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.
Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard
New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University
DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.
Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...
MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.
Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...
Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...
Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.
To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...
The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.
Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...
11.12.2017 | Event News
08.12.2017 | Event News
07.12.2017 | Event News
15.12.2017 | Power and Electrical Engineering
15.12.2017 | Materials Sciences
15.12.2017 | Life Sciences