Researchers follow virus example to make glioblastoma more vulnerable to treatment

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In the harsh war against glioblastoma, scientists are following the example of viruses in how to make aggressive cancer more vulnerable to treatment.

Its target is SAMHD1, a protein that can protect us from viral infections by destroying an essential component of DNA that viruses and cancer need to replicate.

But they found that SAMHD1 also has the seemingly contradictory ability to help repair double-strand breaks in DNA that, if left unrepaired, can be lethal to any cell, including a cancer cell, and if improperly repaired can lead to genetic mutations that they produce cancer.

When DNA breaks, that’s what actually disrupts DNA replication and also protein synthesis, so a double-strand break is lethal to cells.”

Waaqo Daddacha PhD, Cancer Biologist, Department of Biochemistry and Molecular Biology, Medical College of Georgia

Cancer cells, which reproduce much faster than most normal cells, replicate even faster, so they are even more affected by these DNA breaks, which is why critical therapies like radiation and some Chemotherapy drugs used to treat cancer cause these lethal ruptures.

However, aggressive brain cancer quickly becomes resistant to treatment, and median survival hovers around 15 months, Daddacha says.

Now Daddacha and his colleagues report in the journal cancers their surprising finding that in human glioblastoma both SAMHD1 and the essential DNA building block dNTP, which it can destroy, are highly expressed, indicating the likely importance of SAMHD1 in brain tumor aggressiveness and raising questions about what is doing there.

They expected high levels of dNTPs because cancers need a ready supply of this building block to keep up their rapid rate of replication and spread, says Daddacha. Since dNTP levels were high, they also expected low levels of SAMHD1 and that increasing its levels would help protect against glioblastoma.

They would find the opposite to be true, indicating that, as with so many innate properties that cancer usurps, glioblastoma likely alters SAMHD1 function.

“Theoretically, since cancer cells divide rapidly and need more dNTPs to do so, it seems logical that they need less of this protein,” says Daddacha. It also seems logical that SAMHD1 protects against cancer, as it does against viruses, says Daddacha.

Based on what they found, the scientists decided to reduce the levels of SAMHD1, and that’s where the viruses’ ability to remove the multitasking protein came into play.

Viruses implement viral protein X protein, or Vpx, to literally cut SAMHD1 so they have a ready supply of dNTPs, a virus skill set first identified in HIV. So the science team used a virus-like particle, called a vector, to deliver Vpx directly to the glioblastoma. These types of viral vectors are already used in people to deliver a variety of therapies, including some of the COVID-19 vaccines.

They found that by knocking down SAMHD1, Vpx sensitized brain tumor cells to the chemotherapy drug veliparib, which helps block cancer cells from repairing DNA damage, and slowed cell growth in this fast-growing brain tumor. It also made tumor cells more sensitive to temozolomide, or TMZ, another chemotherapy drug often used for glioblastoma, which disrupts the cell’s DNA structure with the idea of ​​killing it. By reducing SAMHD1, Vpx also appeared to reduce an innate ability called homologous recombination, which is promoted by SAMHD1 and enables robust repair of double-strand breaks that also helps prevent cellular mutations that could lead to cancer.

Reducing SAMHD1 levels allowed combination therapies, including radiation, used for glioblastoma to work more synergistically as intended, and reconfirmed the role of SAMHD1 in enabling resistance to standard glioblastoma treatment, the authors write. scientists.

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

As another piece of the emerging puzzle, when the scientists removed SAMHD1, dNTP levels increased somewhat but not dramatically, as they have seen in some other cell types, further evidence that while SAMHD1 still has some impact on the degradation of this DNA’s building block, in this scenario, clearly has another function, says Daddacha.

He suspects that the real benefit of high levels of SAMHD1 for glioblastoma is “self-protection” that relies primarily on the protein’s innate ability to help repair DNA double-strand breaks.

There is overwhelming evidence that glioblastoma’s ability to repair DNA double-strand breaks is key to its resistance to treatment, which makes it logical to focus on the repair process, says Daddacha.

One of the ways that cancer hijacks a protein for its own purposes is by modifying its function, so, for example, it could switch SAMHD1 mainly to DNA repair mode and reduce its natural ability to degrade dNTPs, and Daddacha he suspects that the glioblastoma is changing the function of SAMHD1.

“Clearly, he’s using it to survive,” Daddacha says, which is probably at least part of the way glioblastoma is so tenacious, and a piece of the larger puzzle needed to one day better treat the deadly cancer.

Their findings indicate that SAMHD1 can be targeted and killed using the viral protein Vpx in glioblastoma, Daddacha says, but notes that much work remains to be done before the findings and tool can be used to improve glioblastoma treatment.

Next steps include learning more about what SAMHD1 is doing in glioblastoma and how high levels of it can co-exist with high levels of dNTPs, which it should destroy.

“We will try to find out if SAMHD1 is actually degrading dNTP in cancer cells,” says Daddacha. It may be that high levels of SAMHD1 also help keep high levels of dNTPs in check, she says, because everything needs balance.

They are also refining the safe and specific technique of delivering Vpx with the idea that it could one day be used in people as well, and to determine if the technique also affects glioblastoma growth in other ways.

Glioblastoma is a lethal cancer that is always considered an aggressive stage 4 tumor at diagnosis and patients live an average of 15 months after diagnosis, says Daddacha. When symptoms such as headaches and seizures appear, the tumor has already progressed.

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

SAMHD1, or sterile alpha motif and HD domain-containing protein 1, is ubiquitous in cells, including our brain cells. It is thought to stop viruses like HIV-1 from replicating by cutting out and destroying dNTPs, or deoxynucleoside triphosphates, that normal cells, cancer cells, and viruses need to reproduce. “We make our DNA with a chain of dNTPs,” says Daddacha. SAMHD1 also likely functions normally to help regulate the amount of dNTPs the body needs, she says.

While working on his Ph.D. at the University of Rochester, Daddacha was part of the team that discovered that SAMHD1 degrades the DNA building block dNTP. While doing her postdoctoral studies at Emory University’s Winship Cancer Institute in Atlanta, she further explored SAMHD1’s role with DNA and discovered that it actually has a key role in the DNA repair pathway. Daddacha joined the MCG faculty in 2019.

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Medical College of Georgia at Augusta University

Magazine Reference:

Daddacha, W. and others. (2022). Viral particle-mediated depletion of SAMHD1 sensitizes glioblastoma refractory to DNA-damaging therapies by affecting homologous recombination. cancers. doi.org/10.3390/cancers14184490.

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