The evolving role of diet in prostate cancer risk and progression.

PURPOSE OF REVIEW: This overview examines the rationale for dietary interventions for prostate cancer by summarizing the current evidence base and biological mechanisms for the involvement of diet in disease incidence and progression. RECENT FINDINGS: Recent data have further solidified the association between insulin resistance and prostate cancer with the homeostatic model assessment of insulin resistance. Data also show that periprostatic adipocytes promote extracapsular extension of prostate cancer through chemokines, thereby providing a mechanistic explanation for the association observed between obesity and high-grade cancer. Regarding therapeutics, hyperinsulinemia may be the cause of resistance to phosphatidylinositol-3 kinase inhibitors in the treatment of prostate cancer, leading to new investigations combining these drugs with ketogenic diets. SUMMARY: Given the recently available data regarding insulin resistance and adipokine influence on prostate cancer, dietary strategies targeting metabolic syndrome, diabetes, and obesity should be further explored. In macronutrient-focused therapies, low carbohydrate/ketogenic diets should be favored in such interventions because of their superior impact on weight loss and metabolic parameters and encouraging clinical data. Micronutrients, including the carotenoid lycopene which is found in highest concentrations in tomatoes, may also play a role in prostate cancer prevention and prognosis through complementary metabolic mechanisms. The interplay between genetics, diet, and prostate cancer is an area of emerging focus that might help optimize therapeutic dietary response in the future through personalization.

[Metronomic chemotherapy with oral cyclophosphamide : An individual option for the metastatic castration-resistant prostate cancer patient?] / Metronomische Chemotherapie mit oralem Cyclophosphamid : Eine individuelle Option für den metastasierten kastrationsresistenten Prostatakarzinompatienten?

BACKGROUND: Multiple experimental approaches are meanwhile available for progressive metastatic castration resistant prostate cancer (mCRPC) patients after failure of guideline recommended therapy (i. e., chemotherapy and/or hormonal treatment). We evaluated the outcome of metronomic chemotherapy with cyclophosphamide (CY) in combination with low-dose prednisolone. MATERIALS AND METHODS: A total of 14 mCRPC-patients were treated with CY 50 mg/day (plus prednisolone 10 mg/day) between November 2012 and September 2017 after being resistant or unfit for chemotherapy and/or further hormonal treatment. Time to progression and overall survival (OS) were retrospectively determined by using Kaplan-Meier curves. RESULTS: Eight of 14 (57.1%) patients had undergone radical prostatectomy and 2 (14.3%) external beam radiation. All patients had at least three therapy lines and 50% had ≥5 mCRPC therapies. The median time from first diagnosis to mCRPC was 88 months; the median age was 78 years with a median baseline serum prostate-specific antigen (PSA) level of 341 ng/ml. With a median follow-up of 16.4 months, progression-free survival (PFS) was 71, 64, and 43% after 2, 4, and 6 months, respectively. Median OS was 8.1 months. No relevant adverse events occurred. CONCLUSION: Since CY is a well-tolerated medication with partially good clinical tumor control, it seems to be a convenient, individual treatment option in progressive mCRPC patients after failure of guideline recommended therapy.

Efficacy of Eplerenone in the Management of Mineralocorticoid Excess in Men With Metastatic Castration-resistant Prostate Cancer Treated With Abiraterone Without Prednisone.

BACKGROUND: Abiraterone acetate has been approved for metastatic castration-resistant prostate cancer (mCRPC). Coadministration with prednisone has been recommended to prevent the toxicity from secondary mineralocorticoid excess, such as hypertension, hypokalemia, and edema. However, the use of prednisone is often not desired by patients because of the potential for detrimental effects of long-term therapy with corticosteroids, especially in those with comorbidities such as diabetes or who have received previous immunotherapeutic agents. Eplerenone is a nonsteroidal mineralocorticoid antagonist demonstrated to abrogate mineralocorticoid excess. In the present retrospective study, we report our real-world experience with the use of eplerenone with abiraterone in men with mCRPC who wished to avoid concomitant prednisone therapy. PATIENTS AND METHODS: The incidence and grade (Common Terminology Criteria for Adverse Events, version 4) of mineralocorticoid excess toxicities, baseline demographics, disease characteristics, and progression-free survival (PFS) were collected retrospectively. The patient population included men with mCRPC treated with abiraterone, who were not willing to receive corticosteroids, and thus received eplerenone. Their data were compared with the data from those treated with abiraterone and prednisone during the same period. Continuous variables were assessed using the Wilcoxon rank sum test or Student t test, and categorical variables were assessed using Fischer's exact test or χ2 test, as appropriate. PFS was compared using the Kaplan-Meier method. RESULTS: Of the 106 men treated with abiraterone, 40 received eplerenone and 66 received prednisone. The baseline and disease characteristics, incidence and grade of adverse events related to the syndrome of mineralocorticoid excess, and the median PFS were similar in both cohorts. CONCLUSION: In a real-world population of men with mCRPC treated with abiraterone, corticosteroids can be avoided by concomitant treatment with eplerenone. These data require further validation.

Understanding taxanes in prostate cancer; importance of intratumoral drug accumulation.

BACKGROUND: Resistance to docetaxel is common in metastatic castration-resistant prostate cancer (mCRPC) and may be caused by sub-therapeutic intratumoral drug concentrations. Cabazitaxel demonstrated survival benefit in docetaxel-pretreated and docetaxel-refractory patients. In this study, we investigated whether the superior antitumor activity of cabazitaxel in mCRPC is explained by higher intratumoral cabazitaxel levels. Since recent studies suggest a reduced efficacy of docetaxel following treatment with novel androgen receptor (AR)-targeted agents, we also investigated taxane efficacy in an enzalutamide-resistant tumor model. METHODS: Intratumoral concentrations of docetaxel and cabazitaxel were correlated with antitumor activity in docetaxel-naïve, docetaxel-resistant, and enzalutamide-resistant patient-derived xenografts (PDXs) of prostate cancer. RESULTS: Intratumoral drug levels were negatively related to intrinsic and acquired resistance to docetaxel. Also, the observed stronger antitumor activity of cabazitaxel was associated with increased cumulative exposure and higher intratumoral of cabazitaxel concentrations in all PDXs. CONCLUSIONS: The superior antitumor activity of cabazitaxel in docetaxel- and enzalutamide-resistant tumors can be partly attributed to higher intratumoral drug concentrations. Especially for patients who are intrinsically resistant to docetaxel resulting from suboptimal intratumoral docetaxel concentrations, cabazitaxel may be the preferred chemotherapeutic agent. Prostate 76:927-936, 2016. © 2016 Wiley Periodicals, Inc.

A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are likely to be mechanistic drivers behind the observed tumor growth suppression.

Dietary protein restriction inhibits tumor growth in human xenograft models.

PURPOSE: Data from epidemiological and experimental studies suggest that dietary protein intake may play a role in inhibiting prostate and breast cancer by modulating the IGF/AKT/mTOR pathway. In this study we investigated the effects of diets with different protein content or quality on prostate and breast cancer. EXPERIMENTAL DESIGN: To test our hypothesis we assessed the inhibitory effect of protein diet restriction on prostate and breast cancer growth, serum PSA and IGF-1 concentrations, mTOR activity and epigenetic markers, by using human xenograft cancer models. RESULTS: Our results showed a 70% inhibition of tumor growth in the castrate-resistant LuCaP23.1 prostate cancer model and a 56% inhibition in the WHIM16 breast cancer model fed with a 7% protein diet when compared to an isocaloric 21% protein diet. Inhibition of tumor growth correlated, in the LuCaP23.1 model, with decreased serum PSA and IGF-1 levels, down-regulation of mTORC1 activity, decreased cell proliferation as indicated by Ki67 staining, and reduction in epigenetic markers of prostate cancer progression, including the histone methyltransferase EZH2 and the associated histone mark H3K27me3. In addition, we observed that modifications of dietary protein quality, independently of protein quantity, decreased tumor growth. A diet containing 20% plant protein inhibited tumor weight by 37% as compared to a 20% animal dairy protein diet. CONCLUSIONS: Our findings suggest that a reduction in dietary protein intake is highly effective in inhibiting tumor growth in human xenograft prostate and breast cancer models, possibly through the inhibition of the IGF/AKT/mTOR pathway and epigenetic modifications.