A review of continuous vs intermittent androgen deprivation therapy: Redefining the gold standard in the treatment of advanced prostate cancer. Myths, facts and new data on a perpetual dispute

Kratiras, Z.; Konstantinidis, Charalampos; Skriapas, Konstantinos

doi:10.1590/s1677-5538.ibju.2014.01.02

Cited by 13 publications

(26 citation statements)

References 46 publications

(53 reference statements)

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“…(≈ 150 hours) [14] enables an oscillation period of approximately a week ( Figure 5B). This timescale is comparable with various hormone-deprivation treatments applied in the clinic [35,36] and motivated investigating the effect of various therapies. As a first step, we considered a constant inhibitory signal acting on the Androgen Receptor (AR), to simulate the effect of continuous Androgen Depri-vation Therapy (ADT) -the standard care of therapy for over 75 years for locally advanced and/or metastatic PCa [35].…”

Section: Implications Of Switching Between Clk2-page4 and Hipk1-page4mentioning

confidence: 88%

PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer

Lin

Roy

Jolly

et al. 2018

Preprint

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Prostate-Associated Gene 4 (PAGE4) is a disordered protein implicated in the progression of prostate cancer. PAGE4 can be phosphorylated at two residue sites by Homeodomain-Interacting Protein Kinase 1 (HIPK1) to facilitate its binding to the Activator Protein-1 (AP-1) transcription factor. Contrarily, a further hyperphosphorylation of PAGE4 by CDC-Like Kinase 2 (CLK2) reduces its binding affinity to AP-1, thus affecting androgen receptor (AR) activity levels downstream. Both Small-angle X-ray scattering (SAXS) and Single molecule fluorescence resonance energy transfer (smFRET) experiments show an expansion of PAGE4 upon hyperphosphorylation and a more significant increase in size in its N-terminal half than that in its C terminus.To understand the underlying mechanism behind this structural transition, we performed a set 1 . 14, 2018; of constant temperature molecular dynamics simulations (MDS) with Atomistic AWSEM -a multi-scale model combining detailed atomistic and coarse-grained simulation approaches. By simulating PAGE4 in its wildtype and phosphorylated forms, our simulations reveal that electrostatic interaction drives a transient formation of a N-terminal loop, which causes the change of size in different forms of PAGE4. Phosphorylation also changes the preference of secondary structure formation in different forms of PAGE4, which signifies transition between states that have different degrees of disorder. Finally, we construct a mechanism-based mathematical model capturing the interactions of different forms of PAGE4 with the AP-1 and AR, a key therapeutic target in prostate cancer. Our model predicts intracellular oscillatory dynamics of HIPK1-PAGE4, CLK2-PAGE4 and AR activity, indicating phenotypic heterogeneity in an isogenic cell population. Thus, conformational switching among different forms of PAGE4 may potentially affect the efficiency of therapeutic targeting of AR. CC-BY-NC-ND 4.0 International licenseIt is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint . http://dx.doi.org/10.1101/264010 doi: bioRxiv preprint first posted online Feb.

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Section: Implications Of Switching Between Clk2-page4 and Hipk1-page4mentioning

confidence: 88%

PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer

Lin

Roy

Jolly

et al. 2018

Preprint

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“…Multiple clinical trials have demonstrated that IADT may reduce the adverse effects associated with continuous ADT without any clear difference in survival 26 . Long term efficacy remains to be determined and methods for optimization of IADT will be a critical step in establishing it as a viable treatment option, especially in patients with advanced metastatic disease.…”

Section: Discussionmentioning

confidence: 99%

5α-Reductase Inhibition Coupled with Short Off Cycles Increases Survival in the LNCaP Xenograft Prostate Tumor Model on Intermittent Androgen Deprivation Therapy

et al. 2015

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Purpose Intermittent androgen deprivation therapy (IADT) for patients with PSA progression after treatment for localized prostate cancer is an alternative to the standard continuous ADT. IADT allows for the recovery of testosterone during off-cycles to stimulate regrowth and differentiation of the regressed prostate tumor in order to lessen the side effects of continuous ADT and potentially prolong survival. Previously, IADT coupled with finasteride was shown to prolong survival of animals bearing androgen-sensitive prostate tumors when off-cycle duration was not prolonged and fixed at 10–14 days. Regressed prostate tumor xenografts with testosterone replacement were initially responsive to 5α-reductase inhibition, but resumed growth after several days in the animal models. 5α-reductase inhibition in shorter off-cycles of testosterone recovery could maximize tumor growth inhibition during IADT and perhaps increase survival. Materials and Methods The LNCaP xenograft tumor model was utilized to evaluate the effectiveness of short off-cycles of 4 days coupled with 5α-reductase inhibition on IADT on survival and tumor regrowth. Results Dutasteride inhibited initial testosterone-induced tumor regrowth during both the first and second off-cycle and significantly increased survival. Conclusions These results further support the potential for IADT combined with 5α-reductase inhibition to improve survival in prostate cancer patients when off cycle durations are short or very short.

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“…13 Recent reviews comparing efficacy, side effects, time to castration resistance, overall and cancer-specific survival between intermittent and continuous ADT have been summarised; however, the evidence regarding the tradeoffs between the benefits and risks of intermittent ADT remains inconclusive. [17][18][19][20][21][22][23] Generally the consensus is that overall survival is equivalent between intermittent and continuous ADT in most settings. However, concerns remain with high-risk disease, as one of the larger trials did not meet criteria for non-inferiority of an intermittent regimen in men with metastatic cancer.…”

Section: How Might This Impact On Clinical Practice?mentioning

confidence: 99%

International survey of androgen deprivation therapy (ADT) for non-metastatic prostate cancer in 19 countries.

Liede

Hallett

Hope

et al. 2015

JCO

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Background: Continuous androgen deprivation therapy (CADT) is commonly used for patients with non-metastatic prostate cancer as primary therapy for high-risk disease, adjuvant therapy together with radiation or for recurrence after initial local therapy. Intermittent ADT (IADT), a recently developed alternative strategy for providing ADT, is thought to potentially reduce adverse effects, but little is known about practice patterns relating to it. We aimed to describe factors related to physicians' ADT use and modality for patients with non-metastatic prostate cancer.Methods: A 45 min online survey was completed by urologists and oncologists responsible for treatment decisions for non-metastatic prostate cancer from 19 countries with high or increasing prevalence of nonmetastatic prostate cancer.Results: There were 441 treating physicians who completed the survey which represented 99 177 patients with prostate cancer under their care, of which 76 386 (77%) had non-metastatic prostate cancer. Of patients with non-metastatic prostate cancer, 38% received ADT (37% gonadotropin-releasing hormone (GnRH), 2% orchiectomy); among patients on GnRH, 54% received CADT (≥6 without >3 months interruption), 23% IADT and 23% <6 months. Highest rates of ADT were reported among oncologists (62%) and in Eastern Europe (Czech Republic, Hungary and Poland). Prostate-specific antigen (PSA) levels (65%), Gleason score (52%) and treatment guidelines (48%) were the most common reasons for CADT whereas PSA levels (54%), patient request (48%), desire to maintain sexual function (40%), patient age and comorbidities (38%) were cited most frequently as reasons for IADT.

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A review of continuous vs intermittent androgen deprivation therapy: Redefining the gold standard in the treatment of advanced prostate cancer. Myths, facts and new data on a perpetual dispute

Cited by 13 publications

References 46 publications

PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer

PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer

5α-Reductase Inhibition Coupled with Short Off Cycles Increases Survival in the LNCaP Xenograft Prostate Tumor Model on Intermittent Androgen Deprivation Therapy

International survey of androgen deprivation therapy (ADT) for non-metastatic prostate cancer in 19 countries.

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