Release date: 2017-10-20
Bladder cancer generally occurs in the bladder epithelial cells and is the fifth most common type of cancer in the world. It is estimated that there are 151,000 new cases of bladder cancer each year and more than 52,000 deaths per year. Urinary tract cancer is the most common type of bladder cancer, accounting for about 90% of all bladder cancers. Most bladder cancers can be diagnosed at an early stage, but the rate of recurrence and progression is high, with approximately 78% of patients recurring within 5 years. The survival rate of bladder cancer is related to tumor stage, pathological type and time of diagnosis. The 5-year survival rate for stage IV bladder cancer is only 15%.
Bladder cancer is the most common malignant tumor of the urinary system, and it is very easy to relapse, which seriously endangers human life and health. The incidence of bladder cancer in China is 6.69/100,000, ranking first in urinary system tumors; the mortality rate is 2.53/100,000, and it is increasing year by year. Currently, there is only one chemotherapy for the treatment of malignant bladder cancer, and there has been limited progress in this area over the past two decades.
Based on this, Xiao Bian conducted an inventory of the progress made in bladder cancer research in recent years to readers.
1.ASCO2016: Baishimei PD-1 immunotherapy Opdivo treatment of advanced bladder cancer harvest gratifying objective response rate data
News source: Promising Response Rates with Opdivo (nivolumab) Observed in Advanced Form of Bladder Cancer from Phase 1/2 Study CheckMate -032
US pharmaceutical giant Bristol-Myers Squibb (BMS) recently announced PD-1 immunotherapy in an open-label I/II clinical study (CheckMate-032) at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in 2016. The first data from Opdivo in the treatment of metastatic urothelial carcinoma (mUC, n=87) in patients with progression of platinum-containing chemotherapy.
The primary end point of the study was the objective response rate (ORR) confirmed by the investigator. The minimum follow-up of 9 months showed that the ORR of the Opdivo treatment group was 24.4%. Remission rate data assessed based on PD-L1 expression levels were similar to remission rate data independent of PD-L1 expression levels. In patients with PD-L1 expression levels <1%, the ORR data was 26.8%, and in PD-L1 >1% patients, the ORR data was 24%. At one year, the overall survival rate (OS, secondary endpoint) was 45.6% in the Opdivo treatment group and median OS data was 9.72 months. The safety of Opdivo in the CheckMate-032 study is consistent with the known safety of Opdivo in other types of tumors.
Urinary tract carcinoma (UC) is the most common type of bladder cancer, accounting for approximately 90% of all bladder cancer cases. Patients in the advanced stage are faced with very high rates of disease recurrence and exacerbation, leading to far-reaching medical needs in this area. The data from the CheckMate-032 study supports the further exploration of Opdivo's outcomes and survival benefits in this cancer group.
2.Cell: Comprehensive molecular characterization of muscle invasive bladder cancer to help improve therapy
Doi:10.1016/j.cell.2017.09.007
In a new study, researchers from Baylor College of Medicine, Brigham and Women's Hospital, the University of Texas MD Anderson Cancer Center, the British Columbia Cancer Research Center, and the Broad Institute of Research completed 412 muscles. The comprehensive molecular characterization of invasive bladder cancer samples led them to identify five different bladder cancer subtypes, each with different sensitivities to specific therapies. These results may lead to the development of personalized therapies in the future. The relevant research results were published online in the Cell Journal on October 5, 2017, and the title of the paper is "Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer". These research institutions are part of the Cancer Genome Atlas Research Network (TCGA Research Network).
In 2014, these researchers published a study of 131 bladder cancer samples in the Nature journal: the first comprehensive "multi-omic" feature of molecular changes in this cancer. Description, this is a major advancement in personalized therapy and a feature of the TCGA Research Network project (Nature, 20 March 2014, doi:10.1038/nature12965). The new study expands on the study in 2014, involving a larger research community, integrating more genomic data types, and refining the molecular subtypes of bladder cancer.
Dr. John N. Weinstein, co-author of the paper and co-director of the Department of Bioinformatics and Computational Biology at the MD Anderson Cancer Center at the University of Texas, said, "In this study, we have increased the number of bladder cancer samples we studied by a factor of three, from 2014. The 141 species increased to 412 in 2017, which led to the identification of another 32 frequently mutated genes and the addition of less common mutations that appear to be involved in this cancer. These altered genes are the development of new therapeutic interventions. There are many opportunities. Bladder cancer is one of the highest rates of cancer, and it seems to indicate that APOBEC-characteristic mutations are associated with this higher mutation load and are involved in up to 70% of bladder cancer. Tumors with the highest number of mutations and higher APOBEC levels were associated with higher than average survival rates."
In addition, integration of multiple molecular parameters such as mutations, gene amplification, RNA and protein maps reveals that bladder cancer can be subdivided into four subtypes, but in 2014, these researchers identified five subtypes. type. They suggest that each subtype may be associated with a unique response to treatment, and this needs to be validated in future clinical trials.
3. Chinese scientists have identified a new pathway for the maintenance of human bladder cancer stem cells
Doi:10.1158/1078-0432.CCR-17-0882
Bladder cancer is the most common malignant tumor of the urinary system, and it is very easy to relapse, which seriously endangers human life and health. As the best choice for targeted therapy, bladder cancer stem cells have the potential of self-renewal, immortalization and multi-directional differentiation, and are the root cause of bladder tumorigenesis, development, recurrence and metastasis. However, the molecular mechanism of self-renewal of bladder cancer stem cells remains unclear. Although the transcription factors GLI1, STAT3, BMI1 and CTNNB1 may be involved in the dry maintenance of bladder cancer stem cells, these transcription factors also have important functions in normal bladder stem cells and are not suitable as specific targets for the treatment of bladder cancer. Therefore, it is urgent to clarify the new mechanism of self-renewal of bladder cancer stem cells, and to find new measures to effectively prevent and target bladder cancer.
The research group of the Institute of Microbiology, Chinese Academy of Sciences and the researcher of the Institute of Biophysics of the Chinese Academy of Sciences, Li Wei, etc., identified a new dry maintenance pathway for human bladder cancer stem cells, KMT1A-GATA3-STAT3 signaling pathway. Mechanistic studies have shown that KMT1A protein directly catalyzes the trimethylation of histone H3 lysine (H3K9me3) in the GATA3 promoter region (-1351~-1172) through its methyltransferase activity, thereby repressing Its transcription; GATA3 protein can directly bind to the promoter region of STAT3 gene (-1710~-1530) and repress its transcription. Therefore, histone methyltransferase KMT1A-mediated transcriptional repression of GATA3 gene promotes up-regulation of STAT3 and phosphorylation activation, and finally achieves dry maintenance of bladder cancer stem cells.
This study reveals for the first time the mechanism by which the KMT1A-GATA3-STAT3 signaling pathway promotes self-renewal of bladder cancer stem cells. The high expression of histone methyltransferase KMT1A in bladder cancer stem cells is specific compared to bladder cancer non-stem cells and adjacent tissues. Therefore, KMT1A can be used as the first bladder cancer stem cell-specific marker, and has broad application prospects in the identification of bladder cancer stem cells and targeted therapy of bladder cancer. In addition, the discovery deepens the understanding of the physiological characteristics of bladder cancer stem cells and the occurrence of bladder cancer at the molecular level, and provides a theoretical basis for drug screening and targeted therapy of bladder cancer.
4.BJC: Simple detection technology can predict whether patients have bladder cancer recurrence
Doi:10.1038/bjc.2017.210
Recently, a research report published in the international journal British Journal of Cancer, researchers from the University Hospital of Lyon developed a simple detection method, compared with other current detection methods, this new detection technology Can detect bladder cancer earlier and more accurately. In the article, the researchers tested the wrong protein called TERT in the urine of 348 patients with bladder cancer, which may help at least 80% of patients with bladder cancer predict whether their cancer has recurred, called cytology. The standard method of (cytology) is only able to detect disease recurrence in 34% of patients.
This new detection technology enables the detection of bladder cancer that does not spread to the muscle wall of the bladder earlier than cytology, which may potentially help doctors to help patients develop treatments before symptoms appear. . Researcher Alain Ruffion said that standard cytology testing techniques require doctors to observe the results under a microscope, but the new TERT protein detection technology is machine-readable, with higher accuracy and reliability, and the cost of TERT testing. It's much cheaper than cytology, and it's getting cheaper over time.
Researchers have pointed out that investigators that are not actually able to respond to urinary tract infections are more interesting to researchers because they are very powerful and may not produce results that mislead researchers. Later researchers need to conduct more in-depth research to understand the role of TERT protein errors in the pathogenesis of bladder cancer.
5. EU approves Opdivo for bladder cancer
Shimei Squibb announced on June 2, 2017 that Opdivo (nivolumab) has been approved by EMA for the treatment of adult patients with locally advanced unresectable or metastatic urothelial carcinoma who have failed platinum therapy.
“There are about 151,000 new cases of bladder cancer diagnosed each year in Europe. In the past few decades, the treatment of advanced bladder cancer has been stalled.†Director of the Department of Urology and Multidisciplinary Clinic, Department of Urology, Munich University of Technology Professor Margitta Retz pointed out that “the European Commission's approval of nivolumab for the treatment of such patients is an important advancement, and nivolumab has a significant objective response rate, providing treatment for patients with locally advanced unresectable or metastatic urothelial cancer. An important treatment option."
The approval is based primarily on a clinical study called CheckMate-275. This is a phase II open-label, one-arm, multicenter clinical study evaluating the local progression of nivolumab progression during or after chemotherapy with platinum or after 12 months of neoadjuvant or adjuvant chemotherapy with platinum. Or the efficacy of patients with metastatic urothelial cancer. In this study, 270 patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or intolerable toxicity. The primary endpoint of the study was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 20.0% (95% CI: 15.4, 25.3; 54/270) patients achieved remission after nivolumab treatment. The complete response rate was 3.0% (8/270) and the partial response rate was 17% (46/270).
6.European Urology: Anti-cancer drugs in the body of Plasmodium!
Doi:10.1016/j.eururo.2017.03.021
A recent study showed that a protein extracted from Plasmodium can effectively prevent the growth of chemotherapy-resistant bladder cancer cells. This discovery will provide new treatments for these cancer patients.
Previous studies have shown that VAR2CSA protein in Plasmodium can effectively kill many different types of cancer cells, and in a recent study, the authors gave mice high-grade bladder cancer cells, after which researchers We tested this protein to deliver the drug directly to the tumor tissue. The results show that these tumor cells are able to respond quickly to Plasmodium "drug bombs."
After drug treatment, 80% of animals survived for more than 70 days, while control mice died of bladder cancer.
7. Chinese Academy of Sciences genomics research reveals the origin of bladder cancer stem cells
Doi:10.1016/j.eururo.2016.06.025
Cancer stem cells play an important role in the occurrence, self-renewal, drug resistance and metastasis of tumor cells. The origin and genetic basis of Bladder Cancer Stem Cells, the most common malignancy in the urinary system, remains unclear.
Li Yi, Institute of Biotechnology, Institute of Biophysics, Chinese Academy of Sciences, collaborated with researchers from the Institute of Microbiology, Chinese Academy of Sciences and Shenzhen University to conduct genomics exploration of cancer stem cells using single-cell sequencing technology. Experimental verification.
The researchers used bladder cancer-specific antibody BCMab1 in combination with CD44 antibody to sort bladder cancer stem cells (Bladder Cancer Stem Cells), Bladder Cancer Non-Stem Cells, and bladder epithelium from 3 fresh bladder cancer tissues. A total of 59 cells of Bladder Epithelial Stem Cells and Bladder Epithelial Non-Stem Cells were subjected to single cell MALBAC amplification and whole exon sequencing.
Through evolutionary analysis, it was found that bladder cancer stem cells start from bladder epithelial stem cells or bladder cancer non-stem cells. Identification of 21 key genes that have been mutated in bladder cancer stem cells revealed that 6 genes have not been reported in bladder cancer (ETS1, GPRC5A, MKL1, PAWR, PITX2, RGS9BP). The combination of ARID1A, GPRC5A and MLL2 mutations significantly enhanced the ability of "bladder cancer non-stem cells" to be transformed into "bladder cancer stem cells".
This research uses the single-cell MALBAC amplification technology combined with the whole exome sequencing technology to describe the genomics of bladder cancer stem cells in detail, and experimentally confirmed the scientific problem that "bladder cancer stem cells" originated from "bladder cancer non-stem cells". It reveals the genetic basis of human bladder cancer stem cell origin, and clarifies how the driver mutation in cancerous cells regulates the self-renewal mechanism of bladder cancer stem cells, which is of great significance for the prevention and treatment of human bladder cancer.
The results of this study are Single-cell sequencing reveals variants in ARID1A, GPRC5A and MLL2 driving self-renewal of human bladder cancer stem cells and Reply from Authors re: Xue-Ru Wu. Single-cell sequencing reveals variants in ARID1A, GPRC5A and MLL2 driving self-renewal of human bladder cancer stem cells was published in the international urology academic journal "European Urology". The first author of the former is Li Zhao and the Institute of Microbiology, Yang Zhao, Institute of Biophysics, Chinese Academy of Sciences, and Wu Song, a professor at Shenzhen University, is the author of the communication. The latter's correspondents are Li Wei and Yang Zhao.
8. Lack of Vitamin D may increase the risk of bladder cancer in individuals
News source: Low vitamin D levels linked to increased risk of bladder cancer
Recently, at the annual meeting of the Endocrine Society in Brighton, England, researchers from the University of Warwick published their latest research results, the researchers found that the lack of vitamin D may increase the risk of bladder cancer in individuals, the researchers later More research is needed to confirm this, and the study also points to the importance of maintaining adequate levels of vitamin D in the body.
In countries with insufficient levels of sun exposure, it is difficult to obtain adequate levels of vitamin D from food alone, and vitamin D deficiency occurs in one in five adults in the UK, and three-fifths of the population are in the body. Vitamin D levels are low, and this condition is particularly prevalent in dark-skinned people. In the winter, about 75% of British dark-skinned people experience vitamin D deficiency. In this study, the investigators investigated the relationship between vitamin D and individual bladder cancer. The researchers conducted a comprehensive analysis of seven studies, each of which studied 112 to 1125 participants. Five of these studies have linked lower vitamin D levels to an increased risk of bladder cancer in individuals.
In a separate experiment, the researchers conducted an in-depth analysis of bladder transitional epithelial cells and found that these cells were able to activate and respond to vitamin D, which in turn stimulated the body's immune response, according to researcher Rosemary Bland. The key is because the immune system can effectively prevent cancer by identifying abnormal cells before the body is cancerous.
9. Chemotherapy is a double-edged sword! Nature's publication reveals how chemotherapy promotes bladder cancer evolution and produces drug resistance
Doi:10.1038/ng.3692
Chemotherapy is the first-line treatment option for advanced bladder cancer, but a recent study published in the international academic journal Nature Genetics shows that although chemotherapy can kill most cancer cells, it also pushes the remaining urinary tract. The cloning of skin cancer cells undergoes genetic evolution to produce drug resistance.
Researchers from Cornell University and the University of Trento have recently discovered mutations in urothelial cancer cells after chemotherapy, which provides cancer cells with an evolutionary advantage that survives chemotherapy. They collected tumor samples from 32 patients with advanced urothelial carcinoma who were at different stages of the disease and then used whole exome sequencing to sequence all of the genes encoding the patient's tumor samples. Twenty-eight of the 32 patients developed cancer metastasis shortly after participating in the study or participating in the study. Two patients underwent an autopsy within 6 hours of death. The researchers collected tissue samples from different locations on the body of the deceased patient. The researchers then compared the gene sequences of the tumor cells after chemotherapy and chemotherapy, and identified the same and different genetic mutations in the two tumor cells.
The researchers found that most of the above two tumor cells have different gene mutations. After the tumor spreads, the tumor cells will acquire new mutations, which are different from the tumors in situ, and the occurrence of gene mutations usually occurs very early in the disease development. This research has very important clinical significance for the development of targeted therapies. Clinically, only one tumor site is genome-detected, and it is impossible to capture the complete genetic changes of tumor cells during the entire chemotherapy treatment.
10. Cancer Cell: Researchers found molecular types of early bladder cancer
Doi:10.1016/j.ccell.2016.05.004
A recent study from the Aarhus University Hospital in Denmark and the University of Aarhus showed new molecular subtypes of early bladder cancer. The results of this study can better explain the invasiveness of some bladder cancers and provide a basis for optimizing treatment options.
There are approximately 1900 new cases of bladder cancer in Denmark each year. At the time of diagnosis, only a mass of the bladder surface was found in many patients. These patients will always find many new bumps during the next long period of time. Some patients develop an invasive disease that may require removal of the mass or chemotherapy.
The research team by Torben? Rntoft and Lars Dyrskj? Professor t led the molecular mechanisms of 460 early bladder cancer patients in Denmark, Sweden, New Zealand, Germany, Spain and Serbia. The researchers found that the molecular characteristics of early bladder cancer and the developmental characteristics of the disease can be divided into three main types. This division is important for assessing risk and treatment options.
The researchers found that bladder cancer from a high-risk molecular group that develops into invasive disease carries a molecular pathway of mutation and activation of genes that are common in patients with complete bladder cancer. In addition, the researchers found that in 86% of bladder cancer, genetic mutations affect the structural regulation of the genome. This new understanding helps us to use new drugs for targeted therapy.
11.ASCO2016: Clinical trials show that Nivoluma, an immunotherapeutic drug, can help treat advanced bladder cancer
News source: Nivolumab immunotherapy helps patients with advanced bladder cancer
According to clinical trial results from the MD Anderson Cancer Center at the University of Texas, the immune checkpoint blockade nivolumab can reduce the tumor burden of 24.4% of patients with metastatic bladder cancer, regardless of whether their tumor expresses a Biomarkers associated with drug targets. The study will be published on June 5, 2016 at the annual meeting of the American Society of Clinical Oncology (ASCO).
This phase I/II clinical trial treated 78 patients: 5 (6.4%) had complete remission; 14 (18%) had partial remission, and their tumor burden was reduced by at least 30%; 22 (28.2%) The condition is stable; 30 (38%) deteriorated.
Treatment-related side effects include mild fatigue, itching, elevated levels of lipase, rash, nausea, joint pain, and anemia. Stage III or IV side effects occurred in 20.5% of patients. Two patients discontinued treatment due to adverse events associated with the drug.
After a median follow-up of 213 days, 33.3% of patients continued to receive treatment, and 45.6% of patients survived for at least one year, which Sharma considered to be “better than what we observed in the pastâ€.
12.ASCO2016: Drug Atezolizumab retrains immune system to fight advanced bladder cancer
News source: New drug 'retrains' immune system to fight aggressive bladder cancer
According to an international clinical trial published at the American Society of Clinical Oncology (ASCO) annual meeting on June 5, 2016, a new drug that uses the immune system to attack tumors is highly effective against advanced bladder cancer. .
As part of these latest research findings, 28 of the 119 patients who received the experimental test drug atezolizumab had a tumor shrinkage of more than 30% and prevented new tumor growth. All of these patients received this drug injection as their first treatment for this disease. As a member of a class of drugs known as checkpoint inhibitors, atezolizumab (trade name Tecentriq) was approved for sale by the US FDA last month.
Dr. Arjun Balar, assistant professor at the Lange Medical Center at New York University, said, "Our new findings indicate that atezolizumab represents a significant advance in the treatment of bladder cancer."
13.ASCO2016: Roche PD-L1 immunotherapy Tecentriq first-line treatment of advanced bladder cancer significantly reduced tumor volume
News source: Roche's cancer immunotherapy Tecentriq (atezolizumab) shrank tumours in people with previously untreated advanced bladder cancer
Swiss pharmaceutical giant Roche recently announced in a phase II clinical study (IMvigor210) that PD-L1 tumor immunotherapy Tecentriq (atezolizumab) was used in the past at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in 2016. Update data for patients with locally advanced or metastatic urothelial carcinoma (mUC) who received treatment (first-line therapy) and who were not eligible for cisplatin-based chemotherapy. The data showed that Tecentriq reduced tumor volume in 24% (n=28) of patients, and in the patients who achieved remission, 75% (n=21) of patients continued to have treatment remission during data analysis, median duration of remission Not yet reached. In this study, 7% (n=8) patients achieved complete remission (CR) with a median overall survival (OS) of 14.8 months. In this study, the safety of Tecentriq was consistent with earlier analysis data from the study and was consistent with other studies by Tecentriq as monotherapy.
Ronald's Chief Medical Officer Sandra Horning said the data is very encouraging because about half of patients with this type of bladder cancer cannot tolerate cisplatin-based chemotherapy, and the continued treatment options for alternative treatment options are very limited. Fortunately, most patients who had relief from Tecentriq treatment continued to remit at the time of data analysis.
Source: Medical Valley
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