Addressing Chemoresistance in Pancreatic and Ovarian Cancers: Photodynamic Priming and Repurposing of Tetracyclines using Targeted Photo-Activable Multi-Inhibitor Liposome

解决胰腺癌和卵巢癌的化疗耐药性：使用靶向光激活多抑制剂脂质体进行四环素的光动力启动和再利用

• 批准号: 10594035
• 负责人: Huang Chiao Huang
• 金额: $ 64.84万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594035
• 关键词: ABCB1 gene; ABCG2 gene; ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Address; Animals; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Therapy; Binding; Biodistribution; Biometry; Cancer Biology; Cancer Model; Cancer Patient; Cell Proliferation; Chemoresistance; Chemosensitization; Clinical; Clinical Trials; Combined Modality Therapy; Complex; DNA; DNA Repair; DNA Repair Enzymes; Development; Diffusion; Drug Delivery Systems; Drug Efflux; Drug Kinetics; Drug resistance; Engineering; Epidermal Growth Factor Receptor; Extravasation; Fluorescence; Goals; Human; Image; Knowledge; Ligation; Light; Liposomes; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Medical Oncology; Minocycline; Modality; Modification; Molecular Profiling; Monitor; Nanotechnology; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Photochemistry; Photosensitizing Agents; Play; Pump; Regimen; Regulation; Resistance; Role; Safety; Surface; Surgical Oncology; Technology; Tetracyclines; Therapeutic; Tissues; Topoisomerase-I Inhibitor; Topotecan; Toxic effect; Treatment Efficacy; Treatment outcome; Tumor Debulking; Type I DNA Topoisomerases; Unresectable; Up-Regulation; advanced pancreatic cancer; blind; cancer cell; cancer therapy; cell killing; chemotherapy; clinically relevant; cytotoxic; density; dosimetry; driving force; drug repurposing; fluorescence imaging; image guided; imaging capabilities; imaging system; improved; improved outcome; in vivo; individual patient; inhibitor; intraperitoneal; irinotecan; light dosimetry; liposomal formulation; microendoscope; mortality; mouse model; multidisciplinary; nanoscale; nanotechnology platform; novel; ovarian neoplasm; pancreatic cancer cells; pancreatic cancer model; pancreatic neoplasm; patient derived xenograft model; patient prognosis; predictive marker; repair enzyme; response; safety assessment; spatiotemporal; synergism; targeted treatment; tumor; tumor microenvironment; tyrosyl-DNA phosphodiesterase

ABSTRACT The prognosis for patients with advanced stage ovarian or pancreatic cancer has remained dismal for decades. The poor response rates result, in part, from resistance to salvage chemotherapies, including topoisomerase I (Top1) inhibitors such as irinotecan and topotecan. The full potential of Top1 inhibitors is hindered mainly by two mechanisms: (1) ATP-binding cassettes (ABC) transporters (i.e., P-glycoprotein and ABCG2) that actively pump drugs out of cancer cells, and (2) Upregulation of the DNA repair enzyme, tyrosyl- DNA phosphodiesterase 1, which resolves the topoisomerase I-DNA cleavable complexes to allow DNA religation and cell proliferation. It is becoming increasingly clear that no single treatment is likely to overcome this complex problem, and combination treatments of newly emerging modalities may offer the most promise. Here, we introduce a complementary, two-pronged approach to address chemoresistance: (i) Employing photodynamic priming (PDP) to damage ABC transporters, improve the delivery of Top1 inhibitors, and reduce the normal tissue toxicity, and (ii) Repurposing tetracycline antibiotics to inhibit the DNA damage repair enzyme tyrosyl-DNA phosphodiesterase 1. PDP is a clinically relevant, photochemistry-based modality that involves light activation of photosensitizers to modulate nearby tissues or biomolecules without killing the cells. This proposal leverages image-guided strategies and nanoscale engineering to develop Targeted Photo- Activable Multi-Inhibitor Liposome (TPMIL) that co-delivers PDP, Top1 inhibitors, and tetracycline antibiotics in the appropriate sequence with consideration of their mechanistic interactions. In addition to co-packaging Top1 inhibitors and antibiotics, TPMIL is surface modified with antibody-photosensitizer conjugates to target epidermal growth factor receptor, which is frequently amplified in pancreatic and ovarian cancer. Using a novel hyperspectral fluorescence microendoscope imaging system, we will longitudinally monitor photosensitizer delivery and changes in ABC transporter expression to improve PDP and chemosensitization in vivo (Aim 1). The mechanistic interactions between Top1 inhibitors and tetracycline antibiotics will be investigated in vivo, with and without PDP (Aim 2). Biomarkers predictive of chemosensitization will also be identified. TPMILs will be customized to target ovarian and pancreatic cancer cells while co-delivering photosensitizers, Top1 inhibitors, and tetracycline antibiotics (Aim 3). The safety and therapeutic efficacy of TPMIL will be determined in PDX mouse models (Aim 4). We have demonstrated the clinical feasibility of PDP in patients with locally advanced pancreatic cancer. For metastatic ovarian cancer, we envision a simple and feasible modification to the standard clinical framework. TPMILs will be delivered intraperitoneally after surgical debulking of ovarian tumors, and then light activated to trigger PDP and the release of chemotherapy and antibiotics. The knowledge gained may play a transformative role in the development of improved therapeutic regimens that are tailored to the molecular profile of advanced pancreatic and ovarian cancer in individual patients.

抽象的 晚期卵巢癌或胰腺癌患者的预后一直很差 几十年。反应率低的部分原因是对挽救性化疗的耐药性，包括 拓扑异构酶 I (Top1) 抑制剂，例如伊立替康和拓扑替康。 Top1 抑制剂的全部潜力是 主要受到两种机制的阻碍：(1) ATP 结合盒 (ABC) 转运蛋白（即 P-糖蛋白和 ABCG2) 主动将药物从癌细胞中泵出，以及 (2) DNA 修复酶酪氨酰-的上调 DNA 磷酸二酯酶 1，可分解拓扑异构酶 I-DNA 可切割复合物，使 DNA 再连接和细胞增殖。越来越清楚的是，没有任何一种单一的治疗方法能够克服 对于这个复杂的问题，新兴疗法的联合治疗可能会带来最大的希望。 在这里，我们介绍一种互补的、双管齐下的方法来解决化疗耐药性：(i) 光动力引发 (PDP) 可破坏 ABC 转运蛋白，改善 Top1 抑制剂的递送，并减少 正常组织毒性，以及 (ii) 重新利用四环素抗生素来抑制 DNA 损伤修复 酪氨酰-DNA 磷酸二酯酶 1. PDP 是一种临床相关的、基于光化学的模式， 涉及光敏剂的光激活来调节附近的组织或生物分子而不杀死细胞。 该提案利用图像引导策略和纳米级工程来开发靶向光 可激活的多重抑制剂脂质体 (TPMIL)，可在体内共同递送 PDP、Top1 抑制剂和四环素抗生素 考虑到它们的机械相互作用的适当顺序。除了联合包装Top1 抑制剂和抗生素，TPMIL 通过抗体-光敏剂缀合物进行表面修饰以靶向 表皮生长因子受体，在胰腺癌和卵巢癌中经常被扩增。使用小说 高光谱荧光显微内窥镜成像系统，我们将纵向监测光敏剂 传递和改变 ABC 转运蛋白表达以改善体内 PDP 和化疗增敏（目标 1）。 将在体内研究 Top1 抑制剂和四环素抗生素之间的相互作用机制， 有和没有 PDP（目标 2）。还将鉴定预测化学敏化的生物标志物。 TPMIL 将 定制以靶向卵巢癌细胞和胰腺癌细胞，同时共同提供光敏剂，Top1 抑制剂和四环素抗生素（目标 3）。 TPMIL 的安全性和治疗效果将被确定 在 PDX 小鼠模型中（目标 4）。我们已经证明了 PDP 在局部病变患者中的临床可行性 晚期胰腺癌。对于转移性卵巢癌，我们设想一种简单可行的修改 标准临床框架。 TPMIL 将在卵巢减灭手术后腹腔内递送 肿瘤，然后光激活以触发 PDP 并释放化疗药物和抗生素。这 获得的知识可能在改进治疗方案的开发中发挥变革性作用， 针对个体患者晚期胰腺癌和卵巢癌的分子特征进行定制。