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11 pages, 1298 KiB

Open AccessArticle

Value of Early Circulating Tumor Cells Dynamics to Estimate Docetaxel Benefit in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients

by Rebeca Lozano, David Lorente, Isabel M. Aragon, Nuria Romero-Laorden, Paz Nombela, Joaquim Mateo, Alison H. M. Reid, Ylenia Cendón, Diletta Bianchini, Casilda Llacer, Shahneen K. Sandhu, Adam Sharp, Pasquale Rescigno, Teresa Garcés, Maria I. Pacheco, Penelope Flohr, Christophe Massard, Pedro P. López-Casas, Elena Castro, Johann S. de Bono and David Olmos Show full author list Hide full author list

Cancers 2021, 13(10), 2334; https://doi.org/10.3390/cancers13102334 - 12 May 2021

Cited by 10 | Viewed by 3003

Abstract

Circulating tumor cell (CTC) enumeration and changes following treatment have been demonstrated to be superior to PSA response in determining mCRPC outcome in patients receiving AR signaling inhibitors but not taxanes. We carried out a pooled analysis of two prospective studies in mCRPC [...] Read more.

Circulating tumor cell (CTC) enumeration and changes following treatment have been demonstrated to be superior to PSA response in determining mCRPC outcome in patients receiving AR signaling inhibitors but not taxanes. We carried out a pooled analysis of two prospective studies in mCRPC patients treated with docetaxel. CTCs were measured at baseline and 3–6 weeks post treatment initiation. Cox regression models were constructed to compare 6-month radiographical progression-free survival (rPFS), CTCs and PSA changes predicting outcome. Among the subjects, 80 and 52 patients had evaluable baseline and post-treatment CTC counts, respectively. A significant association of higher baseline CTC count with worse overall survival (OS), PFS and time to PSA progression (TTPP) was observed. While CTC response at 3–6 weeks (CTC conversion (from ≥5 to <5 CTCs), CTC30 (≥30% decline in CTC) or CTC0 (decline to 0 CTC)) and 6-month rPFS were significantly associated with OS (all p < 0.005), the association was not significant for PSA30 or PSA50 response. CTC and PSA response were discordant in over 50% of cases, with outcome driven by CTC response in these patients. The c-index values for OS were superior for early CTC changes compared to PSA response endpoints, and similar to 6-month rPFS. Early CTC declines were good predictors of improved outcomes in mCRPC patients treated with docetaxel in this small study, offering a superior and/or earlier estimation of docetaxel benefit in comparison to PSA or rPFS that merits further confirmation in larger studies. Full article

(This article belongs to the Special Issue New Therapies for Prostate Cancer)

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17 pages, 3480 KiB

Open AccessArticle

SETD1A Promotes Proliferation of Castration-Resistant Prostate Cancer Cells via FOXM1 Transcription

by Liu Yang, Mingli Jin, Sung Jean Park, Seung-Yong Seo and Kwang Won Jeong

Cancers 2020, 12(7), 1736; https://doi.org/10.3390/cancers12071736 - 30 Jun 2020

Cited by 21 | Viewed by 2810

Abstract

Androgen deprivation therapy eventually leads to the development of castration-resistant prostate cancer (CRPC). Here, we demonstrate for the first time that the histone H3K4 methyltransferase SETD1A is a major regulator for the proliferation of metastatic CRPC (mCRPC). The expression of SETD1A was significantly [...] Read more.

Androgen deprivation therapy eventually leads to the development of castration-resistant prostate cancer (CRPC). Here, we demonstrate for the first time that the histone H3K4 methyltransferase SETD1A is a major regulator for the proliferation of metastatic CRPC (mCRPC). The expression of SETD1A was significantly correlated with the survival rate of patients with prostate cancer. SETD1A, which is expressed at a higher level in mCRPC than in primary prostate cancer cells, promotes the expression of FOXM1, a gene encoding a cell proliferation-specific transcription factor. SETD1A is recruited to the promoter region of FOXM1 (forkhead box M1) upon binding to E2F1, a protein that regulates the transcription of FOXM1 and contributes to the trimethylation of H3K4 in the FOXM1 promoter region. In addition, SETD1A is essential for the expression of stem cell factor (e.g., OCT4, octamer-binding transcription factor 4) and stem cell formation in mCRPC, suggesting the importance of SETD1A expression in mCRPC tumor formation. Notably, poor prognosis is associated with high expression of the SETD1A–FOXM1 pair in clinical data sets. Therefore, our study suggests that SETD1A plays an important role in the proliferation of mCRPC by regulating FOXM1 transcription. Full article

(This article belongs to the Special Issue New Therapies for Prostate Cancer)

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15 pages, 3249 KiB

Open AccessArticle

Emerging Therapeutic Activity of Davallia formosana on Prostate Cancer Cells through Coordinated Blockade of Lipogenesis and Androgen Receptor Expression

by Po-Fan Hsieh, Wen-Ping Jiang, Shih-Yin Huang, Praveenkumar Basavaraj, Jin-Bin Wu, Hui-Ya Ho, Guan-Jhong Huang and Wen-Chin Huang

Cancers 2020, 12(4), 914; https://doi.org/10.3390/cancers12040914 - 08 Apr 2020

Cited by 9 | Viewed by 2707

Abstract

Background: Prostate cancer (PCa) is the most prevalent malignancy diagnosed in men in Western countries. There is currently no effective therapy for advanced PCa aggressiveness, including castration-resistant progression. The aim of this study is to evaluate the potential efficacy and determine the molecular [...] Read more.

Background: Prostate cancer (PCa) is the most prevalent malignancy diagnosed in men in Western countries. There is currently no effective therapy for advanced PCa aggressiveness, including castration-resistant progression. The aim of this study is to evaluate the potential efficacy and determine the molecular basis of Davallia formosana (DF) in PCa. Methods: LNCaP (androgen-sensitive) and C4-2 (androgen-insensitive/castration-resistant) PCa cells were utilized in this study. An MTT-based method, a wound healing assay, and the transwell method were performed to evaluate cell proliferation, migration, and invasion. Intracellular fatty acid levels and lipid droplet accumulation were analyzed to determine lipogenesis. Moreover, apoptotic assays and in vivo experiments were conducted. Results: DF ethanol extract (DFE) suppressed proliferation, migration, and invasion in PCa cells. DFE attenuated lipogenesis through inhibition of the expression of sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FASN). Moreover, DFE decreased androgen receptor (AR) and prostate-specific antigen (PSA) expression in PCa cells. We further showed the potent therapeutic activity of DFE by repressing the growth and leading to apoptosis of subcutaneous C4-2 tumors in a xenograft mouse model. Conclusions: These data provide a new molecular basis of DFE in PCa cells, and co-targeting SREBP-1/FASN/lipogenesis and the AR axis by DFE could be employed as a novel and promising strategy for the treatment of PCa. Full article

(This article belongs to the Special Issue New Therapies for Prostate Cancer)

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13 pages, 551 KiB

Open AccessArticle

Influence of Baseline Cardiovascular Comorbidities on Mortality after Androgen Deprivation Therapy for Metastatic Prostate Cancer

by Szu-Yuan Wu, Su-Chen Fang, Olivia Rachel Hwang, Hung-Jen Shih and Yu-Hsuan Joni Shao

Cancers 2020, 12(1), 189; https://doi.org/10.3390/cancers12010189 - 12 Jan 2020

Cited by 10 | Viewed by 2659

Abstract

Few studies have assessed the benefits of androgen deprivation therapy (ADT) in men with metastatic prostate cancer (PC; mPC) at an old age or with major cardiovascular conditions. A retrospective cohort consisted of 3835 men with newly diagnosed mPC from the Taiwan Cancer [...] Read more.

Few studies have assessed the benefits of androgen deprivation therapy (ADT) in men with metastatic prostate cancer (PC; mPC) at an old age or with major cardiovascular conditions. A retrospective cohort consisted of 3835 men with newly diagnosed mPC from the Taiwan Cancer Registry of 2008–2014. Among them, 2692 patients received only ADT in the first year after the cancer diagnosis, and 1143 patients were on watchful waiting. The inverse probability of treatment-weighted Cox model was used to estimate the effects of ADT on all-cause mortality and PC-specific mortality according to age, and the status of congestive heart failure (CHF), coronary arterial diseases (CADs), and stroke at the baseline. After a median follow-up of 2.65 years, 1650 men had died. ADT was associated with a 17–22% risk reduction in all-cause and PC-specific mortality in men without stroke, CAD, or CHF in the 65–79-year group. The survival benefit diminished in men with any of these preexisting conditions. In contrast, ADT was not found to be associated with any survival benefit in the ≥80-year group, even though they did not present with any major cardiovascular disease at the baseline. Patients who had CHF, CAD, or stroke at the baseline did not show a survival benefit following ADT in any of the age groups. Men who have preexisting major cardiovascular diseases or are ≥80 years do not demonstrate a survival benefit from ADT for mPC. The risk–benefit ratio should be considered when using ADT for mPC in older men especially those with major cardiovascular comorbidities. Full article

(This article belongs to the Special Issue New Therapies for Prostate Cancer)

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Review

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20 pages, 283 KiB

Open AccessReview

Neuroendocrine and Aggressive-Variant Prostate Cancer

by Nicholas Spetsieris, Myrto Boukovala, Georgios Patsakis, Ioannis Alafis and Eleni Efstathiou

Cancers 2020, 12(12), 3792; https://doi.org/10.3390/cancers12123792 - 16 Dec 2020

Cited by 39 | Viewed by 4396

Abstract

In prostate cancer, neuroendocrine (NE) differentiation may rarely present de novo or more frequently arises following hormonal therapy in patients with castration-resistant prostate cancer (CRPC). Its distinct phenotype is characterized by an aggressive clinical course, lack of responsiveness to hormonal therapies and poor [...] Read more.

In prostate cancer, neuroendocrine (NE) differentiation may rarely present de novo or more frequently arises following hormonal therapy in patients with castration-resistant prostate cancer (CRPC). Its distinct phenotype is characterized by an aggressive clinical course, lack of responsiveness to hormonal therapies and poor prognosis. Importantly, a subset of CRPC patients exhibits an aggressive-variant disease with very similar clinical and molecular characteristics to small-cell prostate cancer (SCPC) even though tumors do not have NE differentiation. This aggressive-variant prostate cancer (AVPC) also shares the sensitivity of SCPC to platinum-based chemotherapy albeit with short-lived clinical benefit. As optimal treatment strategies for AVPC remain elusive, currently ongoing research efforts aim to enhance our understanding of the biology of this disease entity and improve treatment outcomes for our patients. This review is an overview of our current knowledge on prostate cancer with NE differentiation and AVPC, with a focus on their clinical characteristics and management, including available as well as experimental therapeutic strategies. Full article

(This article belongs to the Special Issue New Therapies for Prostate Cancer)

14 pages, 248 KiB

Open AccessReview

Therapeutic Potential of PARP Inhibitors in the Treatment of Metastatic Castration-Resistant Prostate Cancer

by Albert Jang, Oliver Sartor, Pedro C. Barata and Channing J. Paller

Cancers 2020, 12(11), 3467; https://doi.org/10.3390/cancers12113467 - 21 Nov 2020

Cited by 12 | Viewed by 4340

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is an incurable malignancy with a poor prognosis. Up to 30% of patients with mCRPC have mutations in homologous recombination repair (HRR) genes. Poly (ADP-ribose) polymerase (PARP) inhibitors take advantage of HRR deficiency to kill tumor cells based [...] Read more.

Metastatic castration-resistant prostate cancer (mCRPC) is an incurable malignancy with a poor prognosis. Up to 30% of patients with mCRPC have mutations in homologous recombination repair (HRR) genes. Poly (ADP-ribose) polymerase (PARP) inhibitors take advantage of HRR deficiency to kill tumor cells based on the concept of synthetic lethality. Several PARP inhibitors (PARPis) have been successful in various malignancies with HRR gene mutations including BRCA1/2, especially in breast cancer and ovarian cancer. More recently, olaparib and rucaparib were approved for mCRPC refractory to novel hormonal therapies, and other PARPis will likely follow. This article highlights the mechanism of action of PARPis at the cellular level, the preclinical data regarding a proposed mechanism of action and the effectiveness of PARPis in cancer cell lines and animal models. The article expands on the clinical development of PARPis in mCRPC, discusses potential biomarkers that may predict successful tumor control, and summarizes present and future clinical research on PARPis in the metastatic disease landscape. Full article

(This article belongs to the Special Issue New Therapies for Prostate Cancer)

17 pages, 252 KiB

Open AccessReview

Immunotherapy in Prostate Cancer

by Emily K. Fay and Julie N. Graff

Cancers 2020, 12(7), 1752; https://doi.org/10.3390/cancers12071752 - 01 Jul 2020

Cited by 60 | Viewed by 5192

Abstract

Immunotherapy encompasses a wide range of therapies to engage the immune system to target malignancies. In recent years, immunotherapy has made a major impact on treatment of metastatic cancer and has altered standard of care for many tumor types. However, predicting and understanding [...] Read more.

Immunotherapy encompasses a wide range of therapies to engage the immune system to target malignancies. In recent years, immunotherapy has made a major impact on treatment of metastatic cancer and has altered standard of care for many tumor types. However, predicting and understanding responses across tumor types has been challenging. While some metastatic cancers have shown dramatic responses to immunotherapy, such as melanoma, lung cancer, and renal cell carcinoma, prostate cancer has generally failed to show a significant response. However, small series of prostate cancer patients have shown impressive responses to cellular and immunotherapy. This review summarizes the current data for immunotherapy’s use in prostate cancer, as well as how currently available data might help predict patient responses to immunotherapy. Specifically, we will review vaccine-based therapies, immune checkpoint inhibitors, and future directions that are actively being explored. Full article

(This article belongs to the Special Issue New Therapies for Prostate Cancer)

14 pages, 285 KiB

Open AccessEditor’s ChoiceReview

PSMA Theranostics: Review of the Current Status of PSMA-Targeted Imaging and Radioligand Therapy

by Wallace Jones, Kelly Griffiths, Pedro C. Barata and Channing J. Paller

Cancers 2020, 12(6), 1367; https://doi.org/10.3390/cancers12061367 - 26 May 2020

Cited by 70 | Viewed by 6123

Abstract

Prostate-specific membrane antigen (PSMA) has been the subject of extensive investigation in the past two decades as a promising molecular target for prostate cancer (PCa). Its appealing molecular features have enabled the development of a novel diagnostic and therapeutic—thus “theranostic”—approach to PCa. There [...] Read more.

Prostate-specific membrane antigen (PSMA) has been the subject of extensive investigation in the past two decades as a promising molecular target for prostate cancer (PCa). Its appealing molecular features have enabled the development of a novel diagnostic and therapeutic—thus “theranostic”—approach to PCa. There is now substantial evidence of the high sensitivity of PSMA-targeted imaging for PCa lesions and growing evidence of the therapeutic efficacy of PSMA radioligand therapy for metastatic castration-resistant prostate cancer. This article presents a broad overview of the current status of PSMA theranostics, including current evidence, potential clinical impact, and active areas of research. Full article

(This article belongs to the Special Issue New Therapies for Prostate Cancer)

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