Topic 386: Engineering probiotics to deliver chemopreventative agents to the human gut

结直肠癌（CRC）是美国第二大常见的癌症死亡原因， 美国人每年死于CRC。已成为预防目标的高危人群， 包括患有遗传性CRC综合征如家族性腺瘤性息肉病（FAP）和Lynch综合征患者 综合征化学预防的挑战是如何提供精确的递送，从而避免 不可接受的毒性，在其他健康人群中。为了解决这个问题，我们建议提供 通过广泛消费的益生菌菌株的化学预防剂。我们提出了一种机制， 递送，由此益生菌通过工程化裂解释放化学预防剂， 我们先前建立的用于体内递送治疗剂的裂解范例，其中局部释放 增加了方法的安全性。然后，我们预计，引入预先筛选，体外验证， 将工程化的细菌预防剂引入化学预防导向的CRC小鼠模型将导致 在免疫活性小鼠和人肿瘤小鼠中减少局部肿瘤生长并延长小鼠存活 模型，在结肠内。鉴于美国标准的50岁及以上筛查人群可以 腺瘤发生率高达50%，有很大的机会提供化学预防，以减少 甚至在一般社区中也存在CRC的未来风险。

Colorectal cancer (CRC) is the second most common cause of cancer death in the US, with more than 50,000 Americans dying every year from CRC. High-risk populations that have been targeted for prevention, which include patients with inherited CRC syndromes such as familial adenomatous polyposis (FAP) and Lynch syndrome. The challenge for chemoprevention, is how to provide precision delivery and thus avoid unacceptable toxicity, in an otherwise healthy population. To address this, we propose the delivery of chemopreventative agents via a widely consumed probiotic strain of bacteria. We propose a mechanism of delivery whereby the probiotic bacteria release the chemopreventative agents via engineered lysis, by utilizing our previously established lysis paradigm for the delivery of therapeutics in vivo, where localized release increases the safety of the approach. We then anticipate that introducing pre-screened, in vitro validated engineered bacterial preventatives into a chemoprevention-directed mouse model of CRC will result in reduced local tumor growth and prolonged mouse survival in immunocompetent and human tumor mouse models, within the colon. Given that the standard 50 years and older screening population in the US can have an adenoma rate of up to 50%, there is a large opportunity to provide chemoprevention to reduce the future risk of CRC even within the general community.