Cancers: Makes glioblastoma easier to treat

In the uphill battle against glioblastoma, scientists are looking for clues in viruses about how to make aggressive cancers more treatable
.

They targeted SAMHD1, a protein that protects us from viral infections by disrupting the building blocks of DNA needed for viral
and cancer replication.

But they found that SAMHD1 also has a seemingly paradoxical skill: helping to repair double-strand breaks in DNA that, if not repaired, could be fatal to any cell, including cancer cells; If the fix is wrong, it can lead to genetic mutations that can lead to cancer
.

Dr.
Waaqo Daddacha, a cancer biologist in the Department of Biochemistry and Molecular Biology at the Medical College of Georgia, said: "When DNA is broken, it is actually a disruption of DNA replication and protein synthesis, so double-strand breaks are fatal to cells
.
"

Cancer cells multiply much faster than most normal cells and replicate faster, so they are more affected by these DNA breaks, which is why basic therapies such as radiation and some chemotherapy drugs used to treat cancer produce these deadly breaks
.

However, aggressive brain cancers quickly develop resistance, with an average survival time of about
15 months, Dadacha said.

Now that Daddacha and his colleagues have published a report in the journal Cancer they have surprisingly found that both SAMHD1 and the essential DNA building block dNTP it can destroy are highly expressed in glioblastoma in humans, suggesting that SAMHD1 may be important for the aggressiveness of brain tumors and raises questions
about what it does there.

Daddacha said they expect dNTP levels to be high because cancer needs a readily available supply of this building block to keep it replicating and spreading at a rate
.
They also expected lower SAMHD1 levels due to higher dNTP levels, and increasing their levels would help prevent glioblastoma
.

They found the opposite, suggesting that glioblastoma is likely to alter SAMHD1's function, just as cancer took away so many innate properties
.

"In theory, since cancer cells divide rapidly and need more dNTP to complete this process, it seems logical that
they need less of this protein," Daddacha said.
It also seems logical that SAMHD1 is as protective against cancer as it is against viruses
, Dadadacha said.

Based on their findings, the scientists decided to lower levels of SAMHD1, which is where
the virus's skill at eliminating multitasking proteins comes into play.

Viruses use viral protein X (Vpx) to cleave SAMHD1 so they have sufficient dNTP, a viral skill
first discovered in HIV.
So the scientific team used a virus-like particle, called a vector, to deliver Vpx directly to glioblastoma
.
These types of viral vectors have been used in humans to provide a variety of therapies, including some COVID-19 vaccines
.

They found that by reducing SAMHD1, Vpx sensitized brain tumor cells to the chemotherapy drug velipanib, which helps prevent cancer cells from repairing DNA damage and slows cell growth
in fast-growing brain tumors.
It also makes tumor cells more sensitive
to temozolomide (TMZ).
Temozolomide is another chemotherapy drug commonly used in glioblastoma that destroys the DNA structure of cells, killing them
.
By reducing SAMHD1, Vpx also appears to reduce an innate skill called homologous recombination, which SAMHD1 promotes, which allows double-strand breaks to be repaired well and also helps avoid cell mutations
that can lead to cancer.

The scientists write that combination therapies that lower SAMHD1 levels and use radiation for glioblastoma work synergistically as expected and reconfirm SAMHD1's role
in making glioblastoma resistant to the usual treatments.

In a mouse model with human brain tumor cells, they found that reducing SAMHD1 slowed tumor growth and genetically knocking out SAMHD1 improved survival, the scientific team reports
.

As another piece of the emerging puzzle, Daddacha said, dNTP levels did increase a bit when scientists removed SAMHD1, but not so obviously, as they saw in some other cell types, and more evidence suggests that while SAMHD1 still has some effect on degrading this DNA building block, it clearly has another function
in this case.

He suspects that the real benefit of high levels of SAMHD1 for glioblastoma is "self-protection," which relies heavily on the innate ability of proteins to help repair double-stranded DNA breaks
.

Daddacha says there's plenty of evidence that glioblastoma's ability to repair double-stranded DNA breaks is key to its treatment of drug resistance, which makes the targeted repair process logical
.

One way cancer takes over proteins for its own purposes is by modifying its function, for example, it can turn SAMHD1 into a major DNA repair mode, reducing its natural ability to degrade dNTP, and Daddacha suspects that glioblastoma is altering SAMHD1's function
.

"It's clear that it's using it to survive
," Dadacha said.
This may be at least part of the reason glioblastoma is so tenacious, and part of
a big puzzle needed to better treat this deadly cancer in the future.

Daddacha said their findings suggest that SAMHD1 can be targeted and eliminated using the viral protein Vpx in glioblastoma, but notes that there is still a lot of work to be done before this discovery and the tool can be
used to improve glioblastoma treatment.

The next step includes learning more about SAMHD1's role in glioblastoma and how its high levels coexist with high levels of dNTP, which should destroy dNTP
.

"We will try to find out if SAMHD1 is actually degrading dNTP
in cancer cells," Dadacha said.
High levels of SAMHD1 may also help control high levels of dNTP, he said, because everything needs to be balanced
.

They are also improving safe, specific Vpx delivery technology, with the idea that it could one day be used in humans as well, and to determine whether the technology could also impair glioblastoma growth
in other ways.

Glioblastoma is a deadly cancer that is often considered an aggressive stage 4 tumor at the time of diagnosis, with patients surviving an average of 15 months
after diagnosis, Dadacha said.
When symptoms such as headaches and epilepsy appear, the tumor has progressed
.

Standard treatment includes surgery to remove as much of the tumor as possible, radiation and chemotherapy
.

SAMHD1, or sterile α motifs and HD domain protein 1, is ubiquitous in cells, including our brain cells
.
It is believed to stop viruses like HIV-1 from replicating by cutting and destroying dntp or deoxynucleoside triphosphate, which normal cells, cancer cells, and viruses all need to multiply
.
"We make DNA
out of dntp strands," says Daddacha.
SAMHD1 may also help regulate the amount of DNTP the body needs under normal circumstances, he said
.

While pursuing his PhD at the University of Rochester, Daddacha was part of the team that discovered dNTP, the degrading DNA building block of
SAMHD1.
While a postdoctoral researcher at the Winshipp Cancer Institute at Emory University in Atlanta, he further explored SAMHD1's role in DNA, discovering that it actually plays a key role
in DNA repair pathways.
Daddacha joined the MCG faculty in
2019.