One gene can serve as a potential target for drug-resistant brain cancer glioblastoma multiforme

Research led by doctors and scientists at UCLA Johnson Comprehensive Cancer Center and the UCLA Jane & Terry Seed Institute for Neuroscience and Human Behavior has found that a gene may provide a therapeutic target for the deadly, treatment-resistant glioblastoma (GBM) of the pleomorphic brain cancer
.

The gene, called P300, is able to restore GBM cells damaged by radiation therapy by recombinant DNA and initiate a molecular mechanism that enhances the growth and viability of tumor cells
.
According to researchers conducting studies in mouse models and human GBM cells, blocking P300 disrupts its ability to
initiate this process.
Their findings were published online in
Nature Communications.

Although glioblastoma is considered rare — about 13,000 new cases are expected to be diagnosed in the U.
S.
this year, according to the National Brain Tumor Society — it is the most common primary brain tumor
in adults.
There is currently no known treatment, and the average survival time is measured in months
.
GBM cells and their precursors, glioma stem cells (GSCs), adapt and recover quickly from injury, so chemotherapy and radiation therapy may initially slow tumor progression and eventually promote growth and recurrence
.

By performing single-cell transcriptome sequencing, molecular changes in cancer cells can be identified, and the UCLA-led team showed that radiation therapy-induced stress promotes phenotypic transformation of glioma stem cells to resemble the two types of cells typically found in blood vessels (vascular endothelial-like cells and pericyte-like cells).

They found that these transformed cells promoted tumor growth and recurrence
after treatment.
This transformation is caused
by changes in specific vascular gene regions mediated by the gene P300 or P300 HAT (histone acetyltransferase).

"Our findings suggest that at the single-cell level, 'radiation stress' alters the functional state of glioma cells, but as is sometimes theorized, these transformed cells do not rebuild the vascular system to transport blood supply, but instead provide nutritional support that enables cancer cells to survive and grow
under adverse conditions caused by radiation.
" Harry Cohenbloom, MD, senior author of UCLA's Johnson Comprehensive Cancer Center and Brain Institute, said
senior author.

"Just as P300 plays a key role in altering the molecular structure of glioma stem cells, inhibiting the function of this gene appears to prevent phenotype switching
.
" This suggests that small molecules that inhibit P300 HAT activity may help prevent tumor growth and adaptive resistance to GBM," said
Sree Deepthi Muthukrishnan, Ph.
D.
, assistant project scientist and first author of the study.

While the authors were able to identify some of the candidate factors expressed by vascular-like cells, and their experiments showed a potential role for these factors in promoting the proliferation of radiation tumor cells, they say further research is needed to fully unravel the underlying mechanisms
.
But importantly, factors mediating radiation-induced vaso-like cell trophic effects may be the target of potential therapeutic interventions to prevent GBM recurrence
.