Connecting Genomic Alterations in Liposarcomas with Drug Responses and Identification of New Therapeutic Approaches

将脂肪肉瘤的基因组改变与药物反应联系起来并确定新的治疗方法

• 批准号: 9919544
• 负责人: Harold Phillip Koeffler
• 金额: $ 36.31万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919544
• 关键词: Address; Adult; Affect; Animal Model; Biological Markers; CRISPR screen; CRISPR/Cas technology; Cancer cell line; Cell Line; Cells; Clinical; Clinical Trials; Clone Cells; Collaborations; Collection; DNA Sequence Alteration; Data; Databases; Dependence; Development; Diagnosis; Disease; Drug Addiction; Drug Combinations; Drug Interactions; Drug resistance; Engineering; Evaluation; FDA approved; Family; Gene Mutation; Genes; Genetic; Genetic Determinism; Genetic Engineering; Genetic Predisposition to Disease; Genome; Genomics; Genotype; Histologic; Individual; Institutes; Investigation; Lentivirus Vector; Libraries; Link; Malignant Neoplasms; Manuscripts; Medical; Mesenchymal; Mesenchymal Stem Cells; Modeling; Modification; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Neoplasms; Oregon; Pathway Analysis; Patients; Pharmaceutical Preparations; Phosphotransferases; Recurrence; Resistance; Sampling; Series; Small Interfering RNA; Soft tissue sarcoma; System; Therapeutic; Universities; Unresectable; base; cancer cell; cell transformation; chemotherapy; clinical implementation; clinical investigation; clinically relevant; cohort; drug candidate; drug development; drug discovery; drug market; drug sensitivity; experimental study; genome-wide; high throughput screening; high-throughput drug screening; innovation; insight; liposarcoma; loss of function; mortality; novel; novel strategies; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; personalized medicine; resistance mechanism; response; screening; small molecule; small molecule libraries; stem; targeted treatment; therapeutic target; tumor

PROJECT SUMMARY Approximately 12,000 individuals in the USA will develop soft tissue sarcoma in 2015. In adults, liposarcoma (LPS) is one of the most common types of soft tissue sarcoma. Though rare, LPS tumors are often very aggressive with high morbidity and mortality rates. Resistance to conventional chemotherapeutics and lack of effective targeted therapies create a critical need to develop novel treatment options for patients with this devastating disease. Recent large-scale analyses by us and other groups have provided a comprehensive view of the genomic landscape of LPS. Despite the new insights, these studies, for the most part have not translated into definitive therapeutic strategies. One challenge is determining how individual gene -drug relationships affect drug responses ; a second challenge is that many of the genetic alterations identified in LPS have not been paired to a suitable targeted therapy. Synthetic lethality is an attractive approach for selective therapeutic targeting of cancer cells lacking otherwise obvious actionable genetic vulnerabilities. Large-scale cancer cell line screens helped uncover synthetic lethal interactions that link genetic determinants to drug responses; yet due to the complexity of most cancer cell lines, distinguishing the relevance of single mutations to the impact of a drug remains difficult. In the current proposal we will use an innovative approach to address these challenges. Our aim is to link specific LPS associated genetic alterations with sensitivities to multiple clinically relevant compounds. Thus, our study will begin to bridge the gap between the plethora of genetic alterations that we and others identified in LPS genomes and clinical implementation. We will use a novel screening strategy based on partly transformed mesenchymal stem cells (MSC) which we will genetically engineer to express a series of specific, recurrent LPS genotypic alterations. The resulting panel of isogenic clones and parental control cells will be subjected to high-throughput small molecule and siRNA screens (Collaboration with Dr. J. Tyner, Oregon University, Portland, and Sanford Burnham, La Jolla). Results will be validated and functionally investigated in LPS cell lines and animal models. In addition, we will perform a cutting-edge, genome-wide CRISPR screen to identify drugs that synergize with a leading compound that we will identify in our initial screens. Impact: We will conduct an integrative analysis of drug sensitivities p athway alterations and genotype-specific dependencies in a panel of isogenic MSC clones; results are likely to uncover previously unexpected gene-drug interactions that will allow us to nominate actionable therapeutic targets and suggest combinational treatments to mitigate drug resistance. Ultimately, our study will help guide new clinical trials for various investigational and help develop new genotype- , FDA-approved and drugs, directed therapies for subsets of LPS patients currently lacking satisfactory therapeutic options.

项目摘要 2015年，美国大约有12,000个人将在2015年发展软组织肉瘤。 （LPS）是软组织肉瘤的最常见类型之一。尽管很少见，但LPS肿瘤通常非常 具有高发病率和死亡率的积极性。对常规化学治疗药的抵抗力和缺乏 有效的靶向疗法提出了为患者开发新的治疗选择的迫切需求 毁灭性疾病。我们和其他小组最近进行的大规模分析提供了 综合的 LPS的基因组景观的视图。尽管有新的见解，但这些研究大部分都没有 翻译成 确定的治疗策略。一个挑战是确定单个基因 -药品 关系 影响药物反应 ;第二个挑战是LPS中发现的许多遗传改变 尚未与合适的靶向疗法配对。合成致死性是一种有吸引力的选择性方法 癌细胞的治疗靶向缺乏其他明显的可行遗传脆弱性。大规模 癌细胞系筛查有助于发现合成的致命相互作用，将遗传决定因素与药物联系起来 回应；然而，由于大多数癌细胞系的复杂性，区分了单个突变的相关性 对药物的影响仍然很困难。在当前的建议中，我们将使用一种创新的方法来解决 这些挑战。我们的目的是将特定LPS相关的遗传变化与敏感性联系起来 多种临床相关化合物。因此，我们的研究将开始弥合大量的差距 我们和其他人在LPS基因组和临床实施中发现的遗传改变。我们将使用一个 基于部分转化的间充质干细胞（MSC）的新型筛选策略，我们将在基因上进行基因 工程师表达一系列特定的复发性LPS基因型改变。产生的等源图 克隆和亲本控制细胞将受到高通量小分子和siRNA筛选 （与俄勒冈大学波特兰大学的J. Tyner博士和La Jolla的Sanford Burnham合作）。结果将是 在LPS细胞系和动物模型中进行了验证和功能研究。此外，我们将执行 尖端，全基因组CRISPR屏幕，以识别与我们的主要化合物协同作用的药物 将在我们的初始屏幕中标识。影响：我们将对药物敏感性进行综合分析 P Athway的变化和基因型特异性依赖性在一系列等源MSC克隆中；结果可能是 揭示以前出乎意料的基因 - 药物相互作用，这将使我们能够提名可操作的治疗 靶标并建议组合治疗以减轻耐药性。最终，我们的研究将帮助指导 各种研究的新临床试验，并有助于开发新的基因型 - ，，，， FDA批准和毒品， 目前缺乏令人满意的治疗选择的LPS患者子集的定向疗法。

项目成果

MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma.

• DOI: 10.1038/s41388-021-01661-4
• 发表时间: 2021-03
• 期刊: Oncogene
• 影响因子: 8
• 作者: Ke XY;Chen Y;Tham VY;Lin RY;Dakle P;Nacro K;Puhaindran ME;Houghton P;Pang A;Lee VK;Ding LW;Gery S;Hill J;Chen L;Xu L;Koeffler HP
• 通讯作者: Koeffler HP

Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT).

• DOI: 10.1038/s41467-023-37633-3
• 发表时间: 2023-04-06
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Kusuma, Frances Karla;Prabhu, Aishvaryaa;Tieo, Galen;Ahmed, Syed Moiz;Dakle, Pushkar;Yong, Wai Khang;Pathak, Elina;Madan, Vikas;Jiang, Yan Yi;Tam, Wai Leong;Kappei, Dennis;Droge, Peter;Koeffler, H. Phillip;Jeitany, Maya
• 通讯作者: Jeitany, Maya

Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas.

• DOI: 10.1007/s00018-020-03620-w
• 发表时间: 2021-03
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Jeitany M;Prabhu A;Dakle P;Pathak E;Madan V;Kanojia D;Mukundan V;Jiang YY;Landesman Y;Tam WL;Kappei D;Koeffler HP
• 通讯作者: Koeffler HP

Treatment for ovarian clear cell carcinoma with combined inhibition of WEE1 and ATR.

• DOI: 10.1186/s13048-023-01160-y
• 发表时间: 2023-04-22
• 期刊: JOURNAL OF OVARIAN RESEARCH
• 影响因子: 4
• 作者: Chien, Wenwen;Tyner, Jeffrey W. W.;Gery, Sigal;Zheng, Yueyuan;Li, Li-Yan;Pillai, Mohan Shankar Gopinatha;Nam, Chehyun;Bhowmick, Neil A. A.;Lin, De-Chen;Koeffler, H. Phillip
• 通讯作者: Koeffler, H. Phillip

Topography of transcriptionally active chromatin in glioblastoma.

• DOI: 10.1126/sciadv.abd4676
• 发表时间: 2021-04
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Xu L;Chen Y;Huang Y;Sandanaraj E;Yu JS;Lin RY;Dakle P;Ke XY;Chong YK;Koh L;Mayakonda A;Nacro K;Hill J;Huang ML;Gery S;Lim SW;Huang Z;Xu Y;Chen J;Bai L;Wang S;Wakimoto H;Yeo TT;Ang BT;Müschen M;Tang C;Tan TZ;Koeffler HP
• 通讯作者: Koeffler HP