18 F-sodium fluoride positron emission tomography quantitation of bone metastases in African American and non-African American men with metastatic prostate cancer.

BACKGROUND: Bone is the most common site of metastases in men with prostate cancer. The objective of this study was to explore potential racial differences in the distribution of tumor metastases in the axial and appendicular skeleton. METHODS: We conducted a retrospective review of patients with metastatic prostate cancer to the bone as detected by 18 F-sodium fluoride positron emission tomography/computed tomography (18 F-NaF PET/CT) scans. In addition to describing patients' demographics and clinical characteristics, the metastatic bone lesions, and healthy bone regions were detected and quantified volumetrically using a quantitative imaging platform (TRAQinform IQ, AIQ Solutions). RESULTS: Forty men met the inclusion criteria with 17 (42%) identifying as African Americans and 23 (58%) identifying as non-African Americans. Most of the patients had axial (skull, ribcage, and spine) disease. The location and the number of lesions in the skeleton of metastatic prostate cancer patients with low disease burden were not different by race. CONCLUSIONS: In low-disease burden patients with metastatic prostate cancer, there were no overall differences by race in the location and number of lesions in axial or appendicular skeleton. Therefore, given equal access to molecular imaging, African Americans might derive similar benefits. Whether this holds true for patients with a higher disease burden or for other molecular imaging techniques is a topic for further study.

SNHG1 opposes quiescence and promotes docetaxel sensitivity in prostate cancer.

BACKGROUND: A majority of prostate cancer cells are in a non-proliferating, G0 (quiescent) phase of the cell cycle and may lie dormant for years before activation into a proliferative, rapidly progressing, disease phase. Many mechanisms which influence proliferation and quiescence choices remain to be elucidated, including the role of non-coding RNAs. In this study, we investigated the role of a long non-coding RNA (lncRNA), SNHG1, on cell proliferation, quiescence, and sensitivity to docetaxel as a potential factor important in prostate cancer biology. METHODS: Publically available, anonymous, clinical data was obtained from cBioPortal for analysis. RNAi and prostate cancer cell lines were utilized to investigate SNHG1 in vitro. We measured G0 cells, DNA synthesis, and cell cycle distribution by flow cytometry. Western blotting was used to assess G2 arrest and apoptosis. These parameters were also investigated following docetaxel treatment. RESULTS: We discovered that in prostate cancer patients from The Cancer Genome Atlas (TCGA) data set, high SNHG1 expression in localized tumors correlated with reduced progression-free survival, and in a data set of both primary and metastatic tumors, high SNHG1 expression was associated with metastatic tumors. In vitro analysis of prostate cancer cell lines showed SNHG1 expression correlated with a quiescent versus proliferative phenotype. Knockdown of SNHG1 by RNAi in PC3 and C4-2B cells resulted in an accumulation of cells in the G0 phase. After knockdown, 60.0% of PC3 cells were in G0, while control cultures had 13.2% G0. There were reciprocal decreases in G1 phase, but little impact on the proportion of cells in S and G2/M phases, depending on cell line. DNA synthesis and proliferation were largely halted- decreasing by 75% and 81% in C4-2B and PC3 cells, respectively. When cells were treated with docetaxel, SNHG1-depleted C4-2B and PC3 cells were resistant to G2 arrest, and displayed reduced apoptosis, as indicated by reduced cyclin B1 and cleaved caspase 3, suggesting SNHG1 levels may modulate drug response. CONCLUSIONS: Overall, these results indicate SNHG1 has complex roles in prostate cancer, as it stimulates cell cycle entry and disease progression, but sensitizes cells to docetaxel treatment.

Multigene Profiling of Circulating Tumor Cells (CTCs) for Prognostic Assessment in Treatment-Naïve Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

The substantial biological heterogeneity of metastatic prostate cancer has hindered the development of personalized therapeutic approaches. Therefore, it is difficult to predict the course of metastatic hormone-sensitive prostate cancer (mHSPC), with some men remaining on first-line androgen deprivation therapy (ADT) for several years while others progress more rapidly. Improving our ability to risk-stratify patients would allow for the optimization of systemic therapies and support the development of stratified prospective clinical trials focused on patients likely to have the greatest potential benefit. Here, we applied a liquid biopsy approach to identify clinically relevant, blood-based prognostic biomarkers in patients with mHSPC. Gene expression indicating the presence of CTCs was greater in CHAARTED high-volume (HV) patients (52% CTChigh) than in low-volume (LV) patients (23% CTChigh; * p = 0.03). HV disease (p = 0.005, q = 0.033) and CTC presence at baseline prior to treatment initiation (p = 0.008, q = 0.033) were found to be independently associated with the risk of nonresponse at 7 months. The pooled gene expression from CTCs of pre-ADT samples found AR, DSG2, KLK3, MDK, and PCA3 as genes predictive of nonresponse. These observations support the utility of liquid biomarker approaches to identify patients with poor initial response. This approach could facilitate more precise treatment intensification in the highest risk patients.

CXCL12γ induces human prostate and mammary gland development.

BACKGROUND: Epithelial stem cells (ESCs) demonstrate a capacity to maintain normal tissues homeostasis and ESCs with a deregulated behavior can contribute to cancer development. The ability to reprogram normal tissue epithelial cells into prostate or mammary stem-like cells holds great promise to help understand cell of origin and lineage plasticity in prostate and breast cancers in addition to understanding normal gland development. We previously showed that an intracellular chemokine, CXCL12γ induced cancer stem cells and neuroendocrine characteristics in both prostate and breast adenocarcinoma cell lines. However, its role in normal prostate or mammary epithelial cell fate and development remains unknown. Therefore, we sought to elucidate the functional role of CXCL12γ in the regulation of ESCs and tissue development. METHODS: Prostate epithelial cells (PNT2) or mammary epithelial cells (MCF10A) with overexpressed CXCL12γ was characterized by quantitative real-time polymerase chain reaction, Western blots, and immunofluorescence for lineage marker expression, and fluorescence activated cell sorting analyses and sphere formation assays to examine stem cell surface phenotype and function. Xenotransplantation animal models were used to evaluate gland or acini formation in vivo. RESULTS: Overexpression of CXCL12γ promotes the reprogramming of cells with a differentiated luminal phenotype to a nonluminal phenotype in both prostate (PNT2) and mammary (MCF10A) epithelial cells. The CXCL12γ-mediated nonluminal type cells results in an increase of epithelial stem-like phenotype including the subpopulation of EPCAMLo /CD49fHi /CD24Lo /CD44Hi cells capable of sphere formation. Critically, overexpression of CXCL12γ promotes the generation of robust gland-like structures from both prostate and mammary epithelial cells in in vivo xenograft animal models. CONCLUSIONS: CXCL12γ supports the reprogramming of epithelial cells into nonluminal cell-derived stem cells, which facilitates gland development.

Bone microenvironment signaling of cancer stem cells as a therapeutic target in metastatic prostate cancer.

Prostate cancer (PCa) is one of the most prevalent cancers and the second leading cause of cancer death among US males. When diagnosed in an early disease stage, primary tumors of PCa may be treated with surgical resection or radiation, sometimes combined with androgen deprivation therapy, with favorable outcomes. Unfortunately, the treatment efficacy of each approach decreases significantly in later stages of PCa that involve metastasis to soft tissues and bone. Metastatic PCa is a heterogeneous disease containing host cells, mature cancer cells, and subpopulation of cancer stem cells (CSC). CSCs are highly tumorigenic due to their self-renewing and differentiating potential, clinically resulting in recurrence and resistance to standard therapies. Therefore, there is a large unmet clinical need to develop therapies, which target CSC activity. In this review, we summarize the main signaling pathways that are implicated in the current pre-clinical and clinical studies of recurrent metastatic PCa within the bone microenvironment targeting CSCs and discuss the trajectory of therapeutics moving forward.

Detection and isolation of disseminated tumor cells in bone marrow of patients with clinically localized prostate cancer.

BACKGROUND: Disseminated tumor cells (DTCs) have been reported in the bone marrow (BM) of patients with localized prostate cancer (PCa). However, the existence of these cells continues to be questioned, and few methods exist for viable DTC isolation. Therefore, we sought to develop novel approaches to identify and, if detected, analyze localized PCa patient DTCs. METHODS: We used fluorescence-activated cell sorting (FACS) to isolate a putative DTC population, which was negative for CD45, CD235a, alkaline phosphatase, and CD34, and strongly expressed EPCAM. We examined tumor cell content by bulk cell RNA sequencing (RNA-Seq) and whole-exome sequencing after whole genome amplification. We also enriched for BM DTCs with α-EPCAM immunomagnetic beads and performed quantitative reverse trancriptase polymerase chain reaction (qRT-PCR) for PCa markers. RESULTS: At a threshold of 4 cells per million BM cells, the putative DTC population was present in 10 of 58 patients (17%) with localized PCa, 4 of 8 patients with metastatic PCa of varying disease control, and 1 of 8 patients with no known cancer, and was positively correlated with patients' plasma PSA values. RNA-Seq analysis of the putative DTC population collected from samples above (3 patients) and below (5 patients) the threshold of 4 putative DTCs per million showed increased expression of PCa marker genes in 4 of 8 patients with localized PCa, but not the one normal donor who had the putative DTC population present. Whole-exome sequencing also showed the presence of single nucleotide polymorphisms and structural variants in the gene characteristics of PCa in 2 of 3 localized PCa patients. To examine the likely contaminating cell types, we used a myeloid colony formation assay, differential counts of cell smears, and analysis of the RNA-Seq data using the CIBERSORT algorithm, which most strongly suggested the presence of B-cell lineages as a contaminant. Finally, we used EPCAM enrichment and qRT-PCR for PCa markers to estimate DTC prevalence and found evidence of DTCs in 21 of 44 samples (47%). CONCLUSION: These data support the presence of DTCs in the BM of a subset of patients with localized PCa and describe a novel FACS method for isolation and analysis of viable DTCs.

Reduction of two histone marks, H3k9me3 and H3k27me3 by epidrug induces neuroendocrine differentiation in prostate cancer.

Neuroendocrine prostate cancer (NE PCa) is an aggressive malignancy, often presenting with advanced metastasis. We previously reported that reduction of histone marks regulated by DNMT1 following epidrug (5-Azacitidine, 5-Aza) treatment controls induction of epithelial to mesenchymal (EMT) and a cancer stem cell (CSC) phenotype, which facilitates tumorigenesis in PCa cells. Here, we use the epidrug 5-Aza as a model for how histone marks may regulate the reprogramming of prostate adenocarcinoma into NE phenotypic cells. First, we observed that 5-Aza treatment of PCa cells in vitro induces a neuron-like phenotype. In addition, significant increases in the expression of the NE markers N-Myc downstream regulated gene 1 (NDRG1), enolase-2 (ENO2), and synaptophysin were observed. Critically, a high density of NE cells with synaptophysin expression was found in tumors generated by 5-Aza pretreatment of PCa cells. Importantly, induction of NE differentiation of PCa cells was associated with an enhancement of NDRG1 expression by reduction of two histone marks, H3K9me3 and H3K27me3. Further, more NDRG1 expression was detected in the subset of PCa cells with reduced expression of H3K9me3 or H3K27me3 in the tumors generated by 5-Aza pretreated PCa cells and critically, these biological differences are also observed in small cell carcinoma in advanced stage of human primary PCa tumors. Our results suggest that reduction of histone marks regulated by the epidrug 5-Aza may control induction of a NE phenotype, which facilitates PCa progression. These studies suggest a strong rationale for developing therapeutics, which target epigenetic regulation.

Minimal Residual Disease in Prostate Cancer.

Detection of minimal residual disease (MRD) in prostate cancer over several decades has greatly informed our understanding of dissemination and recurrence, but has not yet been routinely used in clinical care. Investigators have detected MRD by identification of prostate cancer cells in the bone marrow; termed disseminated tumor cells (DTCs) and blood; termed circulating tumor cells (CTCs). Various techniques including PSA-RT PCR, PSA immunocytochemistry, cytokeratin immunocytochemistry, and immune-magnetic depletion of hematopoietic cells followed by EPCAM based positive selection, have been used. Importantly, detection of DTCs correlates with recurrence. Research into prostate cancer CTCs has intensified recently, but their use in MRD evaluation has been more limited. Investigators are using semi-automated platforms to detect and begin to study prostate cancer CTCs in patients with no evidence of disease. PSA immunocytochemistry also detects CTCs and correlates with recurrence. Emerging technologies have the potential to greatly aid research in this exciting field.

Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy.

Many prostate cancer (PCa) recurrences are thought to be due to reactivation of disseminated tumor cells (DTCs). We previously found a role of the TAM family of receptor tyrosine kinases TYRO3, AXL, and MERTK in PCa dormancy regulation. However, the mechanism and contributions of the individual TAM receptors is largely unknown. Knockdown of MERTK, but not AXL or TYRO3 by shRNA in PCa cells induced a decreased ratio of P-Erk1/2 to P-p38, increased expression of p27, NR2F1, SOX2, and NANOG, induced higher levels of histone H3K9me3 and H3K27me3, and induced a G1/G0 arrest, all of which are associated with dormancy. Similar effects were also observed with siRNA. Most importantly, knockdown of MERTK in PCa cells increased metastasis free survival in an intra-cardiac injection mouse xenograft model. MERTK knockdown also failed to inhibit PCa growth in vitro and subcutaneous growth in vivo, which suggests that MERTK has specificity for dormancy regulation or requires a signal from the PCa microenvironment. The effects of MERTK on the cell cycle and histone methylation were reversed by p38 inhibitor SB203580, which indicates the importance of MAP kinases for MERTK dormancy regulation. Overall, this study shows that MERTK stimulates PCa dormancy escape through a MAP kinase dependent mechanism, also involving p27, pluripotency transcription factors, and histone methylation. J. Cell. Biochem. 118: 891-902, 2017. © 2016 Wiley Periodicals, Inc.

Growth Arrest-Specific 6 (GAS6) Promotes Prostate Cancer Survival by G1 Arrest/S Phase Delay and Inhibition of Apoptosis During Chemotherapy in Bone Marrow.

Prostate cancer (PCa) is known to develop resistance to chemotherapy. Growth arrest-specific 6 (GAS6), plays a role in tumor progression by regulating growth in many cancers. Here, we explored how GAS6 regulates the cell cycle and apoptosis of PCa cells in response to chemotherapy. We found that GAS6 is sufficient to significantly increase the fraction of cells in G1 and the duration of phase in PCa cells. Importantly, the effect of GAS6 on G1 is potentiated during docetaxel chemotherapy. GAS6 altered the levels of several key cell cycle regulators, including the downregulation of Cyclin B1 (G2 /M phase), CDC25A, Cyclin E1, and CDK2 (S phase entry), while the upregulation of cell cycle inhibitors p27 and p21, Cyclin D1, and CDK4. Importantly, these changes became further accentuated during docetaxel treatment in the presence of GAS6. Moreover, GAS6 alters the apoptotic response of PCa cells during docetaxel chemotherapy. Docetaxel induced PCa cell apoptosis is efficiently suppressed in PCa cell culture in the presence of GAS6 or GAS6 secreted from co-cultured osteoblasts. Similarly, the GAS6-expressing bone environment protects PCa cells from apoptosis within primary tumors in vivo studies. Docetaxel induced significant levels of Caspase-3 and PARP cleavage in PCa cells, while GAS6 protected PCa cells from docetaxel-induced apoptotic signaling. Together, these data suggest that GAS6, expressed by osteoblasts in the bone marrow, plays a significant role in the regulation of PCa cell survival during chemotherapy, which will have important implications for targeting metastatic disease. J. Cell. Biochem. 117: 2815-2824, 2016. © 2016 Wiley Periodicals, Inc.

Oncogenic signaling in the adult Drosophila prostate-like accessory gland leads to activation of a conserved pro-tumorigenic program, in the absence of proliferation.

Drosophila models for tumorigenesis and metastasis have revealed conserved mechanisms of signaling that are also involved in mammalian cancer. Many of these models use the proliferating tissues of the larval stages of Drosophila development, when tissues are highly mitotically active, or stem cells are abundant. Fewer Drosophila tumorigenesis models use adult animals to initiate tumor formation when many tissues are largely terminally differentiated and postmitotic. The Drosophila accessory glands are prostate-like tissues and a model for some aspects of prostate tumorigenesis using this tissue has been explored. In this model, oncogenic signaling was induced during the proliferative stage of accessory gland development, raising the question of how oncogenic activity would impact the terminally differentiated and postmitotic adult tissue. Here, we show that oncogenic signaling in the adult Drosophila accessory gland leads to activation of a conserved pro-tumorigenic program, similar to that observed in mitotic larval tissues, but in the absence of proliferation. Oncogenic signaling in the adult postmitotic gland leads to tissue hyperplasia with nuclear anaplasia and aneuploidy through endoreduplication, which increases polyploidy and occasionally results in non-mitotic neoplastic-like extrusions. We compare gene expression changes in our Drosophila model with that of endocycling prostate cancer cells induced by chemotherapy, which potentially mediate tumor recurrence after treatment. Similar signaling pathways are activated in the Drosophila gland and endocycling cancer cells, suggesting the adult accessory glands provide a useful model for aspects of prostate cancer progression that do not involve cellular proliferation.

Race-Related Differences in Sipuleucel-T Response among Men with Metastatic Castrate-Resistant Prostate Cancer.

Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is available for treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In this single-arm, two-cohort, multicenter clinical study, potential racial differences in immune responses to sipuleucel-T in men with mCRPC were explored. Patients' blood samples were obtained to assess serum cytokines, humoral responses, and cellular immunity markers before and after treatment. Baseline cumulative product parameters (total nucleated and CD54+ cell counts and CD54 upregulation) were evaluated. IgM titers against the immunogen PA2024, the target antigen PAP, prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were quantified by ELISA. Cytotoxic T-lymphocyte activity was determined by ELISpots, and cytokine and chemokine concentrations were determined by Luminex.Twenty-nine African American (AA) men and 28 non-African American (non-AA) men with mCRPC received sipuleucel-T. Baseline total nucleated cell count, CD54+ cell count, CD54 expression, and cumulative product parameters were higher in non-AA men. Although PSA baseline levels were higher in AA men, there were no racial differences in IgM antibody and IFNγ ELISpots responses against PA2024, PAP, PSA, and PSMA before and after treatment. Expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells, and the levels of Th1 cytokine granulocyte-macrophage colony-stimulating factor and chemokines CCL4 and CCL5, were significantly higher in AA men before and/or after treatment. Despite no difference in the overall survival, PSA changes from baseline were significantly different between the two races. The data suggest that immune correlates in blood differ in AA and non-AA men with mCRPC pre- and post-sipuleucel-T. SIGNIFICANCE: Our novel findings of higher expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells in African American patients with metastatic castrate-resistant prostate cancer (mCRPC) prior and post-sipuleucel-T suggest activation of CD4+ and CD8+ T cells. The data indicate that racial differences observed in these and other immune correlates before and after sipuleucel-T warrant additional investigation to further our understanding of the immune system in African American men and other men with mCRPC.

Clinical implications of Wnt pathway genetic alterations in men with advanced prostate cancer.

BACKGROUND: Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis and metastasis in preclinical models but the impact of genetic alterations in Wnt signaling genes in men with advanced prostate cancer is unknown. METHODS: We utilized the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database for this retrospective analysis. Patients with activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 were defined as Wnt-altered, while those lacking such alterations were defined as Wnt non-altered. We compared patient characteristics and clinical outcomes as well as co-occurring genetic alterations according to Wnt alteration status. RESULTS: Of the 1498 patients included, 193 (12.9%) were Wnt-altered. These men had a statistically significant 2-fold increased prevalence of liver and lung metastases as compared with Wnt non-altered patients at the time of initial diagnosis, (4.66% v 2.15% ; 6.22% v 3.07%), first metastatic disease diagnosis (10.88% v 5.29%; 13.99% v 6.21%), and CRPC development (11.40% v 6.36%; 12.95% v 5.29%). Wnt alterations were associated with more co-occurring alterations in RB1 (10.4% v 6.2%), AR (38.9% vs 25.7%), SPOP (13.5% vs 4.1%), FOXA1 (6.7% vs 2.8%), and PIK3CA (10.9% vs 5.1%). We found no significant differences in overall survival or other clinical outcomes from initial diagnosis, first metastatic disease, diagnosis of CRPC, or with AR inhibition for mCRPC between the Wnt groups. CONCLUSIONS: Wnt-altered patients with prostate cancer have a higher prevalence of visceral metastases and are enriched in RB1, AR, SPOP, FOXA1, and PIK3CA alterations. Despite these associations, Wnt alterations were not associated with worse survival or treatment outcomes in men with advanced prostate cancer.

Repeat Next-Generation Sequencing Testing on Progression in Men With Metastatic Prostate Cancer Can Identify New Actionable Alterations.

PURPOSE: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB. RESULTS: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients. CONCLUSION: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.

HER2 as a potential therapeutic target on quiescent prostate cancer cells.

Quiescent prostate cancer (PCa) cells are common in tumors but are often resistant to chemotherapy. Quiescent PCa cells are also enriched for a stem-like tumor initiating population, and can lead to recurrence after dormancy. Unfortunately, quiescent PCa cells are difficult to identify and / or target with treatment in part because the relevant markers are intracellular and regulated by protein stability. We addressed this problem by utilizing PCa cells expressing fluorescent markers for CDKN1B (p27) and CDT1, which can separate viable PCa cells into G0, G1, or combined S/G2/M populations. We used FACS to collect G1 and G0 PC3 PCa cells, isolated membrane proteins, and analyzed protein abundance in G0 vs G1 cells by gas chromatography mass spectrometry. Enrichment analysis identified nucleocytoplasmic transport as the most significantly different pathway. To identify cell surface proteins potentially identifying quiescent PCa cells for future patient samples or for antibody based therapeutic research, we focused on differentially abundant plasma membrane proteins, and identified ERBB2 (HER2) as a cell surface protein enriched on G0 PCa cells. High HER2 on the cell membrane is associated with quiescence in PCa cells and likely induced by the bone microenvironment. Using a drug conjugated anti-HER2 antibody (trastuzumab emtansine) in a mouse PCa xenograft model delayed metastatic tumor growth, suggesting approaches that target HER2-high cells may be beneficial in treating PCa. We propose that HER2 is deserving of further study in PCa as a target on quiescent cells to prevent recurrence, decrease chemotherapy resistance, or eradicate minimal residual disease.

Biomarker-Directed Therapy in Black and White Men With Metastatic Castration-Resistant Prostate Cancer.

Importance: Black men have higher incidence and mortality from prostate cancer. Whether precision oncology disparities affect Black men with metastatic castration-resistant prostate cancer (mCRPC) is unknown. Objective: To compare precision medicine data and outcomes between Black and White men with mCRPC. Design, Setting, and Participants: This retrospective cohort study used data collected by the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) consortium, a multi-institutional registry with linked clinicogenomic data, from April 2020 to December 2021. Participants included Black and White patients with mCRPC with molecular data. Data were analyzed from December 2021 to May 2023. Exposures: Database-reported race and ethnicity. Main Outcomes and Measures: The primary outcome was the frequency of actionable molecular data, defined as the presence of mismatch repair deficiency (MMRD) or high microsatellite instability (MSI-H), homologous recombination repair deficiency, or tumor mutational burden of 10 mutations per megabase or greater. Secondary outcomes included the frequency of other alterations, the type and timing of genomic testing performed, and use of targeted therapy. Efficacy outcomes were prostate-specific antigen response rate, site-reported radiographic response, and overall survival. Results: A total of 962 eligible patients with mCRPC were identified, including 204 Black patients (21.2%; median [IQR] age at diagnosis, 61 [55-67] years; 131 patients [64.2%] with Gleason scores 8-10; 92 patients [45.1%] with de novo metastatic disease) and 758 White patients (78.8%; median [IQR] age, 63 [57-69] years; 445 patients [58.7%] with Gleason scores 8-10; 310 patients [40.9%] with de novo metastatic disease). Median (IQR) follow-up from mCRPC was 26.6 (14.2-44.7) months. Blood-based molecular testing was more common in Black men (111 men [48.7%]) than White men (317 men [36.4%]; P < .001). Rates of actionable alterations were similar between groups (65 Black men [32.8%]; 215 White men [29.1%]; P = .35), but MMRD or MSI-H was more common in Black men (18 men [9.1]) than White men (36 men [4.9%]; P = .04). PTEN alterations were less frequent in Black men than White men (31 men [15.7%] vs 194 men [26.3%]; P = .003), as were TMPRSS alterations (14 men [7.1%] vs 155 men [21.0%]; P < .001). No other differences were seen in the 15 most frequently altered genes, including TP53, AR, CDK12, RB1, and PIK3CA. Matched targeted therapy was given less frequently in Black men than White men (22 men [33.5%] vs 115 men [53.5%]; P = .008). There were no differences in response to targeted therapy or survival between the two cohorts. Conclusions and Relevance: This cohort study of men with mCRPC found higher frequency of MMRD or MSI-H and lower frequency of PTEN and TMPRSS alterations in Black men compared with White men. Although Black men received targeted therapy less frequently than White men, no differences were observed in clinical outcomes.

Osteoclasts are important for bone angiogenesis.

Increased osteoclastogenesis and angiogenesis occur in physiologic and pathologic conditions. However, it is unclear if or how these processes are linked. To test the hypothesis that osteoclasts stimulate angiogenesis, we modulated osteoclast formation in fetal mouse metatarsal explants or in adult mice and determined the effect on angiogenesis. Suppression of osteoclast formation with osteoprotegerin dose-dependently inhibited angiogenesis and osteoclastogenesis in metatarsal explants. Conversely, treatment with parathyroid hormone related protein (PTHrP) increased explant angiogenesis, which was completely blocked by osteoprotegerin. Further, treatment of mice with receptor activator of nuclear factor-kappaB ligand (RANKL) or PTHrP in vivo increased calvarial vessel density and osteoclast number. We next determined whether matrix metalloproteinase-9 (MMP-9), an angiogenic factor predominantly produced by osteoclasts in bone, was important for osteoclast-stimulated angiogenesis. The pro-angiogenic effects of PTHrP or RANKL were absent in metatarsal explants or calvaria in vivo, respectively, from Mmp9(-/-) mice, demonstrating the importance of MMP-9 for osteoclast-stimulated angiogenesis. Lack of MMP-9 decreased osteoclast numbers and abrogated angiogenesis in response to PTHrP or RANKL in explants and in vivo but did not decrease osteoclast differentiation in vitro. Thus, MMP-9 modulates osteoclast-stimulated angiogenesis primarily by affecting osteoclasts, most probably by previously reported migratory effects on osteoclasts. These results clearly demonstrate that osteoclasts stimulate angiogenesis in vivo through MMP-9.

Prostate cancer dormancy and recurrence.

Prostate cancer can progress rapidly after diagnosis, but can also become undetectable after curative intent radiation or surgery, only to recur years or decades later. This capacity to lie dormant and recur long after a patient was thought to be cured, is relatively unique to prostate cancer, with estrogen receptor positive breast cancer being the other common and well-studied example. Most investigators agree that the bone marrow is an important site for dormant tumor cells, given the frequency of bone metastases and that multiple studies have reported disseminated tumor cells in patients with localized disease. However, while more difficult to study, lymph nodes and the prostate bed are likely to be important reservoirs as well. Dormant tumor cells may be truly quiescent and in the G0 phase of the cell cycle, which is commonly called cellular dormancy. However, tumor growth may also be held in check through a balance of proliferation and cell death (tumor mass dormancy). For induction of cellular dormancy, prostate cancer cells respond to signals from their microenvironment, including TGF-ß2, BMP-7, GAS6, and Wnt-5a, which result in signals transduced in part through p38 MAPK and pluripotency associated transcription factors including SOX2 and NANOG, which likely affect the epi-genome through histone modification. Clinical use of adjuvant radiation or androgen deprivation has been modestly successful to prevent recurrence. With the rapid pace of discovery in this field, systemic adjuvant therapy is likely to continue to improve in the future.

Treatment Intensification Patterns and Utilization in Patients with Metastatic Castration-Sensitive Prostate Cancer.

INTRODUCTION: Patients with mCSPC experience a longer overall survival with treatment intensification by addition of novel hormonal therapy (NHT) or docetaxel to androgen deprivation vs androgen deprivation alone. Real-world data report, however, that nearly half of mCSPC patients do not receive treatment intensification. In this study, treatment patterns and utilization of treatment intensification in mCSPC patients were described using the IQVIA Anonymized Patient Longitudinal Data, a dataset of fully adjudicated pharmacy and medical claims. PATIENTS AND METHODS: Reports on first line (1L) treatment patterns were obtained for years 2015 to 2021. Medicaid, Medicare, Medicare part D, cash transactions, and commercial data were included for years 2012 to 2021. RESULTS: Nationwide, of 66,844 men with newly diagnosed mCSPC since 2015, on average 25% were prescribed NHT, and another 12% were prescribed chemotherapy. No differences were noted in treatment patterns based on U.S. regions and/or rural vs. urban communities. The disparity was observed in prescribing patterns between oncology and urology providers. Oncology providers prescribed 1L NHT on average 32% of the time, while urology providers did so 12% of the time. Furthermore, oncology providers prescribed chemotherapy on average 20% of the time, resulting in 52% of men with mCSPC receiving treatment intensification as 1L therapy. Patients' age group, community or health insurance did not account for the disparity between the 2 specialties. CONCLUSION: Both medical oncology and urology providers need to improve their treatment intensification efforts for men with mCSPC to increase their patients' overall survival.