SBIR Phase I: A bacterial intracellular delivery platform for liver cancer

这个SBIR I期项目开发了一个用于实体肿瘤细胞内药物递送的细菌平台，主要关注肝癌。每年有30,000名男性和女性被诊断为不可切除的肝细胞癌（HCC），其5年生存率为17.6%。这些病人的预后很差。目前，对这些患者没有治愈的治疗方法。目前的治疗标准只增加了总生存期几个月，而且有毒副作用，每年给美国医疗保健系统造成15亿美元的损失。这项技术是基于细菌的固有特征，与健康组织相比，细菌在整个身体内以10万比1的比例定植实体肿瘤。由于这种特异性，开发的细菌平台有可能在肿瘤中特异性地增加剂量，同时减少健康组织中的毒副作用。这个平台将成为一个工具箱，可以针对目前被认为是不可药物的细胞内途径，并将有效剂量的生物制剂直接输送到肿瘤细胞中。细菌对实体肿瘤的亲和力，独立于器官定位，使这种递送方法扩展到其他难以治疗的肿瘤类型，如胰腺、卵巢癌和胃癌。系统性癌症治疗有许多障碍，如血液中的稳定性、穿过细胞膜、内化和内体释放。这些过程阻碍了RNAi和肽在人体内的使用，并阻碍了单克隆抗体靶向细胞内通路。细菌给药平台的开发可以优化药物在肿瘤中的效力，减少健康组织中的副作用。在这项SBIR I期研究中，该平台的疗效将通过靶向对细胞存活至关重要的细胞内通路来测量，目前尚无系统性治疗方法。将根据FDA的指导方针创建一种菌株，该菌株可以可靠地制造而不会失去活性。将制定最佳保存方案，以确保给药后最大的细菌适应性和最大的递送效率。这种细菌传递系统有可能加速将基础癌症研究转化为临床治疗。这些发现可以直接转化为调节哺乳动物基因表达和功能的蛋白质、抗体或shRNA疗法。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This SBIR Phase I project develops a bacterial platform for intracellular drug delivery to solid tumors, with a primary focus on liver cancer. Every year, 30,000 men and women are diagnosed with unresectable hepatocellular carcinoma (HCC), which has a 5-year survival rate of 17.6 %. The prognosis for these patients is poor. Currently, there are no curative treatments for these patients. The current standard-of-care only increases overall survival by months and has toxic side effects, with a cost to the US healthcare system of $1.5B per year. This technology is based on the inherent feature of bacteria to colonize solid tumors throughout the body in ratios of 100,000 to 1 compared to healthy tissue. Due to this specificity, the developed bacterial platform has the potential to increase dosage specifically in tumors, while reducing toxic side effects in healthy tissues. This platform will be a toolbox that can target intracellular pathways that are currently considered undruggable and deliver potent doses of biologicals directly into tumor cells. The affinity of bacteria for solid tumors, independent of organ localization, enables the extension of this delivery method to other hard-to-treat tumor types, such as pancreas, ovarian and gastric cancer. Systemic cancer therapies have many obstacles, such as stability in the blood, traversing the cellular membrane, internalization and endosomal release. These processes impede the use of RNAi and peptides in humans and hamper the targeting of intracellular pathways with monoclonal antibodies. The development of a bacterial drug delivery platform can optimize drug potency in tumors and reduce side effects in healthy tissue. In this SBIR phase I, efficacy of this platform will be measured in HCC by targeting intracellular pathways essential for cell survival, for which no systemic therapy exists. A bacterial strain will be created according to FDA guidelines that can be manufactured reliably without loss of activity. An optimized preservation protocol will be developed to ensure maximal bacterial fitness and maximal delivery efficacy after administration. This bacterial delivery system has the potential to accelerate the translation of fundamental cancer research into clinical therapies. Discoveries could be genetically translated directly into protein, antibody or shRNA therapies that regulate mammalian gene expression and function.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.