Potential of epigenetic therapies in the management of solid tumors.

Cancer is a complex disease with both genetic and epigenetic origins. The growing field of epigenetics has contributed to our understanding of oncogenesis and tumor progression, and has allowed the development of novel therapeutic drugs. First-generation epigenetic inhibitor drugs have obtained modest clinical results in two types of hematological malignancy. Second-generation epigenetic inhibitors are in development, and have intrinsically greater selectivity for their molecular targets. Solid tumors are more genetic and epigenetically complex than hematological malignancies, but the transcriptome and epigenome biomarkers have been identified for many of these malignancies. This solid tumor molecular aberration profile may be modified using specific or quasi-specific epidrugs together with conventional and innovative anticancer treatments. In this critical review, we briefly analyze the strategies to select the targeted epigenetic changes, enumerate the second-generation epigenetic inhibitors, and describe the main signs indicating the potential of epigenetic therapies in the management of solid tumors. We also highlight the work of consortia or academic organizations that support the undertaking of human epigenetic therapeutic projects as well as some examples of transcriptome/epigenome profile determination in clinical assessment of cancer patients treated with epidrugs. There is a good chance that epigenetic therapies will be able to be used in patients with solid tumors in the future. This may happen soon through collaboration of diverse scientific groups, making the selection of targeted epigenetic aberration(s) more rapid, the design and probe of drug candidates, accelerating in vitro and in vivo assays, and undertaking new cancer epigenetic-therapy clinical trails.

Molecular pathogenesis of CLL and its evolution.

In spite of being the most prevalent adult leukemia in Western countries, the molecular mechanisms driving the establishment and progression of chronic lymphocytic leukemia (CLL) remain largely unknown. In recent years, the use of next-generation sequencing techniques has uncovered new and, in some cases, unexpected driver genes with prognostic and therapeutic value. The mutational landscape of CLL is characterized by high-genetic and epigenetic heterogeneity, low mutation recurrence and a long tail of cases with undefined driver genes. On the other hand, the use of deep sequencing has also revealed high intra-tumor heterogeneity and provided a detailed picture of clonal evolution processes. This phenomenon, in which aberrant DNA methylation can also participate, appears to be tightly associated to poor outcomes and chemo-refractoriness, thus providing a new subject for therapeutic intervention. Hence, and having in mind the limitations derived from the CLL complexity thus described, the application of massively parallel sequencing studies has unveiled a wealth of information that is expected to substantially improve patient staging schemes and CLL clinical management.

Current perspectives in the treatment of advanced prostate cancer.

Prostate cancer (PC) continues to be an important world health problem for men. Patients with locally confined PC are treated with either radiotherapy or surgery. However, treatment of more advanced stages of the disease is problematic. Initially, androgen deprivation offers a period of clinical stability, which is however invariably followed by progression to non-responsiveness to hormonal manipulation. Current management of patients with androgen-independent prostate cancer (AIPC) displays modest response rates and achieves only short-term benefit. Recently, knowledge in the complex pathophysiology of advanced PC has led to the identification of mechanisms and target molecules permitting the introduction of new therapies. Consequently, many investigational treatments are ongoing for AIPC in Phase-II and Phase-III trials aiming at the combination of chemotherapeutic regimens along with immunotherapy targeting PC-associated antigens. Other attractive options are gene therapy, as well as the targeting of survival signaling, differentiation, and apoptosis of the malignant PC cells. Further treatment modalities are directed against the tumor microenvironment, bone metastasis, or both. Collectively, the aforementioned efforts introduce a new era in the management of advanced PC. Novel pharmaceutical compounds and innovative approaches, integrated into the concept of individualized therapy will hopefully, during the next decade, improve the outcome and survival for hundreds of thousands of men worldwide.

Cervical cancer screening: state of the art.

PURPOSE OF REVIEW: The objective of cervical cancer screening is to prevent the occurrence of and death from cervical cancer by detecting and treating high-grade squamous intraepithelial lesions. A significant decline in occurrence and mortality from cervical cancer in developed countries has been associated with the application of organized cervical screening programs. The use of the available local health methods in cervical cancer screening can be adjusted in different countries. This review discusses the recent results in traditional and alternative cervical cancer screening. RECENT FINDINGS: The current recommendations of both the American Cancer Society and the American College of Obstetricians and Gynecologists concerning clinical practice guidelines for cervical cancer screening are commented upon. New methods and new technology for cervical cancer screening are described. Attributable failure factors in the screening process, particularly in the coverage, are analyzed. A critical assessment of the suitability of local cervical cancer screening resources is discussed. SUMMARY: Screening is clearly a complex multifactorial process, not a test. Nowadays, with the human papillomavirus vaccine on the horizon, screening is the best strategy for cervical cancer control. Good screening programs, with high coverage, quality control and follow-up included, are the basis of obtaining better results. The Papanicolaou test and its variants are the best methods of cervical cancer screening in high-resource settings. Alternative visual inspection using cervical dyes could be the most useful method in low-resource settings. The challenge for the future may be less of a technical nature and more dependent on local finances and screening policies.

HPV16-specific cytotoxic T lymphocyte responses are detected in all HPV16-positive cervical cancer patients.

OBJECTIVES: The specific CTL response against human papillomavirus (HPV) antigens in women with cervical cancer has been poorly studied. Immunological monitoring of this response is central for understanding the principles that underlie successful immunotherapeutic strategies. The aim of the study was to investigate the HPV16 E6/E7-specific CTL immune response in a group of untreated HPV16-positive cervical cancer patients. METHODS: Peripheral blood mononuclear cells from 21 untreated cervical cancer patients and 4 healthy controls were isolated prior to any therapy. Autologous monocyte-derived dendritic cells (MDDCs) were transiently transfected with HPV16 E6 or E7 expression vectors and used for one round of in vitro restimulation and as target cells in chromium release assays with restimulated peripheral blood lymphocytes. RESULTS: Transfected monocyte-derived dendritic cells were differentiated to exhibit a fully mature phenotype. HPV16 E6 and E7 transgenes were expressed and translated as measured by RT-PCR and intracellular flow cytometry, respectively. All HPV16-associated cervical cancer patients showed evidence of specific CTLs. Lytic activity for HPV16 E6 (11/12) and/or E7 (8/9) was above 30% at the 100:1 effector to target ratio. None of the HPV16-negative cervical cancer patients or healthy controls were above 15% of lysis. CONCLUSIONS: These data suggest that HPV-specific cytolytic immune responses can be detected in all untreated cervical cancer patients. Our approach, using dendritic cells for restimulation and as target cells, may enhance immunomonitoring of cervical cancer patients.

Molecular evaluation of the prevalence of oncogenic human papillomavirus genotypes in cervical acetowhite lesions.

The actual prevalence of cancer-related human papillomavirus (HPV) genotypes in cervical acetowhite lesions has not been established. In this work, the presence of oncogenic types of HPV in cervical acetowhite tissue was evaluated by molecular means. The presence of HPV DNA was determined in a group of women with and without cervical acetowhite lesions by a polymerase chain reaction (PCR) using the MY09/MY11 primers. The presence of 13 oncogenic HPV types was evaluated using the Hybrid Capture II test, and the prevalence of HPV type 16 (HPV16) was studied using an HPV16-specific PCR. HPV DNA was detected in 85.9% patients with acetowhite lesions; oncogenic HPV types were found in 83.7% of them; HPV16 was identified in 51.1% of the cases. HPV DNA was detected in 87.3% of the patients without acetowhite changes. Interestingly only 16.8% were infected by oncogenic genotypes and 2.5% were positive for the presence of HPV16. In conclusion, subclinical infection by oncogenic HPV genotypes is associated with the presence of acetowhite cervical tissue (p < 0.0005). Therefore, women showing acetowhite lesions might be at risk of developing cervical cancer.