Efficacy In Treatment Of Prostate Cancer Research Articles

Tumor ABCC4-mediated release of PGE2 induces CD8+ T cell dysfunction and impairs PD-1 blockade in prostate cancer.

Prostate cancer presents as an immunologically "cold" malignancy, characterized by a lack of response to immunotherapy in the majority of patients. The dysfunction of prostate tumor metabolism is recognized as a critical factor in immune evasion, resulting in reduced effectiveness of immunotherapeutic interventions. Despite this awareness, the precise molecular mechanisms underpinning metabolic dysregulation in prostate cancer and its intricate relationship with immune evasion remain incompletely elucidated. In this study, we introduce the multi-drug resistance protein ABCC4/MRP4 as a key player prominently expressed in prostate cancer, exerting a pivotal role in suppressing the activity of intratumoral CD8+ T cells. Depletion of ABCC4 in prostate cancer cells halts the release of prostaglandin E2 (PGE2), a molecule that diminishes the population of CD8+ T cells and curtails their cytotoxic capabilities. Conversely, constraining the activation of PGE2 signaling in CD8+ T cells effectively improved the efficacy of prostate cancer treatment with PD-1 blockade. During this process, downregulation of the JAK1-STAT3 pathway and depolarization of mitochondria emerge as crucial factors contributing to T cell anergy. Collectively, our research identifies the ABCC4-PGE2 axis as a promising target for reversing dysfunction within tumor-infiltrating lymphocytes (TILs) and augmenting the suboptimal responsiveness to immunotherapy in prostate cancer.

A bioengineered organotypic prostate model for the study of tumor microenvironment-induced immune cell activation.

The prostate tumor microenvironment (TME) is strongly immunosuppressive; it is largely driven by alteration in cell phenotypes (i.e. tumor-associated macrophages and exhausted cytotoxic T cells) that result in pro-tumorigenic conditions and tumor growth. A greater understanding into how these altered immune cell phenotypes are developed and could potentially be reversed would provide important insights into improved treatment efficacy for prostate cancer. Here, we report a microfluidic model of the prostate TME that mimics prostate ducts across various stages of prostate cancer progression, with associated stroma and immune cells. Using this platform, we exposed immune cells to a benign prostate TME or a metastatic prostate TME and investigated their metabolism, gene and cytokine expression. Immune cells exposed to the metastatic TME showed metabolic differences with a higher redox ratio indicating a switch to a more glycolytic metabolic profile. These cells also increased expression of pro-tumor response cytokines that have been shown to increase cell migration and angiogenesis such as Interleukin-1 (IL-1) a and Granulocyte-macrophage colony-stimulating factor (GM-CSF). Lastly, we observed decreased TLR, STAT signaling and TRAIL expression, suggesting that phenotypes derived from exposure to the metastatic TME could have an impaired anti-tumor response. This platform could provide a valuable tool for studying immune cell phenotypes in in vitro tumor microenvironments.

Pentamidine inhibits prostate cancer progression via selectively inducing mitochondrial DNA depletion and dysfunction.

ObjectivesWe investigated the anti‐cancer activity of pentamidine, an anti‐protozoal cationic aromatic diamidine drug, in prostate cancer cells and aimed to provide valuable insights for improving the efficacy of prostate cancer treatment.Materials and methodsProstate cancer cell lines and epithelial RWPE‐1 cells were used in the study. Cell viability, wound‐healing, transwell and apoptosis assays were examined to evaluate the influences of pentamidine in vitro. RNA‐seq and qPCR were performed to analyse changes in gene transcription levels upon pentamidine treatment. Mitochondrial changes were assessed by measuring mitochondrial DNA content, morphology, membrane potential, cellular glucose uptake, ATP production and ROS generation. Nude mouse xenograft models were used to test anti‐tumour effects of pentamidine in vivo.ResultsPentamidine exerted profound inhibitory effects on proliferation, colony formation, migration and invasion of prostate cancer cells. In addition, the drug suppressed growth of xenograft tumours without exhibiting any obvious toxicity in nude mice. Mechanistically, pentamidine caused mitochondrial DNA content reduction and induced mitochondrial morphological changes, mitochondrial membrane potential dissipation, ATP level reduction, ROS production elevation and apoptosis in prostate cancer cells.ConclusionsPentamidine can efficiently suppress prostate cancer progression and may serve as a novel mitochondria‐targeted therapeutic agent for prostate cancer.

Mitochondrial fission promotes self-renewal and tumorigenic potential in prostate cancer

ABSTRACTThe emergence of therapy-resistant cancer stem cells (CSCs) limit the efficacy of prostate cancer treatment. Using genetic knockdown and chemical inhibitors, we demonstrate the critical role of Bromodomain Containing 4 (BRD4) in promoting mitochondrial fission and sustaining CSC expansion. These findings provide a new paradigm for developing novel treatment strategies for prostate cancer.

Radiosensitization by enzalutamide for human prostate cancer is mediated through the DNA damage repair pathway.

Radiation therapy is often combined with androgen deprivation therapy in the treatment of aggressive localized prostate cancer. However, castration-resistant disease may not respond to testosterone deprivation approaches. Enzalutamide is a second-generation anti-androgen with high affinity and activity that is used for the treatment of metastatic disease. Although radiosensitization mechanisms are known to be mediated through androgen receptor activity, this project aims to uncover the detailed DNA damage repair factors influenced by enzalutamide using multiple models of androgen-sensitive (LNCaP) and castration-resistant human prostate cancer (22Rv1 and DU145). Enzalutamide is able to radiosensitize both androgen-dependent and androgen-independent human prostate cancer models in cell culture and xenografts in mice, as well as a treatment-resistant patient-derived xenograft. The enzalutamide-mediated mechanism of radiosensitization includes delay of DNA repair through temporal prolongation of the repair factor complexes and halting the cell cycle, which results in decreased colony survival. Altogether, these findings support the use of enzalutamide concurrently with radiotherapy to enhance the treatment efficacy for prostate cancer.

Prediction of treatment efficacy for prostate cancer using a mathematical model.

Prostate immune system plays a critical role in the regulation of prostate cancer development regarding androgen-deprivation therapy (ADT) and/or immunotherapy (vaccination). In this study, we developed a mathematical model to explore the interactions between prostate tumor and immune microenvironment. This model was used to predict treatment outcomes for prostate cancer with ADT, vaccination, Treg depletion and/or IL-2 neutralization. Animal data were used to guide construction, parameter selection, and validation of our model. Our analysis shows that Treg depletion and/or IL-2 neutralization can effectively improve the treatment efficacy of combined therapy with ADT and vaccination. Treg depletion has a higher synergetic effect than that from IL-2 neutralization. This study highlights a potential therapeutic strategy in effectively managing prostate tumor growth and provides a framework of systems biology approach in studying tumor-related immune mechanism and consequent selection of therapeutic regimens.

Hypofractionated radiation therapy versus conventional radiation therapy in prostate cancer: A systematic review of its safety and efficacy

ContextNew therapeutic alternatives can improve the safety and efficacy of prostate cancer treatment. ObjectivesTo assess whether hypofractionated radiation therapy results in better safety and efficacy in the treatment of prostate cancer. Acquisition of evidenceSystematic review of the literature through searches on PubMed, Cochrane Library, CRD, ClinicalTrials and EuroScan, collecting indicators of safety and efficacy. Synthesis of the evidenceWe included two systematic reviews and a clinical trial. In terms of efficacy, there is considerable heterogeneity among the studies, and no conclusive results were found concerning the superiority of the hypofractionated option over the normal fractionated option. In terms of safety, there were no significant differences in the onset of acute genitourinary complications between the two treatments. However, one of the reviews found more acute gastrointestinal complications in patients treated with hypofractionated radiation therapy. There were no significant differences in long-term complications based on the type of radiation therapy used, although the studies did have limitations. ConclusionsTo date, there are no conclusive results that show that hypofractionated radiation therapy is more effective or safer than normal fractionated radiation therapy in the treatment of localized prostate cancer.

Radioterapia hipofraccionada versus radioterapia convencional en cáncer de próstata: una revisión sistemática sobre eficacia y seguridad

ContextNew therapeutic alternatives can improve the safety and efficacy of prostate cancer treatment. ObjectivesTo assess whether hypofractionated radiation therapy results in better safety and efficacy in the treatment of prostate cancer. Acquisition of evidenceSystematic review of the literature through searches on PubMed, Cochrane Library, CRD, ClinicalTrials and EuroScan, collecting indicators of safety and efficacy. Synthesis of the evidenceWe included 2 systematic reviews and a clinical trial. In terms of efficacy, there is considerable heterogeneity among the studies, and no conclusive results were found concerning the superiority of the hypofractionated option over the normal fractionated option. In terms of safety, there were no significant differences in the onset of acute genitourinary complications between the 2 treatments. However, one of the reviews found more acute gastrointestinal complications in patients treated with hypofractionated radiation therapy. There were no significant differences in long-term complications based on the type of radiation therapy used, although the studies did have limitations. ConclusionsTo date, there are no conclusive results that show that hypofractionated radiation therapy is more effective or safer than normal fractionated radiation therapy in the treatment of localized prostate cancer.

Dutasteride and Enzalutamide Synergistically Suppress Prostate Tumor Cell Proliferation

Dihydrotestosterone is the main active androgen in the prostate and it has a role in prostate cancer progression. After androgen deprivation therapy androgen receptor signaling is still active in tumor cells. Persistent intratumor steroidogenesis and androgen receptor changes are responsible for this continued activity, which influences the efficacy of prostate cancer treatment. We hypothesized that combining a 5α-reductase inhibitor and an antiandrogen would block intratumor androgen synthesis and androgen receptor protein activity. Thus, it would act synergistically to reduce tumor cell proliferation. The expression level of 5α-reductase and androgen receptor in endocrine therapy naïve prostate cancer and castration resistant prostate cancer tissues, and cell line models was determined by microarray and quantitative polymerase chain reaction analysis. Intracellular androgen was measured with radioimmunoassay. Tumor cell proliferation was determined using coloric MTT assay. The synergistic effects of combination treatments on tumor cell proliferation were calculated using the Chou-Talalay equation. In all prostate cancer cases 5α-reductase-1 and 3 were up-regulated. Androgen receptor was up-regulated in metastatic prostate cancer and castration resistant prostate cancer cases. The 5α-reductase inhibitor dutasteride effectively decreased dihydrotestosterone production in prostate cancer and castration resistant prostate cancer cell lines. Furthermore, dutasteride combined with the novel antiandrogen enzalutamide synergistically suppressed endocrine therapy naïve prostate cancer and castration resistant prostate cancer cell proliferation. In this study the combination of a 5α-reductase inhibitor and (novel) antiandrogens synergistically inhibited tumor cell proliferation. These findings support clinical studies of combinations of a 5α-reductase inhibitor and (novel) antiandrogens as first line treatment of prostate cancer and castration resistant prostate cancer.

Abstract 5595: Imaging biomarker development for treatment efficacy for prostate cancer to the bone.

Abstract Approximately 70% of patients with late stage cancers metastasize to the bone. RECIST identifies these tumors as “unmeasureable” for therapeutic response assessment. Cabozantinib (CABO), a tyrosine kinase inhibitor of MET and VEGFR2, has shown promise as an effective therapy for metastatic prostate cancer to the bone. Patients treated with CABO showed a reduction in [Tc99m]-bone scan signal suggesting tumor response to treatment. Nevertheless, a return in signal to pre-treatment levels was observed in these patients following therapy completion. It has yet to be determined if the response observed in bone scans results from tumor death, changes in bone metabolism or vascular alterations in the tumor-stromal microenvironment resulting in reduced transport of the imaging tracer. The study objective was to assess tumor and bone response to CABO in an animal model of bone metastasis using a quantitative multi-modal imaging approach. Twenty-seven male SCID mice were implanted with PC3 cell line in the right tibia. PC3 cells were transfected with a plasmid expressing a bioluminescence imaging (BLI) reporter for measuring apoptosis. When tumor volumes reached 10mm3 by MRI, mice were distributed into 2 groups: CABO at 30 mg/kg (N=13) and vehicle (N=14). Treatments were delivered by oral gavage once a day for three weeks. Starting pre-treatment, MRI and BLI were acquired every third day and CT every week. Tumor and bone volumes were monitored by manually contouring volumes of interest (VOI) on anatomical MRI and CT images, respectively. The apparent diffusion coefficient (ADC), an indirect measure of tumor cellularity, was calculated from diffusion MRI. Mice treated with CABO were found to have significantly higher ADC values and slower growth profile than controls (p<0.05) suggesting a drop in tumor cellularity. Following one week of treatment, BLI signal increased 7 fold over baseline values indicating a delay in tumor apoptosis. In contrast, ADC values and apoptosis activation were unchanged in the controls resulting in significant differences between groups (p<0.05). As determined by CT, control mice had significantly more loss in bone volume than what was observed in the CABO treated mice, with differences first observed at day 14 post-treatment initiation (p<0.05). CABO was found to activate cell death through apoptosis (BLI) resulting in reduced tumor cellularity (ADC) and inhibited tumor growth (anatomical MRI). Increased tumor burden may have reduced osteolytic processes causing less bone loss over controls. Quantitative diffusion MRI and CT, backed by preclinical optical techniques, provide highly sensitive temporal information on the tumor-stromal microenvironment and their interaction to a targeted therapeutic intervention. Translatable quantitative imaging techniques, i.e. MRI and CT, may provide individualized medicine to patients suffering from metastatic prostate cancer to the bone. Citation Format: Joshua S. George, Craig J. Galban, Jean-Christophe Brisset, Benjamin Hoff, Stephanie Galban, Alnawaz Rehemtulla, Brian D. Ross. Imaging biomarker development for treatment efficacy for prostate cancer to the bone. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5595. doi:10.1158/1538-7445.AM2013-5595

Vitamin D3 cryosensitization increases prostate cancer susceptibility to cryoablation via mitochondrial‐mediated apoptosis and necrosis

To investigate the effect and molecular mechanisms of action of Vitamin D(3) (VD(3) ) as a neo-adjunctive agent before cryosurgery in an effort to increase treatment efficacy for prostate cancer (CaP). To eliminate the potential for disease recurrence that exists at the periphery of the freeze lesion, where temperatures may be insufficient to destroy both androgen-sensitive (AS) and androgen-insensitive (AI) CaP. Human CaP cells, LNCaP, were each genetically altered to express the AS and AI phenotypes and subjected to VD(3) treatment and freezing in an in vitro and tissue-engineered model. Cell viability, caspase inhibitor and western blot studies were used to determine the basis of the different responses of AI and AS cells to VD(3) cryosensitization. VD(3) was found to be a highly effective cryosensitizer, resulting in a >50% overall increase in cell death after -15 °C freezing. Fluorescence microscopy, western blot analysis and caspase protease assays confirmed that the increased activation of apoptosis was modulated through a mitochondrial-mediated pathway. Caspase inhibition studies showed that apoptosis played an integral role in cell death, with VD(3) cryosensitivation-induced apoptotic events responsible for >30% of the overall cell death after -15 °C freezing. The present study suggests that the use of VD(3) as a cryosensitizer increases cryoablation efficacy through the increased activity of apoptosis as well as through necrosis. The data show that through VD(3) treatment the overall level of AI CaP cell tolerance to freezing is reduced to a level similar to that of AS CaP. VD(3) pre-treatment in conjunction with cryoablation may increase treatment efficacy and reduce disease recurrence for CaP patients.

Recent Findings in the Pathophysiology of Depression

Recent findings have substantially increased our understanding of the pathophysiology of depression. There has been a correspondingly significant increase in our understanding of the efficacy and tolerability of currently available treatments. The latter database has convincingly demonstrated a large unmet need for the more than one half of depressed patients who fail to achieve remission after an adequate trial of antidepressant monotherapy. Despite our increased understanding of both its pathophysiology and treatment, depression remains highly prevalent, accounting for more disability than any other disorder worldwide. In fact, rates of major depression in the United States rose markedly in the decade from 1991–1992 to 2001– 2002, from 3.33% to 7.06% (1). It is the most significant risk factor for suicide, a leading cause of death worldwide, especially in adolescents, young adults, and elderly individuals. Indeed, suicide is the third leading cause of death in children and adolescents, and childhood depression and bipolar disorder are not uncommon, yet quite understudied. Depression is also an important risk factor both for the development of cardiovascular disease including myocardial infarction and congestive heart failure (2) and for the poor response to treatment in these patients. Figure 1 summarizes the major mood disorders across the life cycle and the diagnostic criteria for major depression. There are still no validated, diagnostically useful biological tests for depression and none that reliably predict a response to one or another of the wellestablished and effective treatments for depression, except perhaps plasma drug concentrations of the older and side effect-prone tricyclic antidepressants. Similarly, although some promising candidates are emerging, there are no biomarkers, such as expression of a gene or tumor marker, that reliably change as a function of treatment response to antidepressants or psychotherapy (e.g., prostate-specific antigen is used to monitor efficacy of prostate cancer treatment). Of considerable concern is the relatively recent realization stemming from several large-scale treatment studies, both of efficacy and effectiveness, that currently available antidepressants and psychotherapy, in particular cognitive behavior therapy (CBT), although clearly more effective than placebo, are as monotherapies associated with response (a 50% or more improvement in depressive symptoms) and remission (return to premorbid state) rates that are clearly unacceptably low. Combination or augmentation therapies comprised, respectively, of more than one antidepressant medication or an antidepressant and a second nonantidepressant drug to enhance the effects of the antidepressant, and combination pharmacotherapy/psychotherapy, although understudied, appear to be associated with better therapeutic responses than monotherapy. However, the increased side effects often, but not always, associated with coprescribing two medications, and the increased cost of treatment with combination psychotherapy and pharmacotherapy or two medications are major obstacles that prevent their wholesale clinical adoption. Second, with few exceptions, there is insufficient evidence of increased efficacy currently available to support a change in clinical practice. The results of the large-scale National Institute of