Development and validation of a prognostic nomogram for overall and disease-specific survival in patients with sarcomatoid urothelial carcinoma.

INTRODUCTION: Sarcomatoid urothelial carcinoma (SUC) is a rare and aggressive variant of bladder cancer with limited data guiding prognosis. In this study, we present the first prognostic nomograms in the literature for 3- and 5-year overall survival (OS) and disease-specific survival (DSS), for patients with SUC derived from the surveillance, epidemiology and end results database (SEER). MATERIALS AND METHODS: Patients with SUC were identified by using the ICD-10 topography codes C67.0-C67.9 (bladder cancer), and the morphologic code 8122 (SUC). Patients were randomly divided into a training cohort (TC) and a validation cohort (VC) (7:3 ratio). Variables significantly associated with OS and DSS were identified with multivariate Cox regression and were used to build the nomograms. Harrel's C-statistic with bootstrap resampling and calibration curves were used for internal (TC) and external (VC) validation. Clinical utility of the nomograms was assessed with the decision curve analysis (DCA). Goodness of fit between the nomograms and the AJCC 8th edition staging system was compared with the likelihood ratio test. RESULTS: A total of 741 patients with SUC were included (507 TC, 234 VC). No statistically significant differences in baseline characteristics were identified between the 2 cohorts. Sex, SEER stage, radical cystectomy and chemotherapy were common variables for the OS and the DSS nomograms with the addition of age in the former. Optimism-corrected C-statistic for the nomograms was 0.68 and 0.67 for OS and DSS respectively. In comparison, C-statistic for AJCC was 0.59 for OS and 0.60 for DSS (P < 0.001). Calibration curves constructed for the nomograms showed appropriate consistency between predicted and actual survival. The nomograms demonstrated optimal clinical utility in the DCA, outperforming the AJCC staging system, by maintaining a higher clinical net benefits than treat all, treat none and AJCC curves, across threshold probabilities. CONCLUSION: We present the first prognostic nomograms developed in patients with SUC. Our models demonstrated superior prognostic performance to the AJCC system, by utilizing a set of variables readily available in daily practice and may serve as useful tools for the individualized risk assessment of these patients.

Molecular Characterization of Malignant Renal Epithelioid Angiomyolipoma: A Review of Two Cases.

OBJECTIVES: Epithelioid angiomyolipoma (EAML, perivascular epithelioid cell tumor) is an uncommon primary renal tumor that may recur or metastasize, although there remain limited data for prediction of these outcomes. Here, we report two cases of renal EAML with molecular testing, adding to the existing literature of potential alterations associated with malignant behavior. METHODS: Tumors diagnosed as malignant renal EAML were identified, and clinical data, radiology, histology, immunohistochemistry, and molecular testing results were reviewed. RESULTS: Two cases of malignant renal EAML were identified, both of which demonstrated TSC2 and TP53 mutations. In ATRX, one had a mutation and the other had a variant of uncertain significance. In addition, one patient had a synchronous classic angiomyolipoma that lacked TP53 and ATRX alterations. CONCLUSIONS: These findings highlight the molecular landscape of malignant renal EAML and expand on the existing literature suggesting a role for TP53 and ATRX alterations in malignant progression of these tumors. The presence of synchronous benign and malignant tumors within the same patient offers a unique opportunity to directly compare the molecular alterations, further supporting the association with aggressive behavior.

Renal Sarcoma: A Population-Based Study.

INTRODUCTION: Renal sarcomas are exceedingly rare and lack a prognostic stage classification. We thus aimed to investigate the contemporary clinicopathologic characteristics and outcomes of renal sarcomas at a national level. PATIENTS AND METHODS: We utilized the Surveillance, Epidemiology, and End Results database to extract data on patients with renal sarcoma diagnosed between 2004 and 2015. We estimated median, 1-, 3-, and 5-year overall survival (OS) probabilities via Kaplan-Meier curves and used multivariable regression to compare OS between different patient groups. RESULTS: We identified 365 patients; at diagnosis, 104 patients (28.5%) had stage I disease (T1N0M0), 133 patients (36.4%) patients had stage II disease (T2-4N0M0), and 117 patients (32.1%) patients had stage III disease (any T, N1, or M1). Median survival was 105 months (interquartile range [IQR], 29 - not reached) for stage I disease, 46 months (IQR 14-118 months) for stage II disease, 8 months (IQR 3-28 months) for stage III disease, and 32 months (IQR, 8-116 months) for the entire cohort. Patient age (hazard ratio [HR] for death [per year] 1.02, 95% confidence interval [95% CI] 1.00-1.04), stage (II vs. I: HR 1.71, 95% CI 1.00-2.92; III vs. I: HR 4.93, 95% CI 2.68-9.05), grade (grade 3 vs. grade 1: 3.07, 95% CI 1.18-8.00; grade 4 vs. grade 1: HR 3.66, 95% CI 1.41-9.49), and possessing medical insurance (HR 0.40, 95% CI 0.16-0.94) were independently and significantly associated with OS. Performance of nephrectomy also trended towards independently improving OS (HR 0.23, 95% CI 0.05-1.09). CONCLUSION: A novel staging classification for renal sarcomas into a 3-stage system based on Tumor Node Metastasis (TNM) criteria produces distinct survival curves, although further studies are needed to robustly assess its validity.

Malignant germ cell tumors in men aged 50 years and over are associated with adverse pathologic features and higher stage at presentation.

BACKGROUND: Germ cell tumors (GCT) are the most common malignancy in men in the third and fourth decades of life. The occurrence of malignant GCT in men aged 50 years or over is rare, and their histopathologic characteristics and outcome is insufficiently characterized in the medical literature. Hence, we report the histopathologic features and clinical outcome of malignant GCTs in men aged ≥50 years at our institution. DESIGN: We performed a retrospective search of our database from 2005 to 2021 to identify men aged 50 years or older with malignant GCT. Cases of spermatocytic tumor were excluded. Clinical and histopathologic features of the tumors were reviewed. RESULTS: Forty-seven cases were identified, showing a sharp decline in incidence over the age of 65. Thirty-nine (83 %) tumors were testicular while eight (17 %) were non-testicular in presentation. Cases included 26 (55 %) seminomas, 15 (32 %) non-seminoma/mixed malignant GCT, and 5 (11 %) regressed testicular germ cell tumors. The most common component in mixed malignant GCTs was embryonal carcinoma (77 %), followed by seminoma and yolk sac tumor (62 % each). Germ cell neoplasia in situ (GCNIS) accompanied 57 % of the cases. Aggressive pathologic features, including lymphovascular invasion, retroperitoneal/lymph node involvement and higher stage at presentation, were identified in a significant proportion of cases (36/47, 77 %). Clinical follow up showed six patients (14 %) died of disease-related causes. CONCLUSION: Our findings expand and corroborate the previously reported data on malignant GCT in older men. Unique characteristics include tendency for higher stage at presentation with adverse pathologic features and more aggressive clinical course.

ARID1A, BRG1, and INI1 deficiency in undifferentiated and dedifferentiated endometrial carcinoma: a clinicopathologic, immunohistochemical, and next-generation sequencing analysis of a case series from a single institution.

Undifferentiated/dedifferentiated endometrial carcinomas (UDEC and DDEC) are rare, aggressive uterine neoplasms, with no specific line of differentiation. A significant proportion of these cases feature mutations of SWI/SNF chromatin remodeling complex members, including ARID1A, SMARCA4, and SMARCB1 genes. To study these entities more comprehensively, we identified 10 UDECs and 10 DDECs from our pathology archives, obtained clinicopathologic findings and follow-up data, and performed immunohistochemical studies for ARID1A, BRG1 (SMARCA4), and INI1 (SMARCB1) proteins. In addition, we successfully conducted targeted next-generation sequencing for 23 samples, including 7 UDECs, and 7 undifferentiated and 9 well/moderately-differentiated components of DDECs. Cases consisted of 18 hysterectomies and 2 curettage/biopsy specimens. Patient age ranged from 47 to 77 years (median, 59 years), with a median tumor size of 8.0 cm (range, 2.5-13.0 cm). All cases demonstrated lymphovascular invasion and the majority (13/20) were FIGO stage III-IV. By immunohistochemistry, ARID1A loss was observed in 15 cases, BRG1 loss in 4, and all cases had intact INI1 expression. A trend for enrichment of the undifferentiated component of DDECs for ARID1A loss was seen, although not statistically significant. Sequencing revealed frequent pathogenic mutations in PTEN, PIK3CA, ARID1A, CTNNB1, and RNF43, a recurrent MAX pathogenic mutation, and MYC and 12p copy number gains. In DDECs, the undifferentiated component featured a higher tumor mutational burden compared to the well/moderately-differentiated component; however, the mutational landscape largely overlapped. Overall, our study provides deep insights into the mutational landscape of UDEC/DDEC, SWI/SNF chromatin remodeling complex member status, and their potential relationships with tumor features.

Effect of different storage conditions on the fit of 3D-printed occlusal devices used to treat temporomandibular disorders.

STATEMENT OF PROBLEM: Research-based storage guidelines for 3-dimensional (3D)-printed occlusal devices are lacking. PURPOSE: The purpose of this in vitro study was to investigate the dimensional stability of the internal surface of 3D-printed occlusal devices under different storage conditions. MATERIAL AND METHODS: Maxillary and mandibular dental casts were scanned and exported to a 3D printer to fabricate 30 occlusal devices. The specimens were stored under 3 different conditions (n=10): air dried and stored under natural light (group DL), stored in a dark container with water (group W), and air dried and stored in a dark container (group D). The intaglio surfaces of the occlusal devices were scanned by a laboratory scanner at 4 time points: immediately after polymerization (t0, control), after 1 day (t1), after 7 days (t2), and after 27 days (t3). The dimensional changes of the fitting surfaces between t0 and t1 (Δt1), t0 and t2 (Δt2), and t0 and t3 (Δt3) were measured by using best fit alignment in a surface analysis software program. In addition, comparisons were made between the posterior and anterior sections. Statistical analysis was completed with Kolmogorov-Smirnov, 1-way ANOVA, Friedman, Kruskal-Wallis, Mann-Whitney, and unpaired t tests. RESULTS: The root mean square (RMS) of group DL between Δt1 and Δt2 (P=.002) and between Δt1 and Δt3 (P=.002) showed a statistically significant difference. The RMS of group W between Δt1 and Δt3 (P=.008) showed a statistically significant difference. When the groups were compared with each other at the different time points, the DL group showed a statistically significant difference compared with groups W and D at Δt1. The examination of different areas of the occlusal device (right molar, incisor, and left molar sites) indicated no statistically significant differences in RMS among all groups (P>.05). CONCLUSIONS: The occlusal devices of group DL showed the least dimensional change of the fitting surface for Δt1 in comparison with group W and D, while no statistically significant differences were found among the groups for Δt2 and Δt3. In terms of the different locations, no statistically significant differences were found among the 3 locations for any given group after 27 days.

Characterization of Casirivimab Plus Imdevimab, Sotrovimab, and Bamlanivimab Plus Etesevimab-Derived Interference in Serum Protein Electrophoresis and Immunofixation Electrophoresis.

BACKGROUND: Therapeutic monoclonal antibodies can be a source of assay interference in clinical serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE), producing monoclonal bands that can be misinterpreted as a monoclonal gammopathy related to a B-cell or plasma cell neoplasm. The extent to which new anti-COVID-19 monoclonal antibodies produce this interference is unknown. METHODS: Casirivimab plus imdevimab, sotrovimab, and bamlanivimab plus etesevimab were spiked into patient serum samples to evaluate for SPEP/IFE interference, to characterize the position of therapy-derived bands relative to a reference band (either combined beta band or beta 1 band, depending on instrument platform), and to confirm heavy and light chain utilization of each medication. Serum samples from patients who had recently received casirivimab plus imdevimab or sotrovimab were also evaluated for comparison. RESULTS: When spiked into serum samples, all tested anti-COVID-19 monoclonal antibodies generated interference in SPEP/IFE. Importantly, the patterns of interference differed between spiked serum samples and serum from patients who had recently received casirivimab plus imdevimab or sotrovimab. CONCLUSIONS: Imdevimab can be added to the growing list of therapeutic monoclonal antibodies that produce sustained interference in SPEP/IFE. Although casirivimab and sotrovimab also produce assay interference in vitro, these antibodies are not reliably detected in serum from recently infused patients. The value of relative band position in recognizing bands that may represent therapeutic monoclonal antibodies is also emphasized. Clinicians and laboratorians should consider therapeutic monoclonal antibody interference in diagnostic SPEP/IFE and review a patient's medication list when new or transient monoclonal bands are identified.

Interferon-γ increases sensitivity to chemotherapy and provides immunotherapy targets in models of metastatic castration-resistant prostate cancer.

Interferon-γ (IFNγ) is a cytokine with limited evidence of benefit in cancer clinical trials to date. However, it could potentially play a role in potentiating anti-tumor immunity in the immunologically "cold" metastatic castration-resistant prostate cancer (mCRPC) by inducing antigen presentation pathways and concurrently providing targets for immune checkpoint blockade therapy. Moreover, it could additionally increase sensitivity to chemotherapy based on its pleiotropic effects on cell phenotype. Here, we show that IFNγ treatment induced expression of major histocompatibility class-I (MHC-I) genes and PD-L1 in prostate cancer cells in vitro. Furthermore, IFNγ treatment led to a decrease in E-cadherin expression with a consequent increase in sensitivity to chemotherapy in vitro. In an in vivo murine tumor model of spontaneous metastatic prostate cancer, IFNγ systemic pretreatment upregulated the expression of HLA-A and decreased E-cadherin expression in the primary tumor, and more importantly in the metastatic site led to increased apoptosis and limited micrometastases in combination with paclitaxel treatment compared to diffuse metastatic disease in control and monotherapy treatment groups. These findings suggest that IFNγ may be useful in combinatorial regimens to induce sensitivity to immunotherapy and chemotherapy in hepatic metastases of mCRPC.

COVID-19 mRNA Vaccines May Cause False Reactivity in Some Serologic Laboratory Tests, Including Rapid Plasma Reagin Tests.

OBJECTIVES: Acute viral infections and some vaccines have been shown to increase false positivity in serologic assays. We assessed if the messenger RNA coronavirus disease 2019 (COVID-19) vaccines could cause false reactivity in common serologic assays in a pilot longitudinal cohort. METHODS: Thirty-eight participants with sera available prevaccination, 2 weeks after each vaccine dose, and monthly thereafter for up to 5 months were tested for common infectious disease serologies and antiphospholipid syndrome (APS) serology markers on the BioPlex 2200, Sure-Vue rapid plasma reagin (RPR), and Macro-Vue RPR. Twenty-two participants received the Moderna vaccine and 16 received the Pfizer vaccine. RESULTS: Most assays had no change in reactivity over the course of the sample draws, including APS markers. Epstein-Barr virus immunoglobulin G (IgG), measles IgG, and rubella immunoglobulin M all had possible false reactivity in one to two participants. RPR tests demonstrated false reactivity, with baseline nonreactive participant samples becoming reactive following vaccination. There were more false reactive participants (7/38) in the BioPlex RPR than in the Sure-Vue (2/38) and Macro-Vue (1/38) tests. All falsely reactive RPR tests were in participants who received the Moderna vaccine. CONCLUSIONS: Serologic assays with results that do not fit the clinical picture following COVID-19 vaccination should be repeated. Effects of false reactivity can last more than 5 months in some assays. In particular, RPR is susceptible to false reactivity, and there is variability among assays. Larger longitudinal studies are needed to determine the incidence and window of false reactivity.

Sarcomatoid Urothelial Carcinoma: A Population-Based Study of Clinicopathologic Characteristics and Survival Outcomes.

INTRODUCTION: Sarcomatoid urothelial carcinoma (SUC) is a rare and aggressive variant of bladder cancer with limited data regarding epidemiology and survival. In this study, we explored clinicopathologic factors and oncologic outcomes of patients with SUC derived from Survival, Epidemiology and End Results (SEER) database, in comparison to conventional UC (CUC). MATERIALS AND METHODS: SEER database was searched for patients with invasive (≥T1) SUC or CUC using the topography codes C67.0 to C67.9 for bladder cancer and the morphologic codes 8120/8122 for CUC/SUC respectively. Demographic/clinicopathologic/treatment/survival data were extracted. Disease-specific survival (DSS) was estimated with the Kaplan-Meier method. Chi-squared tests were used for comparative analysis and Cox proportional hazards model for identifying clinical covariates associated with DSS. RESULTS: A total of 569 patients with SUC and 37,740 with CUC were identified. Overall, there was a male predominant population in both cohorts, although a higher proportion of women were noted in the SUC cohort (32 vs. 25%). Patients with SUC had significantly higher incidence of non-bladder confined disease (T3/4, 37% vs. 22%) and nodal invasion (18% vs. 12%) in comparison to those with CUC (all P < .05). Median DSS was 16 months (95% CI: 12.4-19.6) in the SUC vs. 82 months (95% CI; 75.9-88.1) in the CUC cohort. Presence of SUC histology was independently associated with shorter DSS in the multivariate analysis, when adjusted for other significant clinicopathologic factors. CONCLUSION: SUC was associated with advanced stage and shorter DSS compared to CUC. Further studies are needed to better understand biological underpinnings behind its aggressive behavior and the role of novel systemic treatments.

Absolute quantitative proteomics using the total protein approach to identify novel clinical immunohistochemical markers in renal neoplasms.

BACKGROUND: Renal neoplasms encompass a variety of malignant and benign tumors, including many with shared characteristics. The diagnosis of these renal neoplasms remains challenging with currently available tools. In this work, we demonstrate the total protein approach (TPA) based on high-resolution mass spectrometry (MS) as a tool to improve the accuracy of renal neoplasm diagnosis. METHODS: Frozen tissue biopsies of human renal tissues [clear cell renal cell carcinoma (n = 7), papillary renal cell carcinoma (n = 5), chromophobe renal cell carcinoma (n = 5), and renal oncocytoma (n = 5)] were collected for proteome analysis. Normal adjacent renal tissue (NAT, n = 5) was used as a control. Proteins were extracted and digested using trypsin, and the digested proteomes were analyzed by label-free high-resolution MS (nanoLC-ESI-HR-MS/MS). Quantitative analysis was performed by comparison between protein abundances of tumors and NAT specimens, and the label-free and standard-free TPA was used to obtain absolute protein concentrations. RESULTS: A total of 205 differentially expressed proteins with the potential to distinguish the renal neoplasms were found. Of these proteins, a TPA-based panel of 24, including known and new biomarkers, was selected as the best candidates to differentiate the neoplasms. As proof of concept, the diagnostic potential of PLIN2, TUBB3, LAMP1, and HK1 was validated using semi-quantitative immunohistochemistry with a total of 128 samples assessed on tissue micro-arrays. CONCLUSIONS: We demonstrate the utility of combining high-resolution MS and the TPA as potential new diagnostic tool in the pathology of renal neoplasms. A similar TPA approach may be implemented in any cancer study with solid biopsies.

A Perspective on Therapeutic Pan-Resistance in Metastatic Cancer.

Metastatic spread represents the leading cause of disease-related mortality among cancer patients. Many cancer patients suffer from metastatic relapse years or even decades after radical surgery for the primary tumor. This clinical phenomenon is explained by the early dissemination of cancer cells followed by a long period of dormancy. Although dormancy could be viewed as a window of opportunity for therapeutic interventions, dormant disseminated cancer cells and micrometastases, as well as emergent outgrowing macrometastases, exhibit a generalized, innate resistance to chemotherapy and even immunotherapy. This therapeutic pan-resistance, on top of other adaptive responses to targeted agents such as acquired mutations and lineage plasticity, underpins the current difficulties in eradicating cancer. In the present review, we attempt to provide a framework to understand the underlying biology of this major issue.

PARP Inhibition Suppresses GR-MYCN-CDK5-RB1-E2F1 Signaling and Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer.

PURPOSE: In this study, we addressed the underlying mechanisms for the association between enzalutamide (ENZ) treatment and neuroendocrine prostate cancer (NEPC), and the critical involvement of MYCN, and loss of RB1 function in neuroendocrine differentiation (NED) of prostatic epithelial cells, and the development of NEPC. We further sought to determine whether PARP inhibition could suppress NEPC, and to identify molecular determinants of this therapeutic activity. EXPERIMENTAL DESIGN: We used a novel prostate cancer patient-derived xenograft (PDX) treatment model, prostatic adenocarcinoma and NEPC cell lines, an NEPC organoid line, and NEPC xenograft models to address the mechanistic basis of ENZ-induced NED, and to analyze suppression of NED and NEPC growth by PARP inhibition. RESULTS: We identified an ENZ treatment-associated glucocorticoid receptor (GR)-MYCN-CDK5-RB1-E2F1 signaling pathway that drives NED in prostatic adenocarcinoma PDX and cell line models. Mechanistically, long-term ENZ treatment transcriptionally upregulates signaling of the GR-MYCN axis, leading to CDK5R1 and CDK5R2 upregulation, Rb1 phosphorylation, and N-Myc-mediated and E2F1-mediated NED gene expression. Importantly, olaparib (OLA) or talazoparib (TALA) suppressed these activities, and the combination of OLA and dinaciclib (DINA), an inhibitor of CDK2 and CDK5, which also inhibits Rb1 phosphorylation, suppressed NED and significantly improved therapeutic efficiency in NEPC cells in vitro and in NEPC tumors in vivo. CONCLUSIONS: The results of our study indicate an important role of GR-MYCN-CDK5R1/2-RB1-NED signaling in ENZ-induced and PARP inhibitor-suppressed NEPC. We also demonstrated efficacy for OLA+DINA combination therapy in NEPC xenograft models.

Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration-resistant prostate cancer models.

Previous studies have shown that increased levels of chemokine receptor CXCR7 are associated with the increased invasiveness of prostate cancer cells. We now show that CXCR7 expression is upregulated in VCaP and C4-2B cells after enzalutamide (ENZ) treatment. ENZ treatment induced apoptosis (sub-G1) in VCaP and C4-2B cells, and this effect was further increased after combination treatment with ENZ and CCX771, a specific CXCR7 inhibitor. The levels of p-EGFR (Y1068), p-AKT (T308) and VEGFR2 were reduced after ENZ and CCX771 combination treatment compared to single agent treatment. In addition, significantly greater reductions in migration were shown after combination treatment compared to those of single agents or vehicle controls, and importantly, similar reductions in the levels of secreted VEGF were also demonstrated. Orthotopic VCaP xenograft growth and subcutaneous MDA133-4 patient-derived xenograft (PDX) tumor growth was reduced by single agent treatment, but significantly greater suppression was observed in the combination treatment group. Although overall microvessel densities in the tumor tissues were not different among the different treatment groups, a significant reduction in large blood vessels (>100 µm2 ) was observed in tumors following combination treatment. Apoptotic indices in tumor tissues were significantly increased following combination treatment compared with vehicle control-treated tumor tissues. Our results demonstrate that significant tumor suppression mediated by ENZ and CXCR7 combination treatment may be due, in part, to reductions in proangiogenic signaling and in the formation of large blood vessels in prostate cancer tumors.

Targeting the MYCN-PARP-DNA Damage Response Pathway in Neuroendocrine Prostate Cancer.

Purpose: We investigated MYCN-regulated molecular pathways in castration-resistant prostate cancer (CRPC) classified by morphologic criteria as adenocarcinoma or neuroendocrine to extend the molecular phenotype, establish driver pathways, and identify novel approaches to combination therapy for neuroendocrine prostate cancer (NEPC).Experimental Design and Results: Using comparative bioinformatics analyses of CRPC-Adeno and CRPC-Neuro RNA sequence data from public data sets and a panel of 28 PDX models, we identified a MYCN-PARP-DNA damage response (DDR) pathway that is enriched in CRPC with neuroendocrine differentiation (NED) and CRPC-Neuro. ChIP-PCR assay revealed that N-MYC transcriptionally activates PARP1, PARP2, BRCA1, RMI2, and TOPBP1 through binding to the promoters of these genes. MYCN or PARP1 gene knockdown significantly reduced the expression of MYCN-PARP-DDR pathway genes and NED markers, and inhibition with MYCNsi and/or PARPsi, BRCA1si, or RMI2si significantly suppressed malignant activities, including cell viability, colony formation, and cell migration, in C4-2b4 and NCI-H660 cells. Targeting this pathway with AURKA inhibitor PHA739358 and PARP inhibitor olaparib generated therapeutic effects similar to those of gene knockdown in vitro and significantly suppressed tumor growth in both C4-2b4 and MDACC PDX144-13C subcutaneous models in vivoConclusions: Our results identify a novel MYCN-PARP-DDR pathway that is driven by N-MYC in a subset of CRPC-Adeno and in NEPC. Targeting this pathway using in vitro and in vivo CRPC-Adeno and CRPC-Neuro models demonstrated a novel therapeutic strategy for NEPC. Further investigation of N-MYC-regulated DDR gene targets and the biological and clinical significance of MYCN-PARP-DDR signaling will more fully elucidate the importance of the MYCN-PARP-DDR signaling pathway in the development and maintenance of NEPC. Clin Cancer Res; 24(3); 696-707. ©2017 AACR.

Androgen receptor inhibitor-induced "BRCAness" and PARP inhibition are synthetically lethal for castration-resistant prostate cancer.

Cancers with loss-of-function mutations in BRCA1 or BRCA2 are deficient in the DNA damage repair pathway called homologous recombination (HR), rendering these cancers exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors. This functional state and therapeutic sensitivity is referred to as "BRCAness" and is most commonly associated with some breast cancer types. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only ~20% of prostate cancer patients. We found that castration-resistant prostate cancer (CRPC) cells showed increased expression of a set of HR-associated genes, including BRCA1, RAD54L, and RMI2 Although androgen-targeted therapy is typically not effective in CRPC patients, the androgen receptor inhibitor enzalutamide suppressed the expression of those HR genes in CRPC cells, thus creating HR deficiency and BRCAness. A "lead-in" treatment strategy, in which enzalutamide was followed by the PARP inhibitor olaparib, promoted DNA damage-induced cell death and inhibited clonal proliferation of prostate cancer cells in culture and suppressed the growth of prostate cancer xenografts in mice. Thus, antiandrogen and PARP inhibitor combination therapy may be effective for CRPC patients and suggests that pharmaceutically inducing BRCAness may expand the clinical use of PARP inhibitors.