Leveraging Tumor Suppressor Inactivation for Osteosarcoma Therapy

利用肿瘤抑制因子失活来治疗骨肉瘤

• 批准号: 10435551
• 负责人: BANG H HOANG
• 金额: $ 40.77万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/10435551
• 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; 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; Western Blotting; 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; translational therapeutics; treatment effect; treatment group; tumor; tumor growth; tumor progression; tumorigenesis

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.

项目摘要 骨肉瘤是儿童最常见的恶性骨肿瘤 这是一种恶性肿瘤，通常由于肿瘤进展和转移而导致死亡。尽管 强化的多模式治疗方案，包括细胞毒性化疗和侵袭性化疗。 手术后，30-40%的患者仍然死于复发和转移性疾病。电流 这些患者的治疗选择极其有限。更重要的是，临床 在过去的四十年中，OS患者的结局根本没有改善。我们的远程 目标是通过开发新的抗肿瘤药物， 针对肿瘤生长和转移机制的分子疗法。F-box 蛋白质s期激酶相关蛋白2（Skp 2）是蛋白质s期激酶相关蛋白2的底物识别组分。 Skp 1-Cullin 1-F-box（SCF）复合物，并被认为是一个关键的癌基因，因为它能够 靶向泛素降解的细胞周期调节剂，调节细胞迁移和转移。 Skp 2与辅助蛋白Cks 1相互作用，使p27泛素化，从而降解， 促进细胞周期进展和癌症生长。目前，致癌机制 Skp 2在OS中的治疗潜力在很大程度上是未知的。有具体的、合理的 基于由研究人员生成的初步数据，在OS中靶向SCF-Skp 2轴的原因 PI及其同事：（1）Skp 2在OS组织中的高表达预示着OS患者预后不良， （2）在许多OS细胞类型中观察到高水平的Skp 2，包括已建立的细胞 细胞系、患者来源的异种移植物和来自OS患者的原代培养物;（3）Skp 2缺失 在Rb 1/p53缺陷小鼠模型中有效阻断垂体和前列腺肿瘤发生。在 OS，基因组测序研究揭示了Rb 1/p53共失活的高速率，表明 OS可能对Skp 2阻断敏感;（4）遗传和药物诱导的Skp 2耗竭 减少OS细胞系的增殖和侵袭;（5）小鼠胚胎成纤维细胞 (MEF)Rb 1/p53缺失的OS肿瘤细胞对SCF-Skp 2抑制更敏感 比野生型和Skp 2缺失的细胞。总之，这些数据表明，SCF-Skp 2 复杂的可能提供了一个独特的治疗机会，治疗一个巨大的挑战， 我们假设，在肿瘤的背景下，SCF-Skp 2复合物的阻断， Rb 1/p53失活将减少OS进展。这一假设将由 具体目标1（致癌机制）：定义原癌基因 在Rb 1/p53失活的OS中SCF-Skp 2的作用机制。特异性目的2（翻译 治疗）：为了确定在Rb 1/p53的临床前模型中抑制SCF-Skp 2的作用， 最后，由于癌症类器官代表了一种新兴技术， 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OS类器官中的Skp 2作为概念验证，将结果转化为患者特异性 未来的治疗。本研究的成功完成将转化为目标 SCF-Skp 2复合物阻断骨肉瘤进展。