Molecular Response and Imaging-based Combination Strategies for Optimal PDT

分子响应和基于成像的最佳 PDT 组合策略

• 批准号: 9033077
• 负责人: Tayyaba Hasan
• 金额: $ 141.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-09 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033077
• 关键词: Achievement; Address; Advanced Malignant Neoplasm; Adverse effects; Basal cell carcinoma; Bone Marrow; Cancer Biology; Cancer Model; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; Cutaneous Melanoma; Cystic Neoplasm; Development; Differentiation Inducer; Disease; Disseminated Malignant Neoplasm; Drug Industry; Education; Enhancers; Enzymes; Evaluation; Event; Exposure to; Fluorouracil; Formulation; Funding; Genetically Engineered Mouse; Goals; Health Benefit; Health Care Costs; Human; Image; Imaging technology; In Vitro; Incidence; Industry; Light; Local Therapy; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Methotrexate; Modality; Modeling; Molecular; Molecular Target; Monitor; Morbidity - disease rate; Mus; Nanotechnology; Neoplasm Metastasis; Oncogenic; Outcome; PUVA Photochemotherapy; Pancreas; Pathology; Pathway interactions; Patients; Peer Review; Phase; Photochemistry; Pre-Clinical Model; Prevention; Procedures; Program Research Project Grants; Public Health; Publications; Quality of Care; Quality of life; Radiation therapy; Radioprotection; Reagent; Recruitment Activity; Regimen; Running; Skin; Skin Cancer; Skin Carcinoma; Squamous cell carcinoma; Survival Rate; Technology Transfer; Testing; Therapeutic; Time; Translating; Translations; Treatment Protocols; Treatment outcome; Tyrosine Kinase Receptor Inhibition; Vitamin D; base; bench to bedside; cancer cell; cancer genetics; cancer therapy; chemotherapy; clinical efficacy; clinically significant; cost; dosimetry; heme biosynthesis; image guided; improved; industry partner; inhibitor/antagonist; instrumentation; mortality; multidisciplinary; nanoliposome; novel; novel therapeutics; oncology; optical imaging; outcome forecast; pancreatic neoplasm; phase 2 study; preconditioning; programs; protoporphyrin IX; public health relevance; response; skin lesion; small molecule; spectroscopic imaging; systemic toxicity; therapy outcome; tool; treatment planning; treatment response; tumor

DESCRIPTION (provided by applicant): The complex cancer genetics and the multiple pathways operational in cancer motivate the fundamental hypothesis of this Program: Combination therapies that are mechanistically complementary and directed at non-overlapping molecular targets and pathways will significantly advance cancer treatment outcomes. The current, heavily revised application builds on our own findings, recent advances in the understanding of cancer biology and mechanisms and the progress in imaging technologies, to propose new photodynamic therapy (PDT)-based combination treatments for pancreatic cancer (PanCa) and non-melanoma skin cancers (NMSC). PDT is a photochemistry-based modality that is approved for the treatment of a number of cancer and non-cancer pathologies. Strategically, combinations will be selected such that the first treatment enhances the second. This is achieved by: (i) preconditioning tumors with agents that initiate molecular events that augment PDT and (ii) administering a second treatment specifically tailored to a particular molecular response elicited by the first. This second approach is strengthened by our new nanoconstructs (NCs) capable of simultaneous multi-inhibitor delivery. PDT is a standard component of the combination, while the second modality can be small molecule enhancers, chemo or biologic therapeutics. The choice of the specific combination reagent will be heavily influenced by the likelihood of rapid translation to the clinic in Projects 1 and 2. Toward this gol, we have recruited pharmaceutical industries that are already running clinical trials with reagents that may potentially synergize with PDT. Optical imaging will provide online monitoring of light and photosensitizer dosimetry, treatment planning and molecular response. The Program has 4 projects supported by 3 Cores. Project 1 investigates molecular pathways of small molecules that enhance ALA-PDT to increase therapy response in skin carcinomas in humans. Project 2 uses PDT and combinations ('first in human") to address metastasis in addition to local control by PDT and thus advance the survival and quality of life of patients with PanCa and precancer. Project 3 develops NCs combinations in preclinical models (3D in vitro, orthotopic and genetically engineered mice) to steer clinical studies in Project 2 within the current cycle and, i a more forward looking approach develops targeted multi-inhibitor NCs. Project 4 develops quantitative tools to monitor molecular features of tumor treatment response for integrated dosimetry for standard clinical procedures. Cores provide administration, education, models, instrumentation and technology transfer. Impact: This program positively impacts on the treatment and prevention of two cancers: decreasing mortality and morbidity in PanCa with few therapy options and NMSC with many treatment options but a high incidence, thus putting a heavy societal burden of cost and suffering. These findings could also be translated to other cancers. Scientifically, the tools developed (models, imaging and nanotechnology) provide a platform for the evaluation of new therapeutics and mechanisms.

描述（由申请人提供）：复杂的癌症遗传学和癌症的多种途径激发了该计划的基本假设：机械上是互补的组合疗法，并针对非重叠的分子靶标和途径将显着提高癌症治疗成果。当前的，经过严格修订的应用程序是基于我们自己的发现，了解癌症生物学和机制的最新进展以及成像技术的进步，以提出新的光动力疗法（PDT）基于胰腺癌（PANCA）基于基于非甲状腺瘤癌症的组合治疗。 PDT是一种基于光化学的方式，批准用于治疗多种癌症和非癌症病理。从策略上讲，将选择组合以使第一种治疗增强第二种。这是通过：（i）使用启动分子事件的药物进行预处理的实现，这些肿瘤会增强PDT和（ii）进行第二种治疗，专门针对第一个引起的特定分子反应定制的治疗方法。我们的新纳米结构（NC）能够同时进行多抑制剂传递来加强第二种方法。 PDT是组合的标准组成部分，而第二种方式可以是小分子增强剂，化学疗法或生物学疗法。特定组合试剂的选择将受到项目1和2的快速转化为诊所的可能性的严重影响。对于此GOL，我们已经招募了已经正在运行临床试验的制药行业，这些试验具有可能与PDT协同作用的试剂。光学成像将在线监测光和光敏剂剂量测定，治疗计划和分子响应。该计划有4个由3个核心支持的项目。项目1研究了小分子的分子途径，这些分子增强了ALA-PDT以增加人类皮肤癌的治疗反应。 Project 2 uses PDT and combinations ('first in human") to address metastasis in addition to local control by PDT and thus advance the survival and quality of life of patients with PanCa and precancer. Project 3 develops NCs combinations in preclinical models (3D in vitro, orthotopic and genetically engineered mice) to steer clinical studies in Project 2 within the current cycle and, i a more forward looking approach develops targeted多抑制剂NC。成本和苦难的社会负担也可以转化为其他癌症。