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：第二阶段 SBIR 提案的目标是进一步验证基因定义的 Oncopig 肝细胞癌 (HCC) 模型——能够对不同的 HCC 驱动突变谱进行建模通过诱导 KRASG12D 和 TP53R167H 表达以及随后的 CRISPR 编辑——用于临床前局部实施的个性化 HCC 治疗的评估 HCC 是一种侵袭性肝脏恶性肿瘤。全球第七大最常见癌症和第四大癌症死亡原因，说明了关键需要改进的 HCC 治疗方案，因为 HCC 和其他癌症是由积累引起的。基因驱动突变赋予选择性生长优势，需要个性化癌症模型此外，评估这种致命疾病的靶向治疗方法。结合猪和人类在体型和药物代谢方面的相似性来治疗 HCC 的方法强调了基因定义的 Oncopig HCC 模型用于研究的迫切需求和转化价值重要的是，人们对针对特定驱动突变的新颖和重新设计的疗法产生了广泛的兴趣。在临床前试验中使用 Oncopis（参见支持信）。经动脉靶向 PI3K 抑制剂递送至 Oncopig PTENKO（PI3K 抑制剂响应型）和 KEAP1KO（PI3K 使用临床相关试验设计对 HCC 肿瘤进行最低限度的液体活检。侵入性 HCC 驱动突变量化（参见 Volition 支持信）将促进 HCC 的转化精准医学进入临床实践，但由于常规 HCC 活检的频率较低，目前尚缺乏这种方法基因定义的 Oncopig HCC 模型将进行靶向验证。通过追求以下具体目标进行治疗测试：(1) 表征基因定义的 Oncopig HCC 临床相关的 3 个月诊断监测期内的肿瘤 (2) 证明靶向 PI3K 的递送。通过经动脉栓塞治疗 Oncopig HCC 肿瘤的抑制剂治疗剂量 (3) 证明疗效。在临床相关的 3 个月随访中，经动脉靶向 PI3K 抑制剂治疗 Oncopig PTENKO HCC 经动脉注射后达到可量化的治疗 PI3K 抑制剂浓度的能力。除了临床相关的研究之外，还将在基因定义的 Oncopig HCC 模型中证明交付基于反应差异（与 KEAP1KO HCC 相比，PTENKO 的完全反应率增加了 40%）这项工作将验证基因定义的 Oncopig HCC。靶向治疗评估模型，使 Sus 临床能够提供个性化肿瘤使用 Oncopig 平台进行开发和有针对性的治疗测试服务。关于扩大 Sus Clinicals 该技术的商业化将包括个性化建模的扩展其他癌症的方法、精确诊断评估的使用示范、个性化合并症建模，并扩大营销力度以将制药行业纳入其中。