Previous studies had already shown that Myc was a key protein in
tumour development and had established how to inhibit Myc through gene
therapy. This protein is involved in the development of diverse tumours
and so Myc-targeted therapy could make a positive contribution to the
therapeutic options for different types of cancer.
The study, led by the Vall d'Hebron Institute of Oncology (VHIO),
demonstrated the elimination of mouse lung tumours by inhibiting Myc, a
protein that plays a key role in the development of many different
tumours. The results, published in the journal Genes & Development,
confirm that repeated, long-term treatment does not cause side effects.
Even more importantly, no resistance to treatment has been encountered,
which is one of the biggest concerns with anticancer therapies. These
results show that anticancer therapies based on Myc inhibition are a
safe, effective therapeutic option in new drug development.
Myc is a protein that plays a big role in regulating gene
transcription and it is involved in cell processes such as
proliferation, differentiation and apoptosis (programmed cell death --
an essential part of regenerating tissues and eliminating damaged
cells). It acts as a regulator gene that controls the expression of some
15% of human genes. However, imbalances in this protein bring about
uncontrolled cell growth which in turn can lead to the onset of cancer
in different tissues. In fact, deregulated Myc is found in most tumours,
including cervical, breast, colon, lung and stomach cancer.
From protein to therapy: a long haul
The work conducted by the Mouse Models of Cancer Therapy group at the
VHIO, led by Dr Laura Soucek, shows that Myc can be controlled and
inhibited through a mutant called Omomyc that hijacks Myc and prevents
it from acting. "Even if we clearly identify a mechanism behind tumour
development, it is still extremely complex to pinpoint how to intervene
in cells' internal machinery or modify genetic processes," explained Dr
Soucek. "We have found a way to inhibit Myc through Omomyc," she
continued. "We induced Omomyc expression in mice through gene therapy
and managed to activate and deactivate it by administering an antibiotic
to the mice in their drinking water."
In the study, multiple lung tumours were induced in the mouse (up to
200 tumours in each individual) and Myc inhibition episodes were
achieved by activating Omomyc expression for 4-weeks, followed by 4-week
rest periods. This therapy -- known as metronomic therapy -- was
maintained for more than a year, regularly checking tumour progress in
each mouse. All mice became tumour free after the first inhibition
period, but 63% of cases then relapsed. After the second Myc inhibition
period, only 11% of the initial tumours reappeared. According to Dr
Soucek, "the most important finding was that there were no signs of
resistance to treatment. This is one of the biggest disadvantages of
many anticancer therapies: the disease develops resistance and can
return even more aggressively."
Finally, only two remaining tumours were found after more than one
year of treatment among the mice that received eight inhibition and rest
cycles. Dr Soucek found that Omomyc expression had been suppressed in
these tumours, and this was the only adaptive mechanism that mice
developed to treatment. "These results are hugely positive for us,
because one year of life in a mouse is equivalent to almost 40 human
years. The fact that the results are maintained over time, that there is
no tumour relapse and no resistance, suggests that Myc-targeted therapy
may offer an unprecedented way forward."
A study full of surprises
Previous studies conducted by Dr Soucek had already shown that Myc
inhibition could halt tumour processes, making it an interesting
therapeutic target for new drug development. However, in view of the
protein's major role as a regulator gene, there was concern that
long-term treatment could cause significant and uncontrollable side
effects, such as epithelial tissue or bone marrow atrophy.
The potential for resistance was also questioned, since this occurs
in many other similar treatments. The results of this latest study
confirm that after multiple and periodic applications of Omomyc (the Myc
inhibitor), tumours do not develop any resistance, side effects are
mild and completely reversible, and almost all initial tumours are
eradicated, even in advanced disease. "To make sure resistance was
really non-existent, we applied the worst case scenario," said Dr
Soucek, "which was to assess the effect of Myc inhibition while
suppressing p53 (a cell cycle regulator protein), because without p53, a
tumour can accumulate a large number of mutations. If there were any
chance of a mutation appearing and managing to resist Myc inhibition,
this would have happened in the absence of p53. So we have now
demonstrated that long-term Myc inhibition not only stops lung tumour
growth indefinitely, but also progressively eradicates tumour growth,
without side effects or resistance. These results confirm that Myc is a
firm target for new cancer drugs," she asserted.
These encouraging results provide sufficient scientific evidence to consider taking the next step: inhibiting Myc in patients. "Now our challenge for the future is to make Myc inhibition feasible from a pharmacological point of view, so that it can be administered, and done so safely. This will be the last step before designing clinical trials with Myc inhibitors," explained Dr Soucek. "We're so excited about reaching this turning point and I am quite certain that it will change the course of cancer therapy, despite there being a long road ahead."