Brian Shinder

Androgen-Regulated SPARCL1 in the Tumor Microenvironment Inhibits Metastatic Progression

Prostate cancer is a leading cause of cancer death in men due to the subset of cancers that progress to metastasis. Prostate cancers are thought to be hardwired to androgen receptor (AR) signaling, but AR-regulated changes in the prostate that facilitate metastasis remain poorly understood. We previously noted a marked reduction in secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) expression during invasive phases of androgen-induced prostate growth, suggesting that this may be a novel invasive program governed by AR. Herein, we show that SPARCL1 loss occurs concurrently with AR amplification or overexpression in patient-based data. Mechanistically, we demonstrate that SPARCL1 expression is directly suppressed by androgen-induced AR activation and binding at the SPARCL1 locus via an epigenetic mechanism, and these events can be pharmacologically attenuated with either AR antagonists or HDAC inhibitors. We establish using the Hi-Myc model of prostate cancer that in Hi-Myc/Sparcl1(-/-) mice, SPARCL1 functions to suppress cancer formation. Moreover, metastatic progression of Myc-CaP orthotopic allografts is restricted by SPARCL1 in the tumor microenvironment. Specifically, we show that SPARCL1 both tethers to collagen in the extracellular matrix (ECM) and binds to the cells cytoskeleton. SPARCL1 directly inhibits the assembly of focal adhesions, thereby constraining the transmission of cell traction forces. Our findings establish a new insight into AR-regulated prostate epithelial movement and provide a novel framework whereby SPARCL1 in the ECM microenvironment restricts tumor progression by regulating the initiation of the network of physical forces that may be required for metastatic invasion of prostate cancer.

Germline Variants in Asporin Vary by Race, Modulate the Tumor Microenvironment, and Are Differentially Associated with Metastatic Prostate Cancer

Purpose: Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeat-length have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed. Experimental Design: Germline ASPN D-repeat-length was retrospectively analyzed in 1,600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 noncancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes, including metastasis. Orthotopic xenografts were used to establish allele- and stroma-specific roles for ASPN D variants in metastatic prostate cancer. Results: Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 [HR, 1.72; 95% confidence interval (CI), 1.05–2.81, P = 0.032] and heterozygosity for ASPN D13/14 (HR, 1.86; 95% CI, 1.03–3.35, P = 0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR, 0.44; 95% CI, 0.21–0.94, P = 0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient-based data. Conclusions: We observed associations between ASPN D variants and oncologic outcomes, including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression. Clin Cancer Res; 22(2); 448–58. ©2015 AACR.

Combining immune check-point blockade and cryoablation in an immunocompetent hormone sensitive murine model of prostate cancer

BackgroundProstate cancer remains the second leading cause of cancer related death in men. Immune check point blocking antibodies have revolutionized treatment of multiple solid tumors, but results in prostate cancer remain marginal. Previous reports have suggested that local therapies, in particular cryoablation might increase tumor immunogenicity. In this work, we examine potential synergism between tumor cryoabalation and check point blocking antibodies.MethodsFVB/NJ mice were injected subcutaneously into each flank with either 1 × 106 or 0.2 × 106 isogenic hormone sensitive Myc-Cap cells to establish synchronous grafts. Mice were treated with four intraperitoneal injections of anti-PD-1 (10 mg/kg), anti-CTLA-4 (1 mg/kg), or isotype control antibody with or without adjuvant cryoablation of the larger tumor graft and with or without neo-adjuvant androgen deprivation with degarelix (ADT). Mouse survival and growth rates of tumor grafts were measured. The immune dependency of observed oncological effects was evaluated by T cell depletion experiments.ResultsTreatment with anti-CTLA-4 antibody and cryoablation delayed the growth of the distant tumor by 14.8 days (p = 0.0006) and decreased the mortality rate by factor of 4 (p = 0.0003) when compared to cryoablation alone. This synergy was found to be dependent on CD3+ and CD8+ cells. Combining PD-1 blockade with cryoablation did not show a benefit over use of either treatment alone. Addition of ADT to anti-PD1 therapy and cryoablation doubled the time to accelerated growth in the untreated tumors (p = 0.0021) and extended survival when compared to cryoablation combined with ADT in 25% of the mice. Effects of combining anti-PD1 with ADT and cryoablation on mouse survival were obviated by T cell depletion.ConclusionTrimodal therapy consisting of androgen deprivation, cryoablation and PD-1 blockade, as well as the combination of cryoablation and low dose anti-CTLA-4 blockade showed that local therapies with cryoablation could be considered to augment the effects of checkpoint blockade in prostate cancer.

Predicting clinically significant prostate cancer based on pre-operative patient profile and serum biomarkers

Previous studies have reported association of multiple preoperative factors predicting clinically significant prostate cancer with varying results. We assessed the predictive model using a combination of hormone profile, serum biomarkers, and patient characteristics in order to improve the accuracy of risk stratification of patients with prostate cancer. Data on 224 patients from our prostatectomy database were queried. Demographic characteristics, including age, body mass index (BMI), clinical stage, clinical Gleason score (GS) as well as serum biomarkers, such as prostate-specific antigen (PSA), parathyroid hormone (PTH), calcium (Ca), prostate acid phosphatase (PAP), testosterone, and chromogranin A (CgA), were used to build a predictive model of clinically significant prostate cancer using logistic regression methods. We assessed the utility and validity of prediction models using multiple 10-fold cross-validation. Bias-corrected area under the receiver operating characteristics (ROC) curve (bAUC) over 200 runs was reported as the predictive performance of the models. On univariate analyses, covariates most predictive of clinically significant prostate cancer were clinical GS (OR 5.8, 95% CI 3.1–10.8; P < 0.0001; bAUC = 0.635), total PSA (OR 1.1, 95% CI 1.06–1.2; P = 0.0003; bAUC = 0.656), PAP (OR 1.5, 95% CI 1.1–2.1; P = 0.016; bAUC = 0.583), and BMI (OR 1.064, 95% C.I. 0.998, 1.134; P < 0.056; bAUC = 0.575). On multivariate analyses, the most predictive model included the combination of preoperative PSA, prostate weight, clinical GS, BMI and PAP with bAUC 0.771 ([2.5, 97.5] percentiles = [0.76, 0.78]). Our model using preoperative PSA, clinical GS, BMI, PAP, and prostate weight may be a tool to identify individuals with adverse oncologic characteristics and classify patients according to their risk profiles.

Results of Phase 1 Study on Cytoreductive Radical Prostatectomy in Men with Newly Diagnosed Metastatic Prostate Cancer

Background Preclinical and retrospective data suggest that cytoreductive radical prostatectomy may benefit a subset of men who present with metastatic prostate cancer (mPCa). Herein, we report the results of the first planned Phase 1 study on cytoreductive surgery. Methods From four institutions, 36 patients consented to the study. However, four did not complete surgery because of rapid disease progression (n = 3) and another because of an intraoperatively discovered pericolonic abscess. Men with newly diagnosed clinical mPCa to lymph nodes or bones were eligible. The primary endpoint was the rate of major perioperative complications (Clavien-Dindo Grade 3 or higher) occurring within 90 days of surgery. Results The mean age at surgery was 64.0 years. The 90-day overall complication rate was 31.2% (n = 10), of which two (6.25%) were considered major complications: one acute tubular necrosis requiring temporary dialysis and one death. In men with more than 6 months of follow-up, 67.9% had prostate specific antigen nadir ≤0.2 ng/mL, while one patient experienced a rapid rise in prostate specific antigen and another a widely disseminated disease that resulted in death 5 months after surgery. Altogether, these results demonstrate that cytoreductive radical prostatectomy is safe and surgically feasible in selected patients who present with mPCa . Yet, there may be a small subset of patients in whom surgery may cause a significant harm. Conclusion Therefore, cytoreductive surgery in men with mPCa should be limited to clinical trials until robust data are available.

PD24-10 INTERIM ANALYSIS OF NCT02458716: FEASIBILITY OF CYTOREDUCTIVE PROSTATECTOMY IN MEN NEWLY DIAGNOSED WITH METASTATIC PROSTATE CANCER

ideal T responders), and all T levels recorded were obtained subsequent to achieving a T level 0.7 ng/mL. Serum T levels were measured using a chemiluminescent microparticle immunoassay (Abbott Diagnostics ARCHITECT i2000). Statistical significance was set at p1⁄40.05. Analysis was performed using SPSS v23.0. RESULTS: Mean patient age was 73.7 years. Mean T level was 0.52 ng/mL (std dev1⁄40.34 ng/mL). There was no significant association between patient age and T levels (p1⁄4 .07). Serum T levels did not demonstrate any diurnal variation, as there was no association between time of day that blood samples were drawn and T levels (p1⁄4 .14). After attaining T levels 0.7 ng/mL, 237 (43.0%), 127 (23.0%), and 25 (4.5%) patients subsequently achieved T levels >0.7, >1.1 and >1.7 ng/mL, respectively, with 85% of patients who had a T level >0.7 ng/mL having at least one additional T level measurement >0.7 ng/ml within 5 years. Ideal T levels of 0.7 ng/mL were re-achieved in 185 (78.1%), 84 (66.1%) and 15 (60.0%) of patients who had T levels measurements of >0.7, >1.1, and 1.7 ng/ml, respectively. CONCLUSIONS: Ideal T responders to continuous ADT demonstrate considerable variation in serum T levels on follow up. Elevated T level measurements among patients on continuous ADT must be interpreted in light of these findings. Repeat T level measurements are recommended prior to implementing a change in clinical management.

MP04-05 DECLINING USE OF CONTINENT DIVERSIONS FOR BLADDER CANCER

INTRODUCTION AND OBJECTIVES: The effect of non-muscle invasive bladder cancer (NMIBC) on health-related quality of life (HRQOL) is poorly understood. We evaluated changes in HRQOL in patients with a new diagnosis of NMIBC compared with the general population using the Surveillance Epidemiology and End Results (SEER) Medicare Health Outcomes Survey (MHOS) database. METHODS: We identified 325 Medicare beneficiaries diagnosed with NMIBC between initial and 2-year follow-up using SEERMHOS data (1998-2013). NMIBC patients who underwent cystoscopy with biopsy or transurethral resection of bladder tumor(s) for bladder cancer were propensity matched 1:5 to non-cancer controls (n1⁄41685). Changes from baseline in the physical component score (PCS) and mental component score (MCS), which are normalized to between 0-100, where 50 represents the US population mean, were compared between NMIBC patients and non-cancer controls with c testing and multivariate linear regression analysis. We secondarily assessed differences in urinary symptoms on post-diagnosis surveys with univariate and multivariate models. RESULTS: Pre-diagnosis, mean PCS (39.94 vs 39.54, p 1⁄4 0.71) and mean MCS (52.03 vs 52.17, p 1⁄4 0.82) scores were similar between NMIBC patients and matched non-cancer controls. Postdiagnosis, NMIBC patients had a significantly greater decrease in PCS compared with controls (-2.87 (95% CI -3.87, -1.86) vs. -1.47 (95% CI -1.93, -1.02), p 1⁄4 0.02). Conversely, mean MCS change did not vary between groups (-1.79 (95% CI -2.76, -0.81) vs. -0.72 (95% CI -1.21, -0.23), p 1⁄4 0.09). With respect to urinary function, NMIBC pts were more likely to have worsening of urinary leakage (38.0 % vs 18.7 %, p1⁄4 < 0.01), require physician intervention for urinary symptoms (33.9 % vs 13.7 %, p1⁄4 <0.01 ), and receive treatment for urine leakage (31.6 % vs 12.0 %, p1⁄4 <0.01 ) compared with non-cancer controls (p 1⁄4 <0.01). CONCLUSIONS: The diagnosis of NMIBC is associated with a significant decrease in physical HRQOL, including a significant impact on urinary symptoms and leakage. Further efforts to prospectively evaluate HRQOL in patients with NMIBC should be pursued to inform and improve patient counseling.

Effect of local therapy on the systemic anti-tumor response in prostate cancer.

243 Background: The genomic complexities and adaptability of aggressive cancer implies that it may only be eradicated by equally adaptable systems. Immune checkpoint blockade (such as that targeting PD−1 or CTLA−4) has shown dramatic and durable efficacy in immunogenic malignancies, but little or no benefit in less immunogenic cancers such as prostate cancer. Here we use a mouse model of prostate cancer to investigate whether local therapy can mount or augment an immune response to distant tumors. Methods: Immuno−competent FVB mice were bilaterally implanted with Myc−CAP cells to form isogenic grafts. Two weeks after tumor introduction, ablative therapies including radiation (stereotactically as a single 10 Gy fraction), cryoablation (two freeze−thaw cycles of less than −40 degree Celsius), whole tumor cauterization, or excision were applied to the larger graft in the presence of checkpoint blockade (intra−peritoneal anti−CTLA−4 or anti−PD1) or control injection (hamster anti−mouse IgG). Tumor sizes and m...