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

宫颈癌是全球妇女的第二大死因，85%的死亡发生在 低收入和中等收入国家(低收入和中等收入国家)，尽管已有完善的干预措施 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， 哪种疗法是世界卫生组织(WHO)目前推荐的治疗宫颈早衰的方法 LMIC中的癌症，需要持续供应加压液氮，这是昂贵的，而且很难 运输，而且不能充分治疗晚期病变。最近，热凝固器获得了 接受宫颈癌前病变的消融，因为它能够治疗低级别和高级别的宫颈病变。 癌症前病变级别。然而，热凝(虽然有效)的价位在1500美元到3000美元之间，这是 在社区层面无法访问。这些有据可查的缺点表明了一个明显的未得到满足的临床 需要开发新的治疗策略来预防LMICs中的宫颈癌。为了满足这一未得到满足的需求，我们的 集团最近开发了一种基于乙醇消融的新肿瘤消融技术。乙醇消融 以前是作为一种低成本的治疗包裹性的、无法手术的肝脏肿瘤而开发的，涉及 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，这是一种将乙醇与试剂相结合的新配方 乙基纤维素显著提高了疗效，并导致7个肿瘤中的7个完全消退。乙基 纤维素不仅使乙醇更粘稠(防止回流)，还能在水中形成凝胶。 Medium，它将乙醇隔离在感兴趣的区域。凝胶乙醇不需要难以供应 并且有可能成为超低成本和高度便携的。这项提议的目标是 优化注射程序和给药机制，治疗宫颈侵袭前病变 热凝的替代品。为了实现这一点，我们的目标是：1)建立一种优化凝胶乙醇的方法 2)在大型动物模型中评估优化分娩的安全性和有效性，以及3)进行 人宫颈最佳分娩程序的初步评估。K99阶段包括 目标1中凝胶乙醇注射程序的优化和目标2中提出的临床前研究， 这将为研究前新药(IND)会议和过渡到临床奠定基础 学习。R00阶段包括凝胶乙醇输送机制的优化和转化为 人体研究。对于该奖项的R00部分，建议进行一项独立的临床研究。这些目标将 导致一种优化的凝胶乙醇给药程序，其安全性和有效性在大型动物中得到验证 该模型在人体宫颈上进行了初步评估，为临床翻译奠定了基础。

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.