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: 10197327
• 负责人: Huang Chiao Huang
• 金额: $ 67.32万
• 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/10197327
• 关键词: ABCB1 gene; ABCG2 gene; ATP-Binding Cassette Transporters; Address; Animals; Antibiotics; Antibodies; Binding; Biodistribution; Biometry; Cancer Biology; Cancer Model; Cancer Patient; Cell Proliferation; Chemoresistance; Chemosensitization; Clinical; Clinical Trials; Complex; Custom; DNA; DNA Repair; DNA Repair Enzymes; Development; Diffuse; Drug Delivery Systems; Drug Efflux; Drug Kinetics; Drug resistance; Engineering; Epidermal Growth Factor Receptor; Extravasation; Fluorescence; Formulation; Goals; Human; Image; Knowledge; Light; Liposomes; Malignant Neoplasms; 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; Prognosis; 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; antineoplastic antibiotics; base; blind; cancer cell; cell killing; chemosensitizing agent; 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/antagonist; intraperitoneal; irinotecan; light dosimetry; microendoscope; mortality; mouse model; multidisciplinary; nanoscale; nanotechnology platform; novel; ovarian neoplasm; pancreatic cancer cells; pancreatic cancer model; pancreatic neoplasm; patient derived xenograft model; predictive marker; repair enzyme; response; spatiotemporal; 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仍然令人沮丧 几十年。反应率较差，部分原因是从抗性到打捞化疗，包括 拓扑异构酶I（TOP1）抑制剂，例如虹膜和拓扑替康。 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）积极从癌细胞中泵出药物，以及（2）上调DNA修复酶，酪酶 DNA磷酸二酯酶1，它可以分辨拓扑异构酶I-DNA可裂解复合物以允许DNA 宗教和细胞增殖。越来越清楚的是，没有一种治疗可能无法克服 这个复杂的问题以及新出现的方式的组合治疗可能会带来最大的希望。 在这里，我们介绍了一种补充，两方的方法来解决化学抗性：（i）采用 光动力启动（PDP）损坏ABC转运蛋白，改善TOP1抑制剂的递送并减少 正常的组织毒性，（ii）重新利用四环素抗生素抑制DNA损伤修复 酶基-DNA磷酸二酯酶1。PDP是一种基于光化学的临床相关的，基于光化学的模态 涉及光敏剂的光激活以调节附近的组织或生物分子而无需杀死细胞。 该建议利用图像引导的策略和纳米级工程来开发目标照片 - 可激活的多抑制剂脂质体（TPMIL），可在 通过考虑其机械相互作用的适当序列。除了共包装Top1 抑制剂和抗生素，TPMIL表面用抗体 - 光增敏剂结合物进行了修饰 表皮生长因子受体，经常在胰腺和卵巢癌中扩增。使用小说 高光谱荧光显微镜成像系统，我们将纵向监视光敏剂 ABC转运蛋白表达的递送和变化以改善体内PDP和化学敏化（AIM 1）。 TOP1抑制剂与四环素抗生素之间的机械相互作用将在体内研究， 有和没有PDP（AIM 2）。还将确定化学敏化的生物标志物。 tpmils会 定制以靶向卵巢和胰腺癌细胞，同时共同传递光敏剂，top1 抑制剂和四环素抗生素（AIM 3）。将确定TPMIL的安全性和治疗功效 在PDX鼠标模型中（AIM 4）。我们已经证明了PDP在局部患者中的临床可行性 晚期胰腺癌。对于转移性卵巢癌，我们设想一种简单且可行的修改 标准临床框架。 TPMILS将在手术延伸后进行腹膜内交付 肿瘤，然后激活以触发PDP以及化学疗法和抗生素的释放。这 获得的知识可能在改善治疗方案的发展中起变革性的作用 针对个别患者的晚期胰腺癌和卵巢癌的分子型量身定制。