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：
LAWRENCE B SCHOOK
金额：
$ 96.43万
依托单位：
SUS CLINICALS, INC.
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：
https://reporter.nih.gov/project-details/10760736
关键词：
Aftercare Animals Area Under Curve Arterial Embolization Autologous Biological Biological Markers Biopsy Blood Blood specimen C-reactive protein Cancer Etiology Cancer Model Canis familiaris Cells Cessation of life Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collection Combined Modality Therapy Detection Development Devices Diagnostic Disease Dose Evaluation Family suidae Frequencies Future Genetic Genetic Transcription Genotype Goals Growth Guidelines Histologic Histology Hour Human Image In complete remission Injections KRASG12D Kinetics Left Letters Liver Lobe Malignant Neoplasms Malignant neoplasm of liver Marketing Mass Spectrum Analysis Modeling Monitor Mutation Nucleosomes Oncopig PIK3CG gene Pharmacologic Substance Phase Plasma Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells SCID Mice Site Small Business Innovation Research Grant System Technology Testing Therapeutic Translations Treatment Efficacy Tumor Biology Validation Volition Work X-Ray Computed Tomography cancer therapy cancer type cell free DNA clinical practice clinically relevant clinically significant commercialization comorbidity driver mutation drug metabolism follow-up hepatocellular carcinoma cell line improved in vivo inhibitor inhibitor therapy interest intrahepatic liquid biopsy liver cancer model meetings minimally invasive novel personalized diagnostics personalized therapeutic pre-clinical precision medicine preclinical evaluation preclinical trial response targeted delivery targeted treatment testing services therapeutic development therapeutic evaluation therapeutic target transcriptome sequencing treatment response treatment strategy trial design tumor tumor growth tumor progression tumorigenic

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：此II阶段SBIR提案的目标是进一步验证一般定义的 Oncopig肝细胞癌（HCC）模型 - 适合建模潜水员HCC驱动器突变轮廓通过诱导的KRASG12D和TP53R167H的表达和随后的CRIS PRSTIT-用于临床前评估本地交付的个性化HCC疗法。 HCC是代表侵略性的肝恶性肿瘤全球第七大癌症和癌症死亡的第四最常见原因，说明了关键需要改善HCC治疗选择。由于HCC和其他癌症是由遗传驾驶员突变会议会议选择性增长优势，个性化的癌症模型必须评估了该致命疾病的目标疗法。此外，使用基于跨递送的使用 HCC治疗的方法结合了猪与人之间的大小和药物代谢的相似之处突出显示了一般定义的Oncopig HCC模型的关键需求和翻译价值针对特定驱动器突变的新颖和重新塑造的治疗。重要的是，对在临床前试验中使用Oncopigs（请参阅支持信）。该建议将证明经靶向靶向PI3K抑制剂递送至Oncopig Ptenko（PI3K抑制剂响应）和KEAP1KO（PI3K 使用临床相关试验设计的抑制剂无反应性）HCC肿瘤。使用液体活检最少侵入性HCC驱动器突变量化（请参见Volition支持信）将有助于hcc的翻译精密医学方法进入临床实践，目前由于常规HCC活检而缺乏频率用于生物分析的收集。一般定义的Oncopig HCC模型将被验证通过追求以下特定目的来进行治疗测试：（1）表征遗传定义的Oncopig HCC 在临床上相关的3个月诊断监测期内的肿瘤。（2）证明靶向PI3K的递送抑制剂治疗剂量通过透射栓塞对Oncopig HCC肿瘤。（3）证明效率在临床相关的3个月随访中，用于跨靶向PI3K抑制剂递送用于Oncopig Ptenko HCC 大体时间。跨性别后实现可量化的治疗性PI3K抑制剂浓度的能力除临床相关外，还将证明以一般定义的Oncopig HCC模型的交付反应差异（与KEAP1KO HCC相比，Ptenko的完全响应率增加了40％）关于临床雇用的MRECIST指南。这项工作将验证一般定义的Oncopig HCC 有针对性的治疗评估模型，使SUS临床能够提供个性化肿瘤使用Oncopig平台开发和有针对性的治疗测试服务。未来的工作集中在扩展SUS临床商业化方面，该技术将包括扩展个性化建模其他癌症的方法，证明用于精确诊断评估的用途，个性化合并症建模并扩大营销工作以包括制药部门。