Détection de la fusion ETO2-GLIS2 dans des cellules leucémiques de patients. Le signal rouge correspond au locus ETO2, le signal vert correspond au locus GLIS2 et le signal jaune indique la présence de la fusion ETO2-GLIS2.© Thomas Mercher

Acute myeloid leukemia (AML) mainly affects children, with the prognosis often being poor despite several decades of research into more effective treatments. A new study led by Thomas Mercher (Inserm U1170/Gustave Roussy/Université Paris-Sud-Paris Saclay), and performed in collaboration with Jürg Schwaller (UKBB, Department of Biomedicine, Universität Basel) explains why some forms of leukemia develop in very young children. The study – published in Cancer Discovery, a journal of the American Association for Cancer Research – has also revealed potential new therapeutic targets.

Each year, 2,500 pediatric cancers are diagnosed in France, with one third of cases concerning leukemia – commonly known as blood cancer. Over recent decades, research into pediatric cancer has intensified and treatments have improved, but the prognosis remains particularly unfavorable for these young patients.

Acute myeloid leukemia (AML) accounts for 15% of cases of leukemia diagnosed in children and adolescents. Overall survival at 5 years is around 60%, with relapse being the most common cause of mortality.

Abnormal protein fusion

There are several subtypes of AML. One of the most aggressive, which is linked to treatment resistance and a particularly unfavorable prognosis, is acute megakaryoblastic leukemia (AML-M7). In their new study published in Cancer Discovery, the team focused their efforts specifically on this type of acute myeloid leukemia. Their work is co-financed by the National League Against Cancer.

Through the CONECT-AML collaborative network[1], the scientists obtained samples from young patients with AML-M7. In 2012, their analysis of these samples had already revealed AML-M7 to frequently present genetic alterations that lead to the expression of an abnormal protein resulting from the fusion of the two proteins normally independent in the cell. At that time, although this fusion – known as ETO2-GLIS2 – had been identified in 30% of AML-M7 cases, the researchers could not explain its mechanism of action.

They also wanted to understand why AML-M7 is diagnosed in children who are on average a lot younger (under 2 years of age) than those diagnosed with the other pediatric AML subtypes (on average towards the age of 6).

“One of the objectives of our new study was to look at the mechanism of action of the ETO2-GLIS2 fusion, and to better elucidate its consequences. We wanted to answer two major questions, with the first being why this disease is specific to children – since the fusion is not found in adults, and then what the potential therapeutic avenues could be”, explains Thomas Mercher.

This involved the researchers analyzing the characteristics of human leukemia cells and developing a mouse model to study the consequences of the ETO2-GLIS2 fusion.

Towards new therapeutic avenues

In this model, the researchers showed that this fusion is sufficient in order to rapidly induce aggressive leukemia, if it is activated in fetal hematopoietic cells. However, there is little to link its activation in adult cells with the development of leukemia. Moreover, blocking the ETO2-GLIS2 fusion in the in vivo model brings tumor proliferation to a halt, with the abnormal blood cells once again able to differentiate into normal blood cells.

These findings suggest that some forms of leukemia develop specifically in children because the properties of the fetal cells differ from those of adult cells.

Findings which also make it possible to propose new target mechanisms in fetal cells and pediatric leukemia in order to improve treatments for these patients. “We now want to understand exactly how this fusion works. Targeting it in order to directly inhibit it with molecules that could be used in patients is not something we are able to do at present, so instead we will identify and try to target the surrounding proteins that are important for it to function”, concludes Thomas Mercher.

[1] French network of various teams of researchers, clinical pathologists and pediatric hematologists

Cellules cancéreuses. Expression de la protéine PML en rouge et du gène ZNF703 en vert dans des cellules de la lignée de cancer du sein MCF7. ©Inserm/Ginestier, Christophe

Analysis of the CANTO cohort published in the journal Annals of Oncology will upset received wisdom on the effects that hormone therapy and chemotherapy have on the quality of life in women with breast cancer. Contrary to the commonly held view, 2 years after diagnosis, hormone therapy, a highly effective breast cancer treatment worsens quality of life to a greater extent and for a longer time, especially in menopausal patients. The deleterious effects of chemotherapy are more transient. Given that current international guidelines recommend the prescription of hormone therapy for 5 to 10 years, it is important to offer treatment to women who develop severe symptoms due to hormone antagonist medication and to identify those who might benefit from less prolonged or intensive treatment strategies.   

This work was directed by Dr Inès Vaz-Luis, specialist breast cancer oncologist and researcher at Gustave Roussy in the lab “Predictive Biomarkers and Novel Therapeutic Strategies in Oncology” (Inserm/Université Paris-Sud/Gustave Roussy).  

“This analysis of the CANTO cohort shows for the first time that anti-hormonal treatments do not have lesser effects than chemotherapy on women’s quality of life. Quite the contrary, as the diminution in quality of life which is noted at diagnosis is still present two years later, whereas the impact of chemotherapy is more temporary,” explained Dr Vaz-Luis.

In this study, researchers measured quality of life in 4,262 patients with localised breast cancer (stage I to III) at the time of diagnosis and at one and two years thereafter. Primary treatment for these patients was surgical and, for some of them, administration of chemotherapy and/or radiotherapy. About 75-80% of them then took hormone therapy for at least 5 years. Quality of life was measured using a tool which assesses general quality of life in patients with all types of cancer (EORTC QLQ-C30) combined with a tool more specifically designed for use in breast cancer (QLQ-BR23).

For the population studied as a whole there was an overall deterioration in the quality of life at two years from diagnosis. This deterioration was greater in patients who had received hormone therapy, especially after the menopause. By contrast, chemotherapy had a bigger effect on quality of life in non-menopausal patients, especially in terms of worsening of cognitive functions.  

“It is important in the future that we are able to predict which women are going to develop severe symptoms with anti-hormonal treatment so that we can support them,” added Dr Vaz-Luis. While it has been shown that hormone therapy provides a real benefit in reducing the relapse rate of hormone-dependent cancers[1] which represent 75% of all breast cancers, the deterioration in quality of life may also have a negative effect on patient adherence to treatment. It is, therefore, important to offer them symptomatic treatment, in particular for menopausal symptoms, musculoskeletal pain, depression, severe fatigue and cognitive dysfunction; and to combine this with supportive measures such as physical exercise and cognitive behaviour therapy.

“It will also be important in the future to differentiate prior to treatment patients who are at high risk of relapse from those at lower risk in order to tailor hormone treatment. This may be done to avoid escalation of anti-hormonal treatment in certain patients,” concluded Dr Vaz-Luis, emphasising that “hormone therapy is extremely effective in treating breast cancer, resulting in a reduction by approximately 50% in the risk of relapse, and that the finding of adverse effects does not in any way put into question the excellent risk/benefit ratio of this treatment.”

The CANTO cohort (CANcer TOxicities) comprises 12,000 women with breast cancer treated in 26 French centres. It is sponsored by Unicancer and directed by Professor Fabrice André, specialist breast cancer oncologist at Gustave Roussy, Inserm research director and responsible of the lab “Predictive Biomarkers and Novel Therapeutic Strategies in Oncology” (Inserm/Université Paris-Sud/Gustave Roussy). Its objective is to describe adverse effects associated with treatment, to identify the populations at risk of developing them and to adjust therapy accordingly, so as to afford a better quality of life following cancer.

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[1] [1] J Clin Oncol. 2019 Feb 10;37(5):423-438 : https://doi.org/10.1200/JCO.18.01160https://doi.org/10.1200/JCO.18.01160

Visualisation en coloration multispectrale d’une sous-population de cellules immunitaires infiltrant une tumeur. Inserm/Jerôme Galon

The immune response is activated from a very early stage in the development of precancerous cells. Unfortunately, this response is simultaneously accompanied by the onset of mechanisms that block it, allowing cancer to develop. This is the first time that the immune response has been described in such detail in precancerous stages, here in lung cancer. This research conducted by the team led by Jérôme Galon, Inserm research director at the centre de recherche des cordeliers (Inserm/Université de Paris/Sorbonne Université) in Paris, shows that using immunotherapies at very early stages could potentially help prevent cancer. This research has been published in Nature.

Our understanding of how the immune system works in the context of cancer is continually improving. Jérôme Galon and his Inserm team have made a significant contribution to such advances. After showing that cancer progression depends among other factors on the presence and functionality of T lymphocytes in the tumor microenvironment and the Immunoscore, the researchers have proven that the immune response and its blocking mechanisms are triggered at very early, precancerous stages.

This means that when a cancer develops, many components of immune surveillance but also the mechanisms designed to evade it have already been implemented.

At the moment, patients with precancerous lung lesions can be monitored and the lesions removed if doctors have the slightest suspicion that they are at risk of developing into cancer. But clinicians may be surprised to discover that it may already be possible at this stage to target the immune system in order to combat progression of these lesions. This is what the research by Jérôme Galon and his team has shown. The researchers had access to 122 lung biopsies from smokers at risk of cancer. They found all stages of precancerous to cancerous lesions in these biopsies. For each biopsy, they studied the immune system in the tumor microenvironment. They performed a genomic analysis of the cells present and looked at them using multispectral fluorescence, an imaging technique that uses specific antibodies to target different types of immune cell. This work enabled them to characterize the nature, quantity, and role of the various immune components in the tumor microenvironment at each precancerous and cancerous stage.

The immune response takes place before cancer

This made it possible for them to compare the development pathways of the cancer and the immune response. At the stage of low-grade dysplasia – an extremely early stage, when only a few morphological abnormalities, DNA repair defects, and greater ability to divide can be seen in the cells – the researchers observed activation of local immune cells and the arrival of naive T lymphocytes, i.e. T cells not trained to specifically destroy abnormal cells. At the stage of high-grade

dysplasia – where there is a higher level of morphological and molecular abnormalities – the researchers then observed mass recruitment of innate and adaptive immune cells, with the presence of B and T lymphocytes specific to abnormal cells and initiation of the immune memory response. But such activation is already accompanied at this stage by the triggering of blocking mechanisms called immune checkpoints and of immune suppressive cytokines, molecules that are also designed to block the immune response. This means that the functioning of the immune system is already altered before the cancer itself develops. This discovery in the context of lung cancer still requires confirmation in other types of cancer. Jérôme Galon is already working on doing so in colon cancer.

The researchers believe that this work will have major implications for the future of patient care. First, they highlight the importance of discovering immune biomarkers that will make it possible to better predict the risk of precancerous lesions developing into cancer.

Second, using immunotherapies designed to inhibit the mechanisms that block the immune system, the much talked about immune checkpoints, could be of benefit to patients in the early stages of cancer prevention.

Inserm: Science for Health

Jérôme Galon©Inserm/Mehrak

Inserm researcher Jérôme Galon has been honored by the European Patent Office (EPO) for his Immunoscore^®, a test that predicts relapse risk in patients with certain forms of cancer. An achievement that encapsulates the missions and results of Inserm, a research institute serving good health for all.

The invention of Jérôme Galon – under license from the French National Institute of Health and Medical Research through its private subsidiary Inserm Transfert and marketed under the name Immunoscore^® by the company he co-founded – is used to count the immune cells in patient tumor tissue. The more these immune cells are present in the tumor, the better the patient’s chances of survival. In colorectal cancer, the test has a 95% likelihood of predicting patient survival. Immunoscore^® gives doctors a more complete picture of the disease, enabling them to offer the most appropriate treatments to their patients.

To perform the test, a specialized scanner produces digital images of tumor samples, from which software will count the number of immune cells. An algorithm then calculates the patient’s Immunoscore^® based on the number of T-cells. Clinics throughout the world now use this test to predict relapse risk in patients with colorectal cancer.

“Jérôme Galon’s journey is exemplary in many respects and I offer him my warmest congratulations on winning the European Inventor Award 2019. Through Jérôme, it is the results of our research that are rewarded – when this research succeeds in bringing science and enterprise together. It is also a fine example of our motto at Inserm: Science for health”, declares Inserm Chairman and Chief Executive Officer, Gilles Bloch.

“With 165,000 patent applications filed in Europe every year, I am delighted to receive this award honoring more than 15 years of laboratory work – work that is still ongoing. It is also thanks to the freedom of research afforded to us at Inserm that I was able to embark on this research, over the long term, back when few researchers were interested in cancer immunology. In terms of creating value from this discovery, Inserm Transfert has also played a decisive role by supporting me throughout my journey”, states Galon.

©Adobe Stock

When faced with the most aggressive forms of lung cancer, how can the efficacy of chemotherapy be increased? Teams from Inserm, Université Paris Descartes and the Paris public hospitals system AP-HP have maybe hit on a solution. They have developed a targeted therapy which aims to improve the response to platinum salts – the standard chemotherapy used in lung cancer – by neutralizing the activity of a receptor that contributes to its aggressiveness. This research, published in Cancer Letters, shows that in mice this therapy restores the response to chemotherapy and reduces the risk of metastasis by one half to two thirds.

In metastatic lung cancer, life expectancy remains very limited, with death occurring within 5 years in 85 % of patients. The new treatments available for some patient populations present genuine efficacy, but this is of limited duration and successive relapses are common. Increasing the efficacy of existing treatments and finding new ones therefore remains a priority.

A priority that is being addressed by the team of Inserm researcher Patricia Forgez who, in collaboration with teams from the Paris public hospitals system AP-HP (Cochin, Lariboisière and Saint-Antoine hospitals) and Université Paris Descartes is developing a targeted therapy to increase the sensitivity of the most aggressive tumors to platinum salts, an essential chemotherapy in lung cancer.

In previous research, Forgez and her co-workers had shown that lung tumors and especially those at a metastatic stage overexpress the neurotensin receptor. Neurotensin is a small molecule produced in the intestines and brain that is also found to be abnormally overexpressed in tumors where, by binding to its receptor it triggers the continuous cascade of signals stimulating tumor cell growth, survival and migration. This renders them much more aggressive and with little or no sensitivity to platinum salts. By correlating the neurotensin receptor overexpression with the poorer prognosis observed in patients, the researchers had demonstrated that this receptor has a role to play in tumor progression.[1]

In this new study, the research team has developed an antibody to specifically neutralize the form of neurotensin produced by the tumors.[2] 

The long-term objective is to develop a targeted therapy to block the neurotensin receptor in order to weaken the tumor cells and improve their sensitivity to platinum salts.

“Almost all patients diagnosed with lung cancer receive platinum salts at some point in their treatment, reiterates Jean Trédaniel, study co-author and head of the Paris Saint-Joseph Hospital Group thoracic oncology unit, whether as first-line treatment or following the failure of a targeted therapy or immunotherapy. However, platinum salts are toxic to the body, making it impossible to increase the doses in the event of resistance. Administering this antibody would render the tumor more sensitive to the treatment. What is more, it has been shown in mice to be very well tolerated over the long-term. “

In collaboration with Inserm Transfert, French technology transfer acceleration company SATT Ile-de-France INNOV, and Fair Journey Biologics, the research team is now working on the development of anti-neurotensin antibodies for use in humans, the objective being to embark on a clinical trial. Encouraging results in lung cancer would enable the extension of this therapy to include the other cancers that express neurotensin and its receptor, such as those of the breast, ovary, endometrium, prostate, pancreas, stomach and colon.

[1] This discovery has been protected by a patent filed by Inserm Transfert, the co-owners of which are Inserm and AP-HP. This patent claims that the neurotensin receptor is a marker of tumor aggressiveness and that neurotensin is a potential therapeutic target.

[2] This antibody has been the subject of several patent applications filed by Inserm Transfert on behalf of Inserm and Université Paris Descartes; one of these patents was issued in the USA at the end of 2018.