Worldwide, cancer persists as one of the most important diseases that affect the human being. The knowledge on the molecular bases of cancer generated during the last decades has been successfully translated into small but significant gains in overall cancer survival rates due to better primary prevention measures, improved diagnostic methods and the development of more effective and specific therapies, collectively termed "molecular targeted therapies". In the context of these new forms of treatment, epigenetic or transcriptional cancer therapy is clearly promising.
Epigenetics refers to the function of DNA that does not depend on the coding DNA sequence itself but on the accessory molecules and mechanisms affected by DNA. It is known that epigenetic alterations are equally if not more important than classical genetic alterations to disrupt the function of tumour suppressor genes.The two most studied epigenetic aberrations common to all types of cancer are DNA hypermethylation and histone deacetylation, which cooperate to silence the expression of tumour suppressor genes, just as gene mutations and gene deletions do. The big difference between these two alternative ways that tumour cells use to inactivate tumour suppressor genes is that, while the reversal of genetic alterations is technically almost unfeasible in clinical scenarios, the function of these epigenetically inactivated suppressor genes is easily reactivated by pharmacological means.In this inaugural issue of PLoS ONE, Dr. Dueñas-Gonzalez's group from the Instituto de Investi gaciones Biomédicas of the Universidad Nacional Autónoma de México and the Instituto Nacional de Cancerología, Mexico, demonstrate, for the first time, that a combination of a DNA methylation and a histone deacetylase inhibitor, can reactivate the expression of more than a thousand genes in primary tumours of breast cancer patients.
Among these reactivated genes are those implicated in the regulation of cell proliferation, cell differentiation, programmed cell death, invasion, metastasis and immune recognition of tumour cells, such as p53, p21, eighteen members of the oxidative phosphorylation pathway, interferon-regulatory factors, NM23, negative regulators of Wnt signalling and Major Histocompatibility Complex Class-I and --II genes.In addition, these drugs down-regulate genes such as ABCB5, a recently identified member of the ABC transporter family implicated in multidrug resistance, which is predominantly expressed by tumour "stem" cells. Moreover, in this proof-of-principle study, the Mexican researchers demonstrate that this combination of epigenetic drugs can be safely administered concurrently with classical cytotoxic agents such as doxorubicin and cyclophosphamide, a common drug combination employed in the primary treatment of breast cancer.
Although this study is suggestive of increased anti-tumour effects no definitive conclusions can be drawn from it regarding the clinical efficacy of this therapy, because the study is single arm and the number of patients small; however, it is clearly suggestive that the epigenetic "principle" works and calls for increased preclinical and clinical efforts toward epigenetic cancer therapy.
Researchers used "epigenetic" drugs routinely employed for non-malignant conditions
One important aspect of this study, considers Dr Dueñas-Gonzalez, is that the "epigenetic" drugs used, are "very-well known" and have been routinely employed for almost 30 years to treat non-malignant conditions: the antihypertensive hydralazine and the antiepileptic valproic acid. Advocacy groups are claiming that "big pharma" companies are not interested in pursuing the preclinical and clinical development of this type of drugs --regardless of their potential antitumour efficacy-- simply because they cannot be protected by patents and in consequence huge revenues cannot be expected. If the antitumour efficacy of these epigenetic drugs is eventually demonstrated, they would not only be added to the current anticancer armamentarium, but they will surely be affordable to the vast majority of cancer patients living in low and middle income countries, who find the newer anticancer agents prohibitively expensive. Dr Dueñas-Gonzalez's group has recently completed a couple of single arm studies of this therapy with similar results and launched three placebo-controlled randomised trials in breast, ovarian and cervical cancer patients.
Citation: Arce C, Pérez-Plasencia C, González-Fierro A, de la Cruz-Hernández E, Revilla-Vázquez A, et al (2006) A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer. PLoS ONE 1(1): e98. doi:10.1371/journal.pone.0000098 (http://dx.doi.org/10.1371/journal.pone.0000098)
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