Targeting Non-Canonical STING Signaling to Treat SPOP Mutant Castration-Resistant Prostate Cancer

靶向非经典 STING 信号传导治疗 SPOP 突变去势抵抗性前列腺癌

• 批准号: 10709358
• 负责人: Timothy Charles Thompson
• 金额: $ 66.83万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709358
• 关键词: Aftercare; Androgens; Apoptotic; Automobile Driving; Binding Proteins; Biological Markers; Blood specimen; CHD1 gene; Castrate sensitive prostate cancer; Castration; Cell Survival; Cell model; Cells; Chromatin Remodeling Factor; Clinical; Clinical Data; Clinical Markers; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Consensus; Cullin Proteins; DNA Damage; DNA Sequence Alteration; DNA analysis; Data Set; Epithelium; Equilibrium; Evaluation; Genes; Genetic; Growth; Heterozygote; High Mobility Group Proteins; Human; Immune signaling; Interferon-beta; Interleukin-6; Macrophage; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Methods; Missense Mutation; Modeling; Mus; Mutation; Other Genetics; Pathway interactions; Patients; Phenotype; Phosphorylation; Poly(ADP-ribose) Polymerase Inhibitor; Proteins; Proteomics; Regulation; Resistance; Role; STAT3 gene; Sampling; Signal Transduction; Stat3 protein; Stimulator of Interferon Genes; T-Lymphocyte; Testing; The Cancer Genome Atlas; Therapeutic Effect; Tissue Sample; Treatment Efficacy; Tumor Suppressor Genes; Up-Regulation; castration resistant prostate cancer; cell growth; chromatin protein; cytokine; experimental study; genetic signature; in vivo; mutant; neoplastic cell; neutralizing antibody; paracrine; patient biomarkers; patient subsets; prostate cancer cell; prostate cancer model; recruit; resistance mechanism; response; stable isotope; targeted treatment; therapeutic evaluation; tumor; tumor growth; tumor microenvironment; ubiquitin ligase

PROJECT SUMMARY/ABSTRACT Tumor suppressor gene speckle-type POZ protein (SPOP), a substrate adaptor of cullin3-RING ubiquitin ligase, demonstrates heterozygous missense mutations in up to 15% of prostate cancers, yet the functional significance of these SPOP mutations is largely unknown. We identified SPOP-binding consensus motifs in multiple proteins of the canonical cGAS-STING and non-canonical STING-NF-κB pathways and demonstrated that human and mouse STING protein is a bona fide SPOP target. Analysis of SPOP mutant (SPOPmut) and SPOP wild-type (SPOPwt) castration-resistant prostate cancer (CRPC) clinical data sets revealed a 29-gene “SPOPmut gene signature”, which reflected STING-NF-κB signaling activity and suggested a role for the recruitment of tumor microenvironment (TME)–facilitated tumor cell growth and survival in SPOPmut CRPC. Further evaluation of the “SPOPmut gene signature” in primary, untreated prostate cancer from TCGA revealed a subset of SPOP mutant tumors, as well as a subset of CHD1 mutant (CHD1mut) tumors, that are enriched for the signature. Importantly, co-mutations in SPOP and CHD1 (chromatin remodeling factor) are well documented. In stably transduced human and mouse SPOPmut (SPOPF102C and SPOPF133V)–expressing CRPC models, we demonstrated upregulation of non-canonical STING-NF-κB-IL-6 pathway proteins, STAT3, and HMG proteins involved in promoting secretory pathway activities. We also showed that PARP inhibitor (PARPi) treatment of SPOPmut CRPC cells induces DNA damage, activates canonical cGAS-STING-TBK-IFN-ß signaling and suppresses non- canonical STING-NF-κB-IL-6/STAT3, in part through inhibitory phosphorylation (S754-STAT3), leading to growth suppression and apoptotic signaling. Olaparib (OLA) increased IFN-β secretion and reduced viability to a greater extent in SPOPmut prostate cancer cells than in control cells in coculture with macrophages versus monoculture. In addition, activation of cGAS-STING and induction of IFN-ß in macrophages were demonstrated only in OLA- treated coculture models, and neutralizing antibody experiments showed that paracrine regulation of OLA- mediated growth suppression involved IFN-β induction and IL-6 suppression of SPOPmut prostate cancer cells. We hypothesize that SPOPmut, CHD1 deletion (CHD1del) and SPOP + CHD1 co-mutations in prostate cancers promote PARPi or PARPi + anti-IL-6 therapeutic efficacy through enhanced synthetic lethality driven by increased, unrepaired DNA damage, which leads to a shift in the balance toward canonical cGAS-STING-IFN-ß signaling and suppression of IL-6/STAT3. We propose to analyze the underlying mechanisms of the SPOPmut and CHD1del prostate cancer phenotype and define these genetically driven TME alterations and their protein effectors through macrophage reprogramming using state-of-the-art proteomics (Aim 1); analyze the efficacy of PARPi and anti-IL-6 treatment in SPOPmut (F133V), CHD1del, and SPOPmut;CHD1del RM-1-BM syngeneic CRPC models (Aim 2); and analyze clinical trial tissue and blood samples from PARPi-treated SPOPmut and CHD1mut prostate cancer patients for biomarkers of this genetically driven phenotype (Aim 3).

项目总结/文摘