The first targeted drug for glioma in mainland China was approved for marketing
Glioma, the most common malignant tumor in the adult skull with a high rate of disability and death, has ushered in a breakthrough treatment drug. Recently, the National Medical Products Administration (NMPA) officially approved the use of rivetinib, a small molecule targeted drug independently developed by mainland China, for the treatment of glioma-related indications. It is reported that this is the world's first approved small molecule targeted drug for the treatment of glioma, and it took only more than 6 months from being included in the priority review to being approved for marketing, marking that the mainland has entered the precision diagnosis and treatment mode of glioma ahead of other countries.
According to Jiang Tao, academician of the Chinese Academy of Engineering, director of the Beijing Institute of Neurosurgery, and director of the Neurosurgery Center of Beijing Tiantan Hospital affiliated to Capital Medical University, rigetinib was approved for use in gliomas with IDH-mutant astrocytoma who have failed previous treatment, have PTPRZ1-MET fusion genes, or adult patients with glioblastoma with a history of low-grade disease. Among them, the target PTPRZ1-MET was discovered by his team ahead of international peers, and was written into the "Diagnosis and Treatment Standards for Glioma (2018 Edition)" and the "World Health Organization Classification of Central Nervous System Tumors (Fifth Edition)" formulated by the National Health Commission as an important molecular diagnostic index.
Most of the previously marketed MET inhibitors are multi-target inhibitors, with unclear mechanism of action and strong toxicity and side effects. In order to achieve precise treatment for PTPRZ1- MET-positive patients, Academician Jiang Tao's team has invented a new small molecule single-target inhibitor of MET gene that can efficiently cross the blood-brain barrier - beritinib. The inhibitor has an inhibition rate of up to 95.1% on the activity of MET gene pathway, while it has almost no effect on other pathways, and has the advantages of clear target, clear mechanism of action, safety and controllability. Clinical trial results showed that patients with relapsed glioma treated with rigitinib had a two-fold longer median survival and a 40% lower risk of death at 2 years.
Interview guest in this issue: Jiang Tao
He is an academician of the Chinese Academy of Engineering, director of the Beijing Institute of Neurosurgery, and director of the Neurosurgery Center of Beijing Tiantan Hospital, Capital Medical University. He has been engaged in basic and clinical research on brain tumors for a long time, and has established a precision surgical technology system for gliomas in brain functional areas. Establish a public data platform for glioma genomics in China, formulate new standards for molecular typing of glioma and individualized diagnosis and treatment plans, and promote the transformation of glioma treatment to a precision diagnosis and treatment model based on molecular pathology; It is the first in the world to systematically carry out research on the etiology of the malignant progression of glioma, and for the first time discovered and named a new fusion gene PTPRZ1-MET, and thus independently developed a small molecule targeted drug for this fusion gene in China.
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Health News: Glioma, many people have heard but don't know about it, can you tell us what kind of disease it is?
Jiang Tao: Glioma is the most common adult intracranial malignant tumor, accounting for about 46% of intracranial tumors, and the incidence rate is generally 6/100,000~8/100,000, and the degree of malignancy is very high. In children, it is the second most lethal cancer after leukemia. Among fatal cancers in young men, gliomas rank third; It is also the fourth leading cause of fatal cancer in women.
There are many subtypes of glioma, one of which is called "IDH-mutant high-grade glioma", which is more common in young and middle-aged men. These patients are the backbone of society and the pillars of the family, and once they are gone, it will be a heavy blow to the family.
Surgery and chemoradiotherapy have long been the main treatments for glioma. However, gliomas often infringe on important functional areas of the brain such as language, movement, and logical thinking, and the tumor and brain tissue are entangled, without obvious demarcation, and it is difficult to completely remove them through surgery. Data show that the 5-year overall survival rate of patients with high-grade glioblastoma is less than 10%; For patients who relapse after treatment, even if they undergo surgery again, the survival time after recurrence is only 5 months. As a result, this disease is also one of the most difficult to treat in the field of neurosurgery. It is an urgent clinical problem to clarify the cause of the recurrence of this disease, find drugs that can inhibit its recurrence, and solve the problem of high mortality and disability rate of glioma.
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Health News: What kind of process has our country's scientific research in this field gone through?
Jiang Tao: At the beginning, there was a big gap between us and the international advanced level. More than 20 years ago, there was a gap between elementary school students and college students. All we can do is try to catch up. This is also the task entrusted to me by my teacher, Academician Wang Zhongzhong, an important pioneer of neurosurgery in China.
We start with the basics. In the past, most of our clinical studies on glioma could only rely on the TCGA database in the United States. The database is dominated by Caucasian data, with very little data on Asian patients. The results of the research based on this database have been of limited benefit to Asians. Therefore, in 2004, we adopted the internationally accepted malignant tumor R&D path to set up a R&D team, integrated multiple resources, and launched the "China Glioma Genome Atlas Project (CGGA)", which lasted 16 years to build our Chinese glioma database.
CGGA is used for scientific research by scientists from 175 countries and regions around the world. Through the world's largest, free and open glioma database, medical researchers around the world can search for the most critical information in a large number of genomes to contribute to the treatment of Chinese patients.
In 2014, based on this database, we established the world's first full-grade glioma fusion gene profile, and discovered and named a new fusion gene that promotes the malignant progression of glioma for the first time, PTPRZ1-MET. Further gene functional experiments confirmed that this new fusion gene is a key gene that promotes the malignant progression of glioma. As a new molecular diagnostic marker for glioma, this discovery has been included in the World Health Organization's classification of central nervous system tumors, and is the only work in the field of neuro-oncology in China that has rewritten the world's guidelines in the past 44 years.
Finding this fusion gene is equivalent to finding a "lock" for the malignant progression and recurrence of glioma, and what we have to do is to find the appropriate "key" to unlock. Is there a "key" in the existing medicine that can be unlocked? Some. Among the multi-targeted inhibitors targeting lymphoma, there is one that can inhibit PTPRZ1-MET. However, multi-target drugs must have a large molecular weight. It's okay to do cytology experiments, but once you do animal tests, the effect won't work. Because there is a blood-brain barrier, the molecular weight is large, and the pass rate is not high. If the medicine can't get into the skull, it won't work.
So, we have to make the "key" ourselves. This time, it took more than 3 years and more than 100 compounds to try, and finally, we were the first in the world to design a small molecule compound that targets the PTPRZ1-MET fusion gene and can efficiently cross the blood-brain barrier, that is, britinib.
Research is a relay race. It is precisely because we ran fast in the first stick and discovered the PTPRZ1MET first that the drug research and development of the second stick has a first-mover advantage and leads again.
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Health News: 20 years have passed, in the field of international glioma scientific research, which echelon is Beijing Tiantan Hospital in general?
Jiang Tao: We have also done third-party statistics to conduct comprehensive evaluations from various dimensions, including leading clinical trials, applying for invention patents, and the number of citations of scientific research papers in the world. Based on these results, the single disease of glioma in the Department of Neurosurgery of Beijing Tiantan Hospital is in the leading position in the world.
Most importantly, through these 20 years of hard work, we have established a multidisciplinary, young and energetic R&D team, built a full-process drug R&D system in the Beijing Institute of Neurosurgery, and the R&D of new neuro-oncology drugs has entered the fast lane.
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Health News: Now britinib is on the market. What does its clinical application mean for glioma patients? You said that you hope that in the future, the treatment of glioma will become a chronic disease. Can rigetinib achieve this goal?
Jiang Tao: The clinical application of ristitinib means that there is more hope for patients. Results from our clinical trial showed that britinib increased median survival by a factor of 2 and reduced the risk of death at 2 years by 40% in patients with recurrent glioma. Moreover, this drug can be used in combination with other treatments to create a synergistic effect and further amplify the effect of the treatment.
At the same time, based on the CGGA database, we will continue to look for a series of drugs that act on different links and pathways, and strive to generate more such synergies.
In addition, we have developed a major breakthrough in CAR-T cell (chimeric antigen receptor T cell) immunotherapy for glioma, which has very good results and is expected to be marketed within a few years.
We hope that gliomas can become like chronic diseases such as high blood pressure, and that patients can survive for a long time if they are well controlled. With the help of these new developments and achievements, our goals should be achieved.
Text: Health News reporter Cui Fang Editor: Yang Zhenyu Proofreader: Ma Yang Review: Qin Mingrui Xu Bingnan
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