Prostate cancer is the second most common cause of cancer mortality among men in the United States. While many prostate cancers are indolent, an important subset of patients experiences disease recurrence after conventional therapy and progresses to castration-resistant prostate cancer (CRPC), which is currently incurable. Thus, there is a critical need to identify biomarkers that will distinguish indolent from aggressive disease, as well as novel therapeutic targets for the prevention or treatment of CRPC. In recent years, long noncoding RNAs (lncRNAs) have emerged as an important class of biological molecules. LncRNAs are polyadenylated RNA species that share many similarities with protein-coding genes despite the fact that they are noncoding (not translated into proteins). They are usually transcribed by RNA polymerase II and exhibit the same epigenetic signatures as protein-coding genes. LncRNAs have also been implicated in the development and progression of variety of cancers, including prostate cancer. While a large number of lncRNAs exhibit tissue- and cancer-specific expression, their utility as diagnostic and prognostic biomarkers is just starting to be explored. In this review, we highlight recent findings on the functional role and molecular mechanisms of lncRNAs in the progression of prostate cancer and evaluate their use as potential biomarkers and therapeutic targets.

Acute hematologic toxicity is a frequent adverse effect of beta-emitter targeted radionuclide therapies (TRTs). Alpha emitters have the potential of delivering high linear energy transfer (LET) radiation to the tumor attributed to its shorter range. Antibody-based TRTs have increased blood-pool half-lives, and therefore increased marrow toxicity, which is a particular concern with alpha emitters. Accurate 3D absorbed dose calculations focusing on the interface region of blood vessels and bone can elucidate energy deposition patterns. Firstly, a cylindrical geometry model with a central blood vessel embedded in the trabecular tissue was modeled. Monte Carlo simulations in GATE were performed considering beta (¹⁷⁷Lu, ⁹⁰Y) and alpha emitters (²¹¹At, ²²⁵Ac) as sources restricted to the blood pool. Subsequently, the radioactive sources were added in the trabecular bone compartment in order to model bone marrow metastases infiltration (BMMI). Radial profiles, dose-volume histograms and voxel relative differences were used to evaluate the absorbed dose results. We demonstrated that alpha emitters have a higher localized energy deposition compared to beta emitters. In the cylindrical geometry model, when the sources are confined to the blood pool, the dose to the trabecular bone is greater for beta emitting radionuclides, as alpha emitters deposit the majority of their energy within 70 μm of the vessel wall. In the BMMI model, alpha emitters have a lower dose to untargeted trabecular bone. Our results suggest that when alpha emitters are restricted to the blood pool, as when labeled to antibodies, hematologic toxicities may be lower than expected due to differences in the microdistribution of delivered absorbed dose.

Data from recent high-throughput studies analyzing local and advanced prostate cancer have revealed an incredible amount of biological diversity, which has led to the classification of distinct molecular tumor subtypes. While integrating prostate cancer genomics with clinical medicine is still at its infancy, new approaches to treat prostate cancer are well underway and being studied. With the recognition that DNA damage repair (DDR) mutations play an important role in the pathogenesis of this disease, clinicians can begin to utilize genomic information in complex treatment decisions for prostate cancer patients. In this Review, we discuss the role of DDR mutations in prostate cancer, including deficiencies in homologous repair and mismatch repair (MMR), and how this information is revolutionizing the treatment landscape. In addition, we highlight the potential resistance mechanisms that may result as we begin to target these pathways in isolation and discuss potential combinatorial approaches that may delay or overcome resistance.

Background

We sought to determine temporal trends in the receipt of prostatectomy or locoregional radiation to the prostate for patients with metastatic prostate cancer and to identify predictors of receipt of local treatment.

Methods

We identified 39,976 patients with metastatic prostate cancer diagnosed in 2004-2012 using the National Cancer Database (NCDB). We used logistic multivariable regression to determine trends in the receipt of prostate and/or pelvic radiation or radical prostatectomy after adjusting for demographic and clinical factors.

Results

Patients with metastatic disease were less likely to receive locoregional treatment over time [7.88% in 2004 vs. 5.53% in 2012, adjusted odds ratio (AOR) = 0.97 per year, 95% confidence interval (CI) = 0.95-0.98; P < 0.001]. Cofactors associated with decreased likelihood for locoregional treatment included older age (AOR = 0.96 per year, 95% CI = 0.96-0.96, P < 0.001) and increased comorbidity level (1 comorbidity: AOR = 0.82, 95% CI = 0.73-0.93, P = 0.001; two or more comorbidities: AOR = 0.49, 95% CI = 0.39-0.61, P < 0.001). Decreasing utilization of both radiation and surgery of the primary site contributed to this trend. More specifically, patients with metastatic disease were less likely to receive radiation to the prostate and/or pelvis over time (5.9% in 2004 vs. 4.2% in 2012, AOR = 0.97 per year, 95% CI = 0.95-0.99, P < 0.001). Similarly, there was a trend toward decreased use of radical prostatectomy (2.17% in 2004 compared to 1.31% in 2012, AOR = 0.96 per year, 95% CI 0.93-0.99, P = 0.01).

Conclusion

Despite recent evidence of the possible benefit for locoregional treatment of prostate cancer in the setting of metastatic disease, rates of prostate radiation and radical prostatectomy among this population have actually declined over the 8-year period between 2004 and 2012, suggesting slow adoption of this novel treatment paradigm.

Background

The aim of this study is to elucidate the difference in absorbed dose (D_abs) patterns in radiopharmaceutical therapies between alpha emitters (²²⁵Ac) and beta emitters (¹⁷⁷Lu) when targeting cancer-associated fibroblasts (CAF) or tumor cells. Five spherical models with 3 mm diameter were created, representing spherical tumor masses that contain tumor clusters, interspersed with CAFs. The mean distance from a tumor cell to the nearest CAF (L_mean) varied throughout these models from 92 to 1030 µm. D_abs calculations were performed while selecting either CAFs or tumor cells as sources, with Convolution/Superposition with ¹⁷⁷Lu and Monte Carlo simulations (GATE) with ²²⁵Ac. Analyses were conducted with Dose Volume Histograms and efficacy ratios (ER), which represents the ratio of mean D_abs that is deposited in the target volume.

Results

²²⁵Ac is the most optimal radionuclide when CAFs are both targeted and irradiating themselves, as ERs increase from 1.5 to 3.7 when L_mean increases from 92 to 1030 µm. With ¹⁷⁷Lu, these numbers vary from 1.2 to 2.7. Conversely, when CAFs are sources and tumors are targets with ²²⁵Ac, ERs decreased from 0.8 to 0.1 when L_mean increases from 92 to 1030 µm. With ¹⁷⁷Lu, these numbers vary from 0.9 to 0.3 CONCLUSION: When targeting CAFs to irradiate tumors, the efficacy of using ²²⁵Ac decreases as the average size of the tumor clusters (or L_mean) increases. In such situations, ¹⁷⁷Lu will be more effective than ²²⁵Ac when targeting CAFs due to the longer beta particle range.

Prostate cancer is the most common non-cutaneous cancer among men in the United States. In the last decade there has been a rapid expansion in the field of biomarker assays for diagnosis, prognosis, and treatment prediction in prostate cancer. The evidence base for these assays is rapidly evolving. With several commercial assays available at each stage of the disease, deciding which genomic assays are appropriate for which patients can be nuanced for physicians. In an effort to help guide these decisions in clinical practice, we aim to give an update on the current status of the biomarker field of prostate cancer.

Purpose

Both the performance characteristics of prostate-specific membrane antigen positron emission tomography and insurance approval improves with increasing prostate-specific antigen (PSA) level causing some physicians to delay post-radical prostatectomy salvage radiation therapy (sRT) after PSA failure. Yet, it is unknown for men with at most one high-risk factor (ie, pT3/4 or prostatectomy [p] Gleason score 8-10) whether a PSA level exists above which initiating sRT is associated with increased all-cause mortality (ACM)-risk and was investigated.

Methods

Using a multinational database of 25,551 patients with pT2-4N0 or NXM0 prostate cancer, multivariable Cox regression analysis evaluated whether an association with a significant increase in ACM-risk existed when sRT was delivered above a prespecified PSA level beginning at 0.10 ng/mL and in 0.05 increments up to 0.50 ng/mL versus at or below that level. The model was adjusted for age at and year of radical prostatectomy, established prostate cancer prognostic factors, institution, and the time-dependent use of androgen deprivation therapy.

Results

After a median follow-up of 6.00 years, patients who received sRT at a PSA level >0.25 ng/mL had a significantly higher ACM-risk (AHR, 1.49; 95% CI, 1.11 to 2.00; P = .008) compared with men who received sRT when the PSA was ≤0.25 mg/mL. This elevated ACM-risk remained significant for all PSA cutpoints up to 0.50 ng/mL but was not significant at PSA cutpoint values below 0.25 ng/mL.

Conclusion

Among patients with at most one high-risk factor, initiating sRT above a PSA level of 0.25 ng/mL was associated with increased ACM-risk.

Background

Enzalutamide is an antiandrogen used to treat both metastatic and nonmetastatic prostate cancer. Here we present results from a phase 2 trial designed to determine the safety, tolerability, and efficacy of adding enzalutamide to standard androgen deprivation therapy with radiation therapy in high-risk localized or regional, nonmetastatic patients with prostate cancer.

Methods and materials

Enrollment criteria included at least 2 of the following: stage cT3a/b, prostate specific antigen (PSA) ≥20 ng/mL, Gleason grade 8 to 10, ≥33% core involvement on biopsy, or pelvic lymph node involvement on computed tomography or magnetic resonance imaging. Patients with metastatic disease were excluded. All patients received 24 months of leuprolide and enzalutamide, and 5 weeks of intensity modulated radiation therapy followed by a brachytherapy boost. Adverse events (AE), PSA, testosterone, and basic laboratory tests were then followed for up to 36 months. Primary outcomes were safety and tolerability and PSA complete response rate (PSA-CR, defined as PSA ≤0.3). Secondary outcomes included time to biochemical recurrence (BCR; nadir + 2 ng/mL).

Results

Sixteen patients were enrolled; 2 were ineligible and 3 withdrew before starting treatment. Median age at enrollment was 69.0 years (interquartile range [IQR] 11.5). Median treatment duration was 24.0 months (IQR 11.9). Median follow-up time was 35.5 months (IQR 11.2), and 9 of 11 (81.8%) patients completed the 36 months of follow-up. One of 11 (9%) patients had grade 4 AE (seizure), and no grade 5 AE were reported. Four of 11 (36.4%) patients had grade 3 AE, such as erectile dysfunction and hot flashes. All patients achieved PSA-CR, and median time to PSA-CR was 4.2 months (IQR 1.4). At 24 months follow-up, 0 of 11 (0%) patients had a biochemical recurrence. At 36 months, 1 of 9 (11.1%) patient had a biochemical recurrence. Of note, this patient did not complete the full 24 months of enzalutamide and leuprolide due to AEs.

Conclusions

Enzalutamide in combination with standard androgen deprivation therapy and radiation therapy was well-tolerated and effective warranting further study in a randomized controlled trial.

The androgen receptor (AR) is a central driver of aggressive prostate cancer. After initial treatment with androgen receptor signaling inhibitors (ARSi), reactivation of AR signaling leads to resistance. Alternative splicing of AR mRNA yields the AR-V7 splice variant, which is currently an undruggable mechanism of ARSi resistance: AR-V7 lacks a ligand binding domain, where hormones and anti-androgen antagonists act, but still activates AR signaling. We reveal PKCβ as a druggable regulator of transcription and splicing at the AR genomic locus. We identify a clinical PKCβ inhibitor in combination with an FDA-approved anti-androgen as an approach for repressing AR genomic locus expression, including expression of AR-V7, while antagonizing full-length AR. PKCβ inhibition reduces total AR gene expression, thus reducing AR-V7 protein levels and sensitizing prostate cancer cells to current anti-androgen therapies. We demonstrate that this combination may be a viable therapeutic strategy for AR-V7-positive prostate cancer.

Human prostate cancer can result from chromosomal rearrangements that lead to aberrant ETS gene expression. The mechanisms that lead to fusion-independent ETS factor upregulation and prostate oncogenesis remain relatively unknown. Here, we show that two neighboring transcription factors, Capicua (CIC) and ETS2 repressor factor (ERF), which are co-deleted in human prostate tumors can drive prostate oncogenesis. Concurrent CIC and ERF loss commonly occur through focal genomic deletions at chromosome 19q13.2. Mechanistically, CIC and ERF co-bind the proximal regulatory element and mutually repress the ETS transcription factor, ETV1. Targeting ETV1 in CIC and ERF-deficient prostate cancer limits tumor growth. Thus, we have uncovered a fusion-independent mode of ETS transcriptional activation defined by concurrent loss of CIC and ERF.