Metastatic Progression Of Prostate Cancer Research Articles

Docetaxel-Induced Cell Death Is Regulated by a Fatty Acid-Binding Protein 12-Slug-Survivin Pathway in Prostate Cancer Cells.

Chemotherapy is an important treatment option for advanced prostate cancer, especially for metastatic prostate cancer (PCa). Resistance to first-line chemotherapeutic drugs such as docetaxel often accompanies prostate cancer progression. Attempts to overcome resistance to docetaxel by combining docetaxel with other biological agents have been mostly unsuccessful. A better understanding of the mechanisms underlying docetaxel resistance may provide new avenues for the treatment of advanced PCa. We have previously found that the fatty acid-binding protein 12 (FABP12)-PPARγ pathway modulates lipid-related bioenergetics and PCa metastatic transformation through induction of Slug, a master driver of epithelial-to-mesenchymal transition (EMT). Here, we report that the FABP12-Slug axis also underlies chemoresistance in PCa cells. Cell sensitivity to docetaxel is markedly suppressed in FABP12-expressing cells, along with induction of Survivin, a typical apoptosis inhibitor, and inhibition of cleaved PARP, a hallmark of programmed cell death. Importantly, Slug depletion down-regulates Survivin and restores cell sensitivity to docetaxel in FABP12-expressing cells. Finally, we also show that high levels of Survivin are associated with poor prognosis in PCa patients, with FABP12 status determining its prognostic significance. Our research identifies a FABP12-Slug-Survivin pathway driving docetaxel resistance in PCa cells, suggesting that targeting FABP12 may be a precision approach to improve chemodrug efficacy and curb metastatic progression in PCa.

Abstract 1382: Activation of the cGAS-STING pathway by large oncosomes induces type I IFN inflammation in mesenchymal stem cells that triggers an immunosuppressive phenotype in neutrophils

Abstract Extracellular vesicles (EVs) have been recognized as key players in cancer progression and metastasis, particularly large oncosomes (LO), secreted by invasive cancer cells, represent a distinct class of EVs with unique features. Previous research by the Di Vizio lab revealed LO's ability to alter recipient cell behavior, induce vascular morphogenesis, and carry cancer-specific biomolecules. Our preliminary studies point to a new mechanism of intercellular communication that involves the release of LO-containing DNA from PC cells. Notably, LO from prostate cancer exhibits enhanced potency in reprogramming bone marrow-derived mesenchymal stem cells (BM-MSCs) compared to exosomes (Exo) as observed by RNAseq. When evaluating the response to LO and Exo of BM-MSC, which are emerging as important drivers of bone metastasis, LO induces a robust inflammatory response, including metastasis-relevant chemokines and transcription factors involved in type I IFN response such as IRF7 and RASD2. Further, REACTOME pathway analysis of the differentially expressed genes revealed enrichment of the cGAS-STING pathway in BM-MSCs treated with LO, indicating a potential link between DNA/RNA sensors and the inflammatory response. BM cells isolated from WT and mutant Sting1gt/J mice demonstrated that up-regulation of IRF3 and IFNA1 genes induced by LO is inhibited when STING is absent. Suggesting that nucleic acid sensors engage in the LO-induced immune response in BM cells. Gene ontology analysis (GO) also identified several chemokines involved in neutrophil chemotaxis. In line with the observation from GO, neutrophil chemotaxis was significantly promoted by PC-derived LO-treated BM-MSC. Interestingly, human blood-derived neutrophils exposed to a conditioned medium from EVs-treated BM-MSC significantly increased the percentage of a population of LOX-1high and CD62Llow/− after 6h of culture. This was observed in concert with increased expression of Arginase1 and IL-10, suggesting their differentiation into polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSC). An experimental orthotopic model using the breast cancer bone metastatic 4T1.2 cell line, with increased capacity to shed LO, demonstrated an increase in the presence of PMN-MDSC in the bone marrow of tumor-bearing mice in addition to a complete lack of lymphocyte populations, indicating their immunosuppressive activity that could lead to a pre-metastatic niche formation. This comprehensive study unveils the molecular pathways underlying the immune response to LO in the bone marrow, shedding light on mechanisms that could influence metastatic progression in prostate cancer. The findings underscore the unique role of LO in modulating the BM microenvironment, providing potential targets for therapeutic intervention and biomarkers for early disease detection. Citation Format: Taylon F. Silva, Diana Kitka, Blandine Victor, Chen Qian, Minhyung Kim, Tatyana Vagner, Giorgia Guerra, Catherine Grasso, Sungyong You, Fayyazz Sutterwala, Caroline Jefferies, Paola de Candia, Michael Freeman, Helen Goodridge, Karen Cavassani, Jlenia Guarnerio, Dolores Di Vizio. Activation of the cGAS-STING pathway by large oncosomes induces type I IFN inflammation in mesenchymal stem cells that triggers an immunosuppressive phenotype in neutrophils [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1382.

CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression

Metastatic prostate cancer (PCa) poses a significant therapeutic challenge with high mortality rates. Utilizing CRISPR-Cas9 in vivo, we target five potential tumor suppressor genes (Pten, Trp53, Rb1, Stk11, and RnaseL) in the mouse prostate, reaching humane endpoint after eight weeks without metastasis. By further depleting three epigenetic factors (Kmt2c, Kmt2d, and Zbtb16), lung metastases are present in all mice. While whole genome sequencing reveals few mutations in coding sequence, RNA sequencing shows significant dysregulation, especially in a conserved genomic region at chr5qE1 regulated by KMT2C. Depleting Odam and Cabs1 in this region prevents metastasis. Notably, the gene expression signatures, resulting from our study, predict progression-free and overall survival and distinguish primary and metastatic human prostate cancer. This study emphasizes positive genetic interactions between classical tumor suppressor genes and epigenetic modulators in metastatic PCa progression, offering insights into potential treatments.

Targeting of H19/cell adhesion molecules circuitry by GSK-J4 epidrug inhibits metastatic progression in prostate cancer

BackgroundAbout 30% of Prostate cancer (PCa) patients progress to metastatic PCa that remains largely incurable. This evidence underlines the need for the development of innovative therapies. In this direction, the potential research focus might be on long non-coding RNAs (lncRNAs) like H19, which serve critical biological functions and show significant dysregulation in cancer. Previously, we showed a transcriptional down-regulation of H19 under combined pro-tumoral estrogen and hypoxia treatment in PCa cells that, in turn, induced both E-cadherin and β4 integrin expression. H19, indeed, acts as transcriptional repressor of cell adhesion molecules affecting the PCa metastatic properties. Here, we investigated the role of H19/cell adhesion molecules circuitry on in vivo PCa experimental tumor growth and metastatic dissemination models.MethodsH19 was silenced in luciferase-positive PC-3 and 22Rv1 cells and in vitro effect was evaluated by gene expression, proliferation and invasion assays before and after treatment with the histone lysine demethylase inhibitor, GSK-J4. In vivo tumor growth and metastasis dissemination, in the presence or absence of GSK-J4, were analyzed in two models of human tumor in immunodeficient mice by in vivo bioluminescent imaging and immunohistochemistry (IHC) on explanted tissues. Organotypic Slice Cultures (OSCs) from fresh PCa-explant were used as ex vivo model to test GSK-J4 effects.ResultsH19 silencing in both PC-3 and 22Rv1 cells increased: i) E-cadherin and β4 integrin expression as well as proliferation and invasion, ii) in vivo tumor growth, and iii) metastasis formation at bone, lung, and liver. Of note, treatment with GSK-J4 reduced lesions. In parallel, GSK-J4 efficiently induced cell death in PCa-derived OSCs.ConclusionsOur findings underscore the potential of the H19/cell adhesion molecules circuitry as a targeted approach in PCa treatment. Modulating this interaction has proven effective in inhibiting tumor growth and metastasis, presenting a logical foundation for targeted therapy.

PTEN-regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression

PTEN loss, one of the most frequent mutations in prostate cancer (PC), is presumed to drive disease progression through AKT activation. However, two transgenic PC models with Akt activation plus Rb loss exhibited different metastatic development: Pten/RbPE:−/− mice produced systemic metastatic adenocarcinomas with high AKT2 activation, whereas RbPE:−/− mice deficient for the Src-scaffolding protein, Akap12, induced high-grade prostatic intraepithelial neoplasias and indolent lymph node dissemination, correlating with upregulated phosphotyrosyl PI3K-p85α. Using PC cells isogenic for PTEN, we show that PTEN-deficiency correlated with dependence on both p110β and AKT2 for in vitro and in vivo parameters of metastatic growth or motility, and with downregulation of SMAD4, a known PC metastasis suppressor. In contrast, PTEN expression, which dampened these oncogenic behaviors, correlated with greater dependence on p110α plus AKT1. Our data suggest that metastatic PC aggressiveness is controlled by specific PI3K/AKT isoform combinations influenced by divergent Src activation or PTEN-loss pathways.

PD16-08 COST-EFFECTIVENESS OF SYSTEMIC TREATMENT INTENSIFICATION IN MEN WITH METASTATIC HORMONE-SENSITIVE PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023PD16-08 COST-EFFECTIVENESS OF SYSTEMIC TREATMENT INTENSIFICATION IN MEN WITH METASTATIC HORMONE-SENSITIVE PROSTATE CANCER Niranjan Sathianathen, Nathan Lawrentschuk, Arun Azad, Badrinath Konety, and Declan Murphy Niranjan SathianathenNiranjan Sathianathen More articles by this author , Nathan LawrentschukNathan Lawrentschuk More articles by this author , Arun AzadArun Azad More articles by this author , Badrinath KonetyBadrinath Konety More articles by this author , and Declan MurphyDeclan Murphy More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003271.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: New trials have suggested that treatment intensification with triplet therapy – androgen deprivation therapy, docetaxel and an androgen receptor antagonist – results in improved survival outcomes. However, these novel systemic agents are expensive. Therefore, it is important to assess whether the increased cost is justified in resource-constrained health system. We perform a cost-effective analysis of systemic treatment options for men with metastatic hormone-sensitive prostate cancer based on costs from the United States. METHODS: A state-transition Markov model was developed to simulate the natural progression of metastatic prostate cancer. Model parameters were derived from the published literature and through calibration to observed epidemiological data. The hypothetical cohort of men with metastatic hormone-sensitive prostate cancer could be treated with systemic treatment options that are approved by the FDA: triplet therapy with abiraterone or darolutamide; doublet therapy (abiraterone, apalutamide, enzalutamide or docetaxel with ADT) or ADT only. Once disease progresses to the castration-resistant state, treatment with one of the approved therapies in this setting was initiated. Quality adjusted life years (QALYs) and costs were estimated from a United States health sector perspective. Cost-effectiveness was estimated using the incremental cost effectiveness ratio (ICER). RESULTS: Compared with ADT alone, treatment with doublet therapy with abiraterone, apalutamide, enzalutamide or docetaxel improved quality-adjusted survival by 9.4, 29.6, 17.2 and 1.2 months, respectively. Triplet therapy with abiraterone or darolutamide resulted in an improved quality-adjusted survival of 21.2 and 22.8 months, respectively. Using standard cost-effectiveness metrics, treatment with doublet therapy with docetaxel was high value for money (i.e. is cost effective) with an ICER of $75,546. Doublet therapy with Apalutamide was undominated with an ICER of $245,145 but this is significantly higher than thresholds that would be classified as being cost-effective. Triplet therapy with any strategy was not cost-effective. The cost of darolutamide had to be less than $4,230 (63% discount on listed price) for triplet therapy to be cost-effective. Similarly, the cost of Abiraterone had to be below $4,051 for doublet therapy using it to be cost-effective. CONCLUSIONS: Based on the price of systemic agents in the United States, systemic treatment intensification doublet therapy only using docetaxel was cost-effective. Doublet therapy with androgen-receptor agents or triple therapy was not cost-effective based on standard thresholds. A significant reduction in the price of these agents were required for them to be cost-effective. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e492 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Niranjan Sathianathen More articles by this author Nathan Lawrentschuk More articles by this author Arun Azad More articles by this author Badrinath Konety More articles by this author Declan Murphy More articles by this author Expand All Advertisement PDF downloadLoading ...

Using biological constraints to improve prediction in precision oncology

Many gene signatures have been developed by applying machine learning (ML) on omics profiles, however, their clinical utility is often hindered by limited interpretability and unstable performance. Here, we show the importance of embedding prior biological knowledge in the decision rules yielded by ML approaches to build robust classifiers. We tested this by applying different ML algorithms on gene expression data to predict three difficult cancer phenotypes: bladder cancer progression to muscle-invasive disease, response to neoadjuvant chemotherapy in triple-negative breast cancer, and prostate cancer metastatic progression. Wedeveloped two sets of classifiers: mechanistic, by restricting the training to features capturing specific biological mechanisms; and agnostic, in which the training did not use any a priori biological information. Mechanistic models had a similar or better testing performance than their agnostic counterparts, with enhanced interpretability. Our findings support the use of biological constraints to develop robust gene signatures with high translational potential.

A clinical case of phosphopenic osteomalacia due to paraneoplastic secretion of metastatic prostate cance

Phosphaturic mesenchymal tumor can cause osteomalacia due to excessive secretion of fibroblast growth factor 23 (FGF23), which disrupts the metabolism of phosphate and vitamin D. These tumors are predominantly benign, but less than 5% of them are malignant forms. This article presents the first clinical case in the Russian Federation of a 69-year-old patient with severe hypophosphatemia due to metastatic prostate cancer. Increased secretion of FGF23 are described in the androgen-resistent prostate cancer, which led to pronounced disorders of mineral metabolism, accompanied by a clinical symptom of weakness, pain in the bones, immobilization of the patient. The condition was regarded as worsening against the background of the progression of the disease. However, symptomatic therapy aimed at increasing the level of phosphate significantly improved the patient’s general condition. The medical community should be aware of the possibility of developing hypophosphatemia in patients with weakness and bone pain, which are not always associated with the progression of metastatic prostate cancer.

The ADAM9/WISP-1 axis cooperates with osteoblasts to stimulate primary prostate tumor growth and metastasis.

Background: Metastatic prostate cancer (PCa) predicts a poor prognosis and lower likelihood of survival. Osteoblasts (OBs) are known to be responsible for the synthesis and mineralization of bone, although it is unclear as to whether PCa in the prostate gland cooperates with OBs in bone to promote PCa malignant transformation. We aimed to elucidate how primary PCa cells cooperate with distal OBs and contribute to the vicious cycle that leads to metastatic PCa. Methods: N-cadherin, E-cadherin, and Twist protein expression were measured by Western blot. Twist translocation into the nucleus was detected by the immunofluorescence (IF) assay. Enzyme-linked immunosorbent assay (ELISA) detected protein levels in human serum samples. Levels of candidate protein expression were examined by the human cytokine array. Prostate tumor growth and metastasis were analyzed by orthotopic and metastatic prostate cancer models, respectively. Immunohistochemistry (IHC) staining was used to observe ADAM metallopeptidase domain 9 (ADAM9) and WNT1 inducible signaling pathway protein 1 (WISP-1) expression in tissue. Results: Our in vitro and in vivo analyses have now discovered that primary PCa expressing ADAM9 protein enables the transformation of OBs into PCa-associated osteoblasts (PCa-OBs), inducing WISP-1 secretion from PCa-OBs in the bone microenvironment. The upregulation of WISP-1 in bone provided feedback to primary PCa and promoted PCa cell aggressiveness via epithelial-mesenchymal transition (EMT) activity. Elevated levels of WISP-1 expression were detected in the serum of patients with PCa. ADAM9 levels were overexpressed in tumor tissue from PCa patients; ADAM9 blockade interrupted OB-induced release of WISP-1 and also suppressed primary tumor growth and distal metastasis in orthotopic PCa mouse models. Conclusion: Our study suggests that the ADAM9/WISP-1 axis assists with metastatic PCa progression. Thus, targeting the ADAM9/WISP-1 axis may help to prevent the malignant phenotypes of PCa cells.

LncRNA weighted gene co-expression network analysis reveals novel biomarkers related to prostate cancer metastasis

BackgroundMost prostate cancer patients die from metastasis and lack accurate efficacious biomarkers to monitor the disease behavior, optimize treatment and assess prognosis. Herein, we aimed to identify meaningful lncRNA biomarkers associated with prostate cancer metastatic progression.MethodsBy repurposing microarray probes, 11,624 lncRNAs in prostate cancer were obtained from Gene Expression Omnibus database (GSE46691, N = 545; GSE29079, N = 235; GSE94767, N = 130). Weighted gene co-expression network analysis was applied to determine the co-expression lncRNA network pertinent to metastasis. Hub lncRNAs were screened. RNA-seq and clinical data from the Cancer Genome Atlas prostate cancer (TCGA-PRAD) cohort (N = 531) were analyzed. Transwell assay and bioinformatic analysis were performed for mechanism research.ResultsThe high expression levels of nine hub lncRNAs (FTX, AC005261.1, NORAD, LINC01578, AC004542.2, ZFAS1, EBLN3P, THUMPD3-AS1, GAS5) were significantly associated with Gleason score and increased probability of metastatic progression. Among these lncRNAs, ZFAS1 had the consistent trends of expression in all of the analysis from different cohorts, and the Kaplan-Meier survival analyses showed higher expression of ZFAS1 was associated with shorter relapse free survival. In-vitro studies confirmed that downregulation of ZFAS1 decreased prostate cancer cell migration.ConclusionWe offered some new insights into discovering lncRNA markers correlated with metastatic progression of prostate cancer using the WGCNA. Some may serve as potential prognostic biomarkers and therapeutic targets for advanced metastatic prostate cancer.

Exploring the genetic differences between Primary and Metastatic Prostate Cancer using Bioinformatic Approaches: A Preliminary Study

Screening of prostate cancer (PCa) by measuring prostate cancer antigen has proven beneficial in reducing the mortality and progression of prostate cancer. However, its level can be affected if patients are taking certain drugs and/or suffering from certain medical conditions, causing a false negative. This can lead to PCa being undetected, where when untreated can lead to metastatic prostate cancer (MPC). Hence, in this study, genetic differences between PCa and MPC were explored using bioinformatics approaches to predict potential biomarkers for MPC. The study was divided into two parts, where the first involves feature selection and principal component analysis to differentiate PCa and MPC based on mRNA gene expression. Additionally, top 20 mutated genes for MPC were determined using odds ratio (OR). In the second phase, a predictive model was built using outcome of the mRNA gene expression analysis. The results showed that the mRNA expression of 26 identified genes could differentiate between PCa and MPC. This was further corroborated by the predictive model, where a sensitivity and specificity of 0.616 and 0.017 respectively was achieved. While importance is placed on sensitivity over specificity, further improvements involving more data need to be made to increase the specificity rate. Additionally, genes such as PAG24, BOP1 and GRWD1 should be investigated further as both potential biomarkers as well as potential pathways in MPC progression, based on further protein-protein interaction analysis. OR and protein-protein interaction suggests that androgen signalling pathway may crosstalk with NF-κB signalling and breast cancer pathway. This preliminary study shows that bioinformatics approaches could aid in understanding MPC, which could lead to the discovery of novel targeted therapy and potential biomarkers.

Cancer-specific and net overall survival in older patients with de novo metastatic prostate cancer initially treated with androgen deprivation therapy.

This study aimed to assess survival outcomes in older patients with de novo metastatic prostate cancer who initially received androgen deprivation therapy. The retrospective multicenter study included 2784 men with metastatic prostate cancer who were treated with androgen deprivation therapy between 2008 and 2017. Patients were classified into <75, 75-79, and ≥80 age groups. Propensity score matching was conducted to assess the cancer-specific survival of the groups. The 5-year net overall survival of each group was derived to evaluate relative survival compared with the general population using the Pohar-Perme estimator and the 2019 Japan Life Table. During the follow-up (median, 34 months), 1014 patients died, of which 807 died from metastatic prostate cancer progression. Compared with the <75 group, the cancer-specific survival of the 75-79 group was similar (hazard ratio 1.07; 95% confidence interval 0.84-1.37; P = 0.580), whereas that of the ≥80 group was significantly worse (hazard ratio 1.41; 95% confidence interval 1.10-1.80; P = 0.006). The 5-year net overall survival of the <75, 75-79, and ≥80 age groups were 0.678, 0761, and 0.718, respectively. The 5-year net overall survival of patients aged ≥80 years with low- and high-volume disease were 0.893 and 0.586, respectively, which was comparable with those in patients aged <75 years (0.872 and 0.586, respectively). Older metastatic prostate cancer patients aged ≥80 years had poorer cancer-specific survival compared with younger patients. Conversely, 5-year net overall survival in older patients aged ≥80 years was comparable with that in younger patients aged <75 years.

Extracellular vesicle-based assay for detecting metastases and dynamic monitoring of prostate cancer.

182 Background: There is an unmet need to develop a noninvasive assay to detect the metastatic progression of prostate cancer (PCa) patients for timely treatment. We aim to optimize an extracellular vesicle (EV)-based Digital Scoring Assay to reflect the disease status of PCa. Methods: PCa EV Digital Scoring Assay integrated a PCa-derived EV purification device (i.e., EV Click Chip) and downstream reverse-transcription droplet digital PCR for transcriptomic profiling of PCa-derived EVs. The performance of the Assay for purifying PCa-derived EVs was assessed using artificial plasma samples with spiked EVs. In parallel, a panel of 11 PCa-relevant mRNA markers were selected and validated. PCa EV Digital Scoring Assay in conjugation with the 11-gene panel was tested using plasma from 20 localized, 20 metastatic PCa patients, and serial plasma from three PCa patients. mRNA expressions were computed using weighted Z score method. ROC analysis was utilized to distinguish localized from metastatic PCa. Results: After optimization, the capability of purifying PCa-derived EVs from artificial plasma samples by EV Click Chips (92.5 ± 5.4%) outperformed ultracentrifugation or precipitation methods (41.0 ± 3.2%; 34.9± 2.2%; P &lt; 0.001). Eleven genes, i.e., ACP3, FOLH1, HOXB13, KLK2, KLK3, KLK4, MSMB, RLN1, SLC45A3, STEAP2, and TMPRSS, were selected using The Tissue Atlas and a gene set from a blood-based study as our panel. Strong signals of the panel were detected from three PCa cells (LNCaP, C4-2B, and 22Rv1) and their derived EVs, while rare signals were detected in either WBCs or EVs purified from male healthy donor. In the clinical study, the Z scores calculated from the selected 11-gene panel, were significantly higher in 20 metastatic PCa than 20 localized PCa with an area under the ROC curve of 0.88 (95% CI = 0.78-0.98). Lastly, longitudinal analyses of three PCa patients showed that the Z scores can reflect the clinical progression, response, and stable status, even when disease is undetectable by imaging. Conclusions: We develop a sensitive PCa EV Digital Scoring Assay to distinguish metastatic PCa and reveal the dynamic disease states in a noninvasive manner. This assay holds the potential to augment current imaging tools and tests for timely detection of PCa progression and improve care for patients.

Roles of renin-angiotensin system in the regulation of prostate cancer bone metastasis: a critical review

Mestastatic prostate cancer cells (MPCCs) frequently metastasize to bone, which is a “favorite soil” for colonization and proliferation of MPCCs. Prostate cancer bone mestastasis is tightly associated with tumor-induced bone lesions, most commonly caused from (1) the etiological imbalance between osteoblastic bone formation and osteoclastic bone resorption and from (2) the anti-tumor immune response. Therefore, understanding of prostate cancer biology and prostate cancer bone metastasis has led to the establishment of drug development programs for treatment of the patients with bone metastasis. The renin-angiotensin system (RAS) controls systemic body fluid circulation; nonetheless, the existence of a local RAS in tumors has been reported. Importantly, the local RAS has recently emerged as a potential regulator of tumorigenesis and cancer metastasis. This review summarizes and dissects the critical roles of the local RAS in promoting (1) progression of metastatic prostate cancer, and (2) development and progression of PCa bone metastasis, thereby providing multiple solutions for the potential therapeutic intervention.

Identification of Somatic Gene Signatures in Circulating Cell-Free DNA Associated with Disease Progression in Metastatic Prostate Cancer by a Novel Machine Learning Platform.

Progression from metastatic castration-sensitive prostate cancer (mCSPC) to a castration-resistant (mCRPC) state heralds the lethal phenotype of prostate cancer. Identifying genomic alterations associated with mCRPC may help find new targets for drug development. In the majority of patients, obtaining a tumor biopsy is challenging because of the predominance of bone-only metastasis. In this study, we hypothesize that machine learning (ML) algorithms can identify clinically relevant patterns of genomic alterations (GAs) that distinguish mCRPC from mCSPC, as assessed by next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA). Retrospective clinical data from men with metastatic prostate cancer were collected. Men with NGS of cfDNA performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory at time of diagnosis of mCSPC or mCRPC were included. A combination of supervised and unsupervised ML algorithms was used to obtain biologically interpretable, potentially actionable insights into genomic signatures that distinguish mCRPC from mCSPC. GAs that distinguish patients with mCRPC (n= 187) from patients with mCSPC (n= 154) (positive predictive value= 94%, specificity=91%) were identified using supervised ML algorithms. These GAs, primarily amplifications, corresponded to androgen receptor, Mitogen-activated protein kinase (MAPK) signaling, Phosphoinositide 3-kinase (PI3K) signaling, G1/S cell cycle, and receptor tyrosine kinases. We also identified recurrent patterns of gene- and pathway-level alterations associated with mCRPC by using Bayesian networks, an unsupervised machine learning algorithm. These results provide clinical evidence that progression from mCSPC to mCRPC is associated with stereotyped concomitant gain-of-function aberrations in these pathways. Furthermore, detection of these aberrations in cfDNA may overcome the challenges associated with obtaining tumor bone biopsies and allow contemporary investigation of combinatorial therapies that target these aberrations. The progression from castration-sensitive to castration-resistant prostate cancer is characterized by worse prognosis and there is a pressing need for targeted drugs to prevent or delay this transition. This study used machine learning algorithms to examine the cell-free DNA of patients to identify alterations to specific pathways and genes associated with progression. Detection of these alterations in cell-free DNA may overcome the challenges associated with obtaining tumor bone biopsies and allow contemporary investigation of combinatorial therapies that target these aberrations.

Abstract 2418: PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression

Abstract Background: The loss of PTEN function, one of the most frequent mutations in prostate cancer (CaP), is presumed to drive disease progression through AKT activation. However, two transgenic mouse CaP models, Pten/RbPE:-/- and Akap12-/-;RbPE:-/-, exhibited different CaP and metastasis development even though both shared Rb loss plus Akt activation, based on increased relative AKTpoS473 levels. Experimental Procedures: We analyzed whether PI3K-p110 and/or AKT isoform reliance, using isoform-specific RNAi or small molecule inhibitors, played a role in the different CaP outcomes. Findings: In comparison to Akap12/Rb-null high-grade prostatic intraepithelial neoplasias, Pten/Rb-null adenocarcinomas had increased protein and activation levels of AKT2 and decreased relative levels of Smad4, a known CaP metastasis suppressor. Comparison of isogenic PTEN +/- pairs of human or mouse CaP cell lines indicated that PTEN-deficiency correlated with dependence on both p110β and AKT2 for survival or oncogenic growth/invasiveness, whereas PTEN expression correlated with greater dependence on AKT1 plus p110α. Inhibition of AKT2 in PTEN-null CaP cells induced higher SMAD4 levels and decreased chemotaxis and Matrigel invasiveness. Given that PTEN likely regulates non-redundant roles of the AKT isoforms during CaP progression, we sought to characterize AKT isoform substrates by phosphoproteomics analysis. Specifically, after endogenous kinases were inactivated in mouse Pten/Rb-null adenocarcinoma cell lysates using 5'-fluorosulfonylbenzoyl-5'-adenosine (FSBA), dialyzed samples were subjected to in vitro kinase reactions using enzymatically-active, full-length baculovirus-expressed AKT1, AKT2 or AKT3, or as a negative control, a heat-inactivated mixture of all three isoforms. Tryptic peptides isolated on TiO2 beads were subjected to LC-MS/MS. Data will be shown on the role of AKT isoform-shared vs. -preferred substrates in specific parameters of CaP progression controlled by PTEN. Conclusion: Our data suggest that in the context of RB1 loss, PTEN controls a signaling plasticity and drug sensitivity through specific pairings of PI3K-p110 and AKT isoforms. Citation Format: Karina Miller, Seamus Degan, Yanqing Wang, Sheng-Yu Ku, David W. Goodrich, Irwin H. Gelman. PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2418.

Tumor Induced Osteomalacia in Patients With Metastatic Prostate Cancer: Case Report and Literature Review

Background:Tumor induced osteomalacia (TIO), driven by elevated levels of fibroblast growth factor (FGF23), has been associated with progressive aggressive prostate cancer. FGF23, expressed by osteocytes, plays an important role in tumorigenesis through cell proliferation, chemotaxis, and angiogenesis. FGF23 regulates phosphate homeostasis through feedback loops between the kidney and bone. We present a case report of a patient with TIO and advanced prostate cancer (PC) and review previously published data. Clinical Case: A 63-year old male with castrate-resistant PC with bone metastases presented with symptoms of profound fatigue, memory loss, and brain fog. Laboratory studies demonstrated severe hypophosphatemia (phosphorus 0.8 mg/dL, normal 2.5–4.5 mg/dL), mild hypocalcemia, secondary hyperparathyroidism, normal 25 hydroxy-vitamin D and 1,25-dihydroxy vitamin D. After treatment with IV and oral replacement, phosphorus improved to 2.2 mg/dL. Urinary phosphorous was elevated at 2105 mg/24 hours (normal 400–1300 mg/24 hours) and FGF23 545 RU/mL (normal < 180 RU/mL). His PC treatment regimen extended over 10 years with multiple systemic, radiation, and targeted ablation therapies. He was also on denosumab every 3 months for metastatic bone disease, but it was discontinued due to hypophosphatemia. He is now treated with calcium carbonate-vitamin D 1000 mg-250 IU twice daily, calcitriol 1.5 mcg/daily, Phospha Neutral 250mg 2 tablets four times daily, and abiraterone acetate. His hypophosphatemia, hypocalcemia and secondary hyperparathyroidism has resolved with this regimen. To our knowledge there are 17 cases of TIO in metastatic PC are reported to date. Majority of the patients have similar clinical presentation. Treatment of metastatic PC, as well as calcitriol, phosphorus replacement, octreotide, and cinacalcet were described. Conclusions: FGF23 plays an important role in metastatic prostate cancer progression. TIO is a rare entity in patients with metastatic PC, however mild cases are underdiagnosed due to its nonspecific symptoms and lack of routine screening. The FGF pathway represents a new target for prostate cancer treatment and clinical trials targeting FGF23 pathway in PC are needed for further drug development. Also, the efficacy of burosumab, a novel monoclonal antibody directed against human FGF23 in treatment of hypophosphatemia in metastatic PC requires further investigation.

An Amplified Fatty Acid-Binding Protein Gene Cluster in Prostate Cancer: Emerging Roles in Lipid Metabolism and Metastasis.

Simple SummaryProstate cancer is the second most common cancer in men. In many cases, prostate cancer grows very slowly and remains confined to the prostate. These localized cancers can usually be cured. However, prostate cancer can also metastasize to other organs of the body, which often results in death of the patient. We found that a cluster of genes involved in accumulation and utilization of fats exists in multiple copies and is expressed at much higher levels in metastatic prostate cancer compared to localized disease. These genes, called fatty acid-binding protein (or FABP) genes, individually and collectively, promote properties associated with prostate cancer metastasis. We propose that levels of these FABP genes may serve as an indicator of prostate cancer aggressiveness, and that inhibiting the action of FABP genes may provide a new approach to prevent and/or treat metastatic prostate cancer.Treatment for early stage and localized prostate cancer (PCa) is highly effective. Patient survival, however, drops dramatically upon metastasis due to drug resistance and cancer recurrence. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. It is therefore crucial to decipher the key genetic alterations and relevant molecular pathways driving PCa metastatic progression so that predictive biomarkers and precise therapeutic targets can be developed. Through PCa cohort analysis, we found that a fatty acid-binding protein (FABP) gene cluster (containing five FABP family members) is preferentially amplified and overexpressed in metastatic PCa. All five FABP genes reside on chromosome 8 at 8q21.13, a chromosomal region frequently amplified in PCa. There is emerging evidence that these FABPs promote metastasis through distinct biological actions and molecular pathways. In this review, we discuss how these FABPs may serve as drivers/promoters for PCa metastatic transformation using patient cohort analysis combined with a review of the literature.

Loss of Monocyte in Tumor Microenvironment Promotes Metastasis Based on Large-Scale Prostate Cancer Cohorts

To analyze the differences and distinct features of immune cell infiltration between metastasis and primary prostate cancer. We merged multiple datasets and collected a total of 2115 prostate samples. Using single-sample Gene Sets Enrichment Analysis to calculate the abundance fraction of immune cell infiltration. Weighted-gene correlation network analysis was applied to identify gene modules related to immune infiltration. Single-cell sequencing analysis and invasion assays were used to validate the effects of immune cell on prostate cancer. In metastatic prostate cancer, the immune score was lower compared with primary and benign samples. Concretely, 16 different immune cell types especially mast cell and monocyte presented decreased abundance in the metastatic microenvironment. Furthermore, the loss of monocyte facilitating prostate cancer metastatic progression was validated by trajectory analysis and invasion assays in vitro. We found that loss of immune infiltration was a distinct characteristic of immune infiltration in the metastatic prostate cancer microenvironment. Funding Statement: This work was supported by the National Natural Science Foundation of China [81672546, 81602253, 81772703, 81872083], Natural Science Foundation of Beijing Municipality [7152146, 7172219]. Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: The study was approved by the institutional ethics committees of Peking University First Hospital. All procedures in this study were conducted in accordance with ethical principles.

Prostate cancer-derived MMP-3 controls intrinsic cell growth and extrinsic angiogenesis

Bone metastatic prostate cancer significantly impacts patient quality of life and overall survival, and despite available therapies, it is presently incurable with an unmet need for improved treatment options. As mediators of tumor progression, matrix metalloproteinases (MMPs) can degrade extracellular matrix components and regulate growth factor and cytokine bioactivity. Depending on tissue context, MMPs can either promote or inhibit tumorigenesis. Therefore, it is essential to study individual MMPs in specific cancer contexts and microenvironments to support the design and application of selective MMP inhibitors. Here we report that tumor-derived MMP-3 contributes to bone metastatic prostate cancer progression via intrinsic and extrinsic routes. MMP-3 ablation in prostate cancer cell lines significantly reduced in vitro growth combined with lowered AKT and ERK phosphorylation and total VEGFR1 and FGFR3 protein levels. In vivo, MMP-3 ablated tumors grew at a slower rate and were significantly less vascularized. Quantitative PCR analyses of wild type and MMP-3 silenced prostate cancer cells also demonstrate downregulation of a wide array of angiogenic factors. The extrinsic role for MMP-3 in angiogenesis was supported by in vitro endothelial tube formation assays where the lack of MMP-3 in prostate cancer conditioned media resulted in slower rates of tube formation. Taken together, our results suggest that tumor-derived MMP-3 contributes to prostate cancer growth in bone. These data indicate that selective inhibition of MMP-3 and/or targeting MMP generated products could be efficacious for the treatment of prostate to bone metastases.