Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer.

BackgroundIn the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride.MethodsFrom 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERβ, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers.FindingsWe found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups.InterpretationWe showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT

Changes in serum proteomic patterns by presurgical alpha-tocopherol and L-selenomethionine supplementation in prostate cancer

BACKGROUND: Evidence of the chemopreventive effects of the dietary antioxidants alpha-tocopherol (vitamin E) and l-selenomethionine (selenium) comes from secondary analysis of two phase III clinical trials that found treatment with these antioxidants reduced the incidence of prostate cancer. To determine the effects of selenium and vitamin E in blood and prostate tissue, we undertook a preoperative feasibility study complementary to the currently ongoing Selenium and Vitamin E Cancer Prevention Trial. METHODS: Forty-eight patients with clinically localized prostate cancer enrolled on this 2 x 2 factorial design study were randomized to take selenium, vitamin E, both, or placebo for 3 to 6 weeks before prostatectomy. Sera were collected from patients before and after dietary supplementation. Thirty-nine patients were evaluable, and 29 age-matched disease-free men served as controls. Mass profiling of lipophilic serum proteins of lower molecular weight (2-13.5 kDa) was conducted, and mass spectra data were analyzed using custom-designed software. RESULTS: Weighted voting analyses showed a change in sera classification from cancerous to healthy for some patients with prostate cancer after dietary intervention. ANOVA analysis showed significantly different treatment effects on prediction strength changes among the four groups at a 95% confidence level. Eliminating an outlying value and performing post hoc analysis using Fisher\u27s least significant difference method showed that effects in the group treated with the combination were significantly different from those of the other groups. CONCLUSION: In sera from patients with prostate cancer, selenium and vitamin E combined induced statistically significant proteomic pattern changes associated with prostate cancer-free status

Variant Prostate Carcinoma and Elevated Serum CA-125

Introduction—About 10% of tumors derived from nongynecologic, noncoelomic tissues react with the OC125 antibody. Some patients with advanced prostate cancer were found to have elevated serum CA-125 level. Materials and Methods—We examined the clinical history of 11 patients with castration-resistant prostate cancer and an elevated serum CA-125 level. Pathological review and immunohistochemical staining were performed on tumors from 8 of these patients. Results—Patients with advanced prostate cancer and an elevated serum CA-125 level responded to androgen ablative therapy (median duration, 27 months). They were predisposed to develop persistent or recurrent urinary symptoms and visceral metastases. Eight of 11 patients had a low or undetectable serum prostate-specific antigen level (≤4 ng/ml) or an elevated serum carcinoembryonic antigen level (>6 ng/ml). In 3 of 7 patients whose specimens were available for further review, the tumors contained histologic features compatible with a diagnosis of ductal or endometrioid adenocarcinoma of the prostate. Conclusions—Patients with prostate cancer and an elevated serum CA-125 level have unique clinical and pathologic characteristics. Some of these patients possess tumors compatible with a subtype of prostate cancer known as ductal adenocarcinoma. Additional studies need to be performed to elucidate the biologic basis of the various subtypes of prostate cancer

The MD Anderson prostate cancer patient-derived xenograft series (MDA PCa PDX) captures the molecular landscape of prostate cancer and facilitates marker-driven therapy development

BACKGROUND: Advances in prostate cancer (PCa) lag behind other tumor types partly due to the paucity of models reflecting key milestones in PCa progression. OBJECTIVE: To develop clinically relevant PCa models. DESIGN: Since 1996 we have generated clinically annotated patient-derived xenografts (PDXs) (the MDA PCa PDX series) linked to specific phenotypes reflecting all aspects of clinical PCa. RESULTS: We studied two cell line-derived xenografts and the first 80 PDXs derived from 47 human PCa donors. Of these, 47 PDXs derived from 22 donors are working models and can be expanded either as cell lines (MDA PCa 2a and 2b) or PDXs. The histopathologic, genomic, and molecular characteristics (AR, ERG, and PTEN loss) maintain fidelity with the human tumor and correlate with published findings. PDX growth response to mouse castration and targeted therapy illustrate their clinical utility. Comparative genomic hybridization and sequencing show significant differences in oncogenic pathways in pairs of PDXs derived from different areas of the same tumor. We also identified a recurrent focal deletion in an area that includes the SPOPL gene in PDXs derived from 7 human donors out of 28 studied (25%). SPOPL is a SPOP paralog, and SPOP mutations define a molecular subclass of PCa. SPOPL deletions are found in 7% of TCGA PCas, which suggests that our cohort is a reliable platform for targeted drug development. CONCLUSIONS: The MDA PCa PDX series is a dynamic resource that captures the molecular landscape of PCas progressing under novel treatments and enables optimization of PCa-specific, marker-driven therapy

Stem-Cell Theory of Cancer: Implications for Antiaging and Anticancer Strategies

A stem-cell theory of cancer predicates that not only does the cell affect the niche, the niche also affects the cell. It implicates that even though genetic makeup may be supreme, cellular context is key. When we attempt to solve the mystery of a long cancer-free life, perhaps we need to search no further than the genetics and epigenetics of the naked mole-rat. When we try to unlock the secrets in the longevity and quality of life, perhaps we need to look no further than the lifestyle and habits of the super centenarians. We speculate that people with Down’s syndrome and progeria age faster but have fewer cancers, because they are depleted of stem cells, and, as a consequence, have fewer opportunities for stem cell defects that could predispose them to the development of cancer. We contemplate whether these incredible experiments of nature may provide irrefutable evidence that cancer is a stem-cell disease—fewer aberrant stem cells, fewer cancers; no defective stem cells, no cancer. In this perspective, we investigate a stem-cell origin of aging and cancer. We elaborate an intriguing inverse relationship between longevity and malignancy in the naked mole-rat, in Down’s syndrome, and in progeria. We postulate that stem-cell pools and stemness factors may affect aging and dictate cancer. We propose that a healthy microbiome may protect and preserve stem cell reserves and provide meaningful antiaging effects and anticancer benefits

Curing Cancer: Lessons from a Prototype

Germ cell tumor of the testis (TGCT) is a remarkably curable solid tumor even when it is widely metastatic and patently heterogeneous. It provides invaluable clues about the origin and nature of metastasis and heterogeneity, cancer dormancy and late recurrence, drug sensitivity and resistance, tumor immunity, and spontaneous remission that would enable us to enhance the cure and improve the care of patients with other currently intractable solid tumors. After all, germ cells are primeval stem cells and TGCT are a perfect stem cell tumor for us to investigate a stem cell versus genetic origin of cancer. In many respects, TGCT is a prototype stem cell tumor that will enable us to elucidate the role of differentiation versus dedifferentiation in the evolution of a complex mixed tumor. It will help us decipher relevance of the genome versus the epi-genome in a progenitor cancer stem cell versus a progeny differentiated cancer cell. Importantly, clarification of a cellular context versus the genetic makeup in cancer has immense clinical implications. We postulate a unified theory of cancer derived from seminal TGCT research to improve personalized cancer care. Contrary to current norms and conventional wisdom, we propose that when it concerns a complex rather than simple cancer and a mixed rather than pure tumor (which is practically all solid tumors) multimodal therapy trumps targeted therapy and integrated medicine overrides precision medicine

Curing Cancer: Lessons from a Prototype

Germ cell tumor of the testis (TGCT) is a remarkably curable solid tumor even when it is widely metastatic and patently heterogeneous. It provides invaluable clues about the origin and nature of metastasis and heterogeneity, cancer dormancy and late recurrence, drug sensitivity and resistance, tumor immunity, and spontaneous remission that would enable us to enhance the cure and improve the care of patients with other currently intractable solid tumors. After all, germ cells are primeval stem cells and TGCT are a perfect stem cell tumor for us to investigate a stem cell versus genetic origin of cancer. In many respects, TGCT is a prototype stem cell tumor that will enable us to elucidate the role of differentiation versus dedifferentiation in the evolution of a complex mixed tumor. It will help us decipher relevance of the genome versus the epi-genome in a progenitor cancer stem cell versus a progeny differentiated cancer cell. Importantly, clarification of a cellular context versus the genetic makeup in cancer has immense clinical implications. We postulate a unified theory of cancer derived from seminal TGCT research to improve personalized cancer care. Contrary to current norms and conventional wisdom, we propose that when it concerns a complex rather than simple cancer and a mixed rather than pure tumor (which is practically all solid tumors) multimodal therapy trumps targeted therapy and integrated medicine overrides precision medicine

Considerations for patient selection for focal therapy

Focal therapy for prostate cancer is a nascent and emerging field. As such, the patient selection criteria for this new treatment paradigm are evolving in parallel to both the technology on which this approach depends and to our unfolding understanding of the natural history of prostate cancer. Until, and while, prospective trials of focal therapy are being reported, patient selection criteria will be flexible and very dependent on the therapeutic goals. We must carefully define the therapeutic intentions of focal therapy before engaging in the actual process of determining optimal patient selection. The therapeutic intent will define the most appropriate candidate for such therapy. Patient selection encompasses multiple complex issues including the type of prostate biopsy (12 core transrectal versus mapping transperineal) to the type of imaging (multiparametric magnetic resonance imaging or enhanced ultrasound) to the specific anatomical location of the disease within the prostate (apex, mid-prostate, base) and a comprehensive assessment of the patient’s overall health and life expectancy. It is not as simple as saying a patient with a certain grade or a certain number of cores is or is not appropriate for focal therapy. There are many more considerations for a reasonable and thoughtful approach to this new treatment