Genetics and mechanisms involved in resistance to brain tumor treatments

In an article to be published in the prestigious journal Nature, Mehdi Touat and Franck Bielle (AP-HP/Sorbonne University) from the “Genetics and Development of Brain Tumors” team of l’Institut du Cerveau (Inserm/CNRS/Sorbonne University) and the neuro-oncology and neuropathology departments of the Pitié-Salpêtrière Hospital AP-HP in collaboration with Yvonne Li, Rameen Beroukhim, Pratiti Bandopadhayay and Keith Ligon of the Dana-Farber Cancer Institute (Harvard Medical School, Boston), highlight genetic changes in certain recurrent gliomas that cause the development of resistance to chemotherapy. In addition to its very comprehensive approach to various aspects of molecular and mechanistic analysis, the study deals with the largest sample ever explored in brain tumours.

 

Gliomas are the most common malignant primary brain tumours in adults. Their treatment is particularly difficult, not only because of their location limiting the extent of surgery, but also because they almost always develop resistance to radiotherapy and chemotherapy treatments. Gliomas thus end up relapsing. However, on an individual level, determining why and how they escape treatment is still very difficult in the clinic.

“There were a few described cases of tumour recurrence with what is called hypermutation, i.e. a tumour with an excessively high number of mutations in the genome compared to the average tumour. The biological phenomena causing this unusual phenomenon and their possible link with the development of resistance to treatment were not known. Furthermore, in other types of cancers, immunotherapy is more often effective in cases of hypermutation, but this approach had not been tested in gliomas. “explains Franck Bielle.

 

This study brought together several expert centres in neuro-oncology: the neuro-oncology team at l’Institut du Cerveau, the departments of neuro-oncology and neuropathology and the Tumorotheque of the Hôpital de la Pitié-Salpêtrière (AP-HP/Sorbonne University/SIRIC CURAMUS), and the departments of neuro-oncology and neuropathology and research teams of the Dana-Farber Cancer Institute, Brigham and Women’s Hospital and Boston Children’s Hospital (Harvard Medical School, Boston). By pooling their resources and integrating public databases and data from a partnership with the company Foundation Medicine, they obtained a global sample of 10,000 tumors, the first of this size for a single cancer study.

“The purpose of this work was to determine the mechanisms of hypermutation in gliomas and characterize their role in resistance to standard treatments. Understanding how the tumour resists allows us to adapt treatments and consider new therapeutic approaches such as immunotherapy. To answer these questions, we have combined for the first time the analysis of a very large base of gliomas characterized by high-throughput sequencing, with experimental approaches in experimental glioma models, and the analysis of data from glioma patients treated with immunotherapy. “continues Mehdi Touat.

Initially, the researchers established the prevalence of the hypermutation phenomenon, which is found in up to 50% of recurrences in glioma subtypes with high chemosensitivity at initial diagnosis. They showed a clear association between the hypermutation phenomenon and temozolomide, the most commonly used chemotherapy to treat gliomas. Hypermutations develop only after exposure to temozolomide treatment and, moreover, if temozolomide was effective on the first tumour.

The second step in the work was to understand the mechanism involved in the development of this resistance. Scientists therefore looked for the presence of specific gene alterations in these hypermutated tumours. They identified 4 genes that were mutated almost systematically, all part of a DNA repair pathway called “Mismatch repair” or MMR. By generating artificial mutations of these genes in experimental models, they demonstrate the development of specific resistance to temozolomide. On the other hand, in vitro, temozolomide applied to cells with inactivated MMR genes produces the same hypermutation as that present in patients.

“We show the clear mechanistic link between temozolomide, the inactivation of these MMR genes conferring resistance to this treatment, and continued exposure to this treatment leading to this very characteristic hypermutation in tumour recurrence. We also show that unlike temozolomide, other treatments used in gliomas remain effective in hypermutation recurrence. “says Franck Bielle.

MMR abnormalities are also frequently found in other types of cancers such as colorectal, endometrial or stomach cancers associated with a strong immune response. In gliomas, these treatment-acquired MMR abnormalities have very specific effects not found in other cancers, including a much weaker immune system response. Brain tumours are believed to have such strong immunosuppressive mechanisms that despite the accumulation of tens of thousands of mutations, they are still not recognized by the immune system as abnormal cells to be destroyed.

“This is a very striking difference from other cancers associated with MMR deficiencies, with a significant therapeutic impact. Indeed, in colorectal cancers with MMR system deficiency, some checkpoint inhibitor immunotherapies have been shown to be highly effective. Clinical data from glioma patients treated with the same approach unfortunately do not show sufficient efficacy for patients. “says Mehdi Touat.

“With these results, we will be able to provide information on the response to chemotherapy at the time of tumour diagnosis and during treatment, particularly in case of recurrence after chemotherapy, where the use of high-throughput DNA sequencing techniques would allow us to tailor treatment in a personalised manner. These discoveries do not call into question the use of temozolomide, which has shown significant gains in survival and does not cause hypermutations in the majority of patients. On the other hand, if this phenomenon is identified, the orientation towards a choice of treatment will be more precise and more effective. The question now is first and foremost how other tumours that do not progress to hypermutation eventually resist chemotherapy. We also need to understand the specificities of the microenvironment of these hypermutated gliomas that prevent the immune system from recognizing the tumor and thus pave the way for immunotherapy in neuro-oncology. “concludes the two clinician-researchers.

 

Source

Mechanisms and therapeutic implications of hypermutation in gliomas, Nature 2020.