Validation of the Genetically Malleable Oncopig Hepatocellular carcinoma (HCC) Model for Targeted Therapeutic Development

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。

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.