Glioblastoma is among the most aggressive and destructive to cancer. Although rare compared to other cancers, it is the most common type of brain cancer. Even with intensive care, very few patients survive longer than two years after diagnosis, and less than 10% of patients live longer than five years. Despite extensive studies focusing on the genomic features of glioblastoma, little progress has been made in developing treatment for patients with this deadly disease.
Now, a new study is being led by Washington University School of Medicine in St. Louis. Louis, Pacific Northwest National Laboratory, Case Western Reserve University and the National Cancer Institute (NCI) of the National Institutes of Health (NIH) on a detailed map of the genes, proteins, infiltrating cells and signaling pathways play key roles in driving glioblastoma. The study, of 99 tumors from patients, is the largest and most detailed scheme of this lethal brain tumor.
The research, published Feb. 11 in the journal Cancer Cell, is part of the NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC).
“To improve treatments for this deadly cancer, understanding the tumor cells themselves is important but not enough,” said lead author Li Ding, PhD, professor of medicine and genetics and director of computational biology in the Department of Oncology at the University of Washington. “We also need to understand the interaction of tumor cells with the surrounding environment, including immune cells and the connective tissue and blood vessels. In our study, we performed high-resolution and high-resolution analyzes. depth of 99 glioblastoma tumors.Using new technologies, including proteomics, metabolomics and single cell sequencing, this study is a very deep dive into the biology of glioblastoma tumors, revealing new potential for healing. “
The study identified new activated proteins -; specifically PTPN11 and PLCG1 -; the signaling centers direct tumor growth in some patients; showed patterns of gene expression involved in a process called epithelial-to-mesenchymal transitions that are common in tumor formation; they identified four different categories for the classification of glioblastoma, based on the number and types of immune cells present in the tumors; and they concluded how undeveloped protein modification, acetylation, may explain some functional differences between glioblastoma subtypes.
Acetylation alters protein composition and often opens up DNA-protein structures to enable gene expression. By adding protein acetylation to our study, we were able to complete the loop from protein to gene and gene expression, shedding light on important regulatory changes in glioblastoma. “
Karin Rodland, PhD, Co-Author and Principal Scientist Study, Biomedical Research, Pacific Northwest National Laboratory
“The most direct implications for these decisions are improved design of clinical trials,” said co-author Milan G. Chheda, MD, a professor of medicine who treats patients at the Siteman Cancer Center at Barnes Hospital -Judith and Washington University School of Medicine. “For most clinical trials, we take all comers and give them the same treatment. We do not design trials in the most precise way because we have not fully understood the molecular differences between the tumors of each patient. This leads us to the treatment of failure when in fact it may help certain individuals. “
The new study shows that individual tumors tend to respond differently to targeted treatments. For example, the protective landscape of these mounds varied widely, responding in four different regions. Type 1 tumors contain high numbers of immune cells called macrophages and a few T cells. Type 2 tumors have a moderate number of macrophages. Type 3 tumors contain high numbers of T cells and few macrophages. And type 4 tumors are what Ding calls a immune system, with very few immune cells of any kind.
Thus, immunotherapy aimed at macrophages, for example, may work well in patients with type 1 tumors but not at all in patients with type 4. Still, a clinical trial that is lumping all patients together indicates that such a drug works at all, when it is average across all patients.
“What is particularly appealing about this study is the collection of glioblastoma into four groups based on immune subtypes that emerged by combining a complete proteomic and genomic analysis,” said Henry Rodriguez, director of the Office of Proteomics Research Cancer clinician at the NCI. “This could open the door for effective responses to immune therapies.”
The co-author added Albert H. Kim, MD, PhD, professor of neurological surgery at the University of Washington and director of Siteman’s Brain Tumor Center: “Clinical trials of immunotherapy in glioblastoma have been negative to date. And The fact that there are four different immune subgroups may be one of the reasons behind this. We cannot treat all glioblastoma tumors as one disease. “
A group led by lead author Tao Liu, PhD, of the Pacific Northwest National Laboratory, measured the proteins in the tumor samples as well as two specific modifiers, called phosphorylation and acetylation, that affect bio- cognitive such as cell signaling.
Incorporating these data into the genomic analysis of the tumors revealed a small subset of non-responsive glioblastomas in any of the conventional genomic subtypes. These mixed-subtype tumors were associated with poor clinical outcome, providing the researchers with evidence about the factors influencing tumor invasion that were not apparent from genetic information alone.
“These patterns provide additional information for researchers to understand how the glioblastoma subtypes they have described may differ in biological function,” Liu said. “This multivariate analysis provides an unprecedented level of detail, which begins to connect the missing dots in glioblastoma.”
Added Chheda, “This paper is an example of the advances that can be made when there is deep collaboration between many experts across the country that has the potential to bring together the National Cancer Institute.”
The researchers are conducting further studies to study the best drugs in glioblastoma patients, depending on where their diseases fall on the new tumor map.
Source:
Washington University in St. Louis