Online monitoring and image-guided treatment of chemoresistant micrometastases

描述(申请人提供)：尽管细胞减灭术和化疗取得了进展，但转移性卵巢上皮癌和胰腺导管腺癌的存活率仍然很低，部分原因是化疗耐药的微转移无法用传统的成像方法检测出来。这两种疾病都与腹膜癌有关，即腹膜腔及其常驻器官广泛的肿瘤聚集。为了解决这些“看不见的”肿瘤，我们引入了一系列针对癌细胞的、可激活的成像和治疗剂，与细胞分辨率、多分子荧光显微内窥镜相结合。我们开发了针对癌细胞过度表达的细胞膜分子，包括表皮生长因子受体，作为成像探针的近红外光细胞毒性免疫结合物(PIC)，并将光动力学和抗分子治疗剂结合起来用于肿瘤靶向、可激活的光免疫治疗(TAPIT)。当癌细胞结合、内化和加工时，光动力和荧光成分变得去猝灭(激活)。这一策略克服了偏离目标的光毒性--包括肠道光毒性--这是在盆腔等复杂部位进行光激活治疗的主要临床障碍。这项建议建立在我们之前的工作基础上，该工作表明，在体内，PIC结合卵巢微转移的敏感性和特异性分别为93%和93%，能够准确识别小至30�m的肿瘤并选择性地摧毁微转移。我们建议进一步开发这一平台，以具体解决化疗耐药微转移，这是癌症治疗中的一个关键利基。目前的临床成像技术不能解决手术和化疗留下的微小肿瘤沉积，对于复发的、耐药的肿瘤患者的治疗选择有限。我们预计，这种显微内窥镜引导下的Tapit新范例将补充目前对晚期疾病患者和接受抢救治疗的患者的治疗方式。

DESCRIPTION (provided by applicant): Despite advances in cytoreductive surgery and chemotherapy, survival of metastatic epithelial ovarian cancer and pancreatic ductal adenocarcinoma remain dismal due in part to chemoresistant micrometastases undetectable by traditional imaging modalities. Both of these diseases involve peritoneal carcinomatosis, that is, extensive tumor studding of the peritoneal cavity and its resident organs. To address these "invisible" tumors, we introduce a series of cancer cell-targeted, activatable imaging and therapeutic agents integrated with cellular-resolution, multi-molecular fluorescence microendoscopy. We developed near-infrared photocytotoxic immunoconjugates (PICs) that target cell membrane molecules overexpressed by cancer cells, including the epidermal growth factor receptor, to serve as an imaging probe and combined photodynamic and anti-molecular therapeutic agent for tumor-targeted, activatable photoimmunotherapy (taPIT). The photodynamic and fluorescence components become de-quenched (activated) upon cancer cell binding, internalization and processing. This strategy overcomes off-target phototoxicity-including bowel phototoxicity-the major clinical obstacle for photoactivated treatments in complex sites such as the pelvic cavity. This proposal builds on our prior work that shows the PIC binds ovarian micrometastases with 93% sensitivity and 93% specificity in vivo, enabling accurate recognition of tumors as small as 30 �m and selective destruction of micrometastases. We propose to further develop this platform to specifically address chemoresistant micrometastases, which represent a critical niche in cancer therapy. Current clinical imaging technologies cannot resolve microscopic tumor deposits left behind by surgery and chemotherapy, and there are limited treatment options for patients with recurrent, chemoresistant tumors. We anticipate that this new paradigm for microendoscopy-guided taPIT will complement current treatment modalities for patients with advanced-stage disease and those receiving salvage therapies.