Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Viral Particle-Mediated SAMHD1 Depletion Sensitizes Refractory Glioblastoma to DNA-Damaging Therapeutics by Impairing Homologous Recombination
We previously published about this research in a story titled “Researchers Use Viruses to Learn about Glioblastoma” which can be found here. The study was originally published in the scientific journal Cancers. You can read the full text of the study here.
This research team was led by scientists at the Medical College of Georgia.
Glioblastoma is a highly aggressive cancer of the brain that is notoriously unresponsive to treatment. As a result, average survival time following diagnosis for many patients is a little over a year. There is an urgent need to discover more effective methods of treatment for glioblastoma. The goal of this study was to determine the role of the protein SAMDH1 in glioblastoma and whether it could be targeted in order to make the tumor more treatable.
SAMDH1 is a protein which helps protect healthy cells from viral infection because it is able to destroy a vital component of DNA which cancer cells and viruses utilize in order to replicate. However, the protein can also repair double-strand fractures of the DNA, which, if unrepaired, would ultimately kill the cell. Meanwhile, improper repairs of these fractures can lead to cancer-causing genetic mutations. Cancer cells replicate much quicker than healthy cells, and as a result these DNA breaks have an even stronger effect on them.
The study found that glioblastoma cells have high expression of SAMDH1 and of dNTP, the critical DNA building block that SAMDH1 can wipe out. The researchers anticipated high levels of dNTP since the cells reproduce rapidly but were puzzled by the high SAMDH1 expression. Shouldn’t SAMDH1 be getting rid of dNTP and working against the cancer?
The team decided to see what would happen if they reduced SAMDH1 in the cancer cells. They did this using a viral vector transporting viral protein X (Vpx), which viruses use to attack SAMDH1 and infect cells. What they found was surprising: reducing the expression of SAMDH1 made the glioblastoma vulnerable to treatment with the chemotherapy veliparib. This therapy slowed growth of the cancer and prevented the cancer from repairing its DNA. The cells were also more susceptible to temozolomide, another chemotherapy agent. Targeting SAMDH1 also prevented the protein from performing its double strand repairs.
Further study of glioblastoma mouse models found that reduction of SAMDH1 or genetic ‘knock out’ of the protein improved survival and slowed tumor growth. The team found that dNTP levels increased somewhat when the protein was eliminated. In effect, the researchers concluded that glioblastoma was effectively utilizing SAMDH1 as a protective measure while also reducing its function in targeting dNTP.
Glioblastoma is a rare brain cancer. It is also the most aggressive cancer to originate in the brain. It is characterized by its rapid progression and poor response to most treatments. In most cases, the cause of glioblastoma is not known. A small number of cases evolve from another type of tumor called an astrocytoma. Risk factors for glioblastoma include genetic disorders such as Turcot syndrome and neurofibromatosis, exposure to pesticides, smoking, and a career in petroleum refining or rubber manufacture. Symptoms of glioblastoma include personality changes, headaches, memory loss, seizures, vomiting, and nausea; patients may lose consciousness in late stages. Treatment approaches include anticonvulsants, steroids, chemotherapy, radiation, and surgery. While a small number of patients can survive for several years, treatment is often ineffective, with the tumor relapsing quickly. Five-year survival rate is only three percent. To learn more about glioblastoma, click here.
Why Does it Matter?
The study results illustrate a weak point in glioblastoma as well as a mechanism for how to exploit it. It appears that the cancer’s central mechanism of disease resistance lies in its hijacking of SAMDH1 and using it for double strand DNA repair.
However, there is still a lot of research that will be necessary before these findings can translate into improved treatment for the cancer. The researchers still need to understand more about what SAMDH1 is doing in glioblastoma and how it is possible for it to exist at high levels alongside high dNTP, which it normally destroys. Furthermore, more refinement of the viral vector delivery of Vpx is necessary so that ultimately the approach can be evaluated in patients.