Using Canine Organoids to Advance Therapeutic Drug Development in Bladder Cancer
利用犬类器官推进膀胱癌治疗药物的开发
基本信息
- 批准号:10356600
- 负责人:
- 金额:$ 22.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-15 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAnimal Disease ModelsAnimalsBehaviorBiologicalBiological AssayBiological ModelsCancer PatientCanis familiarisCarboplatinCell LineCisplatinClinicalClinical TrialsCollaborationsDataDevelopmentDrug ScreeningExposure toFoundationsFutureGrantGrowth FactorHealthHeterogeneityHumanImmunocompromised HostMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of urinary bladderMissionModalityModelingMolecularMolecular TargetMusNeoplasm TransplantationOncologyOrganoidsPartial RemissionPatientsPersonsPharmaceutical PreparationsPhenotypePlatinumPopulationPre-Clinical ModelPrediction of Response to TherapyProgressive DiseaseRefractoryResearchResourcesRodent ModelSamplingStable DiseaseSurvival RateTechnologyTestingTherapeuticTherapeutic UsesTimeTransitional Cell CarcinomaTreatment outcomeTumor BiologyTumor SubtypeTumor-DerivedUnited States National Institutes of HealthUrineUrotheliumValidationXenograft Modelbasebiobankcanine modelchemotherapyclinical predictorscomparativecytotoxicitydrug candidatedrug developmentdrug discoverydrug efficacydrug sensitivitydrug testingexome sequencingfollow-upin vivoin vivo evaluationinnovationmanmouse modelmuscle invasive bladder cancernew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticspre-clinicalpreclinical efficacypreclinical studypredictive modelingprospectiveresearch and developmentresearch clinical testingresponsescreeningstudy populationtranscriptome sequencingtreatment comparisontreatment responsetumortumor heterogeneityurinary
项目摘要
PROJECT SUMMARY/ABSTRACT
Muscle-Invasive Bladder Cancer (MIBC) is associated with an extremely poor survival rate of only 40% at 5
years follow-up, which, importantly, has not improved over the last 10 years. Two important factors that contribute
to poor treatment outcomes are (1) the shortage of truly innovative and effective drug candidates for MIBC, and
(2) the phenotypic and molecular heterogeneity of MIBC tumors, which limits the translational value of some
rodent models to evaluate therapeutic drug efficacy. Although murine models have been extensively used for
the study of bladder cancer, they typically do not faithfully reflect the biological behavior of MIBC in human
patients. As opposed to mice, dogs with spontaneously occurring bladder cancer have been shown to be a highly
relevant model for human MIBC. This is highlighted by the fact that canine MIBC presents with very similar
molecular features, tumor heterogeneity and subtypes, as well as clinical and metastatic behavior as humans.
Therefore, canine MIBC constitutes an ideal preclinical study population to evaluate novel therapeutic options
for patients with bladder cancer.
Although clinical trials in dogs with MIBC can be performed in significantly shorter time-frames than in people,
so far, only very few large-scale trials using the canine model have been performed. Validation of predictive ex
vivo assays to evaluate the potential efficacy of novel treatment modalities before formal testing in canine clinical
trials will therefore enhance translational efforts for the development of novel therapeutics. A promising
technology for the ex vivo screening of candidate drug efficacy lies in the culture of patient-derived tumor
organoids (PDOs). Compared with 2D cell lines, 3D PDOs better reflect the underlying biology of the tumor and
are therefore considered more robust ex vivo models to accurately predict clinical response to treatment
compared with molecular testing alone. We therefore propose that future therapeutic leads for MIBC be screened
ex vivo using canine organoids to select the most promising drug candidates. Subsequently, these novel
therapeutics could be tested in vivo in dogs with bladder cancer prior to clinical testing in human patients with
MIBC.
The research proposed in this application is innovative, in our opinion, because it represents a new and
substantive paradigm shift in drug research and development, using the dog as a spontaneous animal disease
model to characterize the preclinical efficacy of chemotherapeutic candidates. This contribution will be significant
as it will streamline the development of new therapeutic strategies in man and man’s best friend with bladder
cancer. Ultimately, the research proposed in this R21 grant will lay the foundation to an R01 application focusing
on the development of new therapeutics using canine MIBC as a preclinical model for candidate drug testing in
collaboration with the NCI.
项目总结/摘要
肌肉浸润性膀胱癌(MIBC)与5岁时仅40%的极差生存率相关
多年的随访,重要的是,这在过去10年中没有改善。两个重要因素促成了
治疗效果不佳的原因是(1)缺乏真正创新和有效的MIBC候选药物,
(2)MIBC肿瘤的表型和分子异质性,这限制了一些
啮齿动物模型以评估治疗药物功效。尽管小鼠模型已被广泛用于
在膀胱癌的研究中,它们通常不能忠实地反映人类MIBC的生物学行为
患者与小鼠相反,患有自发性膀胱癌的狗已被证明是一种高度恶性肿瘤。
人MIBC的相关模型。这是突出的事实,狗MIBC提出了非常相似的,
分子特征、肿瘤异质性和亚型,以及与人类一样的临床和转移行为。
因此,犬MIBC构成了评价新型治疗选择的理想临床前研究人群
治疗膀胱癌的方法
尽管在患有MIBC的狗身上进行临床试验的时间比在人身上要短得多,
到目前为止,只进行了很少的使用犬模型的大规模试验。预测模型的验证
在犬临床正式试验之前,进行体内试验以评估新型治疗方式的潜在疗效
因此,试验将加强新型疗法开发的转化努力。一个有前途
用于候选药物功效的离体筛选的技术在于培养患者来源的肿瘤
类器官(PDO)。与2D细胞系相比,3D PDO更好地反映了肿瘤的潜在生物学,
因此被认为是更稳健的离体模型,以准确预测对治疗的临床反应
与单独的分子测试相比。因此,我们建议筛选MIBC未来的治疗线索
离体使用犬类器官来选择最有希望的候选药物。随后,这些小说
治疗剂可以在患有膀胱癌的狗中进行体内测试,然后在患有膀胱癌的人类患者中进行临床测试。
MIBC。
在我们看来,这项申请中提出的研究是创新的,因为它代表了一种新的,
药物研究和开发的实质性范式转变,将狗作为自发性动物疾病
模型来表征化疗候选物的临床前功效。这一贡献将是巨大的
因为它将简化人类和人类最好的膀胱朋友的新治疗策略的开发,
癌最终,这项R21资助中提出的研究将为R 01申请奠定基础,
使用犬MIBC作为候选药物测试的临床前模型开发新疗法,
与NCI合作。
项目成果
期刊论文数量(0)
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Karin Allenspach其他文献
Karin Allenspach的其他文献
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{{ truncateString('Karin Allenspach', 18)}}的其他基金
Using Canine Organoids to Advance Therapeutic Drug Development in Bladder Cancer
利用犬类器官推进膀胱癌治疗药物的开发
- 批准号:
10539328 - 财政年份:2021
- 资助金额:
$ 22.93万 - 项目类别:
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