Leveraging Tumor Suppressor Inactivation for Osteosarcoma Therapy

利用肿瘤抑制因子失活来治疗骨肉瘤

基本信息

批准号：
10298611
负责人：
BANG H HOANG
金额：
$ 42.04万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298611
关键词：
Address Alanine Amputation Animals Apoptosis Cell Cycle Cell Cycle Progression Cell Line Cells Cessation of life Childhood Clinical Combined Modality Therapy Complex Cytotoxic Chemotherapy Data Defect Disease Dose-Limiting Embryo Emerging Technologies F Box Domain F-Box Proteins Fibroblasts Future Genetic Genetically Engineered Mouse Genomics Goals Growth Histologic Immunoblotting Implant Knowledge Lead Life Malignant Bone Neoplasm Malignant Neoplasms Malignant neoplasm of pituitary gland Malignant neoplasm of prostate Mediating Metastatic Neoplasm to the Lung Modeling Molecular Mus Neoplasm Metastasis Oncogenes Oncogenic Operative Surgical Procedures Organoids Osteoblasts Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Pituitary Gland Play Population Positioning Attribute Pre-Clinical Model Prognosis Proteins Quantitative Reverse Transcriptase PCR Randomized Relapse Role Skp2 Proteins Survival Rate TP53 gene Testing Therapeutic Therapeutic Effect Threonine Tissues Translating Treatment Protocols Treatment-related toxicity Tumor Suppressor Proteins Ubiquitin Ubiquitination base burden of illness cell motility cell type chemotherapy clinically relevant cyclin-dependent kinase inhibitor 1B established cell line immunoregulation implantation improved innovation insight mouse model multicatalytic endopeptidase complex neoplastic cell next generation sequencing novel novel therapeutics osteosarcoma patient derived xenograft model pre-clinical prostate carcinogenesis screening side effect stemness targeted treatment transcriptome transcriptomics translational impact treatment effect treatment group tumor tumor growth tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Osteosarcoma (OS) is the most common malignant bone tumor, found in the pediatric population and often leads to death due to tumor progression and metastasis. Despite intensive, multimodality treatment protocols with cytotoxic chemotherapy and aggressive surgery, 30-40% of patients still succumb to relapsed and metastatic disease. Current treatment options for these patients are extremely limited. More importantly, the clinical outcome for OS patients has not improved at all during the last four decades. Our long-range goals are to reduce OS disease burden and improve long-term survival by developing molecular-based therapies that target mechanisms of tumor growth and metastasis. The F-box protein s-phase kinase-associated protein-2 (Skp2) is the substrate recognition component of the Skp1-Cullin1-F-box (SCF) complex and considered a key oncogene through its ability to target cell cycle regulators for ubiquitin degradation, regulates cell migration and metastasis. Skp2 interacts with the accessory protein Cks1 to ubiquitinate p27 for degradation, thus promoting cell cycle progression and cancer growth. Currently, the oncogenic mechanisms and therapeutic potential of Skp2 in OS is largely unknown. There are specific and rational reasons for targeting the SCF-Skp2 axis in OS, based upon preliminary data generated by the PI and his colleagues: (1) A high Skp2 expression in OS tissues portends a poor prognosis in patients; (2) High levels of Skp2 are observed in many OS cell types, including established cell lines, patient-derived xenografts, and primary cultures from OS patients; (3) Skp2 deletion effectively blocks pituitary and prostate tumorigenesis in Rb1/p53-deficient mouse models. In OS, genomic sequencing studies reveal a high rate of Rb1/p53 co-inactivation, suggesting that OS may be susceptible to Skp2 blockade; (4) Genetic and drug-induced depletion of Skp2 reduces the proliferation and invasion of OS cell lines and; (5) Mouse embryonic fibroblasts (MEF) and OS tumor cells with Rb1/p53 deletion are more sensitive to SCF-Skp2 inhibition than wild-type and Skp2-deleted cells. Taken together, these data suggest that the SCF-Skp2 complex may offer a unique therapeutic opportunity for treating a tremendously challenging cancer such as OS. We hypothesize that blockade of the SCF-Skp2 complex in the context of Rb1/p53 inactivation will reduce OS progression. This hypothesis will be addressed by the following specific aims: Specific Aim 1 (Oncogenic Mechanisms): To define the pro-oncogenic mechanisms of SCF-Skp2 in Rb1/p53-inactivated OS. Specific Aim 2 (Translational Therapeutics): To determine the effect of inhibiting SCF-Skp2 in preclinical models of Rb1/p53- inactivated OS. Finally, since cancer organoids represent an emerging technology that faithfully replicates the tumor's genetic landscape, we will examine the effect of inhibiting SCF- Skp2 in mouse OS organoids as a proof-of-concept to translate findings into patient-specific therapeutics in the future. The successful completion of this study will be translatable to target the SCF-Skp2 complex to block osteosarcoma progression.

项目概要骨肉瘤（OS）是最常见的恶性骨肿瘤，见于儿科人群并经常因肿瘤进展和转移而导致死亡。尽管强化、多模式治疗方案，包括细胞毒性化疗和侵袭性化疗手术后，30-40%的患者仍死于复发和转移性疾病。当前的这些患者的治疗选择极其有限。更重要的是，临床在过去四十年中，OS 患者的预后根本没有改善。我们的远程目标是通过开发减少 OS 疾病负担并提高长期生存率针对肿瘤生长和转移机制的分子疗法。 F 盒蛋白 s 相激酶相关蛋白 2 (Skp2) 是底物识别成分 Skp1-Cullin1-F-box (SCF) 复合体，因其能够泛素降解的靶细胞周期调节因子，调节细胞迁移和转移。 Skp2 与辅助蛋白 Cks1 相互作用，泛素化 p27 进行降解，从而促进细胞周期进展和癌症生长。目前，致癌机制 Skp2 在 OS 中的治疗潜力尚不清楚。有具体的、合理的基于 OS 生成的初步数据，针对 OS 中的 SCF-Skp2 轴的原因 PI和他的同事：（1）OS组织中Skp2的高表达预示着预后不良患者; (2) 在许多 OS 细胞类型中观察到高水平的 Skp2，包括已建立的细胞来自 OS 患者的细胞系、患者来源的异种移植物和原代培养物； (3) Skp2删除在 Rb1/p53 缺陷小鼠模型中有效阻止垂体和前列腺肿瘤发生。在 OS、基因组测序研究揭示了 Rb1/p53 共失活率很高，表明操作系统可能容易受到 Skp2 封锁的影响； (4) 遗传和药物诱导的 Skp2 耗竭减少 OS 细胞系的增殖和侵袭； (5) 小鼠胚胎成纤维细胞 Rb1/p53 缺失的 (MEF) 和 OS 肿瘤细胞对 SCF-Skp2 抑制更敏感比野生型和 Skp2 删除的细胞。综上所述，这些数据表明 SCF-Skp2 复合物可能为治疗极具挑战性的疾病提供独特的治疗机会癌症，例如操作系统。我们假设在以下情况下阻断 SCF-Skp2 复合物 Rb1/p53 失活将减少 OS 进展。这一假设将由具体目标如下：具体目标 1（致癌机制）：定义促癌机制 Rb1/p53 失活操作系统中 SCF-Skp2 的机制。具体目标 2（转化治疗）：确定在 Rb1/p53- 临床前模型中抑制 SCF-Skp2 的效果未激活的操作系统。最后，由于癌症类器官代表了一项新兴技术，忠实地复制肿瘤的遗传景观，我们将检查抑制 SCF- 的效果小鼠操作系统类器官中的 Skp2 作为将研究结果转化为患者特异性的概念验证未来的治疗方法。本研究的成功完成将转化为目标 SCF-Skp2 复合物阻止骨肉瘤进展。