Mechanism-Based Design of Combination Therapies for Pancreatic Cancer

基于机制的胰腺癌联合疗法设计

• 批准号: 7611531
• 负责人: Tayyaba Hasan
• 金额: $ 18.18万
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611531
• 关键词: 3-Dimensional; Acute; Address; Adjuvant; Adverse effects; Amifostine; Apoptosis; Beds; Biodistribution; Biological Assay; Biological Products; Biological Response Modifier Therapy; Blood Vessels; Bone Marrow; Cancer Biology; Cell Line; Cells; Clinical Research; Collaborations; Combined Modality Therapy; Cues; Data; Development; Disease; Dose; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor Receptor; Equilibrium; Exhibits; Fluorescence; Funding; Goals; Growth; Image; In Vitro; Institutes; Investigation; Laboratories; Lead; Leucovorin; Light; Literature; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Metastatic Lesion; Metastatic Neoplasm to the Lung; Methotrexate; Modality; Modeling; Molecular; Molecular Models; Molecular Target; Monitor; Mucous Membrane; Mus; Neoplasm Metastasis; Nodule; Normal tissue morphology; Outcome; Pathology; Pathway interactions; Patients; Pharmacy facility; Photochemistry; Photochemotherapy; Photosensitizing Agents; Phototherapy; Pre-Clinical Model; Primary Neoplasm; Principal Investigator; Process; Protein-Lysine 6-Oxidase; Proteins; Proto-Oncogene Protein c-met; Public Health; Pus; Radiation therapy; Radiation-Protective Agents; Reporting; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Second Primary Cancers; Selection Criteria; Societies; Solid Neoplasm; Specificity; Structure; System; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Treatment Protocols; Treatment outcome; Tumor Burden; Up-Regulation; Vascular Endothelial Growth Factors; Verteporfin; Western Blotting; Work; base; cancer therapy; cell killing; cellular targeting; chemotherapy; cost; design; dosimetry; effective therapy; extracellular; gastrointestinal; gemcitabine; in vivo; in vivo Model; innovation; intravital microscopy; killings; lymph nodes; matrigel; minimally invasive; molecular modeling; neoplastic cell; outcome forecast; oxidation; programs; response; sound; statistics; success; therapeutic target; three-dimensional modeling; treatment response; tumor; uptake

Recognizing that the complexity of cancer biology makes it virtually impossible for any single therapy to be optimally effective, the overall hypothesis of this research is that, two or more therapies that are mechanistically independent and directed at non-overlapping molecular targets and pathways will provide the most effective treatments. In particular, the dismal statistics for Pancreatic Cancer (PanCa) and its tenacious resistance to current therapies demand innovative approaches with sound mechanistic bases. The goal of this Project is to develop mechanism-based Photodynamic Therapy (PDT) combination regimens to synergistically enhance efficiency of PDT in preclinical models of PanCa where PDT alone has already shown promise. The strategy is to combine PDT with a biologic therapy that is specific to the particular molecular response elicited by PDT in an approach we term Combination Photodynamic Biologic Therapy (CPBT). PDT is an effective treatment for cancer, which kills most cells in solid tumors, and although molecular responses instigated by surviving cells could mitigate overall treatment outcome, these same responses also provide an opportunity in new molecular targets that could greatly enhance specificity and efficiency of treatment outcome. The goals of the study will be realized in 5 specific aims. Aim 1 will examine molecular responses to sub-lethal PDT and test CPBT targeted to these responses in in vitro organotypic cultures. Aim 2-5 will utilize an orthotopic model of PanCa where Aim 2 will optimize PDT parameters in vivo and along with information on the success of CPBT in Aim 1, will guide PDT-based combination treatments in vivo, in Aim 3. Since Gem is standard chemotherapy for PanCa, successful combination treatments in Aim 3 will be further examined in combination with Gem in Aim 4. Finally, the two most successful treatments from Aim 4 will be extended to a long-term survival study in Aim 5. Cores B and C will be used throughout; e.g. on-line measurement of molecular responses, PDT dosimetry, pathology and statistical considerations. The promise of PDT in clinical studies and in several preclinical models for PanCa, our significant preliminary findings and collaborations within the program provide the impetus for the proposed investigations. Potential benefits to public health: the studies in Project 3will lead to newtreatment options for PanCa, a disease with a very poor prognosis with current treatments placing a heavy burden on society in terms of cost and suffering.

认识到癌症生物学的复杂性几乎使任何单一疗法都无法成为 最佳有效，这项研究的总体假设是，两种或多种疗法是 机械独立并针对非重叠的分子靶标和途径将提供 最有效的治疗方法。特别是，胰腺癌（panca）及其的惨淡统计数据及其 对当前疗法的顽强抵抗需要使用声音机械基础的创新方法。这 该项目的目标是开发基于机制的光动力疗法（PDT）组合方案 协同提高PDT在PCA的临床前模型中的效率，仅PDT已经存在 显示的承诺。该策略是将PDT与特定特定的生物疗法结合 PDT在一种方法中引起的分子反应，我们称其为组合光动力生物学疗法 （CPBT）。 PDT是一种有效的癌症治疗方法，可杀死实体瘤中的大多数细胞，尽管 幸存细胞促进的分子反应可以减轻整体治疗结果，这些结果相同 响应还为新分子靶标提供了机会，可以极大地提高特异性和 治疗结果的效率。研究的目标将以5个具体目标实现。 AIM 1将检查 分子对亚致死性PDT的反应和对这些反应的CPBT在体外器官型中的响应 文化。 AIM 2-5将利用PANCA的原位模型，其中AIM 2将优化体内PDT参数 以及有关AIM 1中CPBT成功的信息，将指导基于PDT的组合处理 在AIM 3中的体内。由于GEM是PANCA的标准化学疗法，因此成功的联合治疗 AIM 3将与AIM 4中的GEM结合进一步检查。最后，两个最成功的 AIM 4的治疗将扩展到AIM 5中的长期生存研究。 自始至终;例如分子反应，PDT剂量法，病理和统计的在线测量 考虑因素。 PDT在临床研究和几种panca的临床前模型中的承诺，我们 该计划中的重要初步发现和协作为拟议的 调查。对公共卫生的潜在好处：项目3将导致新处理的研究 panca的选择，这种疾病的预后非常差，当前的治疗措施承受着沉重的负担 在成本和痛苦方面的社会。