Computational Molecular Pathology Research for Cancer Diagnostics and Biomarkers

癌症诊断和生物标志物的计算分子病理学研究

• 批准号: 10262734
• 负责人: Robert Simpson
• 金额: $ 113.53万
• 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/10262734
• 关键词: Address; Agreement; Algorithmic Analysis; Algorithms; Animal Model; Applied Research; Area; Automated Pattern Recognition; BRAF gene; Benign; Biological Markers; Biological Models; C-KIT Mutation; Cancer Diagnostics; Cancer Model; Canis familiaris; Cell Line; Cells; Characteristics; Clinical; Combined Modality Therapy; Comprehension; Computer-Assisted Diagnosis; Cutaneous Melanoma; Development; Diagnosis; Diagnostic; Diagnostic Neoplasm Staging; Disease; Effectiveness; Epidemiology; Evaluation; Exhibits; Experimental Models; FRAP1 gene; Genetic Engineering; Germ Lines; Histologic; Human; Image Analysis; Informatics; Investigation; Lesion; Location; MAP Kinase Gene; MEK inhibition; Malignant Neoplasms; Mediator of activation protein; Medical; Medicine; Melanocytic Neoplasm; Melanoma Cell; Methods; Microscopy; Mitotic; Mitotic Activity; Modality; Modeling; Molecular; Molecular Computations; Monitor; Mucous Membrane; Mutation; Neoplasm Metastasis; Neoplasms; Nevus; Oral cavity; Pathogenesis; Pathologic; Pathologist; Pathology; Pathway interactions; Phenotype; Pre-Clinical Model; Proto-Oncogene Proteins c-akt; Reagent; Research; Research Project Grants; Resolution; Resources; Scanning; Signal Transduction; Site; Specimen; Sun Exposure; Techniques; Technology; Time; Tissues; Training; Treatment Efficacy; Ultraviolet Rays; anticancer research; biomarker discovery; cancer biomarkers; cancer type; carcinogenesis; combat; design; digital; digital pathology; human disease; human model; improved; mTOR Signaling Pathway; mTOR inhibition; melanoma; model design; model development; molecular diagnostics; molecular pathology; novel strategies; oral cavity melanoma; outcome forecast; preclinical development; preclinical trial; predictive modeling; prognostic; spectrograph; survival prediction; targeted treatment; technology development; therapeutic development; therapeutic evaluation; tool; tumor; tumor growth; validation studies; whole slide imaging

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. Development and application included algorithms to compute extent of biomarker expression in experimental models. Clinical validation studies were conducted for new approaches using computer assisted diagnostics. Validating digital pathology as substitute for conventional microscopy in diagnosis remains a priority to assure effectiveness. Intermodality concordance studies typically focus on achieving the same diagnosis by digital display of whole slide images and conventional microscopy. Assessment of discrete histological features in whole slide images, such as mitotic figures, has not been thoroughly evaluated in diagnostic practice. To further gauge the interchangeability of conventional microscopy with digital display for primary diagnosis, 12 pathologists examined 113 canine naturally occurring mucosal melanomas exhibiting a wide range of mitotic activity. Design reflected diverse diagnostic settings and investigated independent location, interpretation, and enumeration of mitotic figures. Intermodality agreement was assessed employing conventional microscopy CM40, and whole slide image specimens scanned at 20 times WSI20 and at 40 times WSI40 objective magnifications. An aggregate 1647 mitotic figure count observations were available from conventional microscopy and whole slide images for comparison. The intraobserver concordance rate of paired observations was 0.785 to 0.801, interobserver rate was 0.784 to 0.794. Correlation coefficients between the 2 digital modes, and as compared to conventional microscopy, were similar and suggest noninferiority among modalities, including whole slide image acquired at lower 20 times resolution. As mitotic figure counts serve for prognostic grading of several tumor types, including melanoma, 6 of 8 pathologists retrospectively predicted survival prognosis using whole slide images, compared to 9 of 10 by conventional microscopy, a first evaluation of whole slide images for mitotic figure prognostic grading. This study demonstrated agreement of replicate reads obtained across conventional microscopy and whole slide images. Hence, quantifying mitotic figures served as surrogate histological feature with which to further credential the interchangeability of whole slide images for primary diagnosis. 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. Research has focused on continuing to identify combination therapies and delivery strategies to combat tumor growth and metastasis. These findings continue to establish evidence of synergistic therapeutic efficacy when multiple mediators are simultaneously targeted in melanoma with Ras/ERK and PI3K/mTOR pathway activation.

开展研究是为了确定和开发新的人类疾病动物模型，并开发更好地确定模型相关性的手段，解决研究进展的关键障碍。其他目标包括开发新的研究技术，以评估和应用疾病生物标志物。在开发癌症诊断方法和开发和表征人类癌症新模型的研究资源方面取得了进展。该研究项目包括开发癌症模型的分子诊断能力，开发用于定量病理的癌症标本的自动形态学图像分析方法，以及粘膜黑色素瘤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学图像分析来量化生物标本组织切片中的组织学肿瘤和非肿瘤区域。开发和应用包括计算实验模型中生物标志物表达程度的算法。使用计算机辅助诊断的新方法进行了临床验证研究。验证数字病理学作为传统显微镜诊断的替代品仍然是确保有效性的优先事项。多模态一致性研究通常侧重于通过数字显示整个幻灯片图像和传统显微镜来实现相同的诊断。评估离散组织学特征在整个幻灯片图像，如有丝分裂图形，尚未彻底评估在诊断实践。为了进一步衡量常规显微镜与数字显示器在初级诊断中的互换性，12名病理学家检查了113例犬自然发生的粘膜黑色素瘤，这些瘤表现出广泛的有丝分裂活性。设计反映了不同的诊断设置，并调查了独立的位置、解释和有丝分裂图的枚举。采用常规显微镜CM40，在20倍WSI20和40倍WSI40物镜下扫描整个切片图像标本，评估模态一致性。从常规显微镜和整张载玻片图像中共观察到1647个有丝分裂图，以供比较。配对观察的观察者内一致性率为0.785 ~ 0.801，观察者间一致性率为0.784 ~ 0.794。与传统显微镜相比，两种数字模式之间的相关系数相似，表明模式之间的非劣效性，包括在低20倍分辨率下获得的整个幻灯片图像。由于有丝分裂图计数可用于包括黑色素瘤在内的几种肿瘤类型的预后分级，8位病理学家中有6位回顾性地预测了生存预后，而10位病理学家中有9位使用常规显微镜，这是对有丝分裂图预后分级的首次评估。这项研究证明了在常规显微镜和整个幻灯片图像中获得的重复读数的一致性。因此，定量有丝分裂图像作为替代组织学特征，进一步证明整个幻灯片图像的互换性，以进行初步诊断。黑色素瘤治疗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，自然发生的散发性犬黑色素细胞肿瘤与人类疾病有几个共同特征，这可能使犬类研究成为更相关的临床前模型。犬黑色素瘤很少出现在阳光照射的地方，大多数自发发生在口腔。自然发生的犬类黑色素细胞瘤，和人类一样，包括一些类似痣的良性病变，也包括侵袭性原发性黑色素瘤和广泛转移。与人类一样，不同的黑色素瘤亚型在体细胞和易感生殖系遗传改变、细胞起源、流行病学、与紫外线辐射的关系以及从良性肿瘤到恶性肿瘤的进展方面也可能存在于宠物狗中。与人类皮肤黑色素瘤相比，犬和人粘膜黑色素瘤（MM）似乎不常见BRAF、NRAS和c-kit突变，尽管这两个物种都具有AKT和MAPK信号激活。我们得出结论，犬类自然发生的MM和人类自然发生的MM的临床和组织病理学特征有显著的重叠。犬类自然发生的口腔黑色素瘤作为人类黑色素瘤的临床前模型正在进一步探索。大多数人类和犬MM表现出RAS/ERK和/或PI3K/mTOR信号通路激活。犬MM细胞系具有不同的ERK和AKT/mTOR激活水平，反映了犬自然存在的差异，对MEK抑制和PI3K/mTOR双抑制敏感。研究的重点是继续确定联合疗法和递送策略，以对抗肿瘤的生长和转移。这些发现继续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。