Subtype Of Prostate Cancer Research Articles

Role of non-coding RNA in lineage plasticity of prostate cancer.

The treatment of prostate cancer (PCa) has made great progress in recent years, but treatment resistance always develops and can even lead to fatal disease. Exploring the mechanism of drug resistance is of great significance for improving treatment outcomes and developing biomarkers with predictive value. It is increasingly recognized that mechanism of drug resistance in advanced PCa is related to lineage plasticity and tissue differentiation. Specifically, one of the mechanisms by which castration-resistant prostate cancer (CRPC) cells acquire drug resistance and transform into neuroendocrine prostate cancer (NEPC) cells is lineage plasticity. NEPC is a subtype of PCa that is highly aggressive and lethal, with a median survival of only 7 months. With the development of high-throughput RNA sequencing technology, more and more non-coding RNAs have been identified, which play important roles in different diseases through different mechanisms. Several ncRNAs have shown great potential in PCa lineage plasticity and as biomarkers. In the review, the role of ncRNA in PCa lineage plasticity and its use as biomarkers were reviewed.

CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12/Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten-null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12/Trp53-null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation mediates genomic instability by inducing transcription-replication conflicts. Strikingly, CDK12-mutant organoids and patient-derived xenografts are sensitive to inhibition or degradation of the paralog kinase, CDK13. We therein establish CDK12 as a bona fide tumor suppressor, mechanistically define how CDK12 inactivation causes genomic instability, and advance a therapeutic strategy for CDK12-mutant mCRPC.

Synthetic Lethal Targeting of Cyclin Dependent Kinase-12-Deficient Prostate Cancer with PARP Inhibitors.

CDK12 is a cyclin-dependent kinase (CDK) that is mutated or amplified in multiple cancers. We previously described a subtype of prostate cancer (PC) characterized predominantly by frameshift, loss-of-function mutations in CDK12. This subtype exhibits aggressive clinical features. Using isogenic PC models generated by CRISPR/Cas9-mediated inactivation of CDK12, we conducted a chemical library screen of ~1800 FDA-approved drugs. We inhibited cyclin K and CDK13 and evaluated the effects on poly ADP-ribose polymerase inhibitor (PARPi) sensitivity. CDK12 truncation and kinase domain mutations were expressed in cell lines to determine effects on PARPi sensitivity. Mice bearing control and CDK12 mutant prostate tumors were treated with rucaparib. Finally, we evaluated prostate specific antigen (PSA) responses in patients with CDK12 mutations treated with rucaparib on the TRITON2 trial. Cancer cells lacking CDK12 are more sensitive to PARPi than isogenic wild-type cells, and sensitivity depends on the degree of CDK12 inhibition. Inhibiting cyclin K, but not CDK13, also led to PARPi sensitivity and suppressed homologous recombination. CDK12 truncation mutants remained sensitive to PARPi, whereas kinase domain mutants exhibited intermediate sensitivity. The PARPi rucaparib suppressed tumor growth in mice bearing CDK12-mutated tumors. Finally, 6 of 11 (55%) PC patients with biallelic CDK12 mutations had reductions in serum PSA levels when treated with rucaparib on the TRITON2 clinical trial. In PC, sensitivity to PARPi is dependent on the specific type and zygosity of the CDK12 mutation. PARPi monotherapy may have some activity in PC patients with biallelic inactivating CDK12 alterations.

Abstract C097: PVT1 exon 9-dependent overexpression of RSAD2 is a characteristic of prostate cancer in males of African ancestry

Abstract Aggressive prostate cancer (PCa), including castrate-resistant and neuroendocrine subtypes, is projected to increase in incidence 5% each year. Aggressive PCa disproportionally impacts African American men, has limited effective treatment options and high mortality rates. Although racial disparities are established in PCa development, attributed to multiple contributory factors including systemic racism, differences in socioeconomic status and distrust in the medical system, work is still needed to understand the contribution of biological factors. We found the exon 9 region of plasmacytoma variant translocation 1 (PVT1) overexpressed in aggressive PCa cell lines derived from African American (AA) men. We found PVT1 exon 9 overexpression induced phenotypic changes to normal prostate epithelial cells in vitro and led to tumor formation in vivo. RNA-sequencing analysis revealed 156 significantly differentially expressed genes influenced by PVT1 exon 9 overexpression and radical S-adenosyl methionine domain containing 2 (RSAD2) was the top significantly overexpressed gene (log2Fold change 1.71, p-value < 0.05). We utilized the GSE223405 publicly available dataset to identify whether our identified PVT1 exon 9 downstream genes were enriched in AA prostate cancer cells. RSAD2 was significantly overexpressed in AA prostate cancer cells compared to prostate cancer cells from men of European ancestry (moEA) (log2Fold change 6.18, p-value < 0.05). Comparing normal cells to prostate cancer cells between these groups, we found that normal AA prostate cells had significantly higher expression of RSAD2 (log2fold change 4.25, p-value < 0.001) whereas moEA samples did not (log2fold change 0.837, p-value=0.150). From analysis of data obtained from cBioPortal, we found RSAD2 alteration significantly correlates (p-value < 0.001) with self-identified race and copy number overexpression of RSAD2 was found to be enriched in AA patients (18.16% moEA versus 24% AA). Finally, we found 88.6% of the significantly differentially expressed genes within our PVT1 exon 9 RNA-sequencing dataset were significantly differentially expressed in GSE223405 AA samples and of those, 51.7% of genes exhibited a similar differential expression pattern suggesting that the PVT1 exon 9/RSAD2 dependent pathway may be more prominent in AA men. Mechanistically, we found two differing pathways of RSAD2 overexpression in aggressive prostate cancer cell models, one dependent and one independent of PVT1 exon 9 overexpression, with similar but differing biological functions related to epigenetic processes and metabolism. Ongoing work is investigating the RSAD2 and PVT1 exon 9 expression axis in a diverse set of human prostate cancer tissues and investigating their utilization as a therapeutic target in prostate cancer. Citation Format: Rachel E. Sexton-Bonacci1, Murtaza Barkarar1, Chindeum Udekwu1, Olorunseun O. Ogunwobi1. PVT1 exon 9-dependent overexpression of RSAD2 is a characteristic of prostate cancer in males of African ancestry [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C097.

The third symposium on treatment-induced neuroendocrine prostate cancer: insights and future directions.

Neuroendocrine prostate cancer (NEPC) is a rare and aggressive subtype of prostate cancer (PCa), emerging from advanced treatments and characterized by loss of androgen receptor (AR) signaling and neuroendocrine features, leading to rapid progression and treatment resistance. The third symposium on treatment-induced NEPC, held from 21 to23 June2024, at Harrison Hot Springs Resort, BC, Canada, united leading global researchers and clinicians. Sponsored by the Vancouver Prostate Centre (VPC), Canadian Institute of Health Research, Prostate Cancer Foundation Canadaand Pharma Planter Inc, the event focused on the latest NEPC research and innovative treatment strategies. Co-chaired by Drs. Yuzhuo Wang and Martin Gleave, the symposium featured sessions on NEPC's historical context, molecular pathways, epigenetic regulationand the role of the tumor microenvironment and metabolism in its progression. Keynotes from experts like Dr. Himisha Beltran and Dr. Martin Gleave highlighted the complexity of NEPC. The Emerging Talent session showcased new research, pointing to the future of NEPC treatment. The symposium concluded with a consensus on the need for early detection, targeted therapiesand personalized medicine to effectively combat NEPC, emphasizing the importance of global collaboration in advancing NEPC understanding and treatment.

A case of mixed neuroendocrine carcinoma-acinar adenocarcinoma: Utilization of triplet therapy for prostate cancer.

Neuroendocrine prostate cancer is an aggressive histological subtype of prostate cancer with a poor prognosis. Neuroendocrine prostate cancer is traditionally treated with cisplatin-based chemotherapy, similar to that used in treating small-cell lung cancer. However, the therapeutic effectiveness of chemotherapy for neuroendocrine prostate cancer has been limited. This case report describes a response to triplet therapy using darolutamide, androgen deprivation therapy, and docetaxel, which was administered in a patient with mixed neuroendocrine prostate cancer. A 77-year-old man was newly diagnosed with mixed neuroendocrine prostate cancer. Serum prostate-specific antigen, neuron-specific enolase, and progastrin-releasing peptide levels were 62.2, 40.6, and 60.6 pg/mL, respectively. Multiple lymph node metastases were identified on a computed tomography scan, and bone scintigraphy revealed multiple bone metastases. The clinical stage was determined to be cT3bN1M1b. Ultimately, tumor size and serum markers decreased with triplet therapy. We demonstrated the first case in which triplet therapy had been effective in the treatment of neuroendocrine prostate cancer.

MYBL2 Drives Prostate Cancer Plasticity: Inhibiting Its Transcriptional Target CDK2 for RB1-Deficient Neuroendocrine Prostate Cancer.

Prostate cancers that escape therapy targeting the androgen receptor signaling pathways via phenotypic plasticity are currently untreatable. Our study identifies MYBL2 as a MR-TF in phenotypic plastic prostate cancer and implicates CDK2 inhibition as a novel therapeutic target for this most lethal subtype of prostate cancer.

Neuroendocrine Prostate Cancer Drivers SOX2 and BRN2 Confer Differential Responses to Imipridones ONC201, ONC206, and ONC212 in Prostate Cancer Cell Lines.

Prostate cancer (PCa) is the leading cause death from cancer in men worldwide. Approximately 30% of castrate-resistant PCa's become refractory to therapy due to neuroendocrine differentiation (NED) that is present in <1% of androgen-sensitive tumors. First-in-class imipridone ONC201/TIC10 has shown clinical activity against midline gliomas, neuroendocrine tumors and PCa. We explored the question of whether NED promotes sensitivity to imipridones ONC201 and ONC206 by inducible overexpression of SOX2 and BRN2, well-known neuroendocrine drivers, in human PCa cell lines DU145 or LNCaP. Slight protection from ONC201 or ONC206 with SOX2 and BRN2 overexpression was observed in the inducible LNCaP cells but not in the DU145 cells. At 2 months, there was an apparent increase in CLpP expression in LNCaP SOX2-overexpressing cells but this did not confer enhanced sensitivity to ONC201. DU145 SOX2-overexpressing cells had a significantly reduced ONC201 sensitivity than DU145 control cells. The results support the idea that treatment of castrate-resistant prostate cancer by imipridones may not be significantly impacted by neuroendocrine differentiation as a therapy-resistance mechanism. The results support further testing of imipridones across subtypes of androgen-sensitive and castrate-resistant prostate cancer.

Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.

Insights into immune microenvironment and therapeutic targeting in androgen-associated prostate cancer subtypes

Prostate cancer, one of the most prevalent malignancies among men worldwide, is intricately linked with androgen signaling, a key driver of its pathogenesis and progression. Understanding the diverse expression patterns of androgen-responsive genes holds paramount importance in unraveling the biological intricacies of this disease and prognosticating patient outcomes. In this study, utilizing consensus clustering analysis based on the expression profiles of androgen-responsive genes, prostate cancer patients from the TCGA database were stratified into two distinct subtypes, denoted as C1 and C2. Notably, the C1 subtype demonstrates a significant upregulation of certain genes, such as CGA and HSD17B12, along with a shorter progression-free survival duration, indicating a potentially unfavorable prognosis. Further analyses elucidated the immune infiltration disparities, mutation landscapes, and gene functional pathways characteristic of each subtype. Through integrated bioinformatics approaches and machine learning techniques, key genes such as BIRC5, CENPA, and MMP11 were identified as potential therapeutic targets, providing novel insights into tailored treatment strategies. Additionally, single-cell transcriptome analysis shed light on the heterogeneous expression patterns of these genes across different cell types within the tumor microenvironment. Furthermore, virtual screening identified candidate drugs targeting the BIRC5 receptor, offering promising avenues for drug development. Collectively, these findings deepen our understanding of prostate cancer biology, paving the way for personalized therapeutic interventions and advancing the quest for more effective treatments in prostate cancer management.

Unveiling novel double-negative prostate cancer subtypes through single-cell RNA sequencing analysis

Recent advancements in single-cell RNA sequencing (scRNAseq) have facilitated the discovery of previously unrecognized subtypes within prostate cancer (PCa), offering new insights into cancer heterogeneity and progression. In this study, we integrated scRNAseq data from multiple studies, comprising publicly available cohorts and data generated by our research team, and established the Human Prostate Single cell Atlas (HuPSA) and Mouse Prostate Single cell Atlas (MoPSA) datasets. Through comprehensive analysis, we identified two novel double-negative PCa populations: KRT7 cells characterized by elevated KRT7 expression and progenitor-like cells marked by SOX2 and FOXA2 expression, distinct from NEPCa, and displaying stem/progenitor features. Furthermore, HuPSA-based deconvolution re-classified human PCa specimens, validating the presence of these novel subtypes. We then developed a user-friendly web application, “HuPSA–MoPSA” (https://pcatools.shinyapps.io/HuPSA-MoPSA/), for visualizing gene expression across all newly established datasets. Our study provides comprehensive tools for PCa research and uncovers novel cancer subtypes that can inform clinical diagnosis and treatment strategies.

Proteomic landscape profiling of primary prostate cancer reveals a 16-protein panel for prognosis prediction

Prostate cancer (PCa) is the most common malignant tumor in men. Currently, there are few prognosis indicators for predicting PCa outcomes and guiding treatments. Here, we perform comprehensive proteomic profiling of 918 tissue specimens from 306 Chinese patients with PCa using data-independent acquisition mass spectrometry (DIA-MS). We identify over 10,000 proteins and define three molecular subtypes of PCa with significant clinical and proteomic differences. We develop a 16-protein panel that effectively predicts biochemical recurrence (BCR) for patients with PCa, which is validated in six published datasets andone additional 99-biopsy-sample cohort by targeted proteomics. Interestingly, this 16-protein panel effectively predicts BCR across different International Society of Urological Pathology (ISUP) grades and pathological stages and outperforms the D'Amico risk classification system in BCR prediction. Furthermore, double knockout of NUDT5 and SEPTIN8, two components from the 16-protein panel, significantly suppresses the PCa cells to proliferate, invade, and migrate, suggesting the combination of NUDT5 and SEPTIN8 may provide new approaches for PCa treatment.

Rare histological prostate cancer subtypes: Cancer-specific and other-cause mortality.

To assess cancer-specific mortality (CSM) and other-cause mortality (OCM) rates in patients with rare histological prostate cancer subtypes. Using the Surveillance, Epidemiology, and End Results database (2004-2020), we applied smoothed cumulative incidence plots and competing risks regression (CRR) models. Of 827,549 patients, 1510 (0.18%) harbored ductal, 952 (0.12%) neuroendocrine, 462 (0.06%) mucinous, and 95 (0.01%) signet ring cell carcinoma. In the localized stage, five-year CSM vs. OCM rates ranged from 2 vs. 10% in acinar and 3 vs. 8% in mucinous, to 55 vs. 19% in neuroendocrine carcinoma patients. In the locally advanced stage, five-year CSM vs. OCM rates ranged from 5 vs. 6% in acinar, to 14 vs. 16% in ductal, and to 71 vs. 15% in neuroendocrine carcinoma patients. In the metastatic stage, five-year CSM vs. OCM rates ranged from 49 vs. 15% in signet ring cell and 56 vs. 16% in mucinous, to 63 vs. 9% in ductal and 85 vs. 12% in neuroendocrine carcinoma. In multivariable CRR, localized neuroendocrine (HR 3.09), locally advanced neuroendocrine (HR 9.66), locally advanced ductal (HR 2.26), and finally metastatic neuroendocrine carcinoma patients (HR 3.57; all p < 0.001) exhibited higher CSM rates relative to acinar adenocarcinoma patients. Compared to acinar adenocarcinoma, patients with neuroendocrine carcinoma of all stages and locally advanced ductal carcinoma exhibit higher CSM rates. Conversely, CSM rates of mucinous and signet ring cell adenocarcinoma do not differ from those of acinar adenocarcinoma.

Comparison of Multiparametric MRI-targeted and Systematic Biopsies for Detection of Cribriform and Intraductal Carcinoma Prostate Cancer.

Background Intraductal carcinoma (IDC) and invasive cribriform (Cr) subtypes of prostate cancer (PCa) are an indication of aggressiveness, but the evidence regarding whether MRI can be used to detect Cr/IDC-pattern PCa is contradictory. Purpose To compare the detection of Cr/IDC-pattern PCa at multiparametric MRI (mpMRI)-targeted biopsy versus systematic biopsy in biopsy-naive men at risk for PCa. Materials and Methods This study was a secondary analysis of a prospective randomized controlled trial that recruited participants with a clinical suspicion of PCa between April 2017 and November 2019 at five centers. Participants were randomized 1:1 to either the MRI arm or the systematic biopsy arm. Targeted biopsy was performed in participants with a Prostate Imaging Reporting and Data System score of at least 3. MRI features were recorded, and biopsy slides and prostatectomy specimens were reviewed for the presence or absence of Cr/IDC histologic patterns. Comparison of Cr/IDC patterns was performed using generalized linear mixed modeling. Results A total of 453 participants were enrolled, with 226 in the systematic biopsy arm (median age, 65 years [IQR, 59-70 years]; 196 biopsies available for assessment) and 227 in the mpMRI-targeted biopsy arm (median age, 67 years [IQR, 60-72 years]; 132 biopsies available for assessment). Identification of Cr/IDC PCa was lower in the systematic biopsy arm compared with the mpMRI arm (31 of 196 biopsies [16%] vs 33 of 132 biopsies [25%]; P = .01). No evidence of a difference in mean cancer core length (CCL) (11.3 mm ± 4.4 vs 9.7 mm ± 4.5; P = .09), apparent diffusion coefficient (685 µm2/sec ± 178 vs 746 µm2/sec ± 245; P = .52), or dynamic contrast-enhanced positivity (27 [82%] vs 37 [90%]; P = .33) for clinically significant PCa (csPCa) was observed between participants with or without Cr/IDC disease in the MRI arm. Cr/IDC-positive histologic patterns overall had a higher mean CCL compared with Cr/IDC-negative csPCa (11.1 mm ± 4.4 vs 9.2 mm ± 4.1; P = .009). Conclusion MRI-targeted biopsy showed increased detection of Cr/IDC histologic patterns compared with systematic biopsy. Clinical trial registration no. NCT02936258 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Scialpi and Martorana in this issue.

A Metric to Characterize Differentially Methylated Region Sets Detected from Methylation Array Data

Background: Identifying differentially methylated region (DMR) is a basic but important task in epigenomics, which can help investigate the mechanisms of diseases and provide methylation biomarkers for screening diseases. A set of methods have been proposed to identify DMRs from methylation array data. However, it lacks effective metrics to characterize different DMR sets and enable a straight way for comparison. Methods: In this study, we introduce a metric, DMRn, to characterize DMR sets detected by different methods from methylation array data. To calculate DMRn, firstly, the methylation differences of DMRs are recalculated by incorporating the correlations between probes and their represented CpGs. Then, DMRn is calculated based on the number of probes and the dense of CpGs in DMRs with methylation differences falling in each interval. Result &amp; Discussion: By comparing the DMRn of DMR sets predicted by seven methods on four scenario, the results demonstrate that DMRn can make an efficient guidance for selecting DMR sets, and provide new insights in cancer genomics studies by comparing the DMR sets from the related pathological states. For example, there are many regions with subtle methylation alteration in subtypes of prostate cancer are altered oppositely in the benign state, which may indicate a possible revision mechanism in benign prostate cancer. Conclusion: Futhermore, when applied to datasets that underwent different runs of batch effect removal, the DMRn can help to visualize the bias introduced by multi-runs of batch effect removal. The tool for calculating DMRn is available in the GitHub repository(https://github.com/xqpeng/DMRArrayMetric).

MCTP1 increases the malignancy of androgen-deprived prostate cancer cells by inducing neuroendocrine differentiation and EMT.

Neuroendocrine prostate cancer (PCa) (NEPC), an aggressive subtype that is associated with poor prognosis, may arise after androgen deprivation therapy (ADT). We investigated the molecular mechanisms by which ADT induces neuroendocrine differentiation in advanced PCa. We found that transmembrane protein 1 (MCTP1), which has putative Ca2+ sensing function and multiple Ca2+-binding C2 domains, was abundant in samples from patients with advanced PCa. MCTP1 was associated with the expression of the EMT-associated transcription factors ZBTB46, FOXA2, and HIF1A. The increased abundance of MCTP1 promoted PC3 prostate cancer cell migration and neuroendocrine differentiation and was associated with SNAI1-dependent EMT in C4-2 PCa cells after ADT. ZBTB46 interacted with FOXA2 and HIF1A and increased the abundance of MCTP1 in a hypoxia-dependent manner. MCTP1 stimulated Ca2+ signaling and AKT activation to promote EMT and neuroendocrine differentiation by increasing the SNAI1-dependent expression of EMT and neuroendocrine markers, effects that were blocked by knockdown of MCTP1. These data suggest an oncogenic role for MCTP1 in the maintenance of a rare and aggressive prostate cancer subtype through its response to Ca2+ and suggest its potential as a therapeutic target.

Abstract PR010: CDK12 loss promotes prostate cancer development while exposing vulnerabilities to paralog-based synthetic lethality

Abstract Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with Trp53 inactivation but negatively associated with Pten inactivation—akin to what is observed in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent Trp53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic Cdk12 and Trp53 loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably, Cdk12/Trp53 loss prostate tumors are sensitive to immune checkpoint blockade. Cdk12-null organoids (either with or without Trp53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fidetumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treating CDK12-mutant mCRPC. Citation Format: Jean C. Tien, Yu Chang, Yuping Zhang, Jonathan Chou, Yunhui Cheng, Xiaoju Wang, Jianzhang Yang, Rahul Mannan, Palak Shah, Xiao-Ming Wang, Abbey Todd, Sanjana Eyunni, Caleb Cheng, Xuhong Cao, Yi Bao, James Neiswender, Rachel Brough, Stephen Pettitt, Estefania Labanca, Yuzhuo Wang, Marcin Cieslik, Christopher J. Lord, Ke Ding, Arul M. Chinnaiyan. CDK12 loss promotes prostate cancer development while exposing vulnerabilities to paralog-based synthetic lethality [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR010.

FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer

FOXA family proteins act as pioneer factors by remodeling compact chromatin structures. FOXA1 is crucial for the chromatin binding of the androgen receptor (AR) in both normal prostate epithelial cells and the luminal subtype of prostate cancer (PCa). Recent studies have highlighted the emergence of FOXA2 as an adaptive response to AR signaling inhibition treatments. However, the role of the FOXA1 to FOXA2 transition in regulating cancer lineage plasticity remains unclear. Our study demonstrates that FOXA2 binds to distinct classes of developmental enhancers in multiple AR-independent PCa subtypes, with its binding depending on LSD1. Moreover, we reveal that FOXA2 collaborates with JUN at chromatin and promotes transcriptional reprogramming of AP-1 in lineage-plastic cancer cells, thereby facilitating cell state transitions to multiple lineages. Overall, our findings underscore the pivotal role of FOXA2 as a pan-plasticity driver that rewires AP-1 to induce the differential transcriptional reprogramming necessary for cancer cell lineage plasticity.

Circulating free insulin-like growth factor-I and prostate cancer: a case-control study nested in the European prospective investigation into cancer and nutrition

BackgroundCirculating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk.MethodsWe analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics.ResultsCirculating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade.ConclusionsEstimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk.

Molecular landscape for risk prediction and personalized therapeutics of castration-resistant prostate cancer: at a glance.

Prostate cancer (PCa) is commonly occurred with high incidence in men worldwide, and many patients will be eventually suffered from the dilemma of castration-resistance with the time of disease progression. Castration-resistant PCa (CRPC) is an advanced subtype of PCa with heterogeneous carcinogenesis, resulting in poor prognosis and difficulties in therapy. Currently, disorders in androgen receptor (AR)-related signaling are widely acknowledged as the leading cause of CRPC development, and some non-AR-based strategies are also proposed for CRPC clinical analyses. The initiation of CRPC is a consequence of abnormal interaction and regulation among molecules and pathways at multi-biological levels. In this study, CRPC-associated genes, RNAs, proteins, and metabolites were manually collected and integrated by a comprehensive literature review, and they were functionally classified and compared based on the role during CRPC evolution, i.e., drivers, suppressors, and biomarkers, etc. Finally, translational perspectives for data-driven and artificial intelligence-powered CRPC systems biology analysis were discussed to highlight the significance of novel molecule-based approaches for CRPC precision medicine and holistic healthcare.