Project 2: Optimization of HPPH for HNSCC Selectivity

本PPG的总体目标是为头颈部鳞状细胞癌开发一种新的治疗选择 癌症（HNSCC），其导致与当前治疗方式一样有效的治疗反应， 但能保护器官功能在上一个资助期间，我们证明了HNSCC的HPPH-PDT 在82%的患者中获得了完全缓解。在伴随本试验的辅助研究中，我们使用了 非侵入性荧光光谱法来测量病变内的HPPH水平。虽然是初步的， 研究表明，无反应的病变保持低HPPH水平。同时进行了研究 在这个项目中使用创新的三维共培养系统， 来自同一患者的原发性上皮肺肿瘤细胞和肿瘤相关基质细胞。的结果 研究表明，一些肿瘤细胞不能保留HPPH，并且对PDT杀伤具有抗性。随后的研究 表明HPPH与细胞表面的结合，细胞摄取模式，细胞内定位，亚细胞 再分配、胞吐和保留的能力严重依赖于HPPH大环的结构。 该项目的长期目标是开发HNSCC特异性光敏剂， 在肿瘤细胞中，并导致临床PDT的功效增加。为了实现这一目标，以下假设 将测试：1）光敏剂（PS）保留特性是肿瘤依赖性的，并反映在 对HPPH-PDT的反应; 2）可以鉴定负责PS保留的肿瘤细胞特性3） 可以鉴定HPPH的结构修饰，其将增强PS在肿瘤细胞中的保留; 细胞表面地址的PS，如整合素或表皮生长因子受体（EGFR），将进一步 增强非肿瘤和肿瘤上皮细胞之间的治疗PS差异。测试这些 假设我们将利用本资助期内开发的新颖独特的工具： a）大环修饰的HPPH类似物的化合物“文库”，和B）用于原代培养的3D培养系统， 人HNSCC显示了个体肿瘤的不同保留特征。研究 在这个项目中提出的是令人信服的，因为他们有潜力提高我们对PS的理解 保留并最终导致HNSCC特异性PS的产生，其导致增加的功效， PDT对这种疾病的选择性。这些研究对PPG至关重要，因为它们为我们的研究奠定了基础。 在早期HNSCC治疗中达到100%疗效的长期目标。

The Overall Goal of this PPG is to develop a novel treatment option for head and neck squamous cell carcinoma (HNSCC) that results in treatment responses that are as effective as current treatment modalities, but that preserve organ function. During the last funding period we demonstrated that HPPH-PDT of HNSCC resulted in complete responses in 82% of patients. In the ancillary studies that accompanied this trial we used noninvasive fluorescence spectroscopy to measure HPPH levels within the lesion. Although preliminary, these studies suggested that non-responding lesions retained low HPPH levels. Simultaneous studies were carried out in this Project using an innovative 3-demensional co-culture system that incorporates patient-derived primary epithelial lung tumor cells and tumor-associated stromal cells from the same patient. The results of this study showed that some tumor cells fail to retain HPPH and were resistant to PDT killing. Subsequent studies showed that HPPH binding to the cell surface, mode of cellular uptake, intracellular localization, subcellular redistribution, exocytosis, and retention was critically dependent upon the structure of the HPPH macrocycle. The long-range goal of this Project is to develop HNSCC-specific photosensitizers that are selectively retained in tumor cells and result in increased efficacy of clinical PDT. To accomplish this goal the following hypotheses will be tested: 1) Photosensitizer (PS) retention characteristics are tumor-dependent and are reflected in the response to HPPH-PDT; 2) Tumor cell properties can be identified that are responsible for PS retention 3) Structural modifications of HPPH can be identified that will enhance PS retention in tumor cells; 3) Targeting of PS to cell surface addresses, such as integrins or epidermal growth factor receptor (EGFR), will further enhance the therapeutic PS differential between non-tumor and tumor epithelial cells. To test these hypotheses we will take advantage of the novel and unique tools developed in the current funding period: a) a compound “library” of macrocycle-modified HPPH analogs and b) a 3D culture system for primary human HNSCC that has revealed different retention characteristics for individual tumors. The studies proposed in this project are compelling in that they have the potential to enhance our understanding of PS retention and ultimately lead to the generation of HNSCC-specific PS that result in increased efficacy and selectivity of PDT against this disease. The studies are critical to the PPG as they lay the foundation for our long term goal of achieving 100% efficacy in the treatment of early stage HNSCC.