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

在癌症护理连续体的第一英里预防宫颈癌

• 批准号: 10255525
• 负责人: Jenna Lynne Hook Mueller
• 金额: $ 24.9万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255525
• 关键词: Ablation; Acute; Advanced Development; Adverse event; Aftercare; Animal Model; Area; Award; Caliber; Cause of Death; Cellulose; Cervical; Cervix Uteri; Cessation of life; Clinical; Clinical Research; Cold Therapy; Communities; Continuity of Patient Care; Devices; Disease; Distress; Electrocoagulation; Encapsulated; Epithelial; Ethanol; Exocervix; Family suidae; Formulation; Gel; Goals; Health Services Accessibility; Histopathology; Hour; Human; Hysterectomy; Injections; Intervention; Investigational Drugs; Lesion; Liquid substance; Liver neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Manuals; Methods; Monitor; Necrosis; Nitrogen; Outcome; Patients; Phase; Price; Procedures; Process; Public Health; Research; Resources; Safety; Site; Specimen; Speculums; Techniques; Testing; Time; Tissues; Total Hysterectomy; Toxic effect; Translations; Treatment Cost; Woman; Work; World Health Organization; aqueous; base; cancer care; cervical cancer prevention; clinical translation; cost; design; efficacy validation; improved; in vivo; interest; low and middle-income countries; mechanical properties; meetings; mortality; novel; porcine model; portability; pre-clinical; preclinical study; pressure; prevent; translation to humans; treatment arm; treatment strategy; tumor; tumor ablation

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.

宫颈癌是全球女性第二大死亡原因，其中 85% 的死亡发生在 低收入和中等收入国家（LMIC），尽管事实上存在完善的干预措施 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， 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。 中低收入国家的癌症需要持续供应加压液氮，这是昂贵且难以实现的 运输，并且不能充分治疗晚期病变。最近，热凝器已获得 宫颈癌前病变消融术因其能够治疗低级别和高级别病变而被接受 癌前期。然而，热凝术（虽然有效）的价格为 1500 至 3,000 美元，即 在社区层面无法访问。这些有据可查的缺点表明临床上明显未得到满足 需要制定新的治疗策略来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 研究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 之前被开发为一种低成本的治疗方法，用于治疗封装的、无法手术的肝脏肿瘤，并涉及 手动将纯乙醇注射到恶性组织中。临床前研究表明，虽然手动注射 纯乙醇对治疗上皮病变无效，一种将乙醇与药剂结合的新型配方 乙基纤维素显着提高了疗效，并诱导 7 个肿瘤中的 7 个完全消退。乙基 纤维素不仅使乙醇更加粘稠（防止回流），而且在水溶液中形成凝胶 介质，将乙醇隔离在感兴趣的区域。凝胶乙醇不需要难以供应 消耗品，并且具有超低成本和高度便携的潜力。该提案的目标是 优化注射程序和输送机制，以治疗宫颈浸润前病变 热凝的替代方案。为了实现这一目标，目标是：1）建立优化凝胶乙醇的方法 交付，2) 评估大型动物模型中优化交付的安全性和有效性，以及 3) 进行 对人类子宫颈优化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， 这将为新药研究前 (IND) 会议和过渡到临床奠定基础 研究。 R00 阶段包括凝胶乙醇输送机制的优化和转化 人类研究。建议针对该奖项的 R00 部分进行一项独立的临床研究。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 模型对人类宫颈进行初步评估，这将为临床转化奠定基础。