prostate cancer

Capivasertib combines with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer

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Abstract

Background/objective

To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null and WT prostate tumours.

Methods

Mechanisms associated with docetaxel capivasertib treatment activity in prostate cancer were examined using a panel of in vivo tumour models and cell lines.

Results

Combining docetaxel and capivasertib had increased activity in PTEN null and WT prostate tumour models in vivo. In vitro short-term docetaxel treatment caused cell cycle arrest in the majority of cells. However, a sub-population of docetaxel-persister cells did not undergo G2/M arrest but upregulated phosphorylation of PI3K/AKT pathway effectors GSK3β, p70S6K, 4E-BP1, but to a lesser extent AKT. In vivo acute docetaxel treatment induced p70S6K and 4E-BP1 phosphorylation. Treating PTEN null and WT docetaxel-persister cells with capivasertib reduced PI3K/AKT pathway activation and cell cycle progression. In vitro and in vivo it reduced proliferation and increased apoptosis or DNA damage though effects were more marked in PTEN null cells. Docetaxel-persister cells were partly reliant on GSK3β as a GSK3β inhibitor AZD2858 reversed capivasertib-induced apoptosis and DNA damage.

Conclusion

Capivasertib can enhance anti-tumour effects of docetaxel by targeting residual docetaxel-persister cells, independent of PTEN status, to induce apoptosis and DNA damage in part through GSK3β.

Discussion

Here, we show that combining the AKT inhibitor capivasertib with docetaxel increases anti-tumour effects in PTEN null and PTEN WT prostate tumour models and cell lines. In vivo the combination increased tumour growth inhibition in all models assessed, with significant tumour regressions in 3/6 models. In vitro sequential addition of capivasertib following short-term (24 h) docetaxel incubation reduced cell growth in PTEN null and WT cells. In vitro, acute docetaxel treatment killed a substantial number of cells and induced G2/M arrest. However, in a residual docetaxel-persister cell fraction that remained adherent to the plastic, a dose-dependent increase in phosphorylation of p70S6K, 4E-BP1 and in some cell lines, GSK3β occurred, which was reversed by capivasertib. These cells had progressed through G2/M arrest and remained in cycle without cell division. Generally, capivasertib monotherapy induces a G1/S arrest, and in combination capivasertib reduced cell cycle in docetaxel-persister cells. Moreover in 5/7 cell lines combination treatment increased apoptosis and induction of DNA damage. The fact that the increased apoptosis induced by capivasertib was reversed or reduced by inhibiting GSK3β suggests a direct role for AKT signalling. Although the PI3K/AKT inhibitor taxane combination is effective in preclinical models [1, 46, 47], PI3K-AKT pathway inhibition prior to taxane reduces efficacy as the PI3K-AKT mediated G1/S arrest blocks progression through S phase and G2 where taxanes induce cell death [26]. Inhibiting AKT post-taxane treatment increased tumour growth inhibition in breast, gastric and prostate cancer models [1, 25, 27, 29].

It has been suggested that long term resistance to docetaxel is associated with an increase in AKT phosphorylation [25, 30, 35]. Here in PTEN WT and PTEN null prostate cancer cells, following acute treatment with docetaxel the increased AKT phosphorylation in the docetaxel-persister cells was less apparent in the cell lines tested. Commonly phosphorylation of p70S6K(T421/S424) and 4E-BP1(T37/46), downstream of AKT, was observed. Induction of phospho-GSK3β (S9) was also observed with docetaxel treatment in some cell lines, while in cell lines where increased phosphorylation of GSK3β was less apparent baseline phospho-GSK3β levels were high prior to treatment. Interestingly increased phosphorylation of S6 was not seen in all cell lines, which may indicate that increased PI3K-AKT pathway activation in docetaxel-persister cells influences cell cycle or survival rather than general PI3K-mTOR activation including effects on protein synthesis [36, 48]. Modulation of 4E-BP1 also suggests a cell cycle or cell stress response following docetaxel treatment [37, 38]. One other study has examined the acute response to docetaxel in ER+ breast cancer MCF7 cells where a transient increase in pAKT was observed [49]. However, the induction of signalling downstream of AKT in the absence of increased pAKT signalling has been observed in other settings. In ER+ breast cancer cell lines that have become oestrogen independent following long term oestrogen deprivation, or resistant to the CDK4/6 inhibitor palbociclib increases in pS6 and other markers downstream of AKT are observed but little pAKT is detected or minimal to no change in pAKT [50, 51]. The significance of this warrants further investigation. While the data show persister cells are impacted by capivasertib treatment, we have not performed unbiased phospho-site profiling or reverse phase protein array phospho analysis to look at all changes following docetaxel and combination treatment, therefore changes in other proteins or pathways may be associated with survival of the docetaxel persister cells.

It was clear that across a panel of tumour cells the response to docetaxel and hence the combination was heterogeneous. In vitro combination activity was enhanced in cells with monotherapy sensitivity to capivasertib. However, in vivo additive anti-tumour combination effects were seen in 5 out of 6 models and appeared related to the intrinsic response of tumour models to docetaxel. In models that were more sensitive to docetaxel, capivasertib addition drove regressions, whereas in less sensitive models the combination resulted in cytostatic effects.

Inhibition of AKT signalling can contribute to combination benefit through different mechanisms, and it is possible that more than one mechanism is important in a specific cell line or tumour model. AKT-mediated phosphorylation of GSK3β, p70S6K and 4E-BP1, can enable evasion of apoptosis, cell cycle progression in the face of a G2/M blocker and absence of cell division. These mechanisms may not always be induced by docetaxel, cells may have higher baseline signalling, contributing to both intrinsic and induced resistance that is reduced by capivasertib treatment. For example, high intrinsic GSK3β activity could render docetaxel less effective independent of other PI3K pathway functions. While GSK3β may be an important mediator of persistence following docetaxel treatment, other mechanisms may also contribute, e.g. changes in translation downstream of mTORC1, coupling through 4E-BP1 or alternate non-canonical p70S6K signalling. For example, it is possible that intrinsic activity of AKT in the context of the cell cycle status of the persister cell fraction drives the survival effect. Alternatively pAKT increases may be more transient than the increase seen in GSK3β and p70S6K, but phosphorylation is still regulated by AKT or finally that docetaxel induced cell stress dysregulates phosphatases such as PTEN and PHLPP that control AKT [52, 53]. In addition TSC1, TSC2 [54], and PP2A [55] that regulate P70S6K could also be disrupted which may reduce the activation threshold for signalling molecules down stream of AKT. Indeed, in breast cancer cells reduction of mTORC1-4EBP1 signalling results in a reduction in PTEN protein [56]. It will be important to further evaluate whether other mechanisms that are regulated directly or indirectly by AKT modulation by capivasertib also make a contribution to the combination benefit. Variable sensitivity of prostate cancer cells to taxanes can also be influenced by differences in drug uptake and consequent intracellular levels of drug [57]. Therefore, different features may be important in different cells, and it is likely there is not one single unifying mechanism driving combination benefit. For example, it is possible that on long term treatment there may be engagement of the immune system, changes in the tumour microenvironment (TME) or adaptive responses in the TME, or the tumour cells.

Here, we have examined the acute interaction between docetaxel and capivasertib and sought to mimic the Phase II ProCAID study schedule [23, 24] in vivo and in vitro, but have not assessed prevention of longer-term resistance. The data presented here support the ProCAID study observation that the combination could be broadly effective in prostate cancer. How the pathway is activated remains an interesting question. It may be as a result of cells being in a specific phase of the cell cycle when treated with docetaxel, through inactivation of phosphatase regulation following redox stress, or signalling through other pathways such as activation of DNA damage repair proteins in response to aberrant mitosis [58].

In summary, combining the AKT inhibitor capivasertib with docetaxel in prostate cancer improves anti-tumour effects by targeting the residual surviving cells following docetaxel treatment. The benefit can be driven through different mechanisms downstream of AKT, by reducing AKT mediated cell cycle progression and enhancing induction of apoptosis or DNA damage in cells that persist after docetaxel treatment.

Radioguided Surgery Detects and Removes Metastatic Lymph Nodes in Newly Diagnosed Prostate Cancer Patients

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In patients with newly diagnosed prostate cancer patients, radioguided surgery can detect and remove metastatic pelvic lymph nodes, according to research published in the March issue of The Journal of Nuclear Medicine. Targeting the prostate-specific membrane antigen (PSMA), which is overexpressed in most prostate cancer patients, radioguided surgery can improve nodal staging to guide treatment recommendations for this important patient population.

In newly diagnosed prostate cancer patients, nodal involvement correlates with recurrence, and determining if lymph node metastases are present and where they are located is crucial for clinical decision making and treatment planning. For example, patients with nodal involvement can benefit from adjuvant therapies, such as radiation and chemotherapies, which can improve outcomes.

To date, extended pelvic lymph node dissection (ePLND), a procedure in which as many metastatic lymph nodes as possible are removed from the pelvic area, is considered the best tool for nodal staging. Although the therapeutic effect of ePLND in prostate cancer patients is controversial, evidence suggests that removal of all nodal metastases could maximize locoregional disease control.

“PSMA-radioguided surgery can aid the surgeon in accurately finding and removing all metastatic lymph nodes in newly diagnosed prostate cancer patients. This is specifically important to detect positive lymph nodes just outside the standard pelvic surgical area, or in surgically challenging regions, that would have been missed otherwise,” said Diederik M. Somford, MD, PhD, urologist and principal investigator at the Canisius Wilhelmina Hospital in Nijmegen, Netherlands.

The study included 20 newly diagnosed prostate cancer patients with at least one suggestive lymph node visible on a preoperative 18F-PSMA PET/CT scan. 111In-PSMA-radioguided surgery was performed to remove metastatic lymph nodes, and a postoperative 18F-PSMA PET/CT scan was performed to verify successful removal of suggestive lesions. The safety and feasibility of 111In-PSMA-radioguided surgery was assessed, as well as its accuracy in determining metastatic lymph nodes.

No adverse events related to 111In-PSMA-radioguided surgery were reported. 111In-PSMA radioguided surgery identified and removed 29 of 49 lesions, of which 28 (97 percent) contained lymph node metastases. Another 14 of 49 (29 percent) removed lymph nodes were not detected with 111In-PSMA radioguided surgery, of which two contained metastases.

“Although previous studies have reported on the feasibility of PSMA-radioguided pelvic lymph node surgery, this study is among the first trials to investigate this technique in a larger number newly diagnosed patients,” said Melline G.M. Schilham, MD, executive researcher at the Radboud University Medical Centre in Nijmegen, Netherlands. “The study shows that this novel surgical technique is safe and feasible. Furthermore, each patient underwent postoperative imaging to check whether the lymph nodes were truly removed, which is important to substantiate the reliability of the results.”

“The current results demonstrate the great potential for radioguided surgery in prostate cancer and highlight the expanding role of molecular imaging at the operating room,” noted Mark Rijpkema, PhD, principal investigator at the Radboud University Medical Centre. “Optimization of tracers and larger clinical trials may further improve surgical outcomes in the future by implementing both measurements of removed tissue, as well as real-time measurements during surgery.”

Identifying the tumor immune microenvironment-associated prognostic genes for prostate cancer

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Abstract

Purpose

This study aimed to explore novel tumor immune microenvironment (TIME)-associated biomarkers in prostate adenocarcinoma (PRAD).

Methods

PRAD RNA-sequencing data were obtained from UCSC Xena database as the training dataset. The ESTIMATE package was used to evaluate stromal, immune, and tumor purity scores. Differentially expressed genes (DEGs) related to TIME were screened using the immune and stromal scores. Gene functions were analyzed using DAVID. The LASSO method was performed to screen prognostic TIME-related genes. Kaplan–Meier curves were used to evaluate the prognosis of samples. The correlation between the screened genes and immune cell infiltration was explored using Tumor IMmune Estimation Resource. The GSE70768 dataset from the Gene Expression Omnibus was used to validate the expression of the screened genes.

Results

The ESTIMATE results revealed that high immune, stromal, and ESTIMATE scores and low tumor purity had better prognoses. Function analysis indicated that DEGs are involved in the cytokine–cytokine receptor interaction signaling pathway. In TIME-related DEGs, METTL7B, HOXB8, and TREM1 were closely related to the prognosis. Samples with low expression levels of METTL7B, HOXB8, and TREM1 had better survival times. Similarly, both the validation dataset and qRT-PCR suggested that METTL7B, HOXB8, and TREM1 were significantly decreased. The three genes showed a positive correlation with immune infiltration.

Conclusions

This study identified three TIME-related genes, namely, METTL7B, HOXB8, and TREM1, which correlated with the prognosis of patients with PRAD. Targeting the TIME-related genes might have important clinical implications when making decisions for immunotherapy in PRAD.

1 Introduction

Prostate adenocarcinoma (PRAD) remains the leading cause of cancer related mortality among men in the United States [1]. Despite advances in clinical care, mortality rates remain high, indicating a need for better understanding of the factors influencing PRAD prognosis and treatment response [2, 3].

Recent evidence suggests that PRAD prognosis is heavily dependent on the tumor microenvironment [4]. The tumor immune microenvironment (TIME), comprised of extracellular matrix, stromal cells, and other tumor associated cells, can modulate the tumor’s response to therapy and can influence the progression of the tumor [5]. TIME has been reported to profoundly influence the growth and metastasis of cancer. It affects prognosis, tumor growth, and treatment response through a variety of mechanisms [6]. The composition of the tumor microenvironment can affect prognosis by influencing the proliferation, metastasis, and drug resistance of cancer cells [7]. Factors like the abundance of immune cells, angiogenesis (new blood vessel formation), and cytokines (types of proteins) released by the environment can either inhibit or promote the growth of cancer cells [8]. These signals can also have a large impact on how a patient responds to treatment; for example, certain treatments may be targeted more directly at immunoprivileged environments, and certain drugs tested in preclinical trials may not reach the tumor due to an immunosuppressive microenvironment [9]. In terms of tumor growth, TIME affect the rate of metastasis, and provide signals for cell growth, movement, and survival [10]. TIME could also be a source of genetic mutations, which can lead to the selection of drug resistant tumor cells [11]. Additionally, the presence of certain immune cells can influence the growth and progression of tumors [12]. Finally, the microenvironment can also influence response to treatments. Factors like hypoxia (low oxygen) or the immune cell composition can affect the effectiveness of certain therapies [13]. Additionally, certain signaling pathways in the microenvironment can be targeted by drugs to suppress tumor growth and improve outcomes [14]. Overall, the tumor microenvironment is an essential component of tumor biology and can affect the prognosis, growth, and response to treatments of cancer.

In this study, we downloaded the PRAD RNA-sequencing (RNA-seq) data from the UCSC Xena database. Then, the ESTIMATE method was employed to analyze the immune and stromal scores and tumor purity of PRAD samples. In addition, we analyzed the correlation between TIME and clinical information, from which we obtained the novel TIME-related prognostic genes for PRAD.

Discussion

Multiple factors, stages, and genes are involved in the occurrence and development of PRAD, where TIME is an important factor. Recently, immunotherapy was the novel treatment for PRAD tumors, whereas the clinical outcome was related to the characteristics of malignant tumors, such as hormone dependence, low tumor mutation load, and immunosuppressive microenvironment. Besides, previous studies have found that TIME correlated with the prognosis of patients with PRAD [27]. Thus, further exploration of TIME in PRAD was significant to help doctors make decisions about the treatment method and predict the prognosis for PRAD.

The results of this study revealed that the PRAD samples with high immune and stromal scores had a better prognosis, and those with high tumor purity had a worse prognosis. In addition, we collected the OS, RFS, and DFS of samples to examine the correlation in immune and stromal scores and survival time using KM curves. The results obtained were similar to the ESTIMATE results. These observations were consistent with the results of previous studies. For example, Chen et al. [28] suggested that stromal, immune, and ESTIMATE scores closely correlated with the OS of patients with PRAD. In addition, similar results were obtained in multiple cancer types, such as breast cancer, bladder cancer, and lung adenocarcinoma, indicating that the stromal, immune, and ESTIMATE scores and tumor purity in TIME played a significant role in immunotherapy [29,30,31]. Xiang et al. [32] indicated that the stromal, immune, and ESTIMATE scores and tumor purity in the microenvironment were associated with TIME. Thus, our study screened TIME-related DEGs by comparing stromal scores and immune scores. Subsequently, 1229 TIME-related DEGs were screened using the limma package. GO BP results indicated the involvement of DEGs in the immune response. Immune response regulated the development of PRAD tumors, which played an important role when making decisions for immunotherapy [33, 34]. The DEGs might be novel biomarkers for treating PRAD. In addition, KEGG results indicated that the DEGs were related to the cytokine–cytokine receptor interaction pathway. Previous studies have found that this pathway always involved some immune-related genes that are involved in different cancers, such as renal cell carcinoma and hepatocellular carcinoma [35, 36]. This pathway might be an important factor in the immunotherapy for PRAD. Further experiments must be performed to understand the mechanism of immunotherapy in PRAD.

Previous studies have indicated that the TIME was related to the prognosis of patients with PRAD. In this study, three prognostic DEGs, namely, METTL7B, HOXB8, and TREM1, were identified. The KM curves were used to evaluate the correlation between the three DEGs and patient prognosis, suggesting that patients with low expression levels of METTL7B, HOXB8, and TREM1 had good OS, RFS, and DFS. The results were validated using the external cohort, which obtained the same results as TCGA dataset. Our results were similar with the previous studies that have used external cohorts to validated the prognostic value of the biomarkers in PRAD [37,38,39]. The method further confirmed the results in this study. This novel TIME hub genes-related risk score model provides a new theoretical basis for the prognosis assessment of PRAD patients, which is expected to be further applied in the future clinical management. A prospective study of clinical cohorts recruiting PRAD patients in different stage will help validating this risk score model. The expression of METTL7B, HOXB8, and TREM1 was examined each month. Then, the follow-up was performed to observe the prognosis of PRAD patients. The KM curves and survival analysis will be carried out to the correlation between risk score model and prognosis. This study is expected to be conducted for 5 years or even longer to obtain good persuasiveness.

Meanwhile, significant differences in METTL7B, HOXB8, and TREM1 were found between the controls and tumor samples in both mRNA levels. The three genes might be novel TIME-related biomarkers for PRAD. METTL7B, an alkyl thiol methyltransferase, could metabolize hydrogen sulfide (H2S) [40]. H2S was found to participate in the epithelial–mesenchymal transition and tumor migration and invasion [41]. A recent study found that the expression of METTL7B positively correlated with immunosuppressive cells suggesting that it might play a significant role in modulating TIME [42]. Meanwhile, METTL7B expression was positively associated with CD4 + T cells and dendritic cells. All the results indicated that METTL7B could be used to predict the TIME in PRAD. Moreover, Redecke et al. [43] reported that HOXB8 transfected in mouse bone marrow cells with unlimited proliferative capacity that could enable investigations of immune cell differentiation and function. This study found that HOXB8 is closely correlated with CD4 + T cells. Besides, Zhao et al. [44] pointed out that high expression levels of TREM1 had improved the infiltration of regulatory T cells and reduced the infiltration of CD8 + T cells. Similarly, this study found that the expression of TREM1 could regulate the TIME, including neutrophils and dendritic cells. Previous studies have suggested that CD4 + T cells, CD8 + T cells, neutrophils, and dendritic cells are associated with the impairment of proliferation, cytokine production, and migratory capacities of effector T cells [45]. Besides, Meng et al. [46] firstly pointed out the infiltration of immunocytes among PRAD via the CIBERSORT algorithm. This study indicated that M2 macrophages was related to gene markers, whick could predict the prognosis of PRAD patients. These results were consistent with our study that we found that METTL7B, HOXB8, and TREM1 were positively correlated with M2 macrophages. Regulating the expression levels of METTL7B, HOXB8, and TREM1 may have remarkable clinical applications in enhancing immunotherapy. Immunotherapy has shown good prospects in treating cancer. We will continue to focus on the genes related to tumor microenvironment of PRAD in the future. Further exploration on genes related to tumor microenvironment will help treating patients with PRAD using immunotherapy as soon. Thus, more experiments such as mice experiments, molecular biology research and clinical test need be performed to validate these results in this study.

5 Conclusions

This study explored the expression levels of three TIME-related genes including METTL7B, HOXB8, and TREM1, which correlated with the prognosis of patients with PRAD. Moreover, targeting the TIME-related genes might have important clinical implications when making decisions for immunotherapy in PRAD.

Long-Term Exposure to Nitrate and Trihalomethanes in Drinking Water and Prostate Cancer: A Multicase-Control Study in Spain (MCC-Spain)

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Abstract

Background: Nitrate and trihalomethanes (THMs) in drinking water are widespread and are potential human carcinogens.

Objective: We evaluated the association between drinking-water exposure to nitrate and THMs and prostate cancer.

Methods: During the period 2008-2013, 697 hospital-based incident prostate cancer cases (97 aggressive tumors) and 927 population-based controls were recruited in Spain, providing information on residential histories and type of water consumed. Average nitrate and THMs levels in drinking water were linked with lifetime water consumption to calculate waterborne ingestion. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using mixed models with recruitment area as random effect. Effect modification by tumor grade (Gleason score), age, education, lifestyle, and dietary factors was explored.

Results: Mean (±standard deviation) adult lifetime waterborne ingested nitrate (milligrams per day), brominated (Br)-THMs (micrograms per day), and chloroform (micrograms per day) were 11.5 (±9.0), 20.7 (±32.4), and 15.1 (±14.7) in controls. Waterborne ingested nitrate >13.8 vs. <5.5mg/d was associated with an OR of 1.74 (95% CI: 1.19, 2.54) overall, and 2.78 (95% CI: 1.23, 6.27) for tumors with Gleason scores ≥8

. Associations were higher in the youngest and those with lower intakes of fiber, fruit/vegetables, and vitamin C. Waterborne ingested THMs were not associated with prostate cancer. Residential tap water levels of Br-THMs and chloroform showed, respectively, inverse and positive associations with prostate cancer.

Conclusions: Findings suggest long-term waterborne ingested nitrate could be a risk factor of prostate cancer, particularly for aggressive tumors. High intakes of fiber, fruit/vegetables and vitamin C may lower this risk. Association with residential levels but not ingested chloroform/Br-THM may suggest inhalation and dermal routes could be relevant for prostate cancer.

More Evidence Linking ADT for Prostate Cancer to Adverse Neurocognitive Effect

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Meta-analysis shows increased risk of dementia, Parkinson’s, depression

A computer rendering of prostate cancer.

Men treated with androgen deprivation therapy (ADT) for prostate cancer had a significantly higher risk of dementia and other neurocognitive disorders, according to a meta-analysis of more than 2.5 million patients.

The magnitude of excess risk ranged from 20% for dementia to 66% for depression. The risk of Alzheimer’s disease, vascular dementia, and Parkinson’s disease were all significantly increased among men exposed to ADT versus those who did not receive the hormonal therapy, including those with and without prostate cancer.

“The increased risk of dementia is observed regardless of the treatment modality and duration; however, quantitative analysis is needed to assess the differences between treatment modalities and durations accurately,” concluded David E. Hinojosa-Gonzalez, MD, of Massachusetts General Hospital in Boston, and colleagues in Prostate Cancer and Prostatic Diseasesopens in a new tab or window. “It is important to note that some studies may have used similar databases and overlapping patient cohorts, which could introduce potential bias or duplicate data in this analysis.”

“Clinicians should be vigilant in monitoring prostate cancer patients undergoing ADT for symptoms of cognitive decline and other neurodegenerative disorders,” they added.

The findings add to a large volume of data on the relationship between ADT and neurocognitive functioning. Dozens of studies and reviews have examined the relationship without producing definitive answers. For example, another recent systematic review and meta-analysisopens in a new tab or window included 31 studies, 16 of which showed no association between ADT and cognitive function; 11 of which showed a negative effect on one or more outcomes; and four that yielded inconclusive results.

Another systematic review showed no consistencyopens in a new tab or window among studies, many of which were retrospective. Authors of yet another reviewopens in a new tab or window published just last year concluded that “studies continue to illustrate the varied outcomes in terms of the association of ADT and other systemic treatments for [prostate cancer] with cognitive decline, despite similar methodologies and design. Patient selection, varied neuropsychological testing, and varied duration of ADT probably account for the differences seen.”

Numerous individual studies have yielded suggestive evidence of negative impact of ADT on cognitive function. A review of a national drug-safety databaseopens in a new tab or window showed that men treated with ADT had a 47% higher likelihood of cognitive impairment versus men who did not receive hormonal therapy. The risk was even higher in men treated with newer androgen receptor signaling inhibitors (ARSIs), but the association was not consistent across the ARSI class: increased risk with enzalutamide (Xtandi) and apalutamide (Erleada) but decreased risk with abiraterone (Zytiga).

Prostate cancer specialists note that consideration of the potential adverse effects of ARSIs on cognition should be balanced by consideration of potentially significant clinical benefits. In the landmark ENZAMET trialopens in a new tab or window, enzalutamide was associated with a significant decline in cognitive function but also with a significant improvement in survival for men with metastatic hormone-sensitive prostate cancer, which “outweighed early deterioration in [health-related quality of life].”

Noting the inconsistent and sometimes conflicting evidence reported to date, Hinojosa-Gonzalez and colleagues performed a systematic review of contemporary studies examining the relationship between ADT and neurocognitive function, including dementia, Alzheimer’s disease, vascular dementia, and Parkinson’s disease.

The analysis included studies published through April 2023. Beginning with an initial list of 305 studies, the authors trimmed the number to 27. The studies involved a total of 2,543,483 patients, including 900,994 with prostate cancer treated with ADT, 1,262,905 with prostate cancer not treated with ADT, and 334,682 men without prostate cancer or exposure to ADT.

The data showed that treatment with ADT was associated with significantly increased hazard ratios (HRs) for:

  • Dementia: HR 1.20 (95% CI 1.11-1.29, P<0.00001)
  • Alzheimer’s disease: HR 1.26 (95% CI 1.10-1.43, P=0.0007)
  • Depression: HR 1.66 (95% CI 1.40-1.97, P<0.00001)
  • Parkinson’s disease: HR 1.57 (95% CI 1.31-1.88, P<0.00001)

Additionally, ADT conferred an increased risk of vascular dementia (HR 1.30, 95% CI 0.97-1.73, P<0.00001).

“All analyzed treatment modalities showed an increased risk of dementia,” the authors noted in their discussion. “Orchiectomy had the highest estimated risk; however, it is important to note that this treatment modality also had the least evidence. Furthermore, the employed methodology does not differentiate whether there are statistical differences between types of ADT. Future studies should incorporate comparisons of treatment modalities into the results using network analysis or similar approaches.”

Zinc protects prostate cells by acting as a tumor suppressor

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In the landscape of male cancers, prostate cancer looms large, ranking as the second most common cancer after skin malignancies among American men.  The American Cancer Society’s projections for 2023 paint a stark picture, with approximately 288,300 new cases of prostate cancer and about 34,700 deaths attributed to the disease.

While the incidence of prostate cancer saw a significant decline between 2007 and 2014, reflecting changes in screening recommendations, a recent shift has emerged.  Since 2014, the overall incidence rate has risen by 3% per year, with an even more notable 5% annual increase in advanced-stage prostate cancer cases.  This nuanced scenario sets the stage for exploring proactive strategies, with recent studies spotlighting zinc as a potential guardian against this prevalent disease.

Elevating health defenses against prostate woes

Long heralded for its integral role in immune function and cellular metabolism, this trace mineral has been a stalwart ally in maintaining health.  Traditionally, the recommended daily intake for men has stood at 11 mg, sourced from either dietary choices or supplements.  Yet, recent research unveils a tantalizing prospect: a higher daily zinc dosage might wield the ability to quell prostate tumors, act as a preventive shield against cancer, and fortify defenses against advanced prostate disease.

Crucial to note is the revelation that zinc levels are notably lower in cancerous prostate tissue, adding a layer of significance to the mineral’s potential role in prostate health.

Prostate tissues boast higher concentrations of zinc than any other part of the body, with approximately 10 to 15 times the amount found elsewhere.  This revelation fuels the emerging narrative that a strategic elevation in zinc intake could be a game-changer in the fight against prostate-related health concerns.

What does science have to say about zinc?

Researchers have long suspected that zinc offers at least some protection against prostate cancer, and now science is backing them up.  Studies suggest that high concentrations of zinc can cause apoptosis of damaged prostate cells that could otherwise turn cancerous.

Researchers also found that zinc actually alters the biological makeup of prostate cells, significantly reducing the chance of malignancy.  Conversely, researchers examining existing prostate cancer cells find that zinc levels are lower in malignant cells than in non-cancerous prostate cells.

How to use zinc to keep cancer away

The benefits of zinc can be achieved by taking the mineral as a dietary supplement or by consuming it through one of several food sources.  Oysters are perhaps the highest food source for zinc, with 74 mg per serving.  Grass-fed beef is next, followed by baked beans, and yogurt (preferably of organic varieties).

It is important to note that taking too much zinc is not only non-beneficial, but it can also have a harmful effect on a person’s health and immune system.  In fact, a study published in the Journal of the National Cancer Institute found that consuming zinc in amounts of 150 mg per day or more actually increased a man’s risk of developing advanced prostate cancer.

Naturally, if you’re dealing with a cancer diagnosis – seek the advice of a trusted, holistic medical professional.

Prophylactic Radiation Therapy Versus Standard of Care for Patients With High-Risk Asymptomatic Bone Metastases: A Multicenter, Randomized Phase II Clinical Trial

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ABSTRACT

PURPOSE

External-beam radiation therapy (RT) is standard of care (SOC) for pain relief of symptomatic bone metastases. We aimed to evaluate the efficacy of radiation to asymptomatic bone metastases in preventing skeletal-related events (SRE).

METHODS

In a multicenter randomized controlled trial, adult patients with widely metastatic solid tumor malignancies were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to receive RT to asymptomatic high-risk bone metastases or SOC alone. The primary outcome of the trial was SRE. Secondary outcomes included hospitalizations for SRE and overall survival (OS).

RESULTS

A total of 78 patients with 122 high-risk bone metastases were enrolled between May 8, 2018, and August 9, 2021, at three institutions across an affiliated cancer network in the United States. Seventy-three patients were evaluable for the primary end point. The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). At 1 year, SRE occurred in one of 62 bone metastases (1.6%) in the RT arm and 14 of 49 bone metastases (29%) in the SOC arm (P < .001). There were significantly fewer patients hospitalized for SRE in the RT arm compared with the SOC arm (0 v 4, P = .045). At a median follow-up of 2.5 years, OS was significantly longer in the RT arm (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.89; P = .018), which persisted on multivariable Cox regression analysis (HR, 0.46; 95% CI, 0.23 to 0.85; P = .01).

CONCLUSION

Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced SRE and hospitalizations. We also observed an improvement in OS with prophylactic radiation, although a confirmatory phase III trial is warranted.

© 2023 by American Society of Clinical Oncology

CONTEXT

  • Key Objective
  • To determine if prophylactic radiation to asymptomatic high-risk bone metastases reduces the incidence of skeletal-related events (SRE), including pathologic fracture, spinal cord compression, orthopedic surgery to bone, and/or palliative radiation therapy for pain.
  • Knowledge Generated
  • In this multicenter randomized controlled trial conducted in the United States that included 78 adult patients with metastatic solid tumor malignancies, radiation reduced SRE at 1 year from 29% to 1.6% compared with standard of care. Additionally, overall survival was extended with use of radiation (median 1.7 v 1.0 years) with a hazard ratio 0.49, which maintained significance on adjusted analysis.
  • Relevance (B.G. Haffty)
  • This randomized phase II trial is relevant in demonstrating statistically and clinically significant decreases in SRE including pathological fracture, spinal cord compression, or orthopedic intervention with prophylactic radiation to asymptomatic but high risk bone metastasis.*

Immune Checkpoint Inhibitor Therapy Before Nephrectomy for Locally Advanced and Metastatic Renal Cell Carcinoma

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Abstract

Importance  The therapeutic landscape of advanced renal cell carcinoma (RCC) has rapidly evolved in the past 2 decades, with the advent of cytokines therapy followed by targeted therapies and novel immune checkpoint inhibitors (ICI). This article aims to review the current evidence and ongoing trials of neoadjuvant or prenephrectomy ICI therapy in patients with locally advanced and metastatic RCC.

Observations  A literature search was performed using the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and PubMed as well as relevant medical society meetings for English-language studies, articles, and abstracts published before January 31, 2023. Currently, level I evidence supports the use of ICI-based combination therapy as the first-line treatment of patients with metastatic RCC with the potential option of deferred nephrectomy in those who respond to treatment. Nevertheless, limited prospective data are available regarding the role and outcomes of nephrectomy (cytoreductive or consolidative) in conjunction with ICI therapy in both metastatic and locally advanced RCC. Although data from retrospective case series confirmed the feasibility and safety of deferred nephrectomy in this setting, the sequence of nephrectomy and whether it should be considered in patients with metastatic RCC is a common clinical dilemma. However, although neoadjuvant targeted therapy for nonmetastatic RCCs has been associated with some advantages yet not accepted as a standard, current data from a phase 3 randomized clinical trial failed to demonstrate the oncologic benefit of neoadjuvant nivolumab for locally advanced RCC.

Conclusion and Relevance  The findings of this review suggest that ICI-based combination therapy is the standard of care as the first-line treatment of patients with metastatic RCC. However, the role of neoadjuvant ICIs in locally advanced RCC is an active area of investigation. Deferred nephrectomy after ICI-based immunotherapy for metastatic RCC is feasible and safe yet should be performed in high-volume health centers by experienced surgeons. The multidisciplinary and careful approach is critical for treatment decisions.

Pumpkin Seed Extract Safely Relieves Prostate Symptoms

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A new clinical trial published in the Journal of Medicinal Food demonstrates that supplementation with an oil-free pumpkin seed extract significantly reduces urinary symptoms related to benign prostatic hyperplasia (BPH).1

BPH involves prostate enlargement obstructing urine flow, causing frequent and urgent urination, straining and retention issues. Phytotherapies like pumpkin seeds are often used, but limited quality evidence exists validating traditional use.  

In this rigorously designed 12-week study, 60 men with moderate-severe BPH symptoms took either a pumpkin seed extract tablet or nothing daily. Multiple metrics assessed outcomes including urinary flow, frequency and discomfort questionnaires. 

Remarkably, the pumpkin seed extract reduced overall symptoms by 30%, increased quality of life by over 60%, and noticeably decreased nighttime bathroom visits. It also shrank participants’ post-urination retained bladder volume indicating improved emptying. Benefits started within 4 weeks, strengthening over the 12 weeks.

No negative changes occurred in clinical safety markers, with the extract demonstrating excellent tolerability. The majority of men conveyed an overall reduction in BPH issues, particularly less frequent and urgent urination. 

Unlike prior studies investigating pumpkin seed powders or oils, this novel extract uniquely excludes fats and utilizes hydroethanol to capture water-soluble bioactive compounds. Researchers suggest anti-inflammatory, hormone regulating and muscle relaxing actions likely contribute to symptom relief without side effects. 

For prostate sufferers wishing to avoid medications, this rigorous data validates pumpkin seed extracts as an effective option providing rapid respite. While follow-up placebo-controlled studies are warranted, the profound benefits and safety revealed solidify this phytotherapy’s substantial therapeutic promise.

This adds to previous successes with pumpkin seeds improving overactive bladder and hormone imbalances in women. As a clinically-verified source of prostate support for men, pumpkin seed extracts enable expanding integrative care as a first-line approach before conventional treatments.

Prostate cancer treatments can be avoided or delayed in many cases, study finds

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  • A new long-term study finds a 97% survival rate among men with prostate cancer at 15 years, regardless of whether the disease was treated or not.
  • While it can be difficult to decide on one’s response when faced with a prostate cancer diagnosis, the study suggests that the decision need not be too frightening.
  • Men who decided not to be treated experienced double the chance of eventual metastasis, but even that did not lower their rate of survival.

When a man is diagnosed with prostate cancer, he has two choices to make. He may choose to be treated or to keep a watchful eye on the often slowly progressing disease. If he selects treatment, he then must decide on the type of treatment that seems most suitable.

New research presented this month at the European Association of Urology (EAU) Congress in Milan, Italy reports the results of a study comparing the outcomes associated with each of these choices. The study is the longest-running of its kind.

The study found that 97% of men diagnosed with prostate cancer remained alive at the end of the 15-year study, regardless of whether they were treated or the type of treatment they received.

While the course of their disease varied somewhat depending on their decision, even men whose cancer had metastasized survived.

The study tracked 1,643 men in the United Kingdom aged 50–69 years who were diagnosed with prostate cancer between 1999 and 2009 based on the results of a PSA blood testTrusted Source.

As part of the study, participants agreed to be randomly assigned to actively monitor their disease, radical prostatectomy surgery, or radical radiation-based therapy.

The study appears in the New England Journal of Medicine.

Prostate-specific antigen testing

The PSA or prostate-specific antigen blood test itself is somewhat controversial.

The study’s lead author, Dr. Freddie Hamdy, explained that PSA tests “can be followed by a snowball of further testing, including biopsies of the prostate.” If cancer is found, he said, it is likely localized and low risk.

“With this testing,” Dr. Hamdy warned, a ‘healthy’ man can become a ‘cancer patient’ unnecessarily.”

With this in mind, the U. S. Preventive Services Task Force on Prostate CancerTrusted Source recommended about a decade ago that physicians stop including PSA screenings in checkup bloodwork. Since then, however, diagnoses of advanced prostate cancer detected by other means have significantly increasedTrusted Source, and many physicians have resumed ordering PSA tests for their patients.

Options for people with prostate cancer

Prostate cancer most often — though not always — progresses slowly, taking many years to spread or metastasize beyond the prostate.

The three most common medical responses to a diagnosis of prostate cancer are:

  • active monitoring — in which the cancer is closely monitored through PSA testing and regular prostate biopsies, moving to active treatment only if symptoms arise or cancer grows.
  • radical prostatectomy — in which the entire prostate, and presumably cancer, is removed.
  • radical radiotherapy — the prostate is treated with radiation to kill cancer.

Both radical prostatectomy and radical radiotherapy are frequently accompanied by lifestyle-altering adverse effects, such as erectile, urinary, and bowel dysfunction.

The new study found that adverse effects from prostatectomy and radiation can last 12 years or more.

“Nowadays, it’s not just radiation or surgery that are the options,” noted Dr. Adam Ramin, who was not involved in the study.

“The advantage of that is that in many instances we can actually convert prostate cancer into a chronic disease, you know, just like diabetes or hypertension,” Dr. Ramin said.

He noted that there are many men who may be good candidates for a treatment option called focal therapy. Focal therapy targets cancer through various means, including high intensity focused ultrasound, cryotherapy, laser ablation, and photodynamic therapy.

While the study found that men who opted for active monitoring were twice as likely to see it progress or metastasis, few of them died during the follow-up period.

Of the men who participated in active monitoring, cancer in 9.4% metastasized, compared to men who received a prostatectomy (4.7%) or radiation (5.0%).

For men whose cancer metastasizes, Dr. Ramin reported that while chemotherapies have not changed much over the years, there have been advances in hormonal manipulation-type therapies or androgen suppression therapiesTrusted Source.

“Ten, 15 years ago, we only had one or two different kinds of hormone therapies,” he said. “Now, there’s a whole slew of them which work through different mechanisms.”

Dr. Benjamin H. Kann, also not involved in the study, added:

“New systemic therapies helpful for the metastatic disease include (177)-lutetium-PSMA-617, a radiopharmaceutical that selectively attaches to a specific protein on prostate cancer cell surfaces and destroys the cell.”

Deciding on prostate cancer treatment

“The two most important factors are what we call the stage and the grade of the cancer, and how advanced the cancer is great means how aggressive the cancer is,” said Dr. Ramin.

Dr. Ramin noted that molecular studies performed on biopsied tissue could provide better prognosis indicators in assessing whether a person is a suitable candidate for active monitoring or not.

One of the study’s findings was that because of advances in diagnostic techniques, many of the men who were diagnosed as being at low risk of metastasis years ago would now be diagnosed at intermediate risk.

Dr. Hamdy told the EAU in a press release:

“It’s clear that, unlike many other cancers, a diagnosis of prostate cancer should not be a cause for panic or rushed decision-making.

Patients and clinicians can and should take their time to weigh up the benefits and possible harms of different treatments in the knowledge that this will not adversely affect their survival.”

Dr. Kann said another factor is the person’s overall health and apparent life expectancy: “Men with shorter life expectancies due to age or other significant health issues may be more appropriate to monitor.”

Beyond that, Dr. Hamdy told Medical News Today, the choice may depend on a man’s “priorities in life, their other medical conditions (if any) and fitness, and measuring the ‘trade-off’ between treatment benefits and potential harms, particularly with sexual function, urinary leakage, and bowel symptoms.”