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Journal of Experimental & Clinical... Jul 2023Prostate cancer is a major cause of cancer morbidity and mortality in men worldwide. Androgen deprivation therapy (ADT) has proven effective in early-stage...
BACKGROUND
Prostate cancer is a major cause of cancer morbidity and mortality in men worldwide. Androgen deprivation therapy (ADT) has proven effective in early-stage androgen-sensitive disease, but prostate cancer gradually develops into an androgen-resistant metastatic state in the vast majority of patients. According to our oncogene-induced model for cancer development, senescence is a major tumor progression barrier. However, whether senescence is implicated in the progression of early-stage androgen-sensitive to highly aggressive castration-resistant prostate cancer (CRPC) remains poorly addressed.
METHODS
Androgen-dependent (LNCaP) and -independent (C4-2B and PC-3) cells were treated or not with enzalutamide, an Androgen Receptor (AR) inhibitor. RNA sequencing and pathway analyses were carried out in LNCaP cells to identify potential senescence regulators upon treatment. Assessment of the invasive potential of cells and senescence status following enzalutamide treatment and/or RNAi-mediated silencing of selected targets was performed in all cell lines, complemented by bioinformatics analyses on a wide range of in vitro and in vivo datasets. Key observations were validated in LNCaP and C4-2B mouse xenografts. Senescence induction was assessed by state-of-the-art GL13 staining by immunocytochemistry and confocal microscopy.
RESULTS
We demonstrate that enzalutamide treatment induces senescence in androgen-sensitive cells via reduction of the replication licensing factor CDC6. Mechanistically, we show that CDC6 downregulation is mediated through endogenous activation of the GATA2 transcription factor functioning as a CDC6 repressor. Intriguingly, GATA2 levels decrease in enzalutamide-resistant cells, leading to CDC6 stabilization accompanied by activation of Epithelial-To-Mesenchymal Transition (EMT) markers and absence of senescence. We show that CDC6 loss is sufficient to reverse oncogenic features and induce senescence regardless of treatment responsiveness, thereby identifying CDC6 as a critical determinant of prostate cancer progression.
CONCLUSIONS
We identify a key GATA2-CDC6 signaling axis which is reciprocally regulated in enzalutamide-sensitive and -resistant prostate cancer environments. Upon acquired resistance, GATA2 repression leads to CDC6 stabilization, with detrimental effects in disease progression through exacerbation of EMT and abrogation of senescence. However, bypassing the GATA2-CDC6 axis by direct inhibition of CDC6 reverses oncogenic features and establishes senescence, thereby offering a therapeutic window even after acquiring resistance to therapy.
Topics: Male; Humans; Animals; Mice; Receptors, Androgen; Prostatic Neoplasms; Androgens; Androgen Antagonists; GATA2 Transcription Factor; Nitriles; Androgen Receptor Antagonists; Cell Cycle Proteins; Cell Line, Tumor; Drug Resistance, Neoplasm; Nuclear Proteins
PubMed: 37507762
DOI: 10.1186/s13046-023-02769-z -
Targeted Oncology Sep 2023Darolutamide (NUBEQA) is an oral androgen receptor inhibitor (ARi) that is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in... (Review)
Review
Darolutamide (NUBEQA) is an oral androgen receptor inhibitor (ARi) that is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) and docetaxel. In a pivotal trial, darolutamide plus ADT and docetaxel was superior to placebo plus ADT and docetaxel in prolonging the primary endpoint of overall survival, with improvements also reported in most secondary endpoints. Treatment with darolutamide plus ADT and docetaxel was associated with a manageable tolerability profile. Furthermore, the adverse events reported with darolutamide plus ADT and docetaxel were generally consistent with the safety profiles previously reported for ADT and docetaxel. Darolutamide expands the availability of treatment options in mHSPC and may be useful as a treatment for high-volume disease (typically defined as ≥ 4 bone metastases with spread outside of the pelvis and vertebral column).
Topics: Male; Humans; Prostatic Neoplasms; Docetaxel; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Hormones
PubMed: 37542594
DOI: 10.1007/s11523-023-00984-4 -
Journal of Clinical Oncology : Official... Nov 2023The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR...
PURPOSE
The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods.
MATERIALS AND METHODS
Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the ). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed.
RESULTS
Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively.
CONCLUSION
BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.
Topics: Male; Humans; Prostate; Prostatic Neoplasms; Androgen Antagonists; Prostate-Specific Antigen; Adenocarcinoma
PubMed: 37639648
DOI: 10.1200/JCO.23.00617 -
Expert Opinion on Pharmacotherapy 2023Prostate cancer is the most common malignancy in the male. Androgen-deprivation therapy (ADT) has been the mainstay in the treatment of metastatic prostate cancer... (Review)
Review
INTRODUCTION
Prostate cancer is the most common malignancy in the male. Androgen-deprivation therapy (ADT) has been the mainstay in the treatment of metastatic prostate cancer however, due to the outgrowth of castration-resistant cell population the disease inevitably progresses to an aggressive, difficult to handle stage.
AREAS COVERED
We have reviewed the literature regarding hormonal-directed therapy prostate cancer. New agents, namely abiraterone acetate, combined with prednisone, and next generation antiandrogens (enzalutamide, apalutamide and darolutamide) have shown considerable efficacy, not only in patients with metastatic but also in those with non-metastatic disease, either castration resistant (CRPC) or hormone sensitive (HSPC).
EXPERT OPINION
The addition of abiraterone and of the second-generation antiandrogens to our therapeutic armamentarium has improved prognosis ofprostate cancer in the last decade. Abiraterone is a viable option in patients with metastatic disease (hormone-sensitive and castration-resistant), whereas all next-generation antiandrogens have demonstrated efficacy in terms of metastasis-free and overall survival in non-metastatic CRPC. In addition, enzalutamide has also been found efficacious in mCRPC and mHSPC, while apalutamide in mHSPC. Currently there are no reliable data to indicate a potential superiority of one of these agents over the others in CRPC or HSPC as there are no relevant head to head studies . Sequencing hormone treatment modalities, chemotherapies and immunotherapies have not reached a consensus as yet. Randomized controlled trials are warranted to clearly define the role of novel antiandrogens in the treatment of prostate cancer. The choice of treatment should be individualized following discussion with the patient .
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Treatment Outcome; Hormones
PubMed: 37545430
DOI: 10.1080/14656566.2023.2244415 -
The Prostate Apr 2024Although most patients with prostate cancer (PC) respond to initial androgen deprivation therapy (ADT), castration-resistant disease invariably develops. Progression to... (Review)
Review
BACKGROUND
Although most patients with prostate cancer (PC) respond to initial androgen deprivation therapy (ADT), castration-resistant disease invariably develops. Progression to treatment-emergent neuroendocrine PC (t-NEPC) represents a unique mechanism of resistance to androgen receptor (AR)-targeted therapy in which lineage plasticity and neuroendocrine differentiation induce a phenotypic switch from an AR-driven adenocarcinoma to an AR-independent NEPC. t-NEPC is characterized by an aggressive clinical course, increased resistance to AR-targeted therapies, and a poor overall prognosis.
METHODS
This review provides an overview of our current knowledge of NEPC, with a focus on the unmet needs, diagnosis, and clinical management of t-NEPC.
RESULTS
Evidence extrapolated from the literature on small cell lung cancer or data from metastatic castration-resistant PC (mCRPC) cohorts enriched for t-NEPC suggests an increased sensitivity to platinum-based chemotherapy. However, optimal strategies for managing t-NEPC have not been established, and prospective clinical trial data are limited. Intertumoral heterogeneity within a given patient, as well as the lack of robust molecular or clinical biomarkers for early detection, often lead to delays in diagnosis and prolonged treatment with suboptimal strategies (i.e., conventional chemohormonal therapies for mCRPC), which may further contribute to poor outcomes.
CONCLUSIONS
Recent advances in genomic and molecular classification of NEPC and the development of novel biomarkers may facilitate an early diagnosis, help to identify promising therapeutic targets, and improve the selection of patients most likely to benefit from NEPC-targeted therapies.
Topics: Male; Humans; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Prospective Studies; Adenocarcinoma; Biomarkers; Carcinoma, Neuroendocrine
PubMed: 38173302
DOI: 10.1002/pros.24664 -
The Journal of Clinical Investigation Nov 2023Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3β-hydroxysteroid...
Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) and promotes intracellular androgen biosynthesis. Germline inheritance of the adrenally permissive allele confers worse outcomes in men with advanced PCa. We investigated whether HSD3B1 (1245C) drives resistance to combined androgen deprivation and radiotherapy. Adrenally permissive 3βHSD1 enhanced resistance to radiotherapy in PCa cell lines and xenograft models engineered to mimic the human adrenal/gonadal axis during androgen deprivation. The allele-specific effects on radiosensitivity were dependent on availability of DHEA, the substrate for 3βHSD1. In lines expressing the HSD3B1 (1245C) allele, enhanced expression of DNA damage response (DDR) genes and more rapid DNA double-strand break (DSB) resolution were observed. A correlation between androgen receptor (AR) expression and increased DDR gene expression was confirmed in 680 radical prostatectomy specimens. Treatment with the nonsteroidal antiandrogen enzalutamide reversed the resistant phenotype of HSD3B1 (1245C) PCa in vitro and in vivo. In conclusion, 3βHSD1 promotes prostate cancer resistance to combined androgen deprivation and radiotherapy by upregulating DNA DSB repair. This work supports prospective validation of early combined androgen blockade for high-risk men harboring the HSD3B1 (1245C) allele.
Topics: Humans; Male; Androgen Antagonists; Androgens; DNA; Genotype; Hydroxysteroid Dehydrogenases; Multienzyme Complexes; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 37966114
DOI: 10.1172/JCI165718 -
Current Treatment Options in Oncology Jan 2024Localized high-risk (HR) prostate cancer (PCa) is a heterogenous disease state with a wide range of presentations and outcomes. Historically, non-surgical management... (Review)
Review
Localized high-risk (HR) prostate cancer (PCa) is a heterogenous disease state with a wide range of presentations and outcomes. Historically, non-surgical management with radiotherapy and androgen deprivation therapy was the treatment option of choice. However, surgical resection with radical prostatectomy (RP) and pelvic lymph node dissection (PLND) is increasingly utilized as a primary treatment modality for patients with HRPCa. Recent studies have demonstrated that surgery is an equivalent treatment option in select patients with the potential to avoid the side effects from androgen deprivation therapy and radiotherapy combined. Advances in imaging techniques and biomarkers have also improved staging and patient selection for surgical resection. Advances in robotic surgical technology grant surgeons various techniques to perform RP, even in patients with HR disease, which can reduce the morbidity of the procedure without sacrificing oncologic outcomes. Clinical trials are not only being performed to assess the safety and oncologic outcomes of these surgical techniques, but to also evaluate the role of surgical resection as a part of a multimodal treatment plan. Further research is needed to determine the ideal role of surgery to potentially provide a more personalized and tailored treatment plan for patients with localized HR PCa.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Lymph Node Excision; Combined Modality Therapy; Prostatectomy
PubMed: 38212510
DOI: 10.1007/s11864-023-01162-4 -
Proteomics. Clinical Applications Nov 2023Prostate cancer (PCa) is the most prevalent malignancy of the male genitourinary system, and its etiology suggests that genetics is an essential risk factor for its... (Review)
Review
Prostate cancer (PCa) is the most prevalent malignancy of the male genitourinary system, and its etiology suggests that genetics is an essential risk factor for its development and progression, while exogenous factors may have an significant impact on this risk. Initial diagnosis of advanced PCa is relatively frequent, and androgen deprivation therapy (ADT) is the predominant standard of care for PCa and the basis for various novel combination therapy regimens, and is often required throughout the patient's subsequent treatment. Although diagnostic modalities and treatment options are evolving, some patients suffer from complications, including biochemical relapse, metastasis and treatment resistance. Mechanisms of PCa pathogenesis and progression have been the focus of research. N6-methyladenosine (m6A) is an RNA modification involved in cell physiology and tumor metabolism. It has been observed to affect the evolution of diverse cancers through the regulation of gene expression. Genes associated with m6A are prominent in PCa and are involved in multiple aspects of desmoresistant PCa occurrence, progression, PCa bone metastasis (BM), and treatment resistance. Here, we explore the role of m6A modifications in promoting PCa.
Topics: Humans; Male; Prostatic Neoplasms; Androgen Antagonists; Neoplasm Recurrence, Local; Bone Neoplasms; Risk Factors
PubMed: 37070355
DOI: 10.1002/prca.202200108 -
Urologie (Heidelberg, Germany) Dec 2023In advanced prostate cancer, disease progression during ongoing androgen deprivation therapy (ADT) is referred to as castration-resistant prostate cancer (CRPC). Various... (Review)
Review
BACKGROUND
In advanced prostate cancer, disease progression during ongoing androgen deprivation therapy (ADT) is referred to as castration-resistant prostate cancer (CRPC). Various therapeutic modalities are available for its treatment, including endocrine therapy, chemotherapy, poly (ADP-ribose) polymerase [PARP] inhibition, radionuclide therapy, and radioligand therapy.
OBJECTIVES
This review outlines practical aspects and considerations regarding treatment sequencing in mCRPC.
MATERIALS AND METHODS
The findings are based on existing prospective phase 3 studies that have demonstrated clinically relevant and statistically significant benefits in radiographically progression-free and/or overall survival.
RESULTS
Sequential therapy, aside from numerous patient-specific factors, depends on the treatment patients received in the hormone-sensitive prostate cancer (mHSPC) setting. Following pretreatment with ADT alone or ADT plus docetaxel in the mHSPC context, additional endocrine therapy is the standard approach. In the event of progression under combined endocrine therapy initiated in the mHSPC setting, docetaxel currently serves as the standard for the majority of patients. Patients who received triplet therapy as a pretreatment in the mHSPC scenario can be treated with radioligand therapy or second-line chemotherapy.
CONCLUSION
Various active and well-tolerated treatment options are available for patients with metastatic castration-resistant prostate cancer (mCRPC). The choice of therapy is primarily determined by previous treatments, but many other individual factors are also taken into consideration.
Topics: Male; Humans; Docetaxel; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Prospective Studies
PubMed: 37847397
DOI: 10.1007/s00120-023-02212-3 -
Scientific Reports Aug 2023Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor...
Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for patients with PCa who have a poor prognosis. Here we show that there is a dynamic balance between sortilin and syndecan-1, that reports on different metabolic phenotypes. Using tissue microarrays, we demonstrated by immunohistochemistry that sortilin was highly expressed in low-grade cancer, while syndecan-1 was upregulated in high-grade disease. Mechanistic studies in prostate cell lines revealed that in androgen-sensitive LNCaP cells, sortilin enhanced glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, in androgen-insensitive PC3 cells, syndecan-1 was upregulated, interacted with LPL and colocalised with β integrin to promote lipid metabolism. In addition, androgen-deprived LNCaP cells had decreased expression of sortilin and reduced glucose-metabolism, but increased syndecan-1 expression, facilitating interactions with LPL and possibly β integrin. We report a hitherto unappreciated molecular mechanism for PCa, which may have significance for disease progression and how androgen-deprivation therapy might promote castration-resistant PCa.
Topics: Male; Humans; Prostatic Neoplasms; Prostate; Syndecan-1; Androgen Antagonists; Androgens; Integrin beta3; Neoplastic Processes
PubMed: 37596305
DOI: 10.1038/s41598-023-40347-7