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: 10926605
• 负责人: Robert Simpson
• 金额: $ 238.86万
• 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/10926605
• 关键词: Acute; Address; Allografting; Animals; Applied Research; Area; BRAF gene; Biochemistry; Biological Markers; Biological Models; Body Weight decreased; C-KIT Mutation; CYP3A4 gene; Cancer Diagnostics; Cancer Model; Canis familiaris; Cell Cycle; Cell Line; Cells; Clinical; Clinical Trials; Coagulation Process; Collaborations; Comprehension; Cutaneous; Cutaneous Melanoma; Cytochrome P450; Data; Development; Diagnosis; Diagnostic; Diagnostic Neoplasm Staging; Dimethyl Sulfoxide; Disease; Dose; Dose Limiting; Drug Combinations; Drug Kinetics; Drug resistance; Evaluation; Fibroblasts; Genetic; Genomics; Half-Life; Hematology; Human; Incidence; Inflammation; Informatics; Intervention; Laboratories; Libraries; MAP Kinase Gene; MEK inhibition; MEKs; MYC Family Protein; Malignant Neoplasms; Medical; Medicine; Methods; Modeling; Molecular; Molecular Computations; Monitor; Multiple Myeloma; Mutation; Oral; PI3K/AKT; PIK3CG gene; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Proteasome Inhibitor; Proteinuria; Proto-Oncogene Proteins c-akt; Publishing; Reagent; Recurrence; Refractory; Regression Analysis; Research; Resistance; Reticulocytes; Serum; Sex Differences; Signal Transduction; Signal Transduction Pathway; Source; Sulfate; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Trials; Time; Tissues; Toxic effect; Training; Transforming Growth Factor beta; Translating; Transplantation; Urinalysis; Validation; Variant; Work; absorption; anticancer research; biomarker discovery; cancer biomarkers; cancer therapy; cancer type; carcinogenesis; clinical application; cohort; design; drug development; drug sensitivity; high risk; high-throughput drug screening; human disease; improved; in silico; inhibitor; mTOR Inhibitor; mTOR Signaling Pathway; melanoma; molecular diagnostics; molecular pathology; mucosal melanoma; novel; overexpression; pre-clinical; preclinical efficacy; preclinical trial; predictive modeling; response; side effect; targeted treatment; technology development; therapeutic development; tool; tumor

In research aimed to translate approaches to cancer treatment intended for clinical application, progress was made in developing therapeutic approaches. A high-throughput drug screen in 47 MM cell lines and in silico Huber robust regression analysis of drug responses revealed 43 potentially synergistic combinations. We hypothesized that effective combinations would reduce MYC expression and enhance p16 activity. Six combinations cooperatively reduced MYC protein, frequently over-expressed in MM and also cooperatively increased p16 expression, frequently downregulated in MM. Synergistic reductions in viability were observed with top combinations in proteasome inhibitor-resistant and sensitive MM cell lines, while sparing fibroblasts. Three combinations significantly prolonged survival in a transplantable Ras-driven allograft model of advanced MM closely recapitulating high-risk/refractory myeloma in humans and reduced viability of ex vivo treated patient cells. Common genetic pathways similarly downregulated by these combinations promoted cell cycle transition, whereas pathways most upregulated were involved in TGFbeta/SMAD signaling. These preclinical data identify potentially useful drug combinations for evaluation in drug-resistant MM and reveal potential mechanisms of combined drug sensitivity. Work also continued on drug development for combined targeted therapy for mucosal melanomas. Clinical and pathological correlates between human and canine mucosal melanomas are substantial, and the relatively greater incidence of spontaneous naturally occurring mucosal melanoma in dogs represents a promising opportunity for predictive modeling. Both canine and human mucosal melanomas appear to harbor BRAF, NRAS and c-kit mutations uncommonly, compared to human cutaneous melanomas, although both species share AKT and MAPK signaling activation. The genomic landscapes of human and canine mucosal melanoma appear highly diverse and generally lack recurring hotspot mutations associated with cutaneous melanomas. Although much remains to be determined, evidence indicates that Ras/MAPK and/or PI3K/AKT/mTOR signaling pathway activations are common in both species and may represent targets for therapeutic intervention. Through this research sapanisertib, an mTORC1/2 inhibitor, was selected from a PI3K/mTOR inhibitor library to collaborate with MEK inhibition; the latter preclinical efficacy was demonstrated previously for canine mucosal melanoma. Progress was made in the pharmacokinetics of the two-drug combination. The combination is a rational approach to address the reciprocal cross activation between the two pathways, which can be a source of drug resistance. Consequently, oral dosing for plasma pharmacokinetic (PK) analysis and tolerability to a combination of sapanisertib, a dual TORC1/2 inhibitor, and trametinib, a MEK inhibitor, was evaluated in nontumor-bearing laboratory dogs for its potential application in parallel pathway targeting. Twelve dogs, divided into three equal cohorts, received either the combination or single agents. Animals were monitored for PK following single dose and 17-day repeat dosing, and by clinical observations, hematology, serum biochemistry, coagulation studies and urinalyses. A single trametinib dose (0.025 mg/kg), sulfated as dimethyl sulfoxide which enhanced its absorption, reached mean maximum concentration (Cmax) 0.64 ng/mL [18% coefficient of variation (CV)] at a median time to maximum concentration (Tmax) of 1.5 h (hr), and mean area under the concentration-time curve (AUC) 16.8 hr*ng/mL (14%CV), which were similar when given alone or in combination with sapanisertib. A prolonged half-life afforded 3-4-fold plasma accumulation of trametinib with daily dosing, analogous to humans. Trametinib PK mirrored previous regulatory data in dogs, while exposure approximated some published human values but generally not all patients. Sapanisertib-alone in canine plasma following single 0.1 mg/kg dose [mean Cmax 26.3 ng/mL (21%CV), median Tmax 2.0 hr, and mean AUC 248 hr*ng/mL (41%CV)] resembled levels in human therapeutic trials; whereas canine sapanisertib exposure was reduced when combined with trametinib, a known cytochrome P450 CYP3A4 inducer. Sex differences were not observed for either drug. Side effects upon repeat dosing with either or both drugs may include body weight loss, maldigestion, and cutaneous discoloration. The combination was tolerated without dose limiting toxicity, although clinical laboratory analyses revealed drug-induced acute-phase inflammation, proteinuria, and decreased blood reticulocytes, mild changes not necessitating intervention. Short-term results in dogs with this combination would appear to hold translational promise for clinical trial evaluation to target canine and possibly human melanoma, as well as other cancers having one or both signal transduction pathway activations.

在旨在将癌症治疗方法转化为临床应用的研究中，在开发治疗方法方面取得了进展。在47个MM细胞系中进行高通量药物筛选，并在Silico Huber中对药物反应进行稳健回归分析，发现43种潜在的协同作用组合。我们假设有效的组合将减少MYC的表达并增强p16的活性。6种组合协同降低MYC蛋白，在MM中经常过度表达，也协同增加p16表达，在MM中经常下调。在蛋白酶体抑制剂耐药和敏感的MM细胞系中，观察到最高组合的活性协同降低，同时保留成纤维细胞。在晚期多发性骨髓瘤的可移植RAS驱动的同种异体移植模型中，三种组合显著延长了存活期，与人类高风险/难治性骨髓瘤相似，并降低了体外治疗的患者细胞的存活率。这些组合同样下调的常见遗传途径促进了细胞周期的转变，而大多数上调的途径涉及TGFbeta/SMAD信号。这些临床前数据确定了用于评估耐药MM的潜在有用的药物组合，并揭示了联合药物敏感性的潜在机制。针对黏膜黑色素瘤联合靶向治疗的药物开发工作也在继续。人和犬粘膜黑色素瘤之间的临床和病理相关性很大，而犬自然发生的粘膜黑色素瘤的相对较高的发病率为预测性建模提供了一个有希望的机会。与人类皮肤黑色素瘤相比，犬和人粘膜黑色素瘤似乎都罕见地含有BRAF、NRAS和c-kit突变，尽管这两个物种都有AKT和MAPK信号激活。人类和犬类黏膜黑色素瘤的基因组图谱表现出高度的多样性，通常缺乏与皮肤黑色素瘤相关的复发热点突变。尽管仍有许多有待确定的地方，但有证据表明，RAS/MAPK和/或PI3K/AKT/mTOR信号通路的激活在这两个物种中都很常见，可能是治疗干预的靶点。通过这项研究，从PI3K/mTOR抑制剂文库中选择了mTORC1/2抑制剂Sapanisertib来协同抑制MEK；后者的临床前疗效先前已被证明对犬粘膜黑色素瘤有效。两药联用的药代动力学研究取得了进展。联合用药是解决这两个途径之间相互交叉激活的合理方法，这可能是耐药的一个来源。因此，口服剂量的血浆药代动力学(PK)分析和耐受性的联合，萨帕尼司替布，一种双重的TORC1/2抑制剂，和曲美替尼，一种MEK抑制剂，评估了其潜在的应用于平行通路靶向的非肿瘤实验犬。12只狗被分成三组，分别接受联合或单一药物治疗。动物在单次给药和17天重复给药后监测PK，并通过临床观察、血液学、血清生化、凝血研究和尿液分析进行监测。单剂曲美替尼(0.025 mg/kg)，以二甲基亚砜为促进剂，达到最大吸收的平均浓度(Cmax)为0.64 ng/mL[18%变异系数(CV)]，达到最大浓度的中位时间(Tmax)为1.5h，药-时曲线下的平均面积为16.8hr*ng/mL(14%CV)，与单独给药或联合应用时相似。延长的半衰期使曲美替尼的血浆蓄积量增加了3-4倍，与人类相似。曲美替尼PK反映了之前在狗身上的调节数据，而接触则接近一些已发表的人类价值观，但通常不是所有患者。单次给药0.1 mg/kg后，犬血浆中Sapanisertib的浓度[平均Cmax 26.3 ng/mL(21%CV)，Tmax中值2.0小时，平均AUC 248小时*ng/mL(41%CV)]与人类治疗试验中的水平相似；而与已知的细胞色素P450 CYP3A4诱导剂曲美替尼联合应用时，犬Sapanisertib的暴露减少。两种药物均未观察到性别差异。重复服用其中一种或两种药物的副作用可能包括体重减轻、消化不良和皮肤变色。尽管临床实验室分析显示药物引起的急性期炎症、蛋白尿和网织红细胞减少，但轻微的变化不需要干预，但这种联合是可以耐受的，没有剂量限制毒性。在狗身上使用这种组合的短期结果似乎对靶向狗黑色素瘤和可能的人类黑色素瘤以及具有一个或两个信号转导通路激活的其他癌症的临床试验评估具有翻译前景。

项目成果

Agreement in Histological Assessment of Mitotic Activity Between Microscopy and Digital Whole Slide Images Informs Conversion for Clinical Diagnosis.

显微镜和数字全玻片图像之间有丝分裂活性的组织学评估的一致性为临床诊断的转换提供了信息。

• DOI: 10.1177/2374289519859841
• 发表时间: 2019
• 期刊: Academic pathology
• 影响因子: 1
• 作者: Wei,Bih-Rong;Halsey,CharlesH;Hoover,ShelleyB;Puri,Munish;Yang,HowardH;Gallas,BrandonD;Lee,MaxwellP;Chen,Weijie;Durham,AmyC;Dwyer,JenniferE;Sánchez,MelissaD;Traslavina,RyanP;Frank,Chad;Bradley,Charles;McGill,LawrenceD
• 通讯作者: McGill,LawrenceD

Functional analysis of prognostic gene expression network genes in metastatic breast cancer models.

• DOI: 10.1371/journal.pone.0111813
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Geiger TR;Ha NH;Faraji F;Michael HT;Rodriguez L;Walker RC;Green JE;Simpson RM;Hunter KW
• 通讯作者: Hunter KW

SDF-1α mediates wound-promoted tumor growth in a syngeneic orthotopic mouse model of breast cancer.

• DOI: 10.1371/journal.pone.0060919
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Stuelten CH;Cervoni-Curet FN;Busch JI;Sutton E;Webster JD;Kavalukas SL;Wakefield LM;Barbul A;Niederhuber JE
• 通讯作者: Niederhuber JE

Capacity for resolution of Ras-MAPK-initiated early pathogenic myocardial hypertrophy modeled in mice.

• 发表时间: 2011-04
• 期刊: Comparative medicine
• 影响因子: 0.8
• 作者: B. Wei;Philip L. Martin;S. Hoover;Elizabeth Spehalski;Elizabeth Spehalski;Mia R. Kumar;M. Hoenerhoff;J. Rozenberg;C. Vinson;R. M. Simpson

Digital pathology and image analysis augment biospecimen annotation and biobank quality assurance harmonization.

• DOI: 10.1016/j.clinbiochem.2013.12.008
• 发表时间: 2014-03
• 期刊: Clinical biochemistry
• 影响因子: 2.8
• 作者: Wei BR;Simpson RM
• 通讯作者: Simpson RM