Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its nutrient-scavenging ability, crucial for tumor progression. Here, we investigated the roles of caveolae-mediated endocytosis (CME) in PDAC progression. Analysis of patient data across diverse datasets revealed a strong association of high caveolin-1 (Cav-1) expression with higher histologic grade, the most aggressive PDAC molecular subtypes, and worse clinical outcomes. Cav-1 loss markedly promoted longer overall and tumor-free survival in a genetically engineered mouse model. Cav-1-deficient tumor cell lines exhibited significantly reduced proliferation, particularly under low nutrient conditions. Supplementing cells with albumin rescued the growth of Cav-1-proficient PDAC cells, but not in Cav-1-deficient PDAC cells under low glutamine conditions. In addition, Cav-1 depletion led to significant metabolic defects, including decreased glycolytic and mitochondrial metabolism, and downstream protein translation signaling pathways. These findings highlight the crucial role of Cav-1 and CME in fueling pancreatic tumorigenesis, sustaining tumor growth, and promoting survival through nutrient scavenging.

SPOP Mutations Target STING1 Signaling in Prostate Cancer and Create Therapeutic Vulnerabilities to PARP Inhibitor-Induced Growth Suppression.

PURPOSE: Speckle-type POZ protein (SPOP) is important in DNA damage response (DDR) and maintenance of genomic stability. Somatic heterozygous missense mutations in the SPOP substrate-binding cleft are found in up to 15% of prostate cancers. While mutations in SPOP predict for benefit from androgen receptor signaling inhibition (ARSi) therapy, outcomes for patients with SPOP-mutant (SPOPmut) prostate cancer are heterogeneous and targeted treatments for SPOPmut castrate-resistant prostate cancer (CRPC) are lacking. EXPERIMENTAL DESIGN: Using in silico genomic and transcriptomic tumor data, proteomics analysis, and genetically modified cell line models, we demonstrate mechanistic links between SPOP mutations, STING signaling alterations, and PARP inhibitor vulnerabilities. RESULTS: We demonstrate that SPOP mutations are associated with upregulation of a 29-gene noncanonical (NC) STING (NC-STING) signature in a subset of SPOPmut, treatment-refractory CRPC patients. We show in preclinical CRPC models that SPOP targets and destabilizes STING1 protein, and prostate cancer-associated SPOP mutations result in upregulated NC-STING-NF-κB signaling and macrophage- and tumor microenvironment (TME)-facilitated reprogramming, leading to tumor cell growth. Importantly, we provide in vitro and in vivo mechanism-based evidence that PARP inhibitor (PARPi) treatment results in a shift from immunosuppressive NC-STING-NF-κB signaling to antitumor, canonical cGAS-STING-IFNß signaling in SPOPmut CRPC and results in enhanced tumor growth inhibition. CONCLUSIONS: We provide evidence that SPOP is critical in regulating immunosuppressive versus antitumor activity downstream of DNA damage-induced STING1 activation in prostate cancer. PARPi treatment of SPOPmut CRPC alters this NC-STING signaling toward canonical, antitumor cGAS-STING-IFNß signaling, highlighting a novel biomarker-informed treatment strategy for prostate cancer.

The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62.

Reduced p62 levels are associated with the induction of the cancer-associated fibroblast (CAF) phenotype, which promotes tumorigenesis in vitro and in vivo through inflammation and metabolic reprogramming. However, how p62 is downregulated in the stroma fibroblasts by tumor cells to drive CAF activation is an unresolved central issue in the field. Here we show that tumor-secreted lactate downregulates p62 transcriptionally through a mechanism involving reduction of the NAD+/NADH ratio, which impairs poly(ADP-ribose)-polymerase 1 (PARP-1) activity. PARP-1 inhibition blocks the poly(ADP-ribosyl)ation of the AP-1 transcription factors, c-FOS and c-JUN, which is an obligate step for p62 downregulation. Importantly, restoring p62 levels in CAFs by NAD+ renders CAFs less active. PARP inhibitors, such as olaparib, mimick lactate in the reduction of stromal p62 levels, as well as the subsequent stromal activation both in vitro and in vivo, which suggests that therapies using olaparib would benefit from strategies aimed at inhibiting CAF activity.

Cytopathic effects and local immune responses in repeated neoadjuvant HSV-tk + ganciclovir gene therapy for prostate cancer.

OBJECTIVE: Cytopathic effects and local immune response were analyzed histologically in prostatic cancer (PCa) with in situ herpes simplex virus-thymidine kinase (HSV-tk)/ganciclovir (GCV) gene therapy (GT). METHODS: Four high-risk PCa patients who received HSV-tk/GCV GT were investigated. After two cycles of intraprostatic injection of HSV-tk and administration of GCV, radical prostatectomy was performed. Formalin-fixed, paraffin-embedded sections were evaluated using immunohistochemistry. PCa with hormone therapy (HT, n=3) or without neoadjuvant therapy (NT, n=4) that were equivalent in terms of risk were also examined as reference. Immunoreactively-positive cells were counted in at least three areas in cancer tissue. Labeling indices (LI) were calculated as percentage values. RESULTS: ssDNA LI in GT increased, indicating apoptosis, as well as tumor-infiltrating lymphocytes and CD68-positive macrophages, compared with their biopsies. GT cases showed significantly higher numbers of single-stranded DNA (ssDNA) LI, CD4/CD8-positive T cells and CD68-positive macrophages including M1/M2 macrophages than HT or NT cases. However, there was no significant difference in CD20-positive B cells among the types of case. There were strong correlations between CD8+ T cells and CD68+ macrophages (ρ=0.656, p<0.0001) as well as CD4+ T cells and CD20+ B cells (ρ=0.644, p<0.0001) in PCa with GT. CONCLUSIONS: Enhanced cytopathic effect and local immune response might be indicated in PCa patients with HSV-tk/GCV gene therapy.

ATR Inhibition Induces CDK1-SPOP Signaling and Enhances Anti-PD-L1 Cytotoxicity in Prostate Cancer.

PURPOSE: Despite significant benefit for other cancer subtypes, immune checkpoint blockade (ICB) therapy has not yet been shown to significantly improve outcomes for men with castration-resistant prostate cancer (CRPC). Prior data have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR inhibitors (DDRi), may improve ICB response in solid tumors in part due to induction of mitotic catastrophe and innate immune activation. Discerning the underlying mechanisms of this DDRi-ICB interaction in a prostate cancer-specific manner is vital to guide novel clinical trials and provide durable clinical responses for men with CRPC. EXPERIMENTAL DESIGN: We treated prostate cancer cell lines with potent, specific inhibitors of ATR kinase, as well as with PARP inhibitor, olaparib. We performed analyses of cGAS-STING and DDR signaling in treated cells, and treated a syngeneic androgen-indifferent, prostate cancer model with combined ATR inhibition and anti-programmed death ligand 1 (anti-PD-L1), and performed single-cell RNA sequencing analysis in treated tumors. RESULTS: ATR inhibitor (ATRi; BAY1895433) directly repressed ATR-CHK1 signaling, activated CDK1-SPOP axis, leading to destabilization of PD-L1 protein. These effects of ATRi are distinct from those of olaparib, and resulted in a cGAS-STING-initiated, IFN-ß-mediated, autocrine, apoptotic response in CRPC. The combination of ATRi with anti-PD-L1 therapy resulted in robust innate immune activation and a synergistic, T-cell-dependent therapeutic response in our syngeneic mouse model. CONCLUSIONS: This work provides a molecular mechanistic rationale for combining ATR-targeted agents with immune checkpoint blockade for patients with CRPC. Multiple early-phase clinical trials of this combination are underway.

PARP and CDK4/6 Inhibitor Combination Therapy Induces Apoptosis and Suppresses Neuroendocrine Differentiation in Prostate Cancer.

We analyzed the efficacy and mechanistic interactions of PARP inhibition (PARPi; olaparib) and CDK4/6 inhibition (CDK4/6i; palbociclib or abemaciclib) combination therapy in castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) models. We demonstrated that combined olaparib and palbociblib or abemaciclib treatment resulted in synergistic suppression of the p-Rb1-E2F1 signaling axis at the transcriptional and posttranslational levels, leading to disruption of cell-cycle progression and inhibition of E2F1 gene targets, including genes involved in DDR signaling/damage repair, antiapoptotic BCL-2 family members (BCL-2 and MCL-1), CDK1, and neuroendocrine differentiation (NED) markers in vitro and in vivo In addition, olaparib + palbociclib or olaparib + abemaciclib combination treatment resulted in significantly greater growth inhibition and apoptosis than either single agent alone. We further showed that PARPi and CDK4/6i combination treatment-induced CDK1 inhibition suppressed p-S70-BCL-2 and increased caspase cleavage, while CDK1 overexpression effectively prevented the downregulation of p-S70-BCL-2 and largely rescued the combination treatment-induced cytotoxicity. Our study defines a novel combination treatment strategy for CRPC and NEPC and demonstrates that combination PARPi and CDK4/6i synergistically promotes suppression of the p-Rb1-E2F1 axis and E2F1 target genes, including CDK1 and NED proteins, leading to growth inhibition and increased apoptosis in vitro and in vivo Taken together, our results provide a molecular rationale for PARPi and CDK4/6i combination therapy and reveal mechanism-based clinical trial opportunities for men with NEPC.

Genome-wide DNA methylation profiling of leukocytes identifies CpG methylation signatures of aggressive prostate cancer.

Most of screening-detected prostate cancer (PCa) are indolent and not lethal. Biomarkers that can predict aggressive diseases independently of clinical features are needed to improve risk stratification of localized PCa patients and reduce overtreatment. We aimed to identify leukocyte DNA methylation differences between clinically defined aggressive and non-aggressive PCa. We performed whole genome DNA methylation profiling in leukocyte DNA from 287 PCa patients with Gleason Score (GS) 6 and ≥8 using Illumina 450k methylation arrays. We observed a global hypomethylation in GS≥8 patients compared to GS=6 PCa patients; in contrast, the methylation level in core promoter and exon 1 region was significantly higher in GS≥8 patients than GS=6 PCa. We then performed 5-fold cross validated random forest model training on 1,459 differentially methylated CpG Probes (DMPs) with false discovery rate (FDR) <0.01 between GS=6 and GS≥8 groups. The power of the predictive model was further reinforced by ranking the DMPs with Decreased Gini and re-train the model with the top 97 DMPs (Testing AUC=0.920, predict accuracy =0.847). In conclusion, we identified a CpG methylation signature in leukocyte DNA that is associated with aggressive clinical features of PCa at diagnosis.

Optimizing the diagnosis and management of ductal prostate cancer.

Ductal adenocarcinoma (DAC) is the most common variant histological subtype of prostate carcinoma and has an aggressive clinical course. DAC is usually characterized and treated as high-risk prostatic acinar adenocarcinoma (PAC). However, DAC has a different biology to that of acinar disease, which often poses a challenge for both diagnosis and management. DAC can be difficult to identify using conventional diagnostic modalities such as serum PSA levels and multiparametric MRI, and the optimal management for localized DAC is unknown owing to the rarity of the disease. Following definitive therapy for localized disease with radical prostatectomy or radiotherapy, the majority of DACs recur with visceral metastases at low PSA levels. Various systemic therapies that have been shown to be effective in high-risk PAC have limited use in treating DAC. Although current understanding of the biology of DAC is limited, genomic analyses have provided insights into the pathology behind its aggressive behaviour and potential future therapeutic targets.

Considering the potential for gene-based therapy in prostate cancer.

Therapeutic gene manipulation has been at the forefront of popular scientific discussion and basic and clinical research for decades. Basic and clinical research applications of CRISPR-Cas9-based technologies and ongoing clinical trials in this area have demonstrated the potential of genome editing to cure human disease. Evaluation of research and clinical trials in gene therapy reveals a concentration of activity in prostate cancer research and practice. Multiple aspects of prostate cancer care - including anatomical considerations that enable direct tumour injections and sampling, the availability of preclinical immune-competent models and the delineation of tumour-related antigens that might provide targets for an induced immune system - make gene therapy an appealing treatment option for this common malignancy. Vaccine-based therapies that induce an immune response and new technologies exploiting CRISPR-Cas9-assisted approaches, including chimeric antigen receptor (CAR) T cell therapies, are very promising and are currently under investigation both in the laboratory and in the clinic. Although laboratory and preclinical advances have, thus far, not led to oncologically relevant outcomes in the clinic, future studies offer great promise for gene therapy to become established in prostate cancer care.

Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies.

BACKGROUND: Ductal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC). OBJECTIVE: To assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC. DESIGN, SETTING, AND PARTICIPANTS: A single-center retrospective review of all patients with cT1-4/N0-1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Metastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models. RESULTS AND LIMITATIONS: A total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation. CONCLUSIONS: Men undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed. PATIENT SUMMARY: This study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.

Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer.

Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressors that, together with plasma Cav-1, yield a prognostic signature for disease progression. Mechanistic studies of the underlying tumor supportive onco-metabolism reveal coordinated activities through which Cav-1 enables rewiring of cancer cell lipid metabolism towards a program of 1) exogenous sphingolipid scavenging independent of cholesterol, 2) increased cancer cell catabolism of sphingomyelins to ceramide derivatives and 3) altered ceramide metabolism that results in increased glycosphingolipid synthesis and efflux of Cav-1-sphingolipid particles containing mitochondrial proteins and lipids. We also demonstrate, using a prostate cancer syngeneic RM-9 mouse model and established cell lines, that this Cav-1-sphingolipid program evidences a metabolic vulnerability that is targetable to induce lethal mitophagy as an anti-tumor therapy.

Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma.

Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy.

Genetic variants in epithelial-mesenchymal transition genes as predictors of clinical outcomes in localized prostate cancer.

BACKGROUND: Epithelial-mesenchymal transition (EMT) plays a pivotal role in the progression of prostate cancer (PCa). However, little is known about genetic variants in the EMT pathway as predictors of aggressiveness, biochemical recurrence (BCR) and disease reclassification in localized PCa. PATIENTS AND METHODS: In this multistage study, we evaluated 5186 single nucleotide polymorphisms (SNPs) from 264 genes related to EMT pathway to identify SNPs associated with PCa aggressiveness and BCR in the MD Anderson PCa (MDA-PCa) patient cohort (N = 1762), followed by assessment of the identified SNPs with disease reclassification in the active surveillance (AS) cohort (N = 392). RESULTS: In the MDA-PCa cohort, 312 SNPs were associated with high D'Amico risk (P < 0.05), among which, 14 SNPs in 10 genes were linked to BCR risk. In the AS cohort, 2 of 14 identified SNPs (rs76779889 and rs7083961) in C-terminal Binding Proteins 2 gene were associated with reclassification risk. The associations of rs76779889 with different endpoints were: D'Amico high versus low, odds ratio [95% confidence interval (CI)] = 2.89 (1.32-6.34), P = 0.008; BCR, hazard ratio (HR) (95% CI) = 2.88 (1.42-5.85), P = 0.003; and reclassification, HR (95% CI) = 2.83 (1.40-5.74), P = 0.004. For rs7083961, the corresponding risk estimates were: D'Amico high versus low, odds ratio (95% CI) = 1.69 (1.12-2.57), P = 0.013; BCR, HR (95% CI) = 1.87 (1.15-3.02), P = 0.011 and reclassification, HR (95% CI) = 1.72 (1.09-2.72), P = 0.020. There were cumulative effects of these two SNPs on modulating these endpoints. CONCLUSION: Genetic variants in EMT pathway may influence the risks of localized PCa's aggressiveness, BCR and disease reclassification, suggesting their potential role in the assessment and management of localized PCa.

Leukocyte telomere length is associated with aggressive prostate cancer in localized prostate cancer patients.

BACKGROUND: Telomeres play important roles in cancer initiation and progression. The aim of this study is to investigate whether leukocyte telomere length (LTL) is associated with aggressive prostate cancer (PCa). METHODS: We measured relative LTL in a cohort of 1,889 white PCa patients who were treated and followed up at the University of Texas MD Anderson Cancer Center and assessed its associations with aggressive disease characteristics at diagnosis and biochemical recurrence (BCR) after active treatments (radical prostatectomy and radiotherapy). We further used a Mendelian randomization (MR) approach to compute a weighted genetic risk score (GRS) predictive of LTL using 10 established LTL-associated genetic variants and determined whether this GRS is associated with aggressive PCa. FINDINGS: LTL was significantly shorter in patients with higher Gleason scores at diagnosis. Dichotomized at the median value of LTL, patients with short LTL exhibited a 2.74-fold (95% confidence interval, 1.79-4.18, P = 3.11 × 10-6) increased risk of presenting with GS≥8 disease than those with long LTL in multivariate logistic regression analysis. Moreover, shorter LTL was significantly associated with an increased risk of BCR (hazard ratio = 1.53, 95% confidence interval, 1.01-2.34) compared to longer LTL in localized patients receiving prostatectomy or radiotherapy with a significant dose-response association (P for trend = 0.017) in multivariate Cox proportional hazards regression analysis. In MR analysis, genetically predicted short LTL was also associated with an increased risk of BCR (HR=1.73, 95% CI, 1.08-2.78). INTERPRETATION: Our results showed for the first time that LTL was shorter in PCa patients with high Gleason scores and that short LTL and genetically predicted short LTL are associated with worse prognosis in PCa patients receiving prostatectomy or radiotherapy. FUNDING: Cancer Prevention and Research Institute of Texas (CPRIT) grant (RP140556), National Cancer Institute Specialized Program of Research Excellence (SPORE) grant (CA140388), and MD Anderson Cancer Center start-up fund.

Mitochondrial DNA copy number in peripheral blood leukocytes is associated with biochemical recurrence in prostate cancer patients in African Americans.

Mitochondria play multiple important cellular functions. The purpose of this study was to evaluate whether leukocyte mitochondrial DNA copy number (mtDNAcn) is associated with aggressive prostate cancer (PCa) in African American (AA) men. We measured the mtDNAcn in peripheral blood leukocytes from 317 localized AA PCa patients and evaluated its associations with aggressive disease features at diagnosis and biochemical recurrence (BCR) after treatments. There was no significant difference in mtDNAcn among the clinical features at diagnosis, including age, prostate-specific antigen level, Gleason score and clinical stage under analysis of variance test. However, mtDNAcn was significantly associated with BCR in multivariate Cox analysis. Dichotomized into low and high mtDNAcn groups by the median value of mtDNAcn, patients with low mtDNAcn exhibited a significantly lower risk of BCR (hazard ratio = 0.32, 95% confidence interval: 0.13-0.79) compared to those with high mtDNAcn. There was a significant dose-response in tertile and quartile analyses (P for trend = 0.012 and 0.002, respectively). In Kaplan-Meier survival analyses, patients with higher mtDNAcn exhibited significantly shorter BCR-free survival time than those with lower mtDNAcn in dichotomous, tertile and quartile analyses, with long-rank P values of 0.017, 0.024 and 0.019, respectively. Our results showed for the first time that high leukocyte mtDNAcn was associated with worse prognosis in AA PCa patients.

Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1-2 trial.

BACKGROUND: Taxane-platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer. METHODS: We did a phase 1-2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20-25 mg/m2 and intravenous carboplatin area under the curve (AUC) 3-4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m2 with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov, number NCT01505868. FINDINGS: Between Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m2 and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5-37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5-5·7) to 7·3 months (95% CI 5·5-8·2; hazard ratio 0·69, 95% CI 0·50-0·95, p=0·018). In the phase 2 study, the most common grade 3-5 adverse events were fatigue (7 [9%] of 79 in the cabazitaxel group vs 16 [20%] of 81 in the combination group), anaemia (3 [4%] vs 19 [23%]), neutropenia (3 [4%] vs 13 [16%]), and thrombocytopenia (1 [1%] vs 11 [14%]). There were no treatment-related deaths. INTERPRETATION: Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane-platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned. FUNDING: Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund.

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.

Driver network as a biomarker: systematic integration and network modeling of multi-omics data to derive driver signaling pathways for drug combination prediction.

MOTIVATION: Drug combinations that simultaneously suppress multiple cancer driver signaling pathways increase therapeutic options and may reduce drug resistance. We have developed a computational systems biology tool, DrugComboExplorer, to identify driver signaling pathways and predict synergistic drug combinations by integrating the knowledge embedded in vast amounts of available pharmacogenomics and omics data. RESULTS: This tool generates driver signaling networks by processing DNA sequencing, gene copy number, DNA methylation and RNA-seq data from individual cancer patients using an integrated pipeline of algorithms, including bootstrap aggregating-based Markov random field, weighted co-expression network analysis and supervised regulatory network learning. It uses a systems pharmacology approach to infer the combinatorial drug efficacies and synergy mechanisms through drug functional module-induced regulation of target expression analysis. Application of our tool on diffuse large B-cell lymphoma and prostate cancer demonstrated how synergistic drug combinations can be discovered to inhibit multiple driver signaling pathways. Compared with existing computational approaches, DrugComboExplorer had higher prediction accuracy based on in vitro experimental validation and probability concordance index. These results demonstrate that our network-based drug efficacy screening approach can reliably prioritize synergistic drug combinations for cancer and uncover potential mechanisms of drug synergy, warranting further studies in individual cancer patients to derive personalized treatment plans. AVAILABILITY AND IMPLEMENTATION: DrugComboExplorer is available at https://github.com/Roosevelt-PKU/drugcombinationprediction. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genetic associations of T cell cancer immune response with tumor aggressiveness in localized prostate cancer patients and disease reclassification in an active surveillance cohort.

Determining prostate cancer (PCa) aggressiveness and reclassification are critical events during the treatment of localized disease and for patients undergoing active surveillance (AS). Since T cells play major roles in cancer surveillance and elimination, we aimed to identify genetic biomarkers related to T cell cancer immune response which are predictive of aggressiveness and reclassification risks in localized PCa. The genotypes of 3,586 single nucleotide polymorphisms (SNPs) from T cell cancer immune response pathways were analyzed in 1762 patients with localized disease and 393 who elected AS. The aggressiveness of PCa was defined according to pathological Gleason score (GS) and D'Amico criteria. PCa reclassification was defined according to changes in GS or tumor characteristics during subsequent surveillance biopsies. Functional characterization and analysis of immune phenotypes were also performed. In the localized PCa cohort, seven SNPs were significantly associated with the risk of aggressive disease. In the AS cohort, another eight SNPs were identified as predictors for aggressiveness and reclassification. Rs1687016 of PSMB8 was the most significant predictor of reclassification. Cumulative analysis showed that a genetic score based on the identified SNPs could significantly predict risk of D'Amico high risk disease (P-trend = 2.4E-09), GS4 + 3 disease (P-trend = 1.3E-04), biochemical recurrence (P-trend = 0.01) and reclassification (P-trend = 0.01). In addition, the rs34309 variant was associated with functional somatic mutations in the PI3K/PTEN/AKT/MTOR pathway and tumor lymphocyte infiltration. Our study provides plausible evidence that genetic variations in T cell cancer immune response can influence risks of aggressiveness and reclassification in localized PCa, which may lead to additional biological insight into these outcomes. Abbreviations: PCa, prostate cancer; AS, active surveillance; GS, Gleason score; PSA, prostate specific antigen; TCGA, The Cancer Genome Atlas; SNP, single nucleotide polymorphisms; UFG, unfavorable genotype.