Non-Invasive Imaging of Oral Cavity Cancer

项目摘要/摘要 与直觉相反的是，口腔和口咽癌在美国的发病率和社会影响正在增加 尽管烟草产品的使用量明显减少。这一趋势因以下事实而加剧：近两年- 三分之一的患者在确诊时有淋巴结或远处转移，这大大缩短了5年 存活率。尽管口腔癌的位置很浅，但绝大多数诊断较晚，通常 因为它们仍然是渐近的--早期的病变被错误地认为是良性的。现行标准 对于口腔癌的检测，仍然需要目视检查和基于活检的组织病理学相结合， 这不仅是劳动密集型的，而且需要训练有素的人员和尖端的基础设施- 对于世界上大多数人来说，难以逾越的经济障碍，以及我们没有得到满足的临床需求 选择要解决的问题。 我们最近报道了一种名为PARPI-FL的小分子药物，这是一种非常鼓舞人心的人类第一期临床试验数据 对PARP1具有较高的特异性。PARP1是一种定量的、高表达的活体成像生物标志物 我们发现PARPI-FL对口腔癌的诊断具有95%的敏感性和特异性。 将我们的药物提升到一个新的水平，并在第二阶段试验中验证其临床价值，我们已经与 纪念斯隆·凯特琳癌症中心(MSK)和组装三个特定目标(SA)。在SA1中，我们将 重新设计PARPI-FL的配方和制造，使其更容易为临床医生配制 为患者改善含漱液的口感。在SA2中，我们将优化工作流、阈值 和图像分析，基于我们的I期临床数据并由其提供信息。在SA3中，我们将测试术中 口腔PARPI-FL成像鉴别良恶性的敏感性和特异性 损伤。 如果成功，该项目将为多中心第三阶段临床试验提供坚实的基础，并最终 提高口腔癌的临床护理水平。

Project Summary/Abstract Counterintuitively, the incidence and societal impact of oral and oropharyngeal cancer are increasing in the US despite the markedly decreased use of tobacco products. This trend is exacerbated by the fact that almost two- thirds of patients have lymph node or distant metastases at the time of diagnosis, dramatically reducing 5-year survival rates. Oral cavity cancers are overwhelmingly diagnosed late despite their superficial location, often because they remain asymptotic – and early lesions are erroneously considered benign. The current standard of care for detecting oral cancer is still visual examination in combination with biopsy-based histopathology, which is not only labor-intensive but also requires highly trained personnel and a sophisticated infrastructure – impenetrable economic barriers for most of the world’s population, and precisely the unmet clinical need we have chosen to address. We recently reported very encouraging first-in-human Phase I clinical trial data with PARPi-FL, a small molecule with high specificity for PARP1. PARP1 is a quantitative and highly overexpressed biomarker for in vivo imaging of oral cancer, and we showed that PARPi-FL identifies tumors with sensitivities and specificities >95%. Taking our drug to the next level and validating its clinical value in a Phase II trial, we have partnered with Memorial Sloan Kettering Cancer Center (MSK) and assembled three Specific Aims (SAs). In SA1, we will redesign the formulation and manufacturing of PARPi-FL, making it easier to formulate for the clinicians as well as improving the taste of the gargling solution for the patient. In SA2, we will optimize workflows, thresholding and image analysis, based on and informed by our Phase I clinical data. In SA3, we will test intraoperative PARPi-FL imaging of the oral cavity to determine sensitivity and specificity in discriminating benign and malignant lesions. If successfully, this project will provide a solid foundation for a multicenter Phase III clinical trial and ultimately raise the clinical standard of care for oral cavity cancer.