Metastatic Resistant Prostate Cancer Research Articles

The recovery from taxane mediated apoptosis in PC-3 castration-resistant metastatic prostate cancer cells

Here, we revealed the reversibility of cabazitaxel (CBZ)-induced apoptosis in PC-3 castration resistant metastatic prostate cancer cells (mCRPC) through the hallmarks of apoptosis. The recovery of PC-3 cells from apoptosis upon removal of CBZ at different recovery periods was evaluated by Annexin V, DNA damage, oxidative damage, mitochondrial membrane depolarization, and caspase activation. Our results showed that the administration of CBZ caused apoptosis for 72 h in PC-3 cells. However, recovered cells exhibited decreased nuclear damage, plasma membrane disruption, ROS level, release cytochrome c level and caspase-3 activation with upregulation of Bcl-2 expression upon removal of especially 1 nM CBZ for 24 h recovery period in PC-3 cells. Our study indicates that CBZ treated PC-3 cells can recover after apoptotic cell death. However, advanced molecular analysis should elucidate the relationship between the molecular mechanisms of recovery and taxane response or resistance in PC-3 mCRPC cells.

C reactive protein/Albumin ratio as predictor of prognosis in castration resistant metastatic prostate cancer.

To assess the association of C reactive protein/Albumin ratio (CAR) with progression free survival (PFS) and overall survival (OS) in castration resistant metastatic prostate cancer (mCRPC) patients. A transversal study was conducted, including all patients diagnosed with mCRPC within a Central Hospital Urological Oncology consultation between December 2019 and December 2021 (n = 178) and that were submitted to systemic therapy. CRP and albumin results were collected at the beginning of the systemic treatment for mCRPC in 103 patients and, in 75 patients already under treatment at the start of the study, on that occasion (December 2019). All patients were then followed. CAR was correlated with PFS and OS. OS and PFS were measured from the day the CRP and Alb were collected until the event of interest or the final date of follow-up. The sample was divided in two groups according to an optimal cutoff point found in a ROC curve. The sample showed a median age of 75.76 ± 9.17 years old. Using a cut-off point of 0.22, patients with a CAR ≤ 0.22 (63.2%) showed, compared to CAR > 0.22, longer PFS (15.92 vs. 9.46 months, r = -0.13, p < 0.05) and OS (p = < 0.05, 25,72 vs. 15.79 months, r = -0,24, p < 0.05). Better OS in patients with CAR ≤ 0.22 vs > 0.22 was detected on both the group evaluated at the beginning of systemic treatment (26.96 vs 17.63 months, p < 0.05) and the group of patients already under treatment (23.90 vs 11.54 months, p < 0.05). Dividing the sample according to the first line treatment chosen, we found OS of 26.25 vs 5.9 months (p < 0.05), 27.71 vs 22.57 months (p < 0.05) and 27.36 vs 23.75 months (p = 0.12), for docetaxel, abiraterone and enzalutamide, respectively. According to this study, higher values of CAR are associated with lower PFS and OS in mCRPC patients. We found a cut-off value of 0.22 providing the best discrimination for prognosis. CAR is a good prognosis biomarker, irrespective of the moment of evaluation and chosen treatment option.

Abstract B016: Liquid biopsy biomarker analysis of a phase II trial of sacituzumab govitecan in castrate resistant metastatic prostate cancer

Abstract Background: Sacituzumab Govitecan (SG) is an antibody-drug conjugate targeting Trop-2 and has been approved for use in breast and bladder cancers. Trop-2 has been shown to be overexpressed in multiple solid tumors including prostate cancer. Here we report an interim analysis of longitudinal liquid biopsies collected in a phase II clinical trial of SG to identify biomarkers of response and resistance. Methods: We collected longitudinal blood samples from 20 patients for circulating tumor cell (CTC) and cell-free DNA (cfDNA) analysis as part of an open label Phase II trial of SG in patients with mCRPC (ClinicalTrials.gov Identifier: NCT03725761). Eligibility criteria for the trial included rising PSA and radiographic progression on abiraterone acetate or enzalutamide in the mCRPC setting. Liquid biopsies were collected at baseline, C1D8, and then every 3 cycles until disease progression. cfDNA was sequenced using a custom 822 gene targeted capture panel (IDT). CTCs were isolated with antibodies to either EpCAM or Trop-2 followed by parallel enumeration, EpCAM and Trop-2 protein phenotyping and RNA extraction for AR/NEPC marker transcriptional profiling. Results: Although no PSA50 responses were observed, the 6-month rPFS rate was 45% (64% in chemotherapy naïve patients). For this analysis, these patients will be termed responding patients. The number of Trop-2-postive CTCs at baseline was significantly higher in responding (24.3 ±13.4 per 7.5 mL blood) than non-responding (10.0±3.8) patients. During treatment the number of Trop-2 positive CTCs in responders significantly decreased by C3D1 to 10.0 ±3.8. Interestingly, while the number of Trop-2 positive CTCs continued to decline to 2.8±1.99 cells/7.5 mL, EpCAM-positive CTCs increased from 12.5±10.52 cells/7.5 mL to 23.2±19.49 at end of trial. Gene expression analysis demonstrated high expression of genes specific to adenocarcinoma including AR-splice variants, TMPRSS2, KLK2 and KLK3 in the majority of patients, with conversion to AR-variant negative CTCs identified in responders. Preliminary cfDNA analysis identified one patient with a mutation acquired in the gene encoding topoisomerase 1 (TOP1) upon progression on SG, with additional analysis ongoing. Conclusions: Patients who responded to SG had a more Trop-2 positive CTCs with adenocarcinoma characteristics with expression of AR pathway genes. Longitudinal analysis of liquid biopsy biomarkers identified multiple mechanisms of acquired SG resistance. Decline in Trop2-CTC population with parallel expansion of EpCAM-CTC population in multiple patients suggests loss of Trop2 surface protein expression as resistance mechanism, while identification of a cfDNA TOP1 mutation in one patient at time of progression is consistent with acquired resistance to the topoisomerase inhibitor payload as has been reported in metastatic triple negative breast cancer. Citation Format: Jamie M. Sperger, Amy K. Taylor, Yue Shi, Charlotte N. Stahlfeld, Kyle Helzer, Matthew Bootsma, Katherine R. Kaufmann, Marina N. Sharifi, Christos E. Kyriakopoulos, Susan Slovin, Scott Tagawa, Scott Dehm, Shuang G. Zhao, Joshua M. Lang. Liquid biopsy biomarker analysis of a phase II trial of sacituzumab govitecan in castrate resistant metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B016.

Pretreatment visceral metastases in castration resistant metastatic prostate cancer: role in prediction versus actual site of disease progression

BackgroundTo evaluate the anatomic site(s) of initial disease progression in patients with castration resistant metastatic prostate cancer (mCRPC) in the presence or absence of pre-treatment visceral metastases while on systemic therapy. MethodsThis is a retrospective cohort study of mCRPC patients who have baseline and at least one follow up bone scan and CT chest, abdomen and pelvis (CAP). Disease progression was determined by RECIST and/or ≥ 30% increase in automated bone scan lesion area score. Kaplan–Meier plot was used to estimate the median progression free survival and log-rank tests were used to compare anatomic sites.ResultsOf 203 patients, 61 (30%) had pre-treatment visceral metastases. Patients with baseline visceral disease were 1.5 times more likely to develop disease progression (HR = 1.53; 95% CI, 1.03–2.26). Disease progression was a result of worsening bone scan disease (42% (16/38)) versus visceral (32% (12/38)) or lymph node disease (3% (1/38)) by CT or a combination thereof (23% (9/38)). Median time to progression (TTP) did not differ by anatomic location of initial progression (p = 0.86). Development of new lesions occurred in 50% of those visceral patients with soft tissue only progression and was associated with a significantly longer TTP (3.1 months (2.8–4.3 months) than those with worsening of pre-existing lesions (1.8 months (1.6–2.7 months); p = 0.04.ConclusionsPatients with pre-treatment visceral metastases in mCRPC are more likely to experience disease progression of bone disease with the initial anatomic site of progression similar to those without baseline visceral involvement.

Optimisation of second line antihormonal treatment for castration resistant metastatic prostate cancer

Background: The prognosis of castration resistant metastatic prostate cancer has been improved by several recently introduced therapeutic options, among others the second line antihormonal agents. Still, several questions related to the optimal use of these new drugs have remained open. The following ones were addressed in this paper. (1) Is the use of abiraterone + hydrocortisone inferior to abiraterone + prednisone in terms of overall survival? (2) Is the treatment up to prostate specific antigen (PSA) progression inferior to the treatment up to radiological progression in terms of overall survival? (3) Does the level of initial PSA decrease have a predictive value for the duration of response? Methods: As part of our self-assessment the dataset of 62 patients with castration resistant metastatic prostate cancer who started second line antihormonal therapy at our outpatient clinic before 31st of December 2019 was analysed. Results: 35 patients received abiraterone with prednisone substitution, 12 patients received abireterone with hydrocortisone substitution and 15 patients received enzalutamide. 39 patients were treated until clinical or radiological progression and 23 patients were treated until biological progression. (1) Median overall survival of patients substituted with hydrocortisone was not inferior as compared to patients substituted with prednisone (31 months vs. 17 months). (2) Median overall survival of patients treated until PSA progression was not inferior as compared to patients treated until radiological progression (32 months vs. 17 months). (3) Median overall survival of patients whose first control PSA level was below the normal value was 50% higher than median survival of patients whose first control PSA level was over the normal value (25 months vs. 17 months). Median overall survival of patients treated with abiraterone or enzalutamide was similar (21 months vs. 24 months). Conclusions: The combination of abiraterone + hydrocortisone is not inferior to the combination of abiraterone + prednisone and the treatment up to PSA progression is not inferior to the treatment up to radiological progression in terms of overall survival for patients with castration resistant metastatic prostate cancer.

Novel hormonal agents for metastatic Castration-Resistant Prostate Cancer: comparing outcomes. A single-center retrospective study.

Prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and is the sixth leading cause of cancerrelated deaths amongst men worldwide. Abiraterone and enzalutamide were the first two novel hormonal agents approved for the treatment of metastatic prostate cancer but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs. To evaluate the clinical outcomes of real-world patients submitted to treatment with novel hormonal agents, enzalutamide and abiraterone, for castration resistant metastatic prostate cancer in an academic center. We retrospectively reviewed patients treated for castration-resistant prostate cancer with either abiraterone or enzulatamide between January 1, 2016 and December 31, 2019. The primary endpoints were biochemical response, biochemical progression, radiological progression, clinical deterioration (attributed to disease progression) and death. Enzalutamide had a higher biochemical response rate than abiraterone in patients with mCRPC (77.1% vs 58.1%, p = 0.016). Achieving a biochemical response was associated with a lower risk of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038). Enzalutamide conferred higher biochemical response rate than abiraterone in patients with mCRPC. Despite the trend to better performance of other endpoints in the enzalutamide group, it did not achieve statistical significance. Well-designed prospective studies are needed to elucidate the comparative efficacies of these agents.

Concomitant intraductal carcinoma of the prostate and response to hormonal therapy in metastatic prostate carcinoma

Introduction and objectiveMost prostate cancers are classified as acinar adenocarcinoma. Intraductal carcinoma of the prostate (IDC-P) is a distinct histologic entity that is believed to represent retrograde spread of invasive acinar adenocarcinoma into prostatic ducts and acini.We have analyzed the impact of IDC-P in hormonal naïve and castration resistant metastatic prostate cancer patients. Patients and methodsWe retrospectively evaluated 118 metastatic castration resistant prostate cancer (mCRPC) patients who were initially diagnosed with distant metastases from May 2010 to September 2018. Group 1 patients included 81 metastatic PCa patients with acinar adenocarcinoma and Group 2 included 37 metastatic PCa patients with IDC-P. ResultsMean age at presentation was 76 years (IQR 73.4−78.7) in group 1 and 74 years (68.5−80.6) in group 2. Mean PSA at diagnosis was 619 ng/mL (IQR 85−1113) and 868 ng/mL (IQR 186−1922), respectively. Time to castration resistance was 24.7 months (IQR 16.7–32.7) in group 1 and 10.2 months (IQR 4.2–16.2) in group 2 (P = .007). Time to progression in CPRC patients was: 10.6 months (IQR 5.6–15.6) and at 6.2 months (3.2–9.2), respectively (P = .05). Overall survival was 57.9 months in group 1(CI 95% 56.4–59.5) and 38 months (CI 95% 19.9–48.06) in group 2 (P = .001). In the multivariate analysis, adenocarcinoma subtype was statistically significant P .014, CI 95% (HR 0.058, 0.006−0.56) ConclusionsIDC-P seems to be a subtype of prostate cancer that is associated with a shorter response to hormonal treatment when compared to acinar adenocarcinoma in metastatic patients. New drugs in CRPC scenario as abiraterone and enzalutamide also obtained less response in IDC-P patients. Once IDC-P is identified, clinicians could extrapolate the relative poor response to hormonal therapy. Consequently, follow-up of these patients in this scenario should be more strict.

Carcinoma intraductal de próstata concomitante y respuesta al tratamiento hormonal en el carcinoma de próstata metastásico

Introduction and objectiveMost prostate cancers are classified as acinar adenocarcinoma. Intraductal carcinoma of the prostate (IDC-P) is a distinct histologic entity that is believed to represent retrograde spread of invasive acinar adenocarcinoma into prostatic ducts and acini.We have analyzed the impact of IDC-P in hormonal naïve and castration resistant metastatic prostate cancer patients. Patients and methodsWe retrospectively evaluated 118 metastatic castration resistant prostate cancer (mCRPC) patients who were initially diagnosed with distant metastases from May 2010 to September 2018. Group 1 patients included 81 metastatic PCa patients with acinar adenocarcinoma and Group 2 included 37 metastatic PCa patients with IDC-P. ResultsMean age at presentation was 76 years (IQR 73.4-78.7) in group 1 and 74 years (68.5-80.6) in group 2. Mean PSA at diagnosis was 619 ng/mL (IQR 85-1113) and 868 ng/mL (IQR 186-1922), respectively. Time to castration resistance was 24.7 months (IQR 16.7-32.7) in group 1 and 10.2 months (IQR 4.2-16.2) in group 2 (p = 0.007). Time to progression in CPRC patients was: 10.6 months (IQR 5.6-15.6) and at 6.2 months (3.2-9.2), respectively (p = 0.05). Overall survival was 57.9 months in group 1(CI 95% 56.4-59.5) and 38 months (CI 95% 19.9-48.06) in group 2 (p = 0.001). In the multivariate analysis, adenocarcinoma subtype was statistically significant p 0.014, CI 95% (HR 0.058, 0.006-0.56). ConclusionsIDC-P seems to be a subtype of prostate cancer that is associated with a shorter response to hormonal treatment when compared to acinar adenocarcinoma in metastatic patients. New drugs in CRPC scenario as abiraterone and enzalutamide also obtained less response in IDC-P patients. In daily clinical practice it might be interesting to take into account that patients with IDC-P may present shorter responses to first and second line hormonal treatments.

Enzalutamide versus Abiraterone Acetate as first-line treatment of castration resistant metastatic prostate cancer in geriatric (≥75) patients

Introduction: The efficacy and tolerability of Enzalutamide and Abiraterone Acetate have been reported in elderly patients with metastatic castration resistant prostate cancer (mCRPC). However, there is no randomized study directly comparing antitumor effects between these 2 agents in geriatric patients. We aimed to evaluate the efficacy of Enzalutamide (ENZA) and Abiraterone Acetate (AA) as a first-line treatment of mCRPC in elderly patients. Materials and methods: The geriatric patients (≥75 years of age) with a diagnosis of mCRPC and treated with first-line ENZA or AA were included. The impacts of clinical parameters and treatment modalities on overall survival (mOS) were analyzed retrospectively and Cox regression analysis was performed. Results: One hundred thirty-four mCRPC patients (77 in AA, 57 in ENZA), with a median age of 81 (75–93) were analyzed. The patient and disease characteristics were similar between arms. While there were more grade 1–2 toxicities in AA arm (45.5% vs 17.5%, P = 0.001), the discontinuation due to toxicity was similar between groups (8.5% vs 5.9%, P = 0.81). The mOS was 18.0 months (95% CI, 15.2–20.7) in AA, and 20.0 months (95% CI, 4.4–35.5) in ENZA arm (P = 0.47). In multivariate analysis, high Gleason score (≥8) (HR: 2.0 (95% CI, 1.1–3.4), P = 0.009) and high initial PSA values (≥100 ng/mL) (HR: 2.6 (95% CI, 1.5–4.8), P = 0.001) were poor prognostic factors. The choice of AA vs ENZA was insignificant as a predictor of OS (HR: 0.87 (95%CI, 0.48–1.56), P = 0.65). Conclusion: In the first-line treatment of mCRPC in elderly (≥75) patients, AA and ENZA showed similar results in terms of mPFS and mOS. The clinical impacts of second-generation androgen receptor pathway inhibitors in the elderly population should be tested in prospective randomized studies.

Dual Inhibitory Action of a Novel AKR1C3 Inhibitor on Both Full-Length AR and the Variant AR-V7 in Enzalutamide Resistant Metastatic Castration Resistant Prostate Cancer.

The expanded use of second-generation antiandrogens revolutionized the treatment landscape of progressed prostate cancer. However, resistances to these novel drugs are already the next obstacle to be solved. Various previous studies depicted an involvement of the enzyme AKR1C3 in the process of castration resistance as well as in the resistance to 2nd generation antiandrogens like enzalutamide. In our study, we examined the potential of natural AKR1C3 inhibitors in various prostate cancer cell lines and a three-dimensional co-culture spheroid model consisting of cancer cells and cancer-associated fibroblasts (CAFs) mimicking enzalutamide resistant prostate cancer. One of our compounds, named MF-15, expressed strong antineoplastic effects especially in cell culture models with significant enzalutamide resistance. Furthermore, MF-15 exhibited a strong effect on androgen receptor (AR) signaling, including significant inhibition of AR activity, downregulation of androgen-regulated genes, lower prostate specific antigen (PSA) production, and decreased AR and AKR1C3 expression, indicating a bi-functional effect. Even more important, we demonstrated a persisting inhibition of AR activity in the presence of AR-V7 and further showed that MF-15 non-competitively binds within the DNA binding domain of the AR. The data suggest MF-15 as useful drug to overcome enzalutamide resistance.

MicroRNAs as Guardians of the Prostate: Those Who Stand before Cancer. What Do We Really Know about the Role of microRNAs in Prostate Biology?

Prostate cancer is the second leading cause of cancer-related deaths of men in the Western world. Despite recent advancement in genomics, transcriptomics and proteomics to understand prostate cancer biology and disease progression, castration resistant metastatic prostate cancer remains a major clinical challenge and often becomes incurable. MicroRNAs (miRNAs), about 22-nucleotide-long non-coding RNAs, are a group of regulatory molecules that mainly work through post-transcriptional gene silencing via translational repression. Expression analysis studies have revealed that miRNAs are aberrantly expressed in cancers and have been recognized as regulators of prostate cancer progression. In this critical review, we provide an analysis of reported miRNA functions and conflicting studies as they relate to expression levels of specific miRNAs and prostate cancer progression; oncogenic and/or tumor suppressor roles; androgen receptor signaling; epithelial plasticity; and the current status of diagnostic and therapeutic applications. This review focuses on select miRNAs, highly expressed in normal and cancer tissue, to emphasize the current obstacles faced in utilizing miRNA data for significant impacts on prostate cancer therapeutics.

Pre-therapy visceral metastases in castrate resistant metastatic prostate cancer: Role in tumor progression.

e17586 Background: Visceral metastases in castrate resistant metastatic prostate cancer (mCRPC) are known to develop late in the course of disease and portend a poor prognosis. As patients with visceral metastases still derive a clinical benefit to treatment, understanding patterns of progressive disease (PD) may help differentiate important disease phenotypes in mCRPC. The aim of our study was to evaluate the differences in anatomic sites of PD in patients with pretreatment visceral or bone metastases on time to progression (TTP). Methods: A retrospective review of anonymized patients enrolled in phase 2 and 3 clinical trials was performed. Patients were excluded if lacked Tc bone scan or CT chest, abdomen and pelvis (CT CAP) at baseline. Bone disease was defined by automated bone scan lesion area (BSLA) criteria. All CT CAPs per clinical trial protocol were assessed by RECIST 1.1. Soft tissue PD was noted as target, non-target lesion growth and/or presence of new lesions by anatomic site. Bone PD was defined by &gt; 20% increase in BSLA score. Results: Of the 169 subjects that met our selection criterion, visceral disease was present at baseline in 90 patients (53%). Baseline BSLA score was 90474 mm² in visceral and 80348 mm² in non-visceral patients (p = 0.395). Disease progression occurred in 93 patients (55%). With baseline visceral disease, PD was a result of BSLA in 26 (51%) and visceral disease only in 11 (22%) of patient. Lacking visceral disease at baseline resulted in PD by BSLA in 26 (62%) and visceral disease only in 3 (7%) of patients. There was no significant difference in PFS for baseline visceral/non-visceral involvement; median PFS = 4.5 months in visceral; median PFS = 4.34 months in non-visceral (HR = 1.28; p = 0.244). Conclusions: Patients with visceral disease may still derive a similar clinical benefit from treatment to those without. While the presence of baseline visceral disease was associated with higher rates of PD by visceral involvement, PD by bone disease remained the most common cause of PD regardless of presence of baseline visceral metastases.

MON-500 A Case of Tumor-Induced Osteomalacia Caused by Metastatic Prostate Cancer

Background: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia due to renal phosphate wasting. An overproduction of the phosphatonin fibroblast growth factor 23 (FGF-23) has been implicated in TIO pathogenesis. FGF-23 increases renal phosphate excretion by reducing the expression of sodium-dependent phosphate co-transporters NPT2a and NTP2c in the proximal tubules. TIO is most commonly associated with mesenchymal tumors. Epithelial tumors are estimated to account for only 5% of reported cases of TIO. Here we report a rare case of TIO associated with castration resistant metastatic prostate cancer. Clinical Case: A 59 year old male with high grade castration-resistant metastatic prostate adenocarcinoma presented with worsening fatigue and bone pain. Nine years before presentation, he was treated with prostatectomy, pelvic radiation, and taxotere followed by one year of luteinizing hormone-releasing hormone (LHRH) agonist. Bony metastases were identified 8 years later, and he was treated with a combination of LHRH agonist, RANK-ligand inhibitor denosumab, antiandrogenic therapy abiraterone and prednisone. Due to refractory disease, he received three cycles of sipuleucel-T, a cell-based cancer immunotherapy, and was enrolled in a phase 1B clinical trial involving enzalutamide. Laboratory evaluation included phosphorus 1.2 (2.5-4.5 mg/dL), urine phosphate excretion 1984 (400-1300 mg/24 hour), parathyroid hormone 110 (15-65pg/mL), calcium7.9 (8.7-10.2 mg/dL), vitamin D-25 85.3 (30-100mg/dL), inappropriately low vitamin D 1,25 40 (19.9-79.3 mg/dL) and FGF-23 387 (44-215 ref units/mL). Whole body scan showed widespread osteoblastic metastatic lesions. He was treated with high-dose calcitriol, vitamin D, calcium carbonate, and potassium phosphate with improvement in hypophosphatemia and bone pain. Clinical Lessons: Hypophosphatemic osteomalacia in the setting of advanced prostate cancer was first reported in 1975. The role of FGF-23 as a phosphatonin in such cases has since emerged, due to advancement of laboratory assays and improved understanding of the pathophysiology of TIO. Review of existing literature reveals five reported cases of prostate cancer-associated TIO with associated elevated FGF-23. This condition poses a diagnostic challenge, as TIO-related bone pain and weakness can be mistaken for that associated with bony metastases. Given the inability to resect widely metastatic disease, treatment of such cases consists of reducing tumor burden with chemotherapy and radiation and supplementation with calcitriol and phosphorus. While other FGF pathways have been implicated in prostate cancer-related angiogenesis, drug resistance, and metastases, the role FGF23 may play in an aggressive disease course warrants further investigation, particularly given it may represent a treatment target.

MP28-08 INCIDENCE OF DNA DAMAGE RESPONSE PATHWAY ALTERATIONS BETWEEN LOCALIZED AND METASTATIC PROSTATE CANCER

INTRODUCTION AND OBJECTIVES:Approximately one-third of castration resistant metastatic prostate cancer patients have a dysregulated DNA damage response (DDR) pathway. However, DDR pathway alteratio...

Including Blood Vasculature into a Game-Theoretic Model of Cancer Dynamics

For cancer, we develop a 2-D agent-based continuous-space game-theoretical model that considers cancer cells’ proximity to a blood vessel. Based on castrate resistant metastatic prostate cancer (mCRPC), the model considers the density and frequency (eco-evolutionary) dynamics of three cancer cell types: those that require exogenous testosterone ( T + ), those producing testosterone ( T P ), and those independent of testosterone ( T − ). We model proximity to a blood vessel by imagining four zones around the vessel. Zone 0 is the blood vessel. As rings, zones 1–3 are successively farther from the blood vessel and have successively lower carrying capacities. Zone 4 represents the space too far from the blood vessel and too poor in nutrients for cancer cell proliferation. Within the other three zones that are closer to the blood vessel, the cells’ proliferation probabilities are determined by zone-specific payoff matrices. We analyzed how zone width, dispersal, interactions across zone boundaries, and blood vessel dynamics influence the eco-evolutionary dynamics of cell types within zones and across the entire cancer cell population. At equilibrium, zone 3’s composition deviates from its evolutionary stable strategy (ESS) towards that of zone 2. Zone 2 sees deviations from its ESS because of dispersal from zones 1 and 3; however, its composition begins to resemble zone 1’s more so than zone 3’s. Frequency-dependent interactions between cells across zone boundaries have little effect on zone 2’s and zone 3’s composition but have decisive effects on zone 1. The composition of zone 1 diverges dramatically from both its own ESS, but also that of zone 2. That is because T + cells (highest frequency in zone 1) benefit from interacting with T P cells (highest frequency in zone 2). Zone 1 T + cells interacting with cells in zone 2 experience a higher likelihood of encountering a T P cell than when restricted to their own zone. As expected, increasing the width of zones decreases these impacts of cross-boundary dispersal and interactions. Increasing zone widths increases the persistence likelihood of the cancer subpopulation in the face of blood vessel dynamics, where the vessel may die or become occluded resulting in the “birth” of another blood vessel elsewhere in the space. With small zone widths, the cancer cell subpopulations cannot persist. With large zone widths, blood vessel dynamics create cancer cell subpopulations that resemble the ESS of zone 3 as the larger area of zone 3 and its contribution to cells within the necrotic zone 4 mean that zones 3 and 4 provide the likeliest colonizers for the new blood vessel. In conclusion, our model provides an alternative modeling approach for considering density-dependent, frequency-dependent, and dispersal dynamics into cancer models with spatial gradients around blood vessels. Additionally, our model can consider the occurrence of circulating tumor cells (cells that disperse into the blood vessel from zone 1) and the presence of live cancer cells within the necrotic regions of a tumor.

Research progress in chemo-resistance mechanism of castration resistant prostate cancer

Prostate cancer is one of the most common malignancies in old males. While chemotherapy remains an effective method for metastatic castration resistant prostate cancer (mCRPC), most patients develop chemo-resistance with median survival less than 1 year after six to eight cycles of systematic chemotherapy. Therefore, it is very important to elucidate the mechanisms of CRPC and chemotherapy resistance. This article is to focus on the androgen receptor signaling pathway, micro-RNA, tumor microenvironment, cancer stem cells as well as related molecular events, and to summarize the research progress. Key words: Castration resistant prostate cancer; Chemotherapy resistance; Mechanism

Estimating the Cost of Illness of Prostate Cancer in Iran

PurposeProstate cancer is the second most common cancer among men worldwide. In the past 10 years in Iran, prostate cancer has increased and become more common among hormone-related cancers. As the percentage of seniors in the population increases, the economic burden of this cancer will likely increase significantly. This study aims to estimate direct and indirect costs of treatment at different stages of prostate cancer in Iran. MethodsThis cross-sectional study was conducted on 263 patients diagnosed with prostate cancer who were referred to prostate treatment centers in 2016. Data on direct medical costs were collected by face-to-face interviews with patients and from health care files and medical and financial documents available in the educational or referral centers. Direct nonmedical costs and indirect costs were based on self-reports by patients through face-to-face interview. FindingsThe results indicate that mean (SD) direct medical costs for low-risk metastatic prostate cancer, local nonmetastatic prostate cancer, local regionalized nonmetastatic prostate cancer nonresistant metastatic prostate cancer, and resistant metastatic prostate cancer were $102.79 ($33.03), US$2673.43 ($87.42), $2210.51 ($306.92), $4133.15 ($650.87), and $7747.89 ($455.80), respectively. The results indicate that mean (SD) direct nonmedical costs for low-risk, local, local regionalized, nonresistant, and resistant cancers were $97.06 ($45.00), $339.71 ($58.02), $485.29 ($36.77), $776.47 ($99.25), and $1067.65 ($600.92), respectively, and mean (SD) indirect costs for these categories were $23.85 ($20.44), $83.49 ($65.06), $119.27 ($32.59), $238.54 ($87.35), and $357.81 ($73.00), respectively. ImplicationsThe findings of this research indicate that patients diagnosed with prostate cancer must bear high costs at advanced stages of the disease, whereas in the early stages of the disease, the medical costs are relatively low. The health system of Iran should work to prevent patients from reaching the metastatic stages of the disease by implementing a suitable screening system for timely diagnosis of the disease and its effective treatment.

Serum levels of neuroendocrine differentiation markers predict the prognosis of patients with metastatic castration resistant prostate cancer treated with abiraterone acetate

Objective To determine the influence of abiraterone acetate (AA) on neuroendocrine differentiation (NED) in metastatic castration-resistant prostate cancer (mCRPC) and the prognostic predicting value of the serum NED markers in mCRPC patients treated with AA. Methods We conducted an analysis in 115 chemotherapy-naive mCRPC patients who were treated with chemotherapy in Renji hospital from 2013 to 2017. The median age was 70, ranged from 65 to 76 years old. The median CgA, NSE and PSA levels were 101.1 ng/ml(78.5-150.0 ng/ml), 13.4 ng/ml(10.5-17.6 ng/ml)and 38.8 ng/ml(11.2-123.2 ng/ml), respectively. Among them, 48 cases were classified as the group without AA treatment. The other 67 cases were classified as group after AA failure. In group without AA treatment, the median CgA, NSE and PSA levels were 109.1 ng/ml(80-151.5 ng/ml); 13.8 ng/ml(10.8-18.2 ng/ml)and 39.2 ng/ml(8.6-200 ng/ml), respectively. In group after AA failure, the median CgA, NSE and PSA levels were 105.4 ng/ml(78.8-175.5 ng/ml), 13.8 ng/ml(10.8-17.6 ng/ml)and 39.0 ng/ml(8.4-219.8 ng/ml), respectively. In the group with serial evaluation of NED markers during AA treatment, the median serum CgA, NSE levels at baseline were 115.9 ng/ml(90.1-201.5 ng/ml), 13.3 ng/ml(10.4-18.1 ng/ml), respectively. The endpoints were PSA PFS(progression-free survival) and radiographic PFS(rPFS). Results In 34 patients with serial evaluation, serum NED markers level in 19 patients increased after the failure of AA treatment. Median serum CgA and NSE levels were 115.9 ng/ml(90.1-201.5 ng/ml) and 13.25 ng/ml (10.37-18.14 ng/ml)at baseline. Median serum CgA and NSE levels were 129.6 ng/ml (75.5-230.5 ng/ml) and 14.7 ng/ml(11.8-19.1 ng/ml) after 6 months treatment, respectively. The median serum CgA and NSE levels were 130.4 ng/ml (95.7-205.7 ng/ml) and 15.2 ng/ml(12.4-18.7 ng/ml) at the time of failure of AA treatment, respectively. There was no significant difference of NED markers between baseline and failure of AA treatment (P=0.243). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED(P=0.30; P=0.52). Compared with the NED markers elevation group in the first 6 months of AA treatment and baseline supranormal NED markers group, the NED markers decline group(PSA PFS(17.1 vs. 10.4 months, P<0.001)and rPFS(17.0 vs. 10.4 months, P=0.003)) and baseline normal NED markers group(PSA PFS(14.1 vs. 9.5 months, P=0.001)and rPFS(16.4 vs. 10.5 months, P<0.001)) has a longer median PSA PFS and rPFS respectively. In multivariate Cox analysis, baseline NED markers level and NED markers variation during the first 6 months of AA treatment remained significant predictors of rPFS(P<0.05), and PSA-PFS(P<0.05). Conclusions We found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment, and AA might not significantly lead to progression of NED of mCRPC in general. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of mCRPC patients. Serum NED markers elevation during the first 6 months of AA treatment and elevated baseline NED markers levels indicated poor prognosis in mCRPC treated with AA. Key words: Abiraterone acetate; Neuroendocrine differentiation; Chemotherapy naive; Castration-resistant prostate cancer

Activity of VERU-111, an novel oral α and β tubulin inhibitor, against paclitaxel sensitive and resistant prostate cancer.

302 Background: Following proven efficiacy of docetaxel against hormone sensitive advanced prostate cancer (CHAARTED and STAMPEDE studies), the use of docetaxel for the treatment of hormone sensitive and castrate resistant metastatic prostate cancer has increased. Unfortunately, the utility of taxanes in prostate cancer has been limited because of the development of resistance, the need for IV infusion, and the associated treatment toxicity. VERU-111 is a highly orally available, novel α and β tubulin inhibitor, developed using a rationale design strategy to bind through hydrogen bonds to the α and β subunits of tubulin. VERU-111 inhibits tubulin polymerization and is not a substrate for multi-drug resistance proteins, a common mechanism for taxane resistance. Methods: In this study, dosing regimens of VERU-111 (oral) were tested in comparison with docetaxel (IV) and a vehicle (oral) in PC3 as well as in paclitaxel resistant PC3 (PC3-TXR). xenograft models. VERU-111 was evaluated at 3.3 mg/kg (5 days/week), 10 mg/kg (3 days/week), 15 mg/kg (2 days per week), 15 mg/kg (3 days per week) and 20 mg/kg (1 day/week). The animals were treated for 28 days and tumor volume and percentage size were calculated. Results: In the parental PC-3 model, animals treated with oral VERU-111, in all of the dose schemes tested, performed statistically indistinguishably from the IV docetaxel administration. In the PC3-TXR model, IV docetaxel had no impact on tumor growth whereas oral VERU-111 resulted in almost complete inhibition of tumor growth at 3.3 mg/kg (5 days/week) and 10 mg/kg (3 days/ week) as well as 20 mg/kg (1 day/week). In early toxicity studies, the animals treated with VERU-111 did not suffer any significant safety signals and gained weight during treatment. Conclusions: VERU-111 is a novel, oral α and β tubulin inhibitor that has drug characteristics making it an ideal candidate to be a therapeutic option for hormone sensitive and castrate resistant advanced prostate cancer. VERU-111 can be administered, with efficacy, as infrequent as once per week and will not require daily dosing. Additional toxicity studies are currently being performed with a Phase 1/2 study being planned to begin later this year.

Progression free survival in patients with castrate resistant metastatic prostate cancer: Does sequence matter?

356 Background: Approval of multiple therapeutic agents for castrate resistant prostate cancer (CPRPC) has improved survival and also quality of life. However, how to optimize sequencing is still an ongoing challenge for most clinicians. Methods: A retrospective chart review of patients treated with FDA approved regimens for castrate resistant prostate cancer from 2002 to 2017 at Mayo Clinical Florida was completed. Data on progression free survival of the various treatment sequences including abiraterone, docetaxel, and enzalutamide were reviewed. Results: One hundred patients were included in the study. Those on clinical trial were excluded. All patients were on LHRH agonist /antagonist and were continued while on the subsequent treatments. The first line therapy progression free survival (PFS) was 245 days with abiraterone acetate (AA), 307 days with enzalutamide (E) and docetaxel 285 days, respectively. The second line therapy PFS was 201 days with AA and 166 days with E. When AA was given after E PFS was 97 days and when E was given after AA the PFS was 68 days. E given after docetaxel resulted in a PFS of 390 days for one patient. Conclusions: In this chart review, enzalutamide had the longest PFS when used as the first line therapy and the PFS was improved when used as a second line after docetaxel. This retrospective review suggests therapy sequencing may be optimized to increase progressive free survival in patients with metastatic castrate resistant prostate cancer.