New Therapeutic Targets in Small Cell Lung Cancer that are Epistatic or Synthetic Lethal with pRB Loss

小细胞肺癌的新治疗靶点在 pRB 丢失时上位或合成致死

• 批准号: 10224131
• 负责人: Matthew Gilbert Oser
• 金额: $ 17.71万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224131
• 关键词: ASCL1 gene; Adult; Advisory Committees; Alleles; Area; Award; Binding; Biochemical; Biochemical Genetics; Biological Assay; Breeding; Bypass; CRISPR screen; Cancer Biology; Cancer Etiology; Cancer Patient; Cancer cell line; Candidate Disease Gene; Career Choice; Cells; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Dana-Farber Cancer Institute; Data; Dependence; Dependovirus; Development; Doxycycline; Environment; Faculty; Fluorescence; Future; Genes; Genetic; Genetically Engineered Mouse; Goals; In Vitro; Infection; Laboratories; Lung; Maintenance; Malignant neoplasm of lung; Manuscripts; Medical Oncologist; Mentors; Microscopy; Mitotic; Modeling; Mus; Mutate; Neuroendocrine Tumors; Neurosecretory Systems; Pathogenesis; Patient Care; Patients; Phenotype; Preparation; Proteins; RB1 gene; Repression; Research; Research Personnel; Research Training; Retinoblastoma Protein; Role; Solid Neoplasm; System; TP53 gene; Testing; Tetanus Helper Peptide; Thoracic Oncology; Time; Transcription Coactivator; Transcription Repressor; Transgenic Organisms; Tumor Suppressor Genes; Validation; aurora B kinase; base; candidate validation; career development; driver mutation; genetic approach; histone demethylase; in vivo; insight; loss of function; loss of function mutation; lung small cell carcinoma; medical schools; member; nanoparticle; neuroendocrine cancer; neuroendocrine differentiation; neuroendocrine phenotype; new therapeutic target; novel; novel therapeutics; pre-clinical; programs; research and development; segregation; symposium; targeted treatment; tenure track; therapeutic candidate; therapeutic target; time use; tumor; tumor initiation

Project Summary/Abstract Small cell lung cancer (SCLC) is a high-grade neuroendocrine cancer with no effective targeted therapies. Identifying therapeutic targets in SCLC has been challenging, partly because driver mutations in SCLC are primarily loss of function, involving the tumor suppressor genes RB1 and TP53. While TP53 is highly mutated in many adult solid tumors, the near-universal loss of RB1 (protein pRB) is unique to SCLC. I propose to identify new therapeutic targets in SCLC by investigating epistatic and synthetic lethal interactions with pRB loss, with the former being targets acting downstream of pRB and the latter representing dependencies created specifically by pRB loss. I have employed both of these strategies to identify two novel targets, KDM5A and AURKB, that are required for SCLC proliferation and whose specific function is to regulate neuroendocrine differentiation and chromosomal segregation, respectively. In Aim 1, I will use biochemical and genetic approaches to determine the specific mechanism by which KDM5A regulates ASCL1, a pulmonary neuroendocrine lineage transcriptional activator that is required for SCLC tumor formation. In Aim 2, based on my preliminary data from a CRISPR screen, I hypothesize that other regulators of chromosomal segregation are synthetic lethal with RB1 loss. I will use direct fluorescence-based competition assays to validate true synthetic lethal interactions. I will then use time-lapse microscopy to determine the underlying mechanism by which pRB loss exacerbates the mitotic phenotype caused by loss of other chromosomal segregation genes. In Aim 3, I will ask whether KDM5A is necessary for tumor initiation and/or tumor maintenance in vivo using a novel CRISPR-based genetically-engineered mouse model of SCLC that I developed. I'm a medical oncologist with a research background in cancer biology applying for a K08 award with a long-term goal of becoming a tenure-track independent laboratory investigator. I envision developing an independent research program investigating the mechanisms responsible for SCLC pathogenesis with the ultimate goal of identifying new therapies for SCLC patients. During my proposed K08 research training, I will perform mentored research in the laboratory of Dr. William Kaelin at the Dana-Farber Cancer Institute (DFCI). I plan to spend 90% of my time on research and 10% on patient care seeing thoracic oncology patients. I have organized an outstanding advisory committee to help guide my research and career development with faculty members at DFCI, Harvard Medical School, and MIT that are experts in specific areas of my proposed research including: Dr. Stuart Orkin, Dr. David Pellman, Dr. Tyler Jacks, and Dr. Stephen Blacklow. Dr. Bruce Johnson, a world-renowned lung cancer clinical trialist, will serve as my clinical advisor. This outstanding environment at DFCI supplemented with coursework and conferences will help me achieve my long-term career aspirations.

项目总结/文摘

项目成果

Small-Cell Neuroendocrine Tumors: Cell State Trumps the Oncogenic Driver.

• DOI: 10.1158/1078-0432.ccr-17-3646
• 发表时间: 2018-04-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Oser MG;Jänne PA
• 通讯作者: Jänne PA

Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1.

• DOI: 10.1038/s41467-022-31998-7
• 发表时间: 2022-08-25
• 期刊: Nature communications
• 影响因子: 16.6