Studies on Lineage Plasticity in Prostate Cancer

前列腺癌谱系可塑性的研究

基本信息

批准号：
10722935
负责人：
SAMIR ZAIDI
金额：
$ 27.77万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722935
关键词：
ATAC-seq Adenocarcinoma Advisory Committees Androgen Receptor BRAF gene Biological Biopsy CRISPR/Cas technology Cancer Model Cancer Patient Cancerous Cells Chemicals Clinical Collaborations Combined Modality Therapy Competence DNA Data Doxycycline Drug Combinations Drug resistance Environment Epidermal Growth Factor Receptor Estrogen receptor positive Event Evolution FDA approved FGFR1 gene FGFR3 gene Fibroblast Growth Factor Receptors Funding Future Genetic Genetic Models for Cancer Genitourinary system Genomics Goals Grant Histology Human Kinetics Knockout Mice Lead Lung MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Memorial Sloan-Kettering Cancer Center Mentors Modeling Molecular Morphology Mus NOD/SCID mouse Neurosecretory Systems Oncogenic Oncology Organoids Outcome PIK3CG gene Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phosphorylation Physicians Positioning Attribute Predictive Factor Process Prostate Protein Isoforms Proto-Oncogene Proteins c-akt RB1 gene RNA Randomized Receptor Signaling Research Research Personnel Resistance Resources STAT1 gene STAT3 gene Safety Sampling Science Signal Pathway Signal Transduction TP53 gene Testosterone Therapeutic Time Training Translations Transplantation Tumor Suppressor Genes Tumor Weights XCL1 gene cancer cell castration resistant prostate cancer computerized tools efficacy evaluation enzalutamide in vivo inhibitor malignant breast neoplasm melanoma mouse model multiple omics mutant novel overexpression pharmacologic programs receptor expression resistance mechanism single-cell RNA sequencing subcutaneous success synergism targeted agent targeted cancer therapy therapy resistant transcription factor transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY Despite the remarkable successes of targeted cancer therapies, certain cancers, including lung, breast, and prostate cancer and melanoma, invariably become resistant to therapy. One mechanism of secondary resistance—lineage plasticity—arises when cells transition into aggressive states, and, in the case of prostate cancer, acquire a neuroendocrine histology. This results in a rapid downhill course for a subset of the so–termed castrate–resistant prostate cancer (CRPC) patients. This, in essence, not only poses a clinical challenge, but also confronts us with a wide–open biological question—what are the molecular underpinnings of lineage plasticity, and importantly, can the process be reversed? We have very recently documented that the activation of JAK/STAT and FGFR signaling pathways promote lineage plasticity and result in complete insensitivity to androgen receptor signaling inhibitors (ARSIs) [*Chan, *Zaidi, et al., Science, 2022, PMID: 35981096, *co– first authors]. Importantly, we found that FDA–approved inhibitors of JAK/STAT (ruxolitinib) and FGFR (erdafitinib) synergize to reverse lineage plasticity and restore ARSI sensitivity. We therefore hypothesize that signals downstream of JAK/STAT and FGFR, including novel transcription factors, interact to promote lineage plasticity, and their timed perturbation can reverse plasticity and ARSI insensitivity. Thus, in Specific Aim 1, to study how FGFR signals synergize with JAK/STAT to impart plasticity, we will use chemical inhibitors and CRISPR–Cas9 to delete specific molecules in TP53/RB1–null mouse and human tumor organoids. Specific Aim 2 will focus on further deconvoluting the molecular complexity of lineage plasticity through unbiased single cell paired RNA and ATAC (multiome) sequencing in murine organoids. We expect to identify novel transcription factors and study their DNA accessibility post–TP53/RB1 deletion across the evolution of lineage plasticity, with and without ruxolitinib and/or erdafitinib. In Specific Aim 3, in proof–of–concept in vivo studies, we will examine the efficacy of combined treatment with ruxolitinib plus erdafitinib in reversing lineage plasticity and restoring ARSI sensitivity. For this, the ruxolitinib+erdafitinib combination will be studied in NOD SCID mice grafted either with TP53/RB1–null murine organoids, orthotopically, or with the human tumoroid MSK–PCA3, subcutaneously. These studies will not only inform future therapeutic strategies to subvert drug resistance in CRPC patients but should also provide a unique platform for my Training Aims. Under the tutelage of my primary mentor, Dr. Charles Sawyers, and my Advisory Committee, I expect to enhance my competencies in advanced computation, cancer modeling and genetic editing, and bedside translation. Together with the rich scientific environment and vast array of resources at MSKCC, my research and training should position me to achieve my goal of becoming an independently funded physician–investigator in genitourinary oncology by the end of this grant period.

项目概要尽管靶向癌症治疗取得了显着的成功，但某些癌症，包括肺癌、乳腺癌和前列腺癌和黑色素瘤总是对治疗产生耐药性的一种机制。当细胞转变为攻击状态时，抵抗力（谱系可塑性）就会上升，就前列腺而言癌症，获得神经内分泌组织学，这导致所谓的子集的快速走下坡路。从本质上讲，这不仅带来了临床挑战，而且还对去势抵抗性前列腺癌（CRPC）患者进行了治疗。也让我们面临一个广泛开放的生物学问题——谱系的分子基础是什么可塑性，重要的是，这个过程可以逆转吗？我们最近记录了激活过程 JAK/STAT 和 FGFR 信号通路的存在促进谱系可塑性并导致对雄激素受体信号抑制剂 (ARSI) [*Chan, *Zaidi, et al., Science, 2022, PMID: 35981096, *co– 第一作者]。重要的是，我们发现 FDA 批准的 JAK/STAT (ruxolitinib) 和 FGFR 抑制剂（erdafitinib）协同逆转谱系可塑性并恢复 ARSI 敏感性因此我们捕捉到了这一点。 JAK/STAT 和 FGFR 下游信号（包括新型转录因子）相互作用以促进谱系可塑性，以及它们的定时扰动可以逆转可塑性和 ARSI 不敏感性，因此，在特定目标 1 中，研究 FGFR 信号如何与 JAK/STAT 协同作用以赋予可塑性，我们将使用化学抑制剂和 CRISPR–Cas9 可删除 TP53/RB1 缺失小鼠和人类肿瘤类器官中的特定分子。目标 2 将侧重于通过无偏单项进一步解卷积谱系可塑性的分子复杂性小鼠类器官中的细胞配对 RNA 和 ATAC（多组）测序我们期望鉴定新的转录。因素并研究其在谱系可塑性进化过程中 TP53/RB1 缺失后的 DNA 可及性，在特定目标 3 中，在体内概念验证研究中，我们将检查没有 ruxolitinib 和/或 erdafitinib。鲁索替尼联合厄达菲替尼联合治疗逆转谱系可塑性和恢复的功效为此，将在移植的 NOD SCID 小鼠中研究鲁索替尼 + erdafitinib 组合。与 TP53/RB1 缺失的鼠类器官进行原位注射，或与人肿瘤样 MSK-PCA3 进行皮下注射。这些研究不仅将为未来颠覆 CRPC 患者耐药性的治疗策略提供信息，而且还应该在我的主要导师 Dr. 的指导下为我的培训目标提供一个独特的平台。 Charles Sawyers 和我的咨询委员会，我希望提高我在高级计算方面的能力，癌症建模和基因编辑、临床翻译以及丰富的科学环境和。 MSKCC 拥有大量资源，我的研究和培训应该使我能够实现成为在此资助期结束时，一名独立资助的泌尿生殖肿瘤学医师兼研究员。