The therapeutic efficacy of certain anti-cancer vaccines depends on how they are administered. This is what the team of researchers headed by Eric Tartour at the Paris-Centre de recherche Cardiovasculaire (Université Paris Descartes, INSERM Unit 970 PARCC, AP-HP), in collaboration with researchers from the CNRS[1], have just demonstrated. A paper on the subject was published on 13 February 2013 in Science Translational Medicine. In the case of so-called mucosal cancers of the lungs or ENT area, the vaccine should be administered directly via the mucosa if it is going to be effective (intra-nasally for example). The same vaccine administered in the usual way that immunisation is performed, i.e. intramuscular or sub-cutaneous injection, will be ineffective. In this research, the investigators also identified an important method by which the vaccine acts against tumours. These results will have a major impact on the creation and effectiveness of anti-cancer vaccines targeting mucous tumours.

An Inserm team in Dijon directed by François Ghiringhelli (Inserm unit 866 ‘Lipids, nutrition and cancer’) is to publish an article this week in the Nature Medicine review.  The article suggests that two chemotherapy drugs frequently used to treat digestive and breast cancers may encourage the development of tumours by modulating the anti-tumoural immune response. These results reveal how the immune system can then limit the effectiveness of some cancer chemotherapies. The researchers now intend to block the molecules responsible for negative immune system activation to increase the efficiency of chemotherapy. A clinical trial to test this hypothesis should begin very soon.

Chemotherapy is one of the most frequently used treatments to eliminate cancerous cells. These drugs kill all cells that are multiplying, or block their proliferation (for example, cells responsible for hair growth, explaining the hair loss of treated patients).  In addition to their direct toxic effects, the chemotherapeutic agents also seem to act on the immune system and could make it possible for the body to trigger a direct antitumor immune response in a second phase.

© fotolia

However, this last point is still the subject of hot debate, since some studies suggest, conversely, that chemotherapy eliminates all immune defences.

What now?

The Inserm team directed by Professor François Ghiringhelli (Inserm unit 866 “Lipids, nutrition and cancer”) from the Georges François Leclerc Cancer Research Centre in Dijon observed that two chemotherapeutic agents, 5-fluorouracile and gemcitabine, used to treat colon, breast and pancreas cancers activate a protein complex “inflammasome NLRP3” within some cells in the immune system.

To be more specific, this activation leads to releasing proinflammatory cytokine (interleukin IL-1beta) through these cells. This cytokine “distorts” the immune response related to lymphocytes T and causes the production of another cytokine (cytokine IL-17), which has protumoral properties by encouraging tumour angiogenesis, i.e. vascular irrigation of tumours.

“Our results have made it possible to ascertain that the activation of inflammasome limits the effectiveness of chemotherapy. The challenge was then to see whether we could prevent the activation of inflammasome”

The first was to test the two drugs on inflammasome NLRP3- or cytokine IL-17-deficient mice.  In these cases, the researchers showed that antitumor activity was not only present, but it actually increased, demonstrating that these two elements (NLRP3 and IL-17) slow down the chemotherapy action.

The second strategy was to treat the mice using an IL-1beta inhibitor. Here again, the effectiveness of chemotherapy was again increased.

These results suggest that targeting the inflammasome and IL-1beta channels, combined with the use of these two chemotherapy agents, can improve the effectiveness of the latter. These tumour cells are eliminated and, in parallel, the damaging immune responses are deleted.

A therapeutic trial combining 5-fluorouracil and IL-1 beta is currently being prepared and should begin soon at the Georges François Leclerc Cancer Research in Dijon.

©Inserm

One of the current challenges in terms of cancer treatment is how it can be best adapted to patients: today the emphasis is on personalised treatment (factoring in genetic and metabolic profiles). In response to this growing need for personalisation, there is an increasing demand for fundamental research to develop adapted future treatments. Researchers from Inserm and CNRS from the Institute for genetics and molecular and cellular biology (IGBMC) and from the Research Institute at the Strasbourg school of biotechnology (Irebs) have focussed their efforts on PARG, currently thought to be a promising new therapeutic target in the treatment of cancer. Their work has revealed the role of this molecule in regulating gene expression. The results were published on 25 October 2012 in the on-line Molecular Cell review.

Cells are subjected to various stresses throughout their life. Some of this stress can damage DNA. Fortunately, cells have several mechanisms used to repair these lesions. Breaking two DNA strands is one of the most serious afflictions a chromosome can suffer. The cell must repair this break if it is to continue dividing. Repair actions are either performed in an optimal manner, and the cell resumes its normal division cycle, or the lesion is not repaired correctly, causing the cell to die or the appearance of an anomaly that may trigger cancer.

One of the repair mechanisms used is poly(ADP-ribosyl)ation. In this mechanism, some molecules (PARPs) detect DNA breaks and cause poly(ADP-riboses) synthesis that binds with proteins, thus initialising the lesion repair system. As such, this system can act as a ‘saviour’ if the repairs are correctly completed, but, it can be equally damaging in the event of incorrect repair.

In the case of cancer, to ensure the cells are destroyed, PARP inhibitors are currently undergoing clinical tests as therapeutic adjuvant used to increase the receptivity of cancer cells to specific chemotherapies.

In terms of fundamental research, researchers know that the poly(ADP-ribosyl)ation mechanism is reversible and is closely regulated by Poly(ADP-ribose) glycohydrolase (PARG). PARP and PARG thus seem to make up a tandem of molecules dedicated to maintaining genome integrity. PARG targeting has proved to potentiate the action of genotoxic agents, making this molecule a promising new therapeutic target in the treatment of some cancers, as is the case for PARP.

However, little research has been conducted into PARG, but in light of its close links with PARP, researchers are now taking a very close look at its functions.

In this new work, the researchers have demonstrated that in addition to its genome repair role, PARG was involved in modulating the cell’s transcriptional activity.

Given the keen current interest on PARP and PARG inhibitors in the treatment of cancer, it is essential to gain accurate knowledge of the functions and action modes of these promising therapeutic targets, as well as the consequences of their invalidation. This study is the first to highlight how PARG action mechanism regulates gene expression.

Mice with black fur that turns white? Specialist cancer researchers from Inserm, CNRS, the Institut Curie and the Université Paris-Sud have taken steps to better understand the development of skin cells responsible for pigmentation (known as melanocytes). By genetically manipulating mice with black fur, the researchers identified two key players: B-Raf and C-Raf proteins. These proteins are required for melanocyte stem cell self-maintenance and, as such, correct pigmentation throughout the mice’s life span. Without these two proteins, the mice’s fur turns white.

Their research is published in the review ‘Cell Report’ and paves the way for serious possibilities in terms of stopping the formation of melanomas, tumours that originate from melanocyte cells.

Melanocytes are cells in the organism used for skin, fur and hair pigment. This pigmentation function provides protection from the sun and lends organisms their colour. Malfunctions in these cells may lead to skin cancer known as melanoma. Melanomas are highly aggressive cancers that become very difficult to treat as they develop and metastases occur.

A few years ago, researchers discovered that, in humans, the B-Raf gene (coding gene for protein of the same name) is mutated in more than 50% of melanoma. Spectacular progress has been made in recent years in the treatment of this cancer, thanks to the development of pharmacological inhibitors that target an enzyme: the B-Raf kinase.

However, despite this treatment, cancer returns in several patients, indicating that not all cancerous cells have been eliminated.

In this new research, scientists have tried to understand how melanocytes function normally, to then understand their specific role in cancer. To this end B-Raf protein expression, then, in turn, C-Raf protein expression, were removed from mice with black fur (ideal to clearly see any changes in pigmentation).

Black mice that become white with age

No changes in pigmentation were observed for mice that only had their B-Raf or C-Raf expression removed by researchers from the line of cells producing melanocytes.

Mice that had both coding genes for B-Raf and C-Raf removed simultaneously had a normal colour at birth. However, they progressively lost their pigmentation as they grew. They turned grey from black, before becoming increasingly white.

A. Eychène / F. Bertrand (Institut Curie)

For Alain Eychène, the research team leader, “these observations represent a fault in melanocyte renewal. Since the colour black is present at birth, the pigment cells clearly exist. However, the progressive whitening of the fur, once B-Raf and C-Raf have been removed from the cell line, proves that both these proteins are required for melanocyte renewal”.

As is the case for all cells, melanocytes originate from stem cells; the latter are responsible for renewal during moulting.  This research shows that it is specifically this population of stem cells alone that disappears progressively in mutant mice.

For Alain Eychène, “This is the first in vivo demonstration of the role of RAF proteins in the self-renewal of stem cells”.

The fact that B-Raf and C-Raf are both involved in controlling and renewing pigment stem cells represents another step towards understanding and treating melanoma. By blocking these proteins (using inhibitors) in patients undergoing treatment, it is possible that in time researchers will succeed in eliminating all cancerous stem cells, i.e. the likely cause behind cases of cancer reoccurrence.