Validation of the Genetically Malleable Oncopig Hepatocellular carcinoma (HCC) Model for Targeted Therapeutic Development
用于靶向治疗开发的遗传可塑性 Oncopig 肝细胞癌 (HCC) 模型的验证
基本信息
- 批准号:10760736
- 负责人:
- 金额:$ 96.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-19 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AftercareAnimalsArea Under CurveArterial EmbolizationAutologousBiologicalBiological MarkersBiopsyBloodBlood specimenC-reactive proteinCancer EtiologyCancer ModelCanis familiarisCellsCessation of lifeClinicalClustered Regularly Interspaced Short Palindromic RepeatsCollectionCombined Modality TherapyDetectionDevelopmentDevicesDiagnosticDiseaseDoseEvaluationFamily suidaeFrequenciesFutureGeneticGenetic TranscriptionGenotypeGoalsGrowthGuidelinesHistologicHistologyHourHumanImageIn complete remissionInjectionsKRASG12DKineticsLeftLettersLiverLobeMalignant NeoplasmsMalignant neoplasm of liverMarketingMass Spectrum AnalysisModelingMonitorMutationNucleosomesOncopigPIK3CG genePharmacologic SubstancePhasePlasmaPrimary Malignant Neoplasm of LiverPrimary carcinoma of the liver cellsSCID MiceSiteSmall Business Innovation Research GrantSystemTechnologyTestingTherapeuticTranslationsTreatment EfficacyTumor BiologyValidationVolitionWorkX-Ray Computed Tomographycancer therapycancer typecell free DNAclinical practiceclinically relevantclinically significantcommercializationcomorbiditydriver mutationdrug metabolismfollow-uphepatocellular carcinoma cell lineimprovedin vivoinhibitorinhibitor therapyinterestintrahepaticliquid biopsyliver cancer modelmeetingsminimally invasivenovelpersonalized diagnosticspersonalized therapeuticpre-clinicalprecision medicinepreclinical evaluationpreclinical trialresponsetargeted deliverytargeted treatmenttesting servicestherapeutic developmenttherapeutic evaluationtherapeutic targettranscriptome sequencingtreatment responsetreatment strategytrial designtumortumor growthtumor progressiontumorigenic
项目摘要
PROJECT ABSTRACT: The goal of this Phase II SBIR proposal is to further validate the genetically defined
Oncopig hepatocellular carcinoma (HCC) model—capable of modeling diverse HCC driver mutational profiles
through induced KRASG12D and TP53R167H expression and subsequent CRISPR editing—for preclinical
evaluation of locally delivered, personalized HCC therapies. HCC is an aggressive liver malignancy representing
the 7th most common cancer and the 4th most common cause of cancer death worldwide, illustrating the critical
need for improved HCC treatment options. Since HCC and other cancers are driven by the accumulation of
genetic driver mutations conferring selective growth advantages, personalized cancer models are required to
evaluate targeted therapeutics for this deadly disease. Furthermore, the use of transarterial delivery-based
approaches for HCC treatment combined with similarities in size and drug metabolism between pigs and humans
highlights the critical need and translational value of the genetically defined Oncopig HCC model for investigating
novel and re-purposed therapeutics targeting specific driver mutations. Importantly, there is broad interest in the
use of Oncopigs in preclinical trials (see Support Letters). This proposal will demonstrate differential efficacy of
transarterial targeted PI3K inhibitor delivery to Oncopig PTENKO (PI3K inhibitor responsive) and KEAP1KO (PI3K
inhibitor non-responsive) HCC tumors using a clinically relevant trial design. Use of liquid biopsies for minimally
invasive HCC driver mutation quantification (see Volition Support Letter) will facilitate translation of HCC
precision medicine approaches into clinical practice, currently lacking due to infrequency of routine HCC biopsy
collection for biological profiling. The genetically defined Oncopig HCC model will be validated for targeted
therapeutic testing by pursuing the following Specific Aims: (1) Characterize genetically defined Oncopig HCC
tumors over a clinically relevant 3-month diagnostic monitoring period. (2) Demonstrate delivery of targeted PI3K
inhibitor therapeutic doses to Oncopig HCC tumors via transarterial embolization. (3) Demonstrate efficacy of
transarterial targeted PI3K inhibitor delivery for Oncopig PTENKO HCC in a clinically relevant 3-month follow-up
timeframe. The ability to achieve quantifiable therapeutic PI3K inhibitor concentrations following transarterial
delivery in the genetically defined Oncopig HCC model will be demonstrated, in addition to a clinically relevant
difference in response (40% increase in complete response rate in PTENKO compared to KEAP1KO HCC) based
on clinically employed mRECIST guidelines. This work will validate the genetically defined Oncopig HCC
model for targeted therapeutic evaluation, enabling Sus Clinicals to provide personalized tumor
development and targeted therapeutic testing services using the Oncopig platform. Future work focused
on expanding Sus Clinicals commercialization of this technology will include expansion of personalized modeling
approaches for other cancers, demonstration of use for precision diagnostic evaluation, personalized comorbidity
modeling, and expanding marketing efforts to include the pharmaceutical sector.
项目摘要:SBIR第二阶段提案的目标是进一步验证基因定义的
Oncopig肝细胞癌(HCC)模型-能够模拟不同的HCC驱动突变谱
通过诱导KRASG 12 D和TP 53 R167 H表达以及随后的CRISPR编辑-用于临床前
评估局部交付的个性化HCC治疗。HCC是一种侵袭性肝脏恶性肿瘤,
全球第七大常见癌症和第四大常见癌症死亡原因,说明了
需要改进HCC治疗方案。由于HCC和其他癌症是由
遗传驱动突变赋予选择性生长优势,需要个性化的癌症模型,
评估针对这种致命疾病的靶向疗法。此外,使用基于经动脉递送的
肝细胞癌的治疗方法结合猪和人之间在大小和药物代谢方面的相似性
强调了基因定义的Oncopig HCC模型的关键需求和转化价值,
靶向特定驱动突变的新的和重新用途的治疗剂。重要的是,
在临床前试验中使用Oncopigs(见支持信)。该提案将证明以下方面的不同功效:
向Oncopig PTENKO(PI 3 K抑制剂应答)和KEAP 1 KO(PI 3 K抑制剂应答)的经动脉靶向PI 3 K抑制剂递送
抑制剂无反应)HCC肿瘤的临床相关试验设计。使用液体活检,
侵袭性HCC驱动突变定量(见志愿支持信)将促进HCC的翻译
精确医学进入临床实践,目前由于常规HCC活检不频繁而缺乏
收集生物特征。将验证基因定义的Oncopig HCC模型的靶向
通过追求以下特定目的进行治疗性测试:(1)表征遗传上定义的Oncopig HCC
在临床相关的3个月诊断监测期内观察肿瘤。(2)证明靶向PI 3 K的输送
通过经动脉栓塞治疗Oncopig HCC肿瘤。(3)证明有效性
经动脉靶向给予PI 3 K抑制剂治疗Oncopig PTENKO HCC的临床相关3个月随访
时间表经动脉给药后达到可定量的治疗性PI 3 K抑制剂浓度的能力
将证明在遗传定义的Oncopig HCC模型中的递送,除了临床相关的
缓解差异(与KEAP 1 KO HCC相比,PTENKO的完全缓解率增加40%),
临床使用的mRECIST指南。这项工作将验证基因定义的Oncopig HCC
用于靶向治疗评估的模型,使Sus Clinicals能够提供个性化的肿瘤
开发和有针对性的治疗测试服务使用Oncopig平台。今后的工作重点
在扩大Sus Clinicals的商业化方面,该技术将包括扩大个性化建模
用于其他癌症的方法,用于精确诊断评估的证明,个性化合并症
建模,并扩大营销工作,包括制药部门。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
LAWRENCE B SCHOOK其他文献
LAWRENCE B SCHOOK的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('LAWRENCE B SCHOOK', 18)}}的其他基金
Swine in Biomedical Research Conference 2011 Creating the Building Blocks: Genomi
2011 年猪生物医学研究会议创建构建模块:Genomi
- 批准号:
8118678 - 财政年份:2011
- 资助金额:
$ 96.43万 - 项目类别:
TOXIC EFFECTS OF BENZOPYRENE ON IMMUNOCOMPETENT CELLS
苯并芘对免疫活性细胞的毒性作用
- 批准号:
3252455 - 财政年份:1986
- 资助金额:
$ 96.43万 - 项目类别:
DIMETHYLNITOSAMINE EFFECTS ON CELLULAR IMMUNITY
二甲基硝胺对细胞免疫的影响
- 批准号:
3252463 - 财政年份:1986
- 资助金额:
$ 96.43万 - 项目类别:
DIMETHYLNITROSAMINE EFFECTS ON CELLULAR IMMUNITY
二甲基亚硝胺对细胞免疫的影响
- 批准号:
3252458 - 财政年份:1984
- 资助金额:
$ 96.43万 - 项目类别:
TOXIC EFFECTS OF BENZOPYRENE ON IMMUNOCOMPETENT CELLS
苯并芘对免疫活性细胞的毒性作用
- 批准号:
3250613 - 财政年份:1984
- 资助金额:
$ 96.43万 - 项目类别:
DIMETHYLNITROSAMINE EFFECTS ON CELLULAR IMMUNITY
二甲基亚硝胺对细胞免疫的影响
- 批准号:
3252462 - 财政年份:1984
- 资助金额:
$ 96.43万 - 项目类别:
DIMETHYLNITROSAMINE EFFECTS ON CELLULAR IMMUNITY
二甲基亚硝胺对细胞免疫的影响
- 批准号:
3252461 - 财政年份:1984
- 资助金额:
$ 96.43万 - 项目类别:
DIMETHYLNITROSAMINE EFFECTS ON CELLULAR IMMUNITY
二甲基亚硝胺对细胞免疫的影响
- 批准号:
3252457 - 财政年份:1984
- 资助金额:
$ 96.43万 - 项目类别:
DIMETHYLNITROSAMINE EFFECTS ON CELLULAR IMMUNITY
二甲基亚硝胺对细胞免疫的影响
- 批准号:
2153665 - 财政年份:1984
- 资助金额:
$ 96.43万 - 项目类别:
相似海外基金
The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
- 批准号:
EP/Z000920/1 - 财政年份:2025
- 资助金额:
$ 96.43万 - 项目类别:
Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
- 批准号:
FT230100276 - 财政年份:2024
- 资助金额:
$ 96.43万 - 项目类别:
ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
- 批准号:
MR/X024261/1 - 财政年份:2024
- 资助金额:
$ 96.43万 - 项目类别:
Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
- 批准号:
DE240100388 - 财政年份:2024
- 资助金额:
$ 96.43万 - 项目类别:
Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
- 批准号:
2889694 - 财政年份:2023
- 资助金额:
$ 96.43万 - 项目类别:
Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
- 批准号:
2842926 - 财政年份:2023
- 资助金额:
$ 96.43万 - 项目类别:
Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
- 批准号:
NC/X001644/1 - 财政年份:2023
- 资助金额:
$ 96.43万 - 项目类别:
Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
- 批准号:
2337595 - 财政年份:2023
- 资助金额:
$ 96.43万 - 项目类别:
Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
- 批准号:
2232190 - 财政年份:2023
- 资助金额:
$ 96.43万 - 项目类别:
Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
- 批准号:
23K17514 - 财政年份:2023
- 资助金额:
$ 96.43万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)