Molecular Pathology Research for Cancer Diagnostics and Biomarkers

癌症诊断和生物标志物的分子病理学研究

• 批准号: 9556811
• 负责人: Robert Simpson
• 金额: $ 86.64万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9556811
• 关键词: Address; Algorithmic Analysis; Algorithms; Animal Model; Applied Research; Area; Automated Pattern Recognition; BCL2 gene; BRAF gene; Benign; Biological Markers; Biological Models; Blood; Brain Neoplasms; C-KIT Mutation; CASP3 gene; CCR; Cancer Diagnostics; Cancer Model; Canis familiaris; Cell Cycle Proteins; Cell Line; Cell Survival; Cell model; Cells; Characteristics; Cisplatin; Clinical; Collaborations; Comprehension; Cutaneous; Cutaneous Melanoma; Development; Diagnostic; Diagnostic Neoplasm Staging; Disease; Drug Combinations; Drug Targeting; Drug resistance; EIF4EBP1 gene; Epidemiology; Epidermal Growth Factor Receptor; Evaluation; Exhibits; Extramural Activities; FRAP1 gene; Genetic Engineering; Germ Lines; Gland; Harvest; Histologic; Human; Image Analysis; In Vitro; Investigation; Laboratories; Lesion; MAP Kinase Gene; MEK inhibition; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Malignant neoplasm of thyroid; Mediating; Mediator of activation protein; Medical; Medicine; Melanocytic Neoplasm; Melanoma Cell; Methods; Microdissection; Modeling; Molecular; Molecular Analysis; Monitor; Mus; Mutation; Neoplasm Metastasis; Neoplasms; Nevus; Oral cavity; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phenotype; Pre-Clinical Model; Protein Family; Proto-Oncogene Proteins c-akt; Reagent; Research; Research Personnel; Research Project Grants; Resources; Signal Pathway; Signal Transduction; Site; Slide; Solid Neoplasm; Specimen; Techniques; Technology; The Sun; Tissue Preservation; Tissue Procurements; Tissue imaging; Tissues; Training; Treatment Efficacy; Ultraviolet Rays; United States Food and Drug Administration; Validation; Xenograft procedure; anticancer research; biomarker discovery; cancer biomarkers; cancer diagnosis; cancer type; carbohydrate metabolism; carcinogenesis; clinical diagnostics; comparative; cytotoxicity; digital; human disease; imaging platform; improved; insight; interdisciplinary approach; mTOR Signaling Pathway; mTOR inhibition; melanoma; model design; model development; molecular diagnostics; molecular pathology; non-invasive imaging; novel; oncology program; optical imaging; oral cavity melanoma; preclinical development; preclinical trial; resistance mechanism; spectrograph; targeted treatment; technology development; therapeutic development; therapeutic evaluation; tool; tumor; tumor growth

Research is conducted to characterize and develop new animal models of human disease and to develop the means to better characterize a model's relevance, addressing critical barriers to research progress. Additional aims include the development of new research technologies for the evaluation and application of disease biomarkers. Progress was made in developing cancer diagnostics and in research resources useful in developing and characterizing new models of human cancer. This research project included developing capabilities in molecular diagnostics for cancer models, developing methods for automated morphometric image analysis of cancer specimens for quantitative pathology, and preclinical development of targeted therapy for mucosal melanoma. Unique spatial-spectral image analysis algorithms were developed for applying automated pattern recognition morphometric image analysis to quantify histologic tumor and non-tumor areas in biospecimen tissue sections. Additional progress was made in developing and validating algorithms for cancers of lung, thyroid, prostate gland and cancer metastasis. Contributions to new models important for understanding mechanisms of drug resistance were developed and validated using quantitative optical imaging. Investigations were conducted that led to new insight from novel models involving several cancer types. These included carbohydrate metabolism in prostate cancer, drug resistance mechanisms at the blood placental barrier, MET signaling in cutaneous squamous cancer, EGFR driven lung cancer, and an ovarian cancer cell model of cisplatin-mediated cytotoxicity. New model development is taking place for melanoma treatment. Melanoma represents a significant malignancy in humans and dogs. Distinct from genetically engineered models, sporadic naturally occurring canine melanocytic neoplasms share several characteristics with human disease that could make investigation in dogs a more relevant pre-clinical model. Canine melanomas rarely arise in sun-exposed site and most occur spontaneously in the oral cavity. The spectrum of naturally occurring canine melanocytic neoplasia, as is true in people, includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. As in humans, distinct melanoma subtypes differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in pet dogs. Both canine and human mucosal melanomas (MM) appear to harbor BRAF, NRAS and c-kit mutations uncommonly, compared to human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of naturally occurring canine and human MM. Naturally occurring canine oral cavity melanoma is being explored further as a pre-clinical model for human melanoma. The majority of human and canine MM evaluated exhibited RAS/ERK and/or PI3K/mTOR signaling pathway activation. Canine MM cell lines, with varying ERK and AKT/mTOR activation levels reflective of naturally occurring differences in dogs, were sensitive to MEK inhibition and dual PI3K/mTOR inhibition. Two-drug combination synergistically decreased cell survival in association with caspase 3/7 activation, as well as altered expression of cell cycle regulatory proteins and Bcl-2 family proteins. In combination, the two drugs targeted their respective signaling pathways, potentiating reduction of pathway mediators p-ERK, p-AKT, p-S6, and 4E-BP1 in vitro, and in association with significantly inhibited solid tumor growth in MM xenografts in mice. These findings provide evidence of synergistic therapeutic efficacy when multiple mediators are simultaneously targeted in melanoma with Ras/ERK and PI3K/mTOR pathway activation. An analogous interdisciplinary approach to comparing the suitability of naturally occurring canine brain tumors to inform human brain cancer research was organized with the CCR Comparative Oncology Program and extramural investigators. Conduct of a multi-center clinical diagnostic study in collaboration with the US Food and Drug Administration is leading to useful criteria for validation of whole slide digital pathology tissue image platforms for clinical cancer diagnosis.

进行研究是为了描述和开发新的人类疾病动物模型，并开发更好地描述模型相关性的方法，解决研究进展的关键障碍。其他目标包括为评估和应用疾病生物标记物开发新的研究技术。在开发癌症诊断学和研究资源方面取得了进展，这些资源有助于开发和表征新的人类癌症模型。这项研究项目包括开发癌症模型的分子诊断能力，开发用于定量病理学的癌症标本的自动形态图像分析方法，以及针对粘膜黑色素瘤的靶向治疗的临床前开发。开发了独特的空间光谱图像分析算法，用于应用自动模式识别形态测量图像分析来量化组织学组织切片中的肿瘤和非肿瘤区域。在开发和验证肺癌、甲状腺癌、前列腺癌和癌症转移的算法方面取得了更多进展。对新模型的贡献对了解耐药机制非常重要，并使用定量光学成像进行了验证。进行了调查，从涉及几种癌症类型的新模型中获得了新的见解。这些研究包括前列腺癌的碳水化合物代谢，血胎盘屏障的耐药机制，皮肤鳞癌中的MET信号，EGFR驱动的肺癌，以及顺铂介导的细胞毒性的卵巢癌细胞模型。治疗黑色素瘤的新模式正在开发中。黑色素瘤是人类和狗的一种重要的恶性肿瘤。与基因工程模型不同，零星的自然发生的犬类黑素细胞肿瘤与人类疾病有几个共同的特征，这可能使对狗的研究成为更相关的临床前模型。犬类黑色素瘤很少发生在阳光暴晒的部位，大多数自发发生在口腔。自然发生的犬类黑素细胞瘤的谱系，在人类中是真实的，包括一些类似痣的良性病变，以及侵袭性的原发黑色素瘤，以及广泛的转移。与人类一样，宠物狗中也可能存在不同的黑色素瘤亚型，这些亚型在体细胞和易感生殖系遗传变化、细胞起源、流行病学、与紫外线辐射的关系以及从良性到恶性肿瘤的进展方面都存在差异。与人类皮肤黑色素瘤相比，犬和人粘膜黑色素瘤(MM)似乎都罕见地含有BRAF、NRAS和c-kit突变，尽管这两个物种都有AKT和MAPK信号激活。我们的结论是，自然发生的犬和人类MM的临床和组织病理学特征有显著的重叠。自然发生的犬口腔黑色素瘤正在进一步探索，作为人类黑色素瘤的临床前模型。大多数人和犬多发性骨髓瘤表现出RAS/ERK和/或PI3K/mTOR信号通路的激活。犬MM细胞系对MEK抑制和PI3K/mTOR双重抑制敏感，其ERK和AKT/mTOR活性水平的变化反映了犬自然存在的差异。两种药物联合应用通过激活caspase3/7协同降低细胞存活率，并改变细胞周期调节蛋白和bcl2家族蛋白的表达。这两种药物联合使用，靶向于各自的信号通路，在体外增强了通路介质p-ERK、p-AKT、p-S6和4E-BP1的减少，并显著抑制了小鼠MM移植瘤的实体瘤生长。这些发现为多种介质同时靶向RAS/ERK和PI3K/mTOR通路激活的黑色素瘤提供了协同治疗效果的证据。与CCR比较肿瘤学项目和外部调查人员一起组织了一种类似的跨学科方法，比较自然发生的犬脑肿瘤是否适合为人类脑癌研究提供信息。与美国食品和药物管理局合作进行的一项多中心临床诊断研究正在为验证用于临床癌症诊断的全幻灯片数字病理组织图像平台提供有用的标准。