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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.

项目总结