Progressive Prostate Cancer Research Articles

Gelsolin Governs the Neuroendocrine Transdifferentiation of Prostate Cancer Cells and Suppresses the Apoptotic Machinery.

Interleukin 6 (IL6) is increased in patients with progressive prostate cancer and induces its transdifferentiation to neuroendocrine prostate cancer. Neuroendocrine prostate cancer has become one of the greatest challenges in treating castration-resistant disease and is linked to poor prognosis. It is necessary to understand better the cellular events associated with IL6-mediated neuroendocrine differentiation to prevent it and identify potential new therapeutic targets. In the present study, an IL6-inducible neuroendocrine differentiation model established specifically for this purpose was applied using LNCaP cells. Proteomics and western blot analyses were used to identify proteins involved in neuroendocrine differentiation. Subsequently, the role of gelsolin (GSN) in the neuroendocrine differentiation model was characterized (knock-down analyses, microscopic co-localization analyses, apoptosis assay) and GSN expression levels in patient material were investigated. This study revealed that GSN is a crucial factor in the neuroendocrine differentiation process. It was shown that siRNA-mediated knock-down of GSN can inhibit neuroendocrine differentiation, making it a valid target for preventing IL6-mediated neuroendocrine differentiation.

Fermented Wheat Germ Extract (FWGE) as a Treatment Additive for Castration-Resistant Prostate Cancer: A Pilot Clinical Trial

Castration-resistant prostate cancer (CRPC) is a devastating and incurable disease. Combined therapy using conventional anticancer drugs and a proprietary medical nutriment, fermented wheat germ extract (FWGE), also known as Avemar, has been suggested as a treatment for progressing prostate cancer (PCa) patients, who have become resistant to first line hormonal therapy (gonadotropin releasing hormone, GnRH). The primary aim of this study was to test if this combined therapy would slow down disease progression in CRPC patients. We tested the nontoxic, readily available, inexpensive FWGE, together with the conventional treatment, GnRH analogue, in 36 CRPC patients. Although this is a pilot study, with the drawback of a statistically small sample size, some anticancer clinical activity of FWGE could be seen in the CRPC patients, as measured by prostate specific antigen doubling time (PSADT). We found that the intake of GnRH with FWGE for at least 4 months, improved the overall health as well as the quality of life (QOL) in 4 patients (11%) and was instrumental in extending the PSADT in about 17 (out of 26) patients (65.4%), six of whom were significant. Since no mentionable adverse events were noticed, this treatment may permit the postponement of chemotherapy for these patients.

Abstract 3163: Progressive prostate cancer LNCaP subclones partially retain regressive communications with patient-derived fibroblasts

Abstract The tumor microenvironment of prostate cancer (PCa) plays an important role in disease progression, responsiveness to therapy, or inversely restraint of tumor growth. PCa cell evolution including loss of androgen receptor dependency is associated with intratumor heterogeneity, generating progressive PCa cell subclones. The tumor stroma of PCa contains multiple functionally different populations of fibroblasts that regulate PCa cell progression, e.g., cancer-promoting or cancer-restraining. Fibroblasts secret a number of growth factors, cytokines, the ECM molecules, and miRNAs in a cellular characteristic-specific manner. Thus, we hypothesize that diversity of fibroblasts may induce heterogenous PCa cell progression. To investigate the heterotypical communications between PCa cells and fibroblasts, we used 3 subclones of androgen-sensitive LNCaP cells and 4 patient-derived fibroblasts. Androgen-low-sensitive E9 and F10 cells were obtained from the parental androgen-sensitive LNCaP cell population through use of a limiting dilution method in regular culture condition. In contrast, androgen-insensitive AIDL cells were established from LNCaP cells by continuous passaging under hormone-depleted condition. Commercially available normal human prostate stromal cells (PrSC) was purchased from Lonza Group Ltd. Three original fibroblasts pcPrFs (-M5, -M28, -M31) were isolated from needle biopsy samples of patients with advanced PCa. To examine the effects of fibroblasts on cancer-related gene expression in PCa cells, in vitro co-culture experiment was performed using cell culture insert. In all PCa cells, LNCaP and its subclones, expressions of NFKB1, SRC, and MYC mRNA were not dramatically changed by co-culturing with 3 PCa patient-derived fibroblasts. Only in LNCaP cells, however, they were uniformly down-regulated by co-culturing with PrSC. Only in LNCaP cells, expression of CDH2 mRNA was up-regulated by co-culturing with pcPrF-M5 and pcPrF-M28. In all PCa cells, expression of NKX3-1 mRNA was uniformly up-regulated by co-culturing with pcPrF-M28 and pcPrF-M31. In LNCaP, E9, and F10 cells but not in AIDL cells, expression of GSTP1 mRNA was uniformly up-regulated by co-culturing with pcPrF-M31. Cell growth of LNCaP cells was not remarkably affected by co-culturing with pcPrF-M28 and pcPrF-M31. The heterogeneous stromal compartment in PCa tissues contains multiple functionally different populations of fibroblasts that are also associated with intratumor heterogeneity. Our data showed that up-regulations of NKX3-1 and GSTP1 mRNA expression by co-culturing with pcPrF-M28 and pcPrF-M31 were commonly observed in LNCaP subclones differing in androgen sensitivity. This result suggests that certain fibroblasts may restrain PCa cell progression by up-regulations of tumor suppressor gene expression even in progressive poorly differentiated PCa cells. Citation Format: Kenichiro Ishii, Chise Matsuda, Yasuhisa Nakagawa, Taku Shirai, Yoshifumi Hirokawa, Takeshi Sasaki, Kazuhiro Iguchi, Masatoshi Watanabe. Progressive prostate cancer LNCaP subclones partially retain regressive communications with patient-derived fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3163.

Recommandations pratiques pour la prise en charge du déficit en testostérone

The Francophone Society of Sexual Medicine (SFMS) and the Andrology and Sexual Medicine Committee (CAMS) of the French Association of Urology (AFU) have brought together a panel of experts to develop French recommendations for the management of testosterone deficiency (TD). Systematic review of the literature between 01/2000 and 07/2019. Use of the method of recommendations for clinical practice (RPC) and the AGREE II grid. TD is defined as the association of clinical signs and symptoms suggestive of TD with a decrease in testosterone levels or serum androgen activity. Diagnosis requires a T lower than the reference values in young men on 2 successive assays. Sexual disorders are often at the forefront, and concern the whole male sexual function (desire, arousal, pleasure and orgasm). The most evocative symptoms are: decrease in sexual desire, disappearance of nocturnal erections, fatigue, loss of muscle strength. Overweight, depressed mood, anxiety, irritability and malaise are also frequently found. TD is more common in cases of metabolic, cardiovascular, chronic, andrological diseases, and in cases of corticosteroid, opioid, antipsychotic, anticonvulsant, antiretroviral, or cancer treatment. Since SHBG is frequently abnormal, we recommend that free or bioavailable T is preferred over total T. The treatment of TD requires a prior clinical (DRE, breast examination) and biological (PSA, CBC) assessment. Contraindications to T treatment are: progressive prostate or breast cancer, severe heart failure or recent cardiovascular event, polycytemia, complicated BPH, paternity project. It is possible in cases of sleep apnea syndrome, psychiatric history, stable heart disease, prostate cancer under active surveillance and after one year of complete remission of a low or intermediate risk localized prostate cancer treated in a curative manner. It includes long-term testosterone supplementation and life-style counseling. Treatment is monitored at 3, 6, 12months and annually thereafter. It is clinical (annual DRE) and biological (total T, PSA, CBC), the most frequent side effect being polyglobulia. These recommendations should help improve the management of TD.

MiRNA-21 as Reliable Serum Diagnostic Biomarker Candidate for Metastatic Progressive Prostate Cancer: Meta-analysis Approach.

Background:Prostate cancer is the second leading cause of cancer death in men, moreover when it develops metastasis. However, PSA detection in serum as current gold standard to measure disease progressivity had wide variability leading to confounding outcomes. MicroRNA-21 has diagnostic values for cancer over period of time researched, yet results are still inconclusive.Objective:The aim of the study was to conduct recent meta-analysis to assess reliability of miRNA-21 as diagnostic biomarker especially in progressivity of prostate cancer.Methods:Published papers from PubMed, Science Direct, and Embase” as of 1 July 2021 assessing circulating miRNA-21 in progressivity of prostate cancer patients were analyzed using Comprehensive Meta-Analysis tool. Pooled sensitivity, specificity, positive and negative likelihood ratio (LR) and SROC assessed with 95 % confidence intervals were estimated using fixed-effects or random-effects models.Results:In total, we included 6 papers total of 651 samples reporting miRNA-21 capability of detecting progressive prostate cancer. The pooled sensitivity and specificity showed 0.91 (95% CI 0.88-0.94, I2=0%) and 0.89 (95% CI 0.85-0.92, I2=44.8%), respectively. Positive and negative likelihood ratio showed 7.18 (95% CI 4.31-11.96, I2=56%) and 0.11 (95% CI 0.07-0.16, I2=11.8%). SROC were assessed and got Area Under Curve around 97.4%.Conclusion:miRNA-21 could serve as biomarkers of prostate cancer progressivity since remarkable diagnostic value of circulating miRNA-21 in prostate cancer metastasis process.

CD44 expression in Prostatic lesions: A prognostic guide

BACKGROUND AND AIMS: The cell surface glycoprotein CD44 plays an important role in mediating cell to cell and cell to matrix interaction, hence promoting the maintenance of tissue integrity and inhibiting tumour metastasis. The present study is aimed to evaluate the expression of CD44 by immunohistochemistry in prostatic core biopsies and transurethral resection of prostate (TURP) specimens in prostatic lesions. METHODS: A total of 63 prostatic samples were enrolled in the study which included cases of benign prostatic hyperplasia, prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Immunohistochemical expression of CD44 was studied to assess its association with histopathological findings and clinical data in the aforementioned samples. RESULTS: CD44 expression was strongly expressed in inflammatory and non-neoplastic cells as compared to neoplastic cells. Within the later, intensity of CD44 expression was stronger in well-differentiated than in poorly differentiated tumours. Loss of CD44 expression was associated with greater tumour aggressiveness. The positive expression of CD44 expression on immunohistochemistry was strongly associated with lower S. PSA levels, Gleason’s scores & grades. Consequently, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of negative CD44 expression for the diagnosis of prostatic adenocarcinoma were 93.3%,79.3%,82.4%,92% and 86.4% respectively. CONCLUSION: There is a great requirement for markers that distinguish slowly progressive from rapidly progressive prostate cancers in paraffin-embedded tissues. CD44 promotes the maintenance of tissue integrity and its expression in prostate cancer is associated with reduced tumour aggressiveness. The up-regulation of the expression of CD44 by certain microRNAs can be utilized as a novel therapeutic agent against prostatic adenocarcinoma.

EGFR/FOXO3A/LXR-α Axis Promotes Prostate Cancer Proliferation and Metastasis and Dual-Targeting LXR-α/EGFR Shows Synthetic Lethality

Prostate cancer is the second leading cause of cancer-related death in men. Early prostate cancer has a high 5-year survival rate. However, the five-year survival rate is low in progressive prostate cancer, which manifests as bone metastasis. The EGF receptor overexpression increases during disease progression and in the development of castration-resistant disease, and may be a potential therapeutic target. Liver X receptors (LXRs) are ligand-dependent nuclear receptor transcription factors and consist of two subtypes, LXR-α and LXR-β, which can inhibit tumor growth in various cancer cells. We revealed that LXR-α, but not LXR-β, was reduced in prostate cancer tissues compared with adjacent normal tissues. LXRs’ agonist GW3965 enhanced the inhibitory action of LXR-α on the proliferation and metastasis of prostate cancer cells. Furthermore, our results support the notion that LXR-α is regulated by the EGFR/AKT/FOXO3A pathway. As an EGFR inhibitor, Afatinib could weaken AKT activation and increase the expression level of FOXO3A in prostate cancer. In addition, we indicated that the combination of Afatinib and GW3965 simultaneously increased and activated LXR-α, which led to an increase of tumor suppressors, and eventually inhibited tumor progression. Therefore, the combination of EGFR inhibitor and LXRs agonist may become a potential treatment strategy for prostate cancer, especially metastatic prostate cancer.

Androgen driven evolutionary population dynamics in prostate cancer growth

<p style='text-indent:20px;'>Prostate cancer worldwide is regarded the second most frequent diagnosed cancer in men with (899,000 new cases) while in common cancer it is the fifth. Regarding the treatment of progressive prostate cancer the most common and effective is the intermittent androgen deprivation therapy. Usually this treatment is effective initially at regressing tumorigenesis, mostly a resistance to treatment can been seen from patients and is known as the castration-resistant prostate cancer (CRPC), so there is no any treatment and becomes fatal. Therefore, we proposed a new mathematical model for the prostate cancer growth with fractional derivative. Initially, we present the model formulation in detail and then apply the fractional operator Atangana-Baleanu to the model. The fractional model will be studied further to analyze and show its existence of solution. Then, we provide a new iterative scheme for the numerical solution of the prostate cancer growth model. The analytical results are validated by considering various values assigned to the fractional order parameter <inline-formula><tex-math id="M1">\begin{document}$ \alpha. $\end{document}</tex-math></inline-formula></p>

Efficacy of repeated PSMA PET-directed radiotherapy for oligorecurrent prostate cancer after initial curative therapy

PurposeTo assess the outcome of prostate cancer (PCa) patients diagnosed with oligorecurrent disease and treated with a first and a second PSMA (prostate-specific membrane antigen ligand) PET(positron-emission tomography)-directed radiotherapy (RT).Patients and methodsThirty-two patients with oligorecurrent relapse after curative therapy received a first PSMA PET-directed RT of all metastases. After biochemical progression, all patients received a second PSMA PET-directed RT of all metastases. The main outcome parameters were biochemical progression-free survival (bPFS) and androgen deprivation therapy-free survival (ADT-FS). The intervals of BPFS were analyzed separately as follows: the interval from the last day of PSMA PET-directed RT to the first biochemical progression was defined as bPFS_1 and the interval from second PSMA PET-directed RT to further biochemical progression was defined as bPFS_2.ResultsThe median follow-up duration was 39.5 months (18–60). One out of 32 (3.1%) patients died after 47 months of progressive metastatic prostate cancer (mPCa). All patients showed biochemical responses after the first PSMA PET-directed RT and the median prostate-specific antigen (PSA) level before RT was 1.70 ng/mL (0.2–3.8), which decreased significantly to a median PSA nadir level of 0.39 ng/mL (range <0.07–3.8; p = 0.004). The median PSA level at biochemical progression after the first PSMA PET-directed RT was 2.9 ng/mL (range 0.12–12.80; p = 0.24). Furthermore, the PSA level after the second PSMA PET-directed RT at the last follow-up (0.52 ng/mL, range <0.07–154.0) was not significantly different (p = 0.36) from the median PSA level (1.70 ng/mL, range 0.2–3.8) before the first PSMA PET-directed RT. The median bPFS_1 was 16.0 months after the first PSMA PET-directed RT (95% CI 11.9–19.2) and the median bPFS_2 was significantly shorter at 8.0 months (95% CI 6.3–17.7) after the second PSMA PET-directed RT (p = 0.03; 95% CI 1.9–8.3). Multivariate analysis revealed no significant parameter for bPFS_1, whereas extrapelvic disease was the only significant parameter (p = 0.02, OR 2.3; 95% CI 0.81-4.19) in multivariate analysis for bPFS_2. The median ADT-FS was 31.0 months (95% CI 20.1–41.8) and multivariate analysis showed that patients with bone metastases, compared to patients with only lymph node metastases at first PSMA PET-directed RT, had a significantly higher chance (p = 0.007, OR 4.51; 95% CI 1.8–13.47) of needing ADT at the last follow-up visit.ConclusionIf patients are followed up closely, including PSMA PET scans, a second PSMA PET-directed RT represents a viable treatment option for well-informed and well-selected patients.

Pattern and Presentation of Prostate Cancer at a Referral Centre in the Brong Ahafo Region of Ghana; A 10-Year Retrospective Study

Introduction: Prostate cancer is gradually reaching a very high incidence in Africa, especially in the Sub-Saharan region. Understanding the dynamics in occurrence of the disorder is one approach to developing effective public health programmes and interventions that will help curb the rising incidence. Objective: This study was aimed at providing comprehensive and credible data on prostate cancer by assessing the incidence, trend and presentation in the Brong Ahafo Region of Ghana. We sought to provide region-specific hardcore data that will help to assess the issue and provide remedies. Methodology: All prostate disease cases recorded from the year 2009 to 2018 were retrospectively reviewed. Subjects from 40 years and above were eligible for screening. Diagnostic and screening tools for prostate cancer at the study site include family history, serum prostate specific antigen (PSA) test, digital rectal examination, urological ultrasound scan and histopathology (biopsy). Age, PSA values and year of screening/diagnosis were also retrieved from patient folders for the study. Histological findings and parameters considered in the study included diagnosis, carcinoma grading, perineural invasion (PNI) and percentage of affected tissues (%TA). Results: Prostate cancer cases were 369, representing 36.4% of the 1,014 prostate diseases studied. The highest annual incidence was recorded in 2014 with 51 cases (13.8%). The ages of patients ranged from 46 to 101 years with a modal age range of 70 - 79 years and a mean ± SD of 72.2 ± 9.8. The mean PSA value recorded was 37.1ng/ml (±107.3) with predominance in the 11 - 20.9 ng/ml range. Majority of Group Grade 2-5 (79%) constituted progressive prostate cancer. There was no significant correlation (p = 0.091) between grade of prostate cancer and perineural invasion. Conclusion: There is a high incidence of prostate cancer in the Brong Ahafo Region of Ghana (32 per 100,000), predominantly advanced prostatic carcinoma. Reported cases also show high %TA (38.7%) and PNI (38.0%). Early screening for prostate diseases should be encouraged to avoid progression to advanced stage and public health interventions are needed to address some of these issues.

Морфологические факторы риска прогрессирования у больных раком предстательной железы после лучевой терапии

To study an importance of new 2016 WHO histologic grading system for prostate cancer in evaluating the risk of progressing after conformal external beam radiation therapy, brachytherapy 125I and androgen deprivation therapy. A total of 53 patients with prostate acinar adenocarcinoma were undergone to conformal external beam radiation therapy, brachytherapy 125I and androgen deprivation therapy. Age of patients was 54-80 years (68.11+/-4.7 years). T3 and T2 prostate cancer was diagnosed in 42 (79.3%) and 11 (20,7%) patients, respectively. Baseline PSA level ranged from 5.5 ng/ml to 311 ng/ml (39.7+/-7.9 ng/ml). According to the new grading system (the WHO classification, 2016), all patients were divided into five risk groups. Median follow-up was 64.9 months. The biochemical progression was seen in two patients, while three patients had metastatic disease. All patients with progressing prostate cancer were from IV and V prognostic groups. The 5-year progression-free survival rates for patients of IV-V and I-III groups were 44, 4% and 100%, respectively. According to the results of combination treatment (conformal external beam radiotherapy, brachytherapy 125I and hormonal therapy), progression-free survival rate in patients of IV (Gleason 4+4=8) and V (Gleason 4+5=9 or 5+5=10) groups, according to new WHO grading system were significantly lower, in comparison with patients of I (Gleason 3+3=6), II (Gleason 3+4=7) and III groups (Gleason 4+3=7). Our study showed that new WHO classification allows to predict the progression of prostate cancer not only after prostatectomy, but also after conformal external beam radiation therapy, combined with brachytherapy 125I and androgen deprivation therapy.

Changes in conditional net survival and dynamic prognostic factors in patients with newly diagnosed metastatic prostate cancer.

247 Background: The treatment strategy for patients with newly diagnosed metastatic hormone naïve prostate cancer (mHNPC) has changed in recent years. Thus, an accurate assessment of prognosis is critical. Conditional net survival provides the more appropriate method of estimating survival from cancer. The purpose of this study was to identify predictive factors associated with conditional net survival in patients with mHNPC initially treated with androgen deprivation therapy (ADT). Methods: The medical records of 605 consecutive patients with mHNPC who initially received ADT were retrospectively reviewed. The Pohar Perme estimator was used to calculate conditional net cancer-specific survival (CSS) and overall survival (OS) for up to five years subsequent to the diagnosis. Using multiple imputation, proportional hazard ratios for conditional CSS and OS were calculated with adjusted Cox regression models. Results: During follow-up (median, 2.95 years), 208 patients died, 169 from progressive prostate cancer. At baseline, the 5-year CSS and OS rates were 65.5% and 58.2%, respectively. The overall conditional 5-yearnet OS rate at baseline was 0.582, and the overall conditional 5-year net OS rates for patients who survived for1, 2, 3, 4, and 5 years were 0.566 (−0.16), 0.615 (+3.3), 0.550 (−0.32), 0.702 (+1.2), and 0.811 (+2.29), respectively. Conditional 5-year net CSS and OS survival gradually increased for all the patients. In patients given a 5-year survivorship, the conditional 5-year net CSS and OS rates improved to 0.906 and 0.811, respectively. Only the extent of disease score (EOD) ≥2 remained a prognostic factor for CSS and OS up to 5 years; as survival time increased, other variables were no longer independent prognostic factors. Conclusions: The conditional 5-year net CSS and OS in patients with mHNPC gradually increased; thus, the risk of mortality decreased with increasing survival. The patient’s risk profile changed over time. EOD remained an independent prognostic factor for CSS and OS after 5-year follow-up. Conditional net survival can play a role in clinical decision-making, providing intriguing information for cancer survivors.

Patient-reported outcomes (PRO) from a phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration-resistant prostate cancer (mCRPC).

45 Background: We performed the 1st dose-escalation study of PSMA-targeted radionuclide therapy with 177Lu-PSMA-617. Using dose-fractionation, we intended to deliver a dose-intense regimen designed to minimize radioresistance due to repopulation. Radionuclide therapy may be able to treat symptoms due to tumor and therefore may be associated with improvement in PRO. Methods: Inclusion: progressive mCRPC following potent AR-pathway inhibitor (ARPI, e.g. abi/enza) and taxane (or unfit/refuse chemo) without limit of # prior therapies, adequate organ function, ECOG performance status 0-2, without preselection for PSMA expression. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15 (7.4 to 22 GBq in phase 1; 22.2 GBq in phase 2). PRO tools included FACT-P and BPI-SF at baseline and follow up. Results: 44 men with median age 69 (range 55-91), median PSA 182.97 (range 0.89-5541) were treated. 93% with bone, 45% nodal, 18% lung, 9% liver, 9% other visceral metastases. 55% with at least 1 prior chemo regimen, 52% &gt;2 prior ARPI, 27% with Ra223, 30% sip-T, 5% 177Lu-J591. 59.1% with &gt;50% PSA decline (66.7% at 22.2 GBq, n=21), median overall survival 16 months (95% CI 11-NR). High grade (Gr) toxicity was rare with 6.8% Gr 3 anemia and 2.3% Gr 3 platelets. Gr 1/2 treatment-emergent AE’s include 81.8% with pain flare, 61.4% xerostomia, 29.5% fatigue, 25% platelets, 25% anemia, 25% pain, 15.5% nausea. FACT-P scores tended to improve in all categories by D22 (1 week later), with overall FACT-P scores improving by mean of 8.9 points (p=0.07) at D22 and remaining improved at 12 wks. All BPI scores also improved, with BPI overall severity score improving by mean of 3.0 at D22 (p=0.008) and remained better than baseline at 12 wks. There was no clear association with any AE and PRO changes, but those with PSA decline tended to have improved pain scores (p=0.1). Conclusions: A single cycle of up to 22.2 GBq of 177Lu-PSMA-617 is safe with fractionated (D1 &amp; D15) dosing, with encouraging early efficacy signals in a population unselected for PSMA expression and improved quality of life and pain scores by validated PRO instruments. Clinical trial information: NCT03042468.

ADRB2 expression in progressive metastatic castration-resistant prostate cancer.

145 Background: The net oncogenic effect of the G protein-coupled receptor β2 adrenergic receptor ADRB2, which may induce neuroendocrine differentiation via cyclic AMP and protein kinase A and whose expression is epigenetically regulated by EZH2, is controversial. ADRB2 expression and associated clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) are unknown. Methods: This was a retrospective analysis of a cohort of men with mCRPC who were prospectively enrolled in the multi-center SU2C/PCF/AACR West Coast Prostate Cancer Dream Team study, in which biopsies of a metastatic site were obtained at disease progression. Specimens underwent laser capture microdissection and RNA-seq. ADRB2 expression was stratified by histology and transcriptional cluster based on prior unsupervised hierarchical transcriptome clustering, and correlated with EZH2 expression. ADRB2 expression (lowest quartile) was correlated with OS from time of biopsy by log rank test and a multivariable Cox proportional hazard model. Results: One-hundred and twenty-seven men with progressive mCRPC underwent metastatic biopsies and had sufficient tumor for RNA-seq. ADRB2 expression was lowest in the small cell-enriched transcriptional cluster (P&lt;0.001), and correlated inversely with EZH2 expression (r=-0.28, P&lt;0.01). Men with low ADRB2 expression had a shorter median OS than those with high (9.5 vs 18.9 mo, P=0.02). In multivariable analysis adjusting for small cell histology, performance status, LDH, and visceral metastases, high ADRB2 expression was associated with a trend towards longer OS (HR=0.65, 95% CI 0.41-1.02, P=0.06). Conclusions: Low ADRB2 expression is associated with worse OS in men with progressive mCRPC, and may be a means by which EZH2 confers resistance to antiandrogen therapy. Indirect ADRB2 stimulation with EZH2 inhibitors may improve outcomes. Validation in independent cohorts is necessary.

KEYNOTE-046 (Part B): Effects of ADXS-PSA in combination with pembrolizumab on survival in metastatic, castration-resistant prostate cancer patients with or without prior exposure to docetaxel.

126 Background: ADXS-PSA, an attenuated Listeria monocytogenes-based immunotherapy targeting prostate-specific antigen (PSA), is currently being evaluated in combination with pembrolizumab as a treatment for progressive metastatic castration-resistant prostate cancer (mCRPC) in the phase 1/2 KEYNOTE-046 trial (Part B). Methods: A total of 37 patients received 1x109 CFU + 200 mg pembro IV every 3 wks, for up to 2 yrs or until progression/toxicity. Results: At entry, patients were ~70 yrs with median a Gleason score of 9, and bone predominant disease (70%). MSI-High was negative in 36 pts who were able to be tested. Eighteen (48.6%) patients had received prior docetaxel, 15 pts of whom (83.3%) had also received 1-2 next generation hormonal agents (NGHAs). Nineteen (51.3%) had not received prior docetaxel and 16 of these pts (84.2%) had received 1-2 NGHAs. Overall, 16 out of 37 pts (43%) had a decreased PSA post-BL with 6/37 (16%) pts achieving a confirmed PSA reduction ≥50% from baseline. The median OS (months) for the whole group (37 pts) was 33.6 m (95% CI, range 15.4-33.6 months). The mOS for pts with and without prior exposure to docetaxel was 16 m (5.9 -33.6) and NR at 30 months of follow-up (15.4-NR), respectively. Prolonged survival was observed in pts regardless of prior therapies, microsatellite stable (MSS) status or PSA delta &lt;50% or ≥50%. Conclusions: Results with ADXS-PSA in combination with pembrolizumab in mCRPC, with or without prior docetaxel, show promising clinical activity to be further assessed in randomized studies. Clinical trial information: NCT02325557.

NMR-based metabolomics analysis identifies discriminatory metabolic disturbances in tissue and biofluid samples for progressive prostate cancer

BackgroundProstate cancer (PCa) is one of the most common cancers in men, but its metabolic characteristics during tumor progression are still far from being fully understood. MethodsThe metabolic profiles of matched tissue, serum and urine samples from the same patients were analyzed using a 1H NMR-based metabolomics approach. We identified several important metabolites that significantly altered at different stages of PCa, including benign prostatic hyperplasia (BPH), early PCa (EPC), advanced PCa (APC), metastatic PCa (MPC) and castration-resistant PCa (CRPC). Metabolic correlation networks among tissue, serum and urine samples were examined using Pearson’s correlation. ResultsThe changes in metabolic phenotypes during the progression of PCa were more noticeable in tissue samples when compared with serum and urine samples. Herein we identified a series of important metabolic disturbances, including decreased trends of citrate, creatinine, acetate, leucine, valine, glycine, lysine, histidine, glutamine and choline as well as increased trends of uridine and formate. These metabolites are mainly implicated in energy metabolism, amino acid metabolism, choline and fatty acid metabolism as well as uridine metabolism. We also found that energy metabolism in tumor tissues was positively associated with amino acid metabolism in serum and urine. Additionally, CRPC patients had a peculiar metabolic phenotype, especially decreased amino acid metabolism in serum. ConclusionsThe present study characterizes metabolic disturbances in both tissue and biofluid samples during PCa progression and provides potential diagnostic biomarkers and therapeutic targets for PCa.

A Single-arm, Open-label, Phase II Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

A Single-arm, Open-label, Phase II Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

Changes in conditional net survival and dynamic prognostic factors in patients with newly diagnosed metastatic prostate cancer initially treated with androgen deprivation therapy.

BackgroundThe purpose of this study was to identify predictive factors associated with conditional net survival in patients with metastatic hormone‐naive prostate cancer (mHNPC) initially treated with androgen deprivation therapy (ADT).MethodsAt nine hospitals in Tohoku, Japan, the medical records of 605 consecutive patients with mHNPC who initially received ADT were retrospectively reviewed. The Pohar Perme estimator was used to calculate conditional net cancer‐specific survival (CSS) and overall survival (OS) for up to 5 years subsequent to the diagnosis. Using multiple imputation, proportional hazard ratios for conditional CSS and OS were calculated with adjusted Cox regression models.ResultsDuring a median follow up of 2.95 years, 208 patients died, of which 169 died due to progressive prostate cancer. At baseline, the 5‐year CSS and OS rates were 65.5% and 58.2%, respectively. Conditional 5‐year net CSS and OS survival gradually increased for all the patients. In patients given a 5‐year survivorship, the conditional 5‐year net CSS and OS rates improved to 0.906 and 0.811, respectively. Only the extent of disease score (EOD) ≥2 remained a prognostic factor for CSS and OS up to 5 years; as survival time increased, other variables were no longer independent prognostic factors.ConclusionsThe conditional 5‐year net CSS and OS in patients with mHNPC gradually increased; thus, the risk of mortality decreased with increasing survival. The patient's risk profile changed over time. EOD remained an independent prognostic factor for CSS and OS after 5‐year follow‐up. Conditional net survival can play a role in clinical decision‐making, providing intriguing information for cancer survivors.

GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer.

The prognosis of patients with progressive prostate cancers that are hormone refractory and/or have bone metastasis is poor. Multiple therapeutic targets to improve prostate cancer patient survival have been investigated, including orphan GPCRs. In our study, we identified G Protein-Coupled Receptor Class C Group 5 Member A (GPRC5A) as a candidate therapeutic molecule using integrative gene expression analyses of registered data sets for prostate cancer cell lines. Kaplan-Meier analysis of TCGA data sets revealed that patients who have high GPRC5A expression had significantly shorter overall survival. PC3 prostate cancer cells with CRISPR/Cas9-mediated GPRC5A knockout exhibited significantly reduced cell proliferation both in vitro and in vivo. RNA-seq revealed that GPRC5A KO PC3 cells had dysregulated expression of cell cycle-related genes, leading to cell cycle arrest at the G2/M phase. Furthermore, the registered gene expression profile data set showed that the expression level of GPRC5A in original lesions of prostate cancer patients with bone metastasis was higher than that without bone metastasis. In fact, GPRC5A KO PC3 cells failed to establish bone metastasis in xenograft mice models. In addition, our clinical study revealed that GPRC5A expression levels in prostate cancer patient samples were significantly correlated with bone metastasis as well as the patient's Gleason score (GS). Combined assessment with the immunoreactivity of GPRC5A and GS displayed higher specificity for predicting the occurrence of bone metastasis. Together, our findings indicate that GPRC5A can be a possible therapeutic target and prognostic marker molecule for progressive prostate cancer.

Abstract CT098: KEYNOTE-046: Effects of ADXS-PSA with or without pembrolizumab on survival and antigen spreading in metastatic, castration-resistant prostate cancer patients

Abstract Background: ADXS-PSA, an attenuated Listeria monocytogenes-based immunotherapy targeting prostate-specific antigen (PSA), is currently being evaluated as a treatment for progressive metastatic castration-resistant prostate cancer (mCRPC) in the Phase I/II KEYNOTE-046 trial as a monotherapy (Part A; PA) and in combination with pembrolizumab (Part B; PB). Methods: This Phase I/II trial evaluated pts with mCRPC, ≥18 yrs who received ≤2 prior chemo-/targeted-/immunotherapies or ≤1 prior chemotherapy in a metastatic setting. Part A (PA; n = 13) pts received ADXS-PSA doses 1x109; 5 x109 or 1x1010 CFU IV every 3 wks and Part B (PB; n = 37) pts received 1x109 CFU + 200 mg pembro IV every 3 wks with a 4thpembro dose 3 wks later (in 12 wks cycles), for up to 2 yrs or until progression/toxicity. Safety/tolerability, antitumor activity and effect on PSA levels have been reported for both groups (Stein M et al., Keynote-046, ASCO 2018). Updates on OS and T cell reactivity to PSA and to other prostate cancer antigens (i.e., prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), and prostein) are herein presented for PA and PB pts. Results: At entry, PA and PB pts were ~70 yrs with a Gleason score &amp;gt;8 and the majority had received prior abiraterone and/or enzalutamide. PB pts had higher median baseline (BL) PSA (40.6 vs. 20.8 ng/mL), and more prior enzalutamide (53 vs. 26%) and chemotherapy (49 vs. 36%) use vs PA pts. Overall, 2 PA (14%) v 16 PB pts (43%) had a decreased PSA post-BL. Of these, 7 PB (19%) vs. 0 PA pts achieved a confirmed PSA reduction ≥50% from BL. The median OS (months) in PB pts was 23 (17.4 -NR) vs. 8.5 (3.8-20.10) in PA pts. Median OS in PB pts with PSA reduction ≥50% from BL has not been reached as 100% (6/6) of pts are still alive. T cell reactivity, as measured by ELISpot assays, showed that 100% of PA (9/9) pts and 100% of PB (16/16) pts exhibited increases in the frequencies of T cells reactive to at least one prostate cancer antigen other than PSA, which is indicative of antigen spreading. Conclusions: ADXS-PSA ± pembro elicited a broad antitumor T cell response in all mCRPC pts tested but only ADXS-PSA + pembro reduced PSA ≥50% from BL and prolonged OS in these select pts. Clinical trial information: NCT02325557. Citation Format: Mark Stein, Lawrence Fong, Ronald Tutrone, Anthony Mega, Elaine T. Lam, Surya Vangala, Justin Dennie, Robert Petit, Andres Gutierrez, Sandy Hayes, Naomi Haas. KEYNOTE-046: Effects of ADXS-PSA with or without pembrolizumab on survival and antigen spreading in metastatic, castration-resistant prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT098.