Science sub-journal discovered drug targets for the treatment of rare, deadly neurocarcinoma MPNST

With the exception of professionals and those close to young people with this rare cancer, few people have heard of malignant peripheral nerve sheathoma (MPNST).

Of the nearly 331 million people in the United States, about 13,000 people are diagnosed with any form of soft tissue sarcoma
each year.
According to the National Cancer Institute and the American Cancer Society, only 5 to 10 percent of these cases are MPNST
.

Unfortunately, MPNST is devastating because it rarely happens
.
Despite existing forms of surgery, radiation, and chemotherapy, MPNST has a 5-year survival rate of between 23% and 69%, depending largely on how
far the cancer has spread at the time of diagnosis.

Now, a new study from Cincinnati Children's Hospital offers one of the
strongest possibilities for improving treatment in years.
The study is still in the preclinical stage, but after conducting a series of experiments, dissecting these tumor cells one by one each time to understand how they form and spread, the scientists used their insights to find significant disease improvements
in mice.

Translating these findings into better chemotherapy methods is still years away, but a new path has been opened
.
This path may also benefit people
other than MPNST patients.
Qing Richard Lu said: "In discovering and studying this previously unrecognized subset of mesenchymal neural crest-like cells and their role in driving this cancer malignant process, we have identified multiple druggable targets that warrant further investigation as a potential treatment for
MPNST.
"

From NF1 to MPNST

About half of MPNST cases occur in patients previously diagnosed with neurofibromatosis type 1 (NF1), a genetic disorder that causes non-malignant but often life-disrupting neurotumors to appear in different parts
of the body.

Experts at Cincinnati Children's Hospital have been pioneers in studying NF1, resulting in many basic scientific discoveries that led to the approval of serubitinib by the U.
S.
Food and Drug Administration in 2020, the first treatment
approved for children 2 years of age and older.
This study delves into how MPNST is generated
from NF1.

Two genes became targets

The team found that NF tumors transformed into malignant tumors
by acquiring subsets of cells with the function of "mesenchymal neural crest dry-like state.
" Signals from these cells remodel the tumor microenvironment, promote rapid tumor growth, and spread through a process called epithelial-mesenchymal transformation (EMT), which confers malignant characteristics to benign tumor cells such as migration, invasion, and chemotherapy resistance
.

This study details a network of transcription factors that regulate the transmission
of many complex molecular signals.
Specifically, the team identified two genes, ZEB1 and ALDH1A1, that are essential
for producing MPNST cells.
Knocking out these genes in mice slows tumor growth and reduces tumor cell proliferation
.

"Detecting the activity of these genes could serve as biomarkers to detect which NF1 patients may be on the
more dangerous cancer pathway.
" Disrupting the ability of these genes to accelerate tumor growth could help treat the disease
.
”

Next step

Lu and his colleagues have begun research to identify small molecule compounds that can affect signaling pathways that support subpopulations of dangerous cells in MPNST tumors
.
In the meantime, they have published molecular and cellular blueprints of the transcriptional states and malignant transformation drivers of MPNSTs on an interactive web server https://viz.
stjude.
cloud/yu-lab/collection/MPNST-Lu-lab~11 for scientists to analyze
.