抑制剂基因座表达的影响以及这些 SCLC 模型中抗原呈递机制的功能效力。两种 GEM 模型（一种 RP 和一种 RPM）已通过 MRI 成像模式和浸润性免疫系统特异性的组织病理学标记物进行了全面表征，为后续使用联合检查点抑制和靶向治疗的耐受性和疗效实验奠定了基础。 CAPR 临床前肺建模项目与 CCR 临床研究员 Anish Tomas 博士合作，根据从铂敏感与铂耐药肿瘤患者中收集的临床活检，建立并表征了几种 SCLC PDX 模型。这些模型已针对 SCLC 特异性生物标志物的表达进行了评估，这些生物标志物可预测对共济失调毛细血管扩张和 Rad 相关 (ATR) 和拓扑异构酶 1 联合抑制的临床反应，以及针对复制应激和癌症选择性转录的其他治疗组合被认为是一线治疗干预后病情进展的复发性 SCLC 患者的有效治疗选择。结合对已建立的 PDX 模型中细胞群亚型的深入评估，以探索 SCLC 癌细胞群的可塑性与治疗干预反应之间的相关性，目前正在分析这些数据，以设计一系列最有意义和信息丰富的临床前疗效。使用这些模型进行研究。