Management Of Metastatic Prostate Cancer Research Articles

TOward a comPrehensive supportive Care intervention for Older men with metastatic Prostate cancer (TOPCOP3): A pilot randomized controlled trial and process evaluation

IntroductionCurrent management of metastatic prostate cancer (mPC) includes androgen receptor axis-targeted therapy (ARATs), which is associated with substantial toxicity in older adults. Geriatric assessment and management and remote symptom monitoring have been shown to reduce toxicity and improve quality of life in patients undergoing chemotherapy, but their efficacy in patients being treated with ARATs has not been explored. The purpose of this study is to examine whether these interventions, alone or in combination, can improve treatment tolerability and quality of life (QOL) for older adults with metastatic prostate cancer on ARATs. Materials and MethodsTOPCOP3 is a multi-centre, factorial pilot clinical trial coupled with an embedded process evaluation. The study includes four treatment arms: geriatric assessment and management (GA + M); remote symptom monitoring (RSM); geriatric assessment and management plus remote symptom monitoring; and usual care and will be followed for six months. The aim is to recruit 168 patients between two cancer centres in Toronto, Canada. Eligible participants will be randomized equally via REDCap. Participants in all arms will complete a comprehensive baseline assessment upon enrollment following the Geriatric Core dataset, as well as follow-up assessments at 1.5, 3, 4.5, and 6 months. The co-primary outcomes will be grade 3–5 toxicity and QOL. Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. QOL will be measured by patient self-reporting using the EuroQol 5 dimensions of health questionnaire. Secondary outcomes include fatigue, insomnia, and depression. Finally, four process evaluation outcomes will also be observed, namely feasibility, fidelity, and acceptability, along with implementation barriers and facilitators. DiscussionData will be collected to observe the effects of GA + M and RSM on QOL and toxicities experienced by older adults receiving ARATs for metastatic prostate cancer. Data will also be collected to help the design and conduct of a definitive multicentre phase III randomized controlled trial. This study will extend supportive care interventions for older adults with cancer into new areas and inform the design of larger trials.Trial registration: The trial is registered at clinicaltrials.gov (registration number: NCT05582772).

Contemporary Systemic Therapy Intensification for Prostate Cancer: A Review for General Practitioners in Oncology.

Prostate cancer accounts for a significant proportion of cancer diagnoses in Canadian men. Over the past decade, the therapeutic landscape for the management of metastatic prostate cancer has undergone rapid changes. Novel strategies use hormonal agents, chemotherapy, homologous recombination repair inhibitors, and radioligand therapy or combination strategies in addition to androgen deprivation therapy. In this review, we summarize the available data addressing key therapeutic areas along the disease continuum and focus on practical aspects for general practitioners in oncology managing patients with metastatic prostate cancer.

Does use of apalutamide enhance outcomes in combination with radiotherapy in metastatic hormone-sensitive prostate cancer? A real-world experience from the UK.

73 Background: Management of metastatic prostate cancer has undergone a significant change over the past decade, with the introduction of several novel agents and repurposing of others. Latest update from STAMPEDE trials shown prostate radiotherapy (RT) improves OS, without detriment in QoL in metastatic home sensitive prostate cancer mHSPC along with Docetaxel in those with low volume metastatic disease. There is no published data on impact of radiotherapy to prostate on Apalutamide treated mHSPC patients. Here we report our real-world experience of Apalutamide in mHSPC with radiotherapy. Methods: Patients with mHSPC (N = 266) from 5 UK centres, were treated with Apalutamide (240 mg) and ADT along with radiotherapy to prostate as per treating clinician’s discretion. The primary endpoint was objective rate (ORR) as determined by patients achieving a PSA decline of ≥90% (PSA90) and ≥50% (PSA50) and secondary endpoints included biochemical progression free survival (bPFS) and safety. Results: The median age for the whole cohort was 73.4 years (interquartile range 52 - 91), A total of 11.6% had received prior radical treatment (prostatectomy or radiotherapy for localised disease) and 88.4% had de novo metastatic disease. Median baseline PSA was 47 ng/ml (range 0.4-17100). The proportion of patients PSA90 and PSA50 at 3, 6 and 12 months is shown in the Table. Median PSA nadir was 0.1 ng/ml(rage 0.01- 48.2) and median time to reach nadir was 6 months (range 3-24 months). 13.5% (35) patients were treated with radiotherapy (RT) after at least 3 months (range 3 -6 months) of starting apalutamide. Patients received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) of radiotherapy (68 % vs 32%). Higher number of patients in RT group had achieved PSA90 compared to no radiotherapy cohort (97.14 % vs 87.3%, p =0.15). Patients treated with RT had median post treatment of PSA 0.01 ng/ml compared to 0.1 ng/ml in non RT group (p=0.0062). After median follow up of 8.4 months, proportion of patients shown biochemical progression in RT vs non RT group were 5.7 % vs 15 % respectively (p= 0.04). Patients with de novo metastatic disease have shown poor PSA response and higher chance of progression compared to patients who had initial radical treatment. Radiotherapy was well tolerated, with 17 % adverse events (Radiation Therapy Oncology Group grade 3–4) reported in radiotherapy group. Conclusions: Early experience of using apalutamide and radiotherapy in mHSPC showed improved PSA response and delayed progression. Treatment was well tolerated. Further follow up and clinical trials are needed to understand the impact on overall survival. [Table: see text]

Radioligand Therapy With 177Lu-PSMA-I&T in Patients With Metastatic Prostate Cancer: Oncological Outcomes and Toxicity Profile.

This study aimed to investigate the oncological outcomes and toxicity profile of 177Lu-PSMA-I&T radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC), as well as our initial experience in metastatic hormone-sensitive prostate cancer (mHSPC). A total of 38 consecutive patients with metastatic prostate cancer (33 mCRPC and 5 mHSPC) received 177Lu-PSMA-I&T RLT, with a median of 2 cycles per patient (range, 1-7). Response to RLT was evaluated based on prostate-specific antigen (PSA) changes and imaging response. Clinical progression-free survival and overall survival were used to report oncological outcomes. Toxicity was assessed using the Common Toxicity Criteria for Adverse Events criteria. In mCRPC, 22 (69%), 18 (56%), and 11 (34%) patients achieved any PSA decline, PSA response of ≥30%, and PSA response of ≥50%, respectively. The clinical progression-free survival and overall survival after the first cycle of RLT were 6.3 and 21.4 months, respectively. In mHSPC, 177Lu-PSMA-I&T RLT resulted in excellent PSA response (93.0%-99.9%) in all cases. Clinical progression and cancer-related mortality occurred in only 1 case. Toxicity profile was favorable in both mHSPC and mCRPC. 177Lu-PSMA-I&T RLT demonstrated favorable PSA response (≥30%) in over half of the patients with mCRPC and excellent PSA response in all patients with mHSPC. Toxicity profile was favorable in both mHSPC and mCRPC settings. Further studies are needed to evaluate the role of 177Lu-PSMA-I&T RLT in the management of metastatic prostate cancer.

The cost burden of metastatic prostate cancer in the US populations covered by employer-sponsored health insurance.

Recent advancements in the clinical management of metastatic prostate cancer include several costly therapies and diagnostic tests. The objective of this study was to provide updated information on the cost to payers attributable to metastatic prostate cancer among men aged 18 to 64 years with employer-sponsored health plans and men aged 18 years or older covered by employer-sponsored Medicare supplement insurance. By using Merative MarketScan commercial and Medicare supplemental data for 2009-2019, the authors calculated differences in spending between men with metastatic prostate cancer and their matched, prostate cancer-free controls, adjusting for age, enrollment length, comorbidities, and inflation to 2019 US dollars. The authors compared 9011 patients who had metastatic prostate cancer and were covered by commercial insurance plans with a group of 44,934 matched controls and also compared 17,899 patients who had metastatic prostate cancer and were covered by employer-sponsored Medicare supplement plans with a group of 87,884 matched controls. The mean age of patients with metastatic prostate cancer was 58.5 years in the commercial samples and 77.8 years in the Medicare supplement samples. Annual spending attributable to metastatic prostate cancer was $55,949 per person-year (95% confidence interval [CI], $54,074-$57,825 per person-year) in the commercial population and $43,682 per person-year (95% CI, $42,022-$45,342 per person-year) in the population covered by Medicare supplement plans, both in 2019 US dollars. The cost burden attributable to metastatic prostate cancer exceeds $55,000 per person-year among men with employer-sponsored health insurance and $43,000 among those covered by employer-sponsored Medicare supplement plans. These estimates can improve the precision of value assessments of clinical and policy approaches to the prevention, screening, and treatment of prostate cancer in the United States.

Design, development, and in-vitro/in-vivo evaluation of docetaxel-loaded PEGylated solid lipid nanoparticles in prostate cancer therapy

Docetaxel (DOC) is a potent anticancer molecule widely used to treat various cancers. However, its therapeutic efficacy as a potential anticancer agent has been limited owing to poor aqueous solubility, short circulation time, rapid reticuloendothelial system uptake, and high renal clearance, which consecutively showed poor bioavailability. In the present investigation, we developed polyethylene glycol (PEG) decorated solid lipid nanoparticles (SLN) using the solvent diffusion method to increase the biopharmaceutical properties of DOC. PEG monostearate (SA-PEG2000) was initially synthesized and characterized using various analytical techniques. Afterwards, DOC-loaded SLN was synthesized with and without SA-PEG2000and systematically characterized for in-vitro and in-vivo properties. Spherical-shaped SA-PEG2000-DOC SLN showed hydrodynamic diameter and zeta potential of 177 nm and −13 mV, respectively. During the in-vitro release study DOC-loaded SLN showed a controlledrelease of approximately 54.35 % ± 5.46 within 12 h with Higuchi release kinetics in the tumor microenvironment (pH 5.5).In an in-vitro cytotoxicity study,SA-PEG2000-DOC SLN showedsignificantlylower IC50values(p < 0.001)compared to DOC-SLN and DOC aloneagainst prostate cancer cell lines (PC-3). Similarly, an in-vitro cellular uptake study showed a significant increase in intracellular DOC concentration for SA-PEG2000-DOC SLN. Additionally, inin-vivostudies,PEGylated SLN of DOC showed around 2- and 15-fold increase in the maximum concentration of drug (Cmax) and area under the curve (AUC), respectively, as compared to plain DOC solution due to the uniquehydrophilicity and hydrophobicity balance and electrical neutrality of specially designed PEG architect. The biological half-life (t1/2) and mean residence time (MRT) was found to increase from 8.55 and 11.43 to 34.96 and 47.68 h, respectively, with SA-PEG2000-DOC SLN. Moreover, the bio-distribution study indicates high DOC concentration in the plasma which signifies the more pronounced blood residence time of SA-PEG2000-DOC SLN. In a nutshell, SA-PEG2000-DOC SLNwasfound to bea promising and efficient drug delivery platform for the management of Metastatic Prostate cancer.

Management of Metastatic Prostate Cancer

Androgen deprivation therapy is a well-established standard of care for the management of metastatic prostate cancer; however, recent studies have investigated additional therapeutic options, escalation strategies, and primary directed therapy for patients with advanced disease. Treatment decisions are based on clinical parameters, disease characteristics, and patient factors. At the NCCN 2023 Annual Conference, a panel of experts used 3 case studies to develop an evidence-based approach for the treatment of patients with metastatic prostate cancer. The session focused on the current research regarding both systemic and local therapy options in each clinical context.

Underutilization of best systemic therapy in patients with metastatic prostate cancer.

111 Background: Advancement of treatment pathways in the management of metastatic prostate cancer (mPC) has identified newer systemic agents associated with survival advantage over androgen deprivation therapy (ADT) alone. Despite FDA approvals and guideline recommendations outlining standard of care (SOC) intensification of (ADT) with such additional systemic therapies such as docetaxel or novel hormonal therapies (NHT), these treatments are not being utilized uniformly by all practitioners. Our objective is to assess the utilization of such advanced therapies in patients with mPC and study differences in prescribing patterns. Methods: Between 2017 to present, we retrospectively identified all consecutive men with prostate cancer in a single health system. Electronic health record ICD code inquiries were used to identify patients. The population was further restricted utilizing diagnosis codes to include only those with metastatic prostate cancer and to exclude patients with second primary cancers. All treatment modalities and demographic information were analyzed to assess for prescribing patterns. Results: In total, 5,761 men had a diagnosis of prostate cancer. Exclusion criteria applied stepwise removed those with age &lt;18 years (2 patients) and secondary malignancies (1046 patients), resulting in 4,713 men for analysis. Of these, 665 men were found to have mPC and included in the final cohort. Mean patient age was 70.3 ± 9.6 years. We found no statistically significant difference in SOC prescribing pattern based on race, ethnicity, insurance type, zip code, 2020 United States census household median income, nor year of treatment. There was, however, overall low utilization of intensification of ADT with docetaxel or NHT at 42%, with 58% of patients still being treated with only first generation antiandrogens or luteinizing hormone releasing hormone agonists. Conclusions: In a large health system, we found that next generation care can be provided independent of insurance payor profile, race, ethnicity, and socioeconomic status. However, despite guidelines to support newer systemic agents for patients with mPC, we continue to observe that it is underused in clinical practice. Additional studies are needed to identify potential clinician and patient barriers, as well as prescribing pattern failures that are limiting the implementation of evidence-based treatment beneficial to overall survival.

French AFU Cancer Committee Guidelines - Update 2022-2024: prostate cancer - Management of metastatic disease and castration resistance

The objective of the French Urology Association Cancer Committee is to propose an update of the recommendations for the management of prostate cancer. A systematic review of the literature from 2020 to 2022 was conducted by the CCAFU on the elements of therapeutic management of metastatic and castration-resistant prostate cancer (PC), while evaluating the references and their levels of evidence. Androgen deprivation therapy (ADT) remains the standard treatment for metastatic prostate cancer. ADT intensification is now a standard of care in the management of metastatic prostate cancer. This intensification is discussed in relation to the patient and the characteristics of the disease. For all metastatic hormone-sensitive PC (synchronous and metachronous), the overall survival benefit associated with good tolerability makes the combination of ADT and novel hormonal agents (NHA) a standard. For patients with high-volume/high-risk de novo metastatic disease, treatment with docetaxel in addition to ADT + NHA can be discussed for eligible patients. In patients with castration-resistant prostate cancer (CRPC), the contribution of new therapies that have become available in recent years, as well as the advent of precision medicine, help to improve the control of tumour progression and survival, and highlight the value of testing for alterations in DNA repair genes within the tumour tissue or constitutionally. This update of the French recommendations should help to improve the management of patients with prostate cancer.

A novel methylated cell-free DNA marker panel to monitor treatment response in metastatic prostate cancer.

Aim: This study examined circulating cell-free DNA (cfDNA) biomarkers associated with androgen treatment resistance in metastatic castration resistance prostate cancer (mCRPC). Materials & methods: We designed a panel of nine candidate cfDNA methylation markers using droplet digital PCR (Methyl-ddPCR) and assessed methylation levels in sequentially collected cfDNA samples from patients with mCRPC. Results: Increased cfDNA methylation in eight out of ninemarkers during androgen-targeted treatment correlated with a faster time to clinical progression. Cox proportional hazards modeling and logistic regression analysis further confirmed thathigher cfDNA methylation during treatment was significantly associated with clinical progression. Conclusion: Overall, our findings have revealed a novel methylated cfDNA marker panel that could aid in the clinical management of metastatic prostate cancer.

Progression time of de novo metastases in relation to castration resistant prostate cancer at a tertiary care hospital in Southern Thailand

Objective: Androgen deprivation therapy (ADT) is often the treatment of choice in metastatic prostate cancer patients. However, there is currently an insufficiency of biomarker-related data that can be used in order to predict how the disease would respond to ADT. In this study we evaluated the clinical response to ADT, including factors which are affecting the progression of the disease into castration-resistant prostate cancer (CRPC) in patients with de novo metastatic prostate cancer. Materials and Methods: This retrospective study incorporated patients with metastatic prostate cancer who received ADT at our center from January 2008 to December 2019. Baseline characteristics, mode of ADT, prostate-specific antigen (PSA), blood chemistry, Gleason score (GS) grade group, location, and the number of metastases were analyzed. The risk factors affecting the progression of the disease were identified. Results: Data from 125 patients were included in the study. One hundred patients (80%) were classified as suffering from high volume metastatic prostate cancer and six patients (6%) with visceral metastasis. Baseline PSA in high volume and low volume metastatic prostate cancer were defined as 500 ng/ml and 215.1 ng/ ml respectively. Eighty-one patients (64.8%) received a gonadotrophin-releasing hormone (GnRH) agonist while 42 patients (33.6%) underwent bilateral orchi- ectomy. Time to CRPC in high and low volume metastasis was 12 months and 23 months respectively. Patients with Alkaline Phosphatase (ALP) ≥350 U/L had 8.5 months to CRPC while patients with ALP &lt;350 U/L had 15 months. High GS grade group (3-5), short time to PSA nadir (&lt;6 months), PSA nadir level (≥ 2 ng/ ml), and serum ALP ≥350 U/L were independent factors associated with shorter time to CRPC. Conclusion: The clinical management of metastatic prostate cancer is challenging; the main aims of treatment are to prolong overall survival whilst maintaining quality of life. Patients with aggressive tumors, high volume metastasis, short time to nadir (TTN), high PSA nadir level, and high ALP level were independent factors associated with shorter time to CRPC.

Use of Glycoproteins—Prostate-Specific Membrane Antigen and Galectin-3 as Primary Tumor Markers and Therapeutic Targets in the Management of Metastatic Prostate Cancer

Simple SummaryProstate specific membrane antigen and galectins are proteins expressed on cell surface and their expression is associated with cancer growth and spread. The goal of this research was to look at the pattern of these two glycoproteins in the human prostate cancer microenvironment. Prostate specific membrane antigen and galectins-1,3 and 8 were the most frequently detected glycoproteins in various phases of this disease. Furthermore, prostate specific membrane antigen and galectin-3 expression are good indicators of tumor aggressiveness, and their combined expression can be valuable tool for prostate cancer diagnosis and treatment in future. Together, our findings reveal a tightly regulated “Prostate specific membrane antigen-galectin-pattern” that accompanies disease in prostate cancer and point to a key role for combined prostate specific membrane antigen and galectin-3 inhibitors in prostate cancer treatment along with standard chemotherapy.Galectins and prostate specific membrane antigen (PSMA) are glycoproteins that are functionally implicated in prostate cancer (CaP). We undertook this study to analyze the “PSMA-galectin pattern” of the human CaP microenvironment with the overarching goal of selecting novel-molecular targets for prognostic and therapeutic purposes. We examined CaP cells and biopsy samples representing different stages of the disease and found that PSMA, Gal-1, Gal-3, and Gal-8 are the most abundantly expressed glycoproteins. In contrast, other galectins such as Gal-2, 4–7, 9–13, were uniformly expressed at lower levels across all cell lines. However, biopsy samples showed markedly higher expression of PSMA, Gal-1 and Gal-3. Independently PSA and Gleason score at diagnosis correlated with the expression of PSMA, Gal-3. Additionally, the combined index of PSMA and Gal-3 expression positively correlated with Gleason score and was a better predictor of tumor aggressiveness. Together, our results recognize a tightly regulated “PSMA-galectin- pattern” that accompanies disease in CaP and highlight a major role for the combined PSMA and Gal-3 inhibitors along with standard chemotherapy for prostate cancer treatment. Inhibitor combination studies show enzalutamide (ENZ), 2-phosphonomethyl pentanedioic acid (2-PMPA), and GB1107 as highly cytotoxic for LNCaP and LNCaP-KD cells, while Docetaxel (DOC) + GB1107 show greater efficacy in PC-3 cells. Overall, 2-PMPA and GB1107 demonstrate synergistic cytotoxic effects with ENZ and DOC in various CaP cell lines.

Liquid Biopsy Based Circulating Biomarkers in Metastatic Prostate Cancer.

Prostate cancer is the most dominant male malignancy worldwide. The clinical presentation of prostate cancer ranges from localized indolent to rapidly progressing lethal metastatic disease. Despite a decline in death rate over the past years, with the advent of early diagnosis and new treatment options, challenges remain towards the management of metastatic prostate cancer, particularly metastatic castration sensitive prostate cancer (mCSPC) and castration resistant prostate cancer (mCRPC). Current treatments involve a combination of chemotherapy with androgen deprivation therapy and/or androgen receptor signalling inhibitors. However, treatment outcomes are heterogeneous due to significant tumor heterogeneity indicating a need for better prognostic biomarkers to identify patients with poor outcomes. Liquid biopsy has opened a plethora of opportunities from early diagnosis to (personalized) therapeutic disease interventions. In this review, we first provide recent insights about (metastatic) prostate cancer and its current treatment landscape. We highlight recent studies involving various circulating biomarkers such as circulating tumor cells, genetic markers, circulating nucleic acids, extracellular vesicles, tumor-educated platelets, and the secretome from (circulating) tumor cells and tumor microenvironment in metastatic prostate cancer. The comprehensive array of biomarkers can provide a powerful approach to understanding the spectrum of prostate cancer disease and guide in developing improved and personalized treatments for patients.

Integration of Liquid Biopsies in Clinical Management of Metastatic Prostate Cancer.

The field of liquid biopsies is constantly evolving through novel technologies. This review outlines current data on liquid biopsies and application to clinical management of metastatic prostate cancer. To date, there are three platforms with FDA approval for use in the setting of metastatic prostate cancer and others which have been clinically validated. There is substantial evidence supporting the use of circulating tumor cell (CTC) enumeration to guide prognosis in metastatic castration-resistant prostate cancer (mCRPC). Additional evidence supports targeted sequencing of CTC and cell-free DNA (cfDNA) to guide androgren-directed therapy, identify candidates for treatment with PARP inhibitors, and monitor development of resistance. As a real-time and minimally invasive approach, utilization of liquid biopsies has the potential to drastically impact the treatment of metastatic prostate cancer and improve overall survival. With further clinical validation, additional liquid biopsy is likely to enter standard clinical practice.

Biomarkers for Treatment Response in Advanced Prostate Cancer.

Multiple treatment options with different mechanisms of action are currently available for the management of metastatic prostate cancer. However, the optimal use of these therapies-specifically, the sequencing of therapies-is not well defined. In order to obtain the best clinical outcomes, patients need to be treated with the therapies that are most likely to provide benefit and avoid toxic therapies that are unlikely to be effective. Ideally, predictive biomarkers that allow for the selection of the therapies most likely to be of benefit would be employed for each treatment decision. In practice, biomarkers including tumor molecular sequencing, circulating tumor DNA, circulating tumor cell enumeration and androgen receptor characteristics, and tumor cell surface expression (PSMA), all may have a role in therapy selection. In this review, we define the established prognostic and predictive biomarkers for therapy in advanced prostate cancer and explore emerging biomarkers.

P074 - Management of metastatic prostate cancer in older patients

P074 - Management of metastatic prostate cancer in older patients

Recent Advances in the Management of Metastatic Prostate Cancer.

Management of metastatic prostate cancer has undergone a revolution over the past decade with the introduction of several novel agents and repurposing of others. Several clinical trials reported improved outcomes with the intensification of androgen deprivation therapy by the addition of docetaxel chemotherapy or novel hormonal agents (abiraterone, enzalutamide, or apalutamide) in the metastatic castration-sensitive state. Relugolix has been recently approved as the first oral gonadotropin-releasing hormone receptor antagonist agent with a superior cardiovascular side-effect profile, and serum testosterone suppression compared with a gonadotropin-releasing hormone agonist, leuprolide. Poly-ADP ribose polymerase inhibitors (olaparib and rucaparib) have demonstrated significant clinical benefit for patients harboring deleterious mutations in genes belonging to the homologous recombination repair pathway and have received Food and Drug Administration approval. Recently, lutetium-177-prostate-specific membrane antigen-617 with standard of care treatment has shown to improve overall survival in men with advanced-stage prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer. These recent approvals, successes, and the ongoing investigation of multiple novel agents are expected to continue to dramatically improve survival outcomes of men with metastatic prostate cancer in the coming years.

650TiP PARADIGM: Plasma analysis for response assessment and to direct the management of metastatic prostate cancer (mPCa)

Adding docetaxel or androgen receptor signalling inhibitor (ARSI) at start of androgen deprivation therapy (ADT) for mPCa improves progression-free survival (PFS) and overall survival (OS). Duration of benefit is variable; although serum PSA at 7 months (mth) associates with differential outcome, physicians still lack the tools to identify who will develop early resistance and require alternative or intensified treatments.

Screening of hub genes and evaluation of the growth regulatory role of CD44 in metastatic prostate cancer.

Prostate cancer (PCa) is the most common cancer type in men worldwide. Currently, the management of metastatic PCa (mPCa) remains a challenge to urologists. The analysis of hub genes and pathways may facilitate the understanding of the molecular mechanism of PCa. In the present study, to identify the hub genes in the mPCa, the three datasets GSE3325, GSE6919 and GSE38241 were downloaded from the platform of the Gene Expression Omnibus and function enrichment analysis of differentially expressed genes (DEGs) was performed. A total of 168 DEGs were obtained and the DEGs were significantly enriched in ‘cell junction’ and ‘cell adhesion’, among others. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis demonstrated that DEGs were enriched in three pathways including ‘focal adhesion’, ‘renal cell carcinoma’ and ‘Hippo signaling pathway’. The results of the protein-protein interaction network revealed that the hub genes in mPCa were separately PTEN, Rac GTPase-activating protein 1, protein regulator of cytokinesis 1, PDZ binding kinase, centromere-associated protein E, NUF2 component of NDC80 kinetochore complex, TPX2 microtubule nucleation factor, SOX2, CD44 and ubiquitin-like with PHD and ring finger domains 1. As a hub gene, CD44 was differentially expressed in PCa, as determined by Oncomine analysis. Further experiments in vivo demonstrated that SB-3CT, a selective matrix metalloproteinase inhibitor that has been reported to block CD44 cleavage and inhibit the downstream signaling pathway, suppressed the tumorigenicity of PCa cells by decreasing the expression levels of pyruvate dehydrogenase kinase 1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4. Moreover, the combination therapy with SB-3CT and docetaxel was more effective in inhibiting PCa compared with monotherapy. In conclusion, the identification of DEGs and the in vivo experimental results helped to elucidate the molecular mechanisms of PCa and provided a potential strategy for the treatment of PCa.

2020 Korean guidelines for the management of metastatic prostate cancer.

In 2017, Korean Society of Medical Oncology (KSMO) published the Korean management guideline of metastatic prostate cancer. This paper is the 2nd edition of the Korean management guideline of metastatic prostate cancer. We updated recent many changes of management in metastatic prostate cancer in this 2nd edition guideline. The present guideline consists of the three categories: management of metastatic hormone sensitive prostate cancer; management of metastatic castration resistant prostate cancer; and clinical consideration for treating patients with metastatic prostate cancer. In category 1 and 2, levels of evidence (LEs) have been mentioned according to the general principles of evidence-based medicine. And grades of recommendation (GR) was taken into account the quality of evidence, the balance between desirable and undesirable effects, the values and preferences, and the use of resources and GR were divided into strong recommendations (SR) and weak recommendations (WR). A total of 16 key questions are selected. And we proposed recommendations and described key evidence for each recommendation. The treatment landscape of metastatic prostate cancer is changing very rapid and many trials are ongoing. To verify the results of the future trials is necessary and should be applied to the treatment for metastatic prostate cancer patients in the clinical practice. Especially, many prostate cancer patients are old age, have multiple underlying medical comorbidities, clinicians should be aware of the significance of medical management as well as clinical efficacy of systemic treatment.