Preventing Cervical Cancer in the First Mile of the Cancer Care Continuum

宫颈癌是全球女性死亡的第二大原因，85%的死亡发生在 低收入和中等收入国家（LMIC），尽管事实上， 侵袭性疾病预防宫颈癌的障碍之一是获得可靠的治疗。冷冻疗法， 这是目前世界卫生组织（WHO）推荐的治疗宫颈癌前病变的疗法， 癌症，需要持续供应加压液氮，这是昂贵的，很难 运输，并且不能充分治疗晚期病变。最近，热凝固器获得了 接受宫颈癌前病变消融术，因为它能够治疗低度和高度 癌症前期的分级。然而，热凝（虽然有效）的价格为1500美元至3,000美元， 在社区一级无法接触。这些有据可查的缺陷表明， 因此，需要制定新的治疗策略，以预防中低收入国家的宫颈癌。为了满足这一未满足的需求，我们的 该小组最近开发了一种基于乙醇消融的新型肿瘤消融技术。乙醇消融 是以前开发的一种低成本的治疗封装，不能手术的肝肿瘤， 将纯乙醇手动注射到恶性组织中。临床前研究表明，虽然手动注射 纯乙醇在治疗上皮病变方面无效， 乙基纤维素显著提高了疗效，并诱导7个肿瘤中的7个完全消退。乙酯 纤维素不仅使乙醇更粘稠（防止回流）， 介质，其隔离感兴趣区域中的乙醇。凝胶乙醇不需要难以供应 并且具有超低成本和高度便携的潜力。本提案的目的是 优化注射程序和输送机制，以治疗宫颈的预侵入性病变， 热凝的替代方法。为此，本文的主要工作是：1）建立了一种优化凝胶乙醇的方法 递送，2）在大型动物模型中评估优化递送的安全性和有效性，以及3）进行 在人类子宫颈中优化的分娩程序的初步评估。K99阶段包括 优化目标1中的凝胶乙醇注射程序和目标2中提出的临床前研究， 这将为研究前新药（IND）会议和临床过渡奠定基础。 问题研究R 00阶段包括凝胶乙醇递送机制的优化和转化， 人类研究一项独立的临床研究被提议用于该奖项的R 00部分。这些目标将 导致优化的凝胶乙醇输送程序，其安全性和有效性在大型动物中得到验证 该模型在人类宫颈中进行了初步评估，这将为临床翻译奠定基础。

Cervical cancer is the second leading cause of death for women worldwide with 85% of deaths occurring in low- and middle-income countries (LMICs), despite the fact that well-established interventions exist for pre- invasive disease. One of the barriers to cervical cancer prevention is reliable access to treatment. Cryotherapy, which is the current therapy recommended by the World Health Organization (WHO) for treating cervical pre- cancer in LMICs, requires a continuous supply of pressurized liquid nitrogen, which is expensive and difficult to transport, and does not adequately treat advanced lesions. More recently, the thermocoagulator has gained acceptance for ablation of cervical pre-cancer lesions because of its ability to treat both low-grade and high- grade pre-cancers. However, thermocoagulation (while effective) has a price point of $1500 to $3,000, which is inaccessible at the community level. These well-documented shortcomings demonstrate a clear unmet clinical need to develop new treatment strategies to prevent cervical cancer in LMICs. To meet this unmet need, our group has recently developed a novel tumor ablation technique based on ethanol ablation. Ethanol ablation was previously developed as a low-cost treatment for encapsulated, inoperable liver tumors, and involves manual injection of pure ethanol into malignant tissue. Preclinical studies showed that while manual injection of pure ethanol is ineffective in treating epithelial lesions, a novel formulation that combines ethanol with an agent ethyl cellulose substantially improved efficacy and induced complete regression of 7 out of 7 tumors. Ethyl cellulose not only makes ethanol more viscous (which prevents backflow) but also forms a gel in an aqueous medium, which sequesters ethanol in the region of interest. Gel ethanol does not require hard-to-supply consumables and has the potential to be ultra-low-cost and highly portable. The goal of this proposal is to optimize the injection procedure and delivery mechanism to treat pre-invasive lesions of the cervix as an alternative to thermocoagulation. To achieve this, the aims are to: 1) establish a method to optimize gel ethanol delivery, 2) assess the safety and efficacy of optimized delivery in a large animal model, and 3) conduct an initial assessment of an optimized delivery procedure in the human cervix. The K99 phase includes the optimization of the gel ethanol injection procedure in Aim 1 and the preclinical studies proposed in Aim 2, which will lay the groundwork for a pre-investigational new drug (IND) meeting and transitioning to clinical studies. The R00 phase includes the optimization of a gel ethanol delivery mechanism and translation to human studies. An independent clinical study is proposed for the R00 portion of the award. These aims will lead to an optimized gel ethanol delivery procedure whose safety and efficacy are validated in a large animal model with an initial assessment in human cervices, which will lay the groundwork for clinical translation.