Genomics of Cancer and a New Era for Cancer Prevention

A primary justification for dedicating substantial amounts of research funding to large-scale cancer genomics projects of both somatic and germline DNA is that the biological insights will lead to new treatment targets and strategies for cancer therapy. While it is too early to judge the success of these projects in terms of clinical breakthroughs, an alternative rationale is that new genomics techniques can be used to reduce the overall burden of cancer by prevention of new cases occurring and also by detecting them earlier. In particular, it is now becoming apparent that studying the genomic profile of tumors can help to identify new carcinogens and may subsequently result in implementing strategies that limit exposure. In parallel, it may be feasible to utilize genomic biomarkers to identify cancers at an earlier and more treatable stage using screening or other early detection approaches based on prediagnostic biospecimens. While the potential for these techniques is large, their successful outcome will depend on international collaboration and planning similar to that of recent sequencing initiatives.Since the publication of the initial human genome sequence in 2002, at a cost of around US$3 thousand million, DNA sequencing has advanced to the extent where whole genomes can be sequenced in days for around one millionth of the cost [1]. This has led to a scientific tour de force in projects that aim to understand the genetics of cancer. Large-scale initiatives such as the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas (TCGA) for somatic variation, as well as the OncoArray Network for genome-wide studies of germline variation, have harnessed international expertise in oncology, genomics, and bioinformatics with very high levels of funding and have resulted in the coordinated genotyping, sequencing, and cataloging of many thousands of cancer cases [2]. Comprehensive genomic data from all completed cases are being made available to the research community, along with basic clinical information on some, allowing for extensive additional analyses. This initiative has led to a new understanding of how to define specific cancer subtypes and has vastly increased the pace of progress in elucidating the underlying biology of cancer [3].The most prominent visible outcome of the increased understanding of cancer biology is that targeted treatments have been developed or are being tested that aim to block specific molecules that spur the growth or spread of cancer. Although there are some exciting success stories such as the vastly improved survival with imatinib and chronic myelogenous leukemia (CML) or the increased efficacy of Herceptin treatment for women with Her2-positive breast cancer, most of this new generation of targeted treatments promise, at most, only a partial respite from the disease. The typical scenario is that the underlying cancer is not totally eradicated, remnants of the disease evolve and overcome any treatment, and the relapse is severe [4].New targeted therapies are also expensive to develop and to prescribe, some costing over US$100,000 for each patient per year, while being applicable for a smaller number of patients with the relevant subtype of disease. Disease resistance may be overcome through new strategies that combine therapies for specific pathways, and combination therapy of two or more drugs that target independent pathways is likely to hold even greater promise for improving response [5]. Other approaches such as combined use of immune checkpoint inhibitors are also providing exciting results [6], although there remain concerns that the strategy of developing targeted therapies for late-stage disease may be fundamentally flawed, given the inherent complexity and heterogeneity of such tumors [7,8]. A complementary approach would be to focus also on early detection of localized cancer, including the use of screening, when survival is usually a lot more favorable [3], as well as primary prevention in identifying the causes and minimizing exposure. The role of genomics in primary and secondary prevention of cancer has received less attention than treatment, although it is perhaps here that genomics will have its most important contribution in the long term.     

Prostate Cancer Prevention Through Pomegranate Fruit

Prostate cancer (CaP) is the second leading cause of cancer-related deaths among U.S. males with a similar trend in many Western countries. CaP is an ideal candidate disease for chemoprevention because it is typically diagnosed in men over 50 years of age, and thus even a modest delay in disease progression achieved through pharmacological or nutritional intervention could significantly impact the quality of life of these patients. In this regard we and others have proposed the use of dietary antioxidants as candidate CaP chemopreventive agents. The fruit pomegranate derived from the tree Punica granatum has been shown to possess strong antioxidant and anti-inflammatory properties. In a recent study, we showed that pomegranate fruit extract (PFE), through modulations in the cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery, resulted in inhibition of cell growth followed by apoptosis of highly aggressive human prostate carcinoma PC3 cells. These events were associated with alterations in the levels of Bax and Bcl-2 shifting the Bax:Bcl-2 ratio in favor of apoptosis. Further, we showed that oral administration of a human acceptable dose of PFE to athymic nude mice implanted with CWR22R1 cells resulted in significant inhibition of tumor growth with concomitant reduction in secretion of prostate-specific antigen (PSA) in the serum. The outcome of this study could have a direct practical implication and translational relevance to CaP patients, because it suggests that pomegranate consumption may retard CaP progression, which may prolong the survival and quality of life of the patients.     

花青素防治乳腺癌研究进展

花青素是自然界分布最广泛的水溶性植物色素之一,主要存在于植物的花、叶和果实中。近年来,流行病学、动物肿瘤模型和离体细胞研究资料提示花青素对多种肿瘤具有化学防治作用。本文就花青素防治乳腺癌的研究进展及其作用机制作一综述。     

Finasteride Concentrations and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial

ObjectiveIn the Prostate Cancer Prevention Trial (PCPT), finasteride reduced the risk of prostate cancer by 25%, even though high-grade prostate cancer was more common in the finasteride group. However, it remains to be determined whether finasteride concentrations may affect prostate cancer risk. In this study, we examined the association between serum finasteride concentrations and the risk of prostate cancer in the treatment arm of the PCPT and determined factors involved in modifying drug concentrations.MethodsData for this nested case-control study are from the PCPT. Cases were drawn from men with biopsy-proven prostate cancer and matched controls. Finasteride concentrations were measured using a liquid chromatography-mass spectrometry validated assay. The association of serum finasteride concentrations with prostate cancer risk was determined by logistic regression. We also examine whether polymorphisms in the enzyme target and metabolism genes of finasteride are related to drug concentrations using linear regression.

Results and Conclusions

Among men with detectable finasteride concentrations, there was no association between finasteride concentrations and prostate cancer risk, low-grade or high-grade, when finasteride concentration was analyzed as a continuous variable or categorized by cutoff points. Since there was no concentration-dependent effect on prostate cancer, any exposure to finasteride intake may reduce prostate cancer risk. Of the twenty-seven SNPs assessed in the enzyme target and metabolism pathway, five SNPs in two genes, CYP3A4 (rs2242480; rs4646437; rs4986910), and CYP3A5 (rs15524; rs776746) were significantly associated with modifying finasteride concentrations. These results suggest that finasteride exposure may reduce prostate cancer risk and finasteride concentrations are affected by genetic variations in genes responsible for altering its metabolism pathway.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00288106","term_id":"NCT00288106"}}NCT00288106     

十字花科植物中莱菔硫烷防癌机制研究进展

十字花科蔬菜中的异硫氰酸酯--莱菔硫烷(sulforaphane,SF)可以在癌症的起始、发展和增生3个阶段阻滞癌细胞的生长发育,降低癌症发生的风险,其前体物主要存在于西兰花中.本文主要对国内外近年来有关SF对化学致癌物代谢酶的影响、激活抗氧化基因活性、激活转录因子、阻滞细胞周期、诱导细胞凋亡等方面的研究进展进行综述,以探讨SF的防癌机制,为防癌抗癌食品和药物的研发提供参考.     

Adherence to Cancer Prevention Guidelines in 18 African Countries

Background

Cancer rates in Africa are projected to double by 2030 due to aging and increased exposure to cancer risk factors, including modifiable risk factors. We assessed adherence to 5 modifiable cancer risk factors across 18 African countries.

Methods

Data on adults 18 years and older were obtained from the 2002–2004 World Health Survey. Adherence to current World Cancer Research Fund guidelines on smoking, alcohol, body weight, physical activity, and nutrition was assessed. Adherence scores ranged from 0 (no guideline met) to 5 (all guidelines met). Determinants of adherence were assessed using multivariable linear regression adjusted for individual and country level characteristics.

Results

Across all countries, adherence to the guidelines among adults was high for smoking (72%–99%) and alcohol (85%–100%), but low for body weight (1.8%–78%), physical activity (3.4%–84%) and nutrition (1.4%–61%). Overall adherence score ranged from 2.32 in Mali to 3.72 in Comoros. In multivariable models, residing in low versus high SES households was associated with reduced adherence by 0.24 and 0.21 points for men and women respectively after adjusting for age, gender, education, and marital status (p<0.001). Every % increase in GDP spent on health was associated with increased adherence by 0.03 in men and 0.09 in women (p<0.001).

Conclusions

The wide variation in adherence to cancer prevention guidelines observed across countries and between population sub-groups suggests the need for targeted public health efforts to improve behaviors related to body weight, physical activity and nutrition.     

Complementary Roles in Cancer Prevention: Protease Inhibitor Makes the Cancer Preventive Peptide Lunasin Bioavailable

Background

The lower incidence of breast cancer among Asian women compared with Western countries has been partly attributed to soy in the Asian diet, leading to efforts to identify the bioactive components that are responsible. Soy Bowman Birk Inhibitor Concentrate (BBIC) is a known cancer preventive agent now in human clinical trials.

Methodology/Principal Findings

The objectives of this work are to establish the presence and delineate the in vitro activity of lunasin and BBI found in BBIC, and study their bioavailability after oral administration to mice and rats. We report that lunasin and BBI are the two main bioactive ingredients of BBIC based on inhibition of foci formation, lunasin being more efficacious than BBI on an equimolar basis. BBI and soy Kunitz Trypsin Inhibitor protect lunasin from in vitro digestion with pancreatin. Oral administration of ³H-labeled lunasin with lunasin-enriched soy results in 30% of the peptide reaching target tissues in an intact and bioactive form. In a xenograft model of nude mice transplanted with human breast cancer MDA-MB-231 cells, intraperitoneal injections of lunasin, at 20 mg/kg and 4 mg/kg body weight, decrease tumor incidence by 49% and 33%, respectively, compared with the vehicle-treated group. In contrast, injection with BBI at 20 mg/kg body weight shows no effect on tumor incidence. Tumor generation is significantly reduced with the two doses of lunasin, while BBI is ineffective. Lunasin inhibits cell proliferation and induces cell death in the breast tumor sections.

Conclusions/Significance

We conclude that lunasin is actually the bioactive cancer preventive agent in BBIC, and BBI simply protects lunasin from digestion when soybean and other seed foods are eaten by humans.