Gene Removal Could Keep Tumors in Remission

Scientists discovered that a gene called KLHDC8 — or S?E-1 — inhibits the therapeutic drugs designed to halt the growth of a deadly, rapidly developing form of brain tumor known as a glioma.

After this gene is removed, brain-tumor patients have less chance of relapse. The discovery could help in the prevention and treatment of cancer by allowing doctors to target the tumors on a genetic level.

Under the current protocol of attacking cancerous tumors, doctors are forced to increase treatments — such as chemotherapy and radiation therapy — because their effectiveness decreases over time. However, these treatments can be toxic at high levels, and have adverse effects on the patients.

Researchers began investigating why patients would respond to drugs and then relapse. They removed the known fuel for cancer growth, a protein called epidermal growth factor receptor (EGFR), in experiments on mice.

“When you’re looking at cancer and you want to target the cancer with a therapeutic [drug], you really need to know if the molecule that you’re targeting is required by the tumor to continue to grow,” said Frank Furnari, associate adjunct professor at the UCSD School of Medicine.

By removing EGFR, scientists found it to be one of the main factors in starting, developing and maintaining gliomas. However, they discovered that — though the tumor would stop at first, and the mice would appear to recover — the cancer continued growing without the help of EGFR. There had to be something else causing tumor growth, they concluded.

The second factor was found to be KLHDC8 — present in high volumes in gliomas when EGFR was gone. The gene was deactivating the drugs that were trying to prevent tumor growth.
Glioma treatment would thus need to target both EGFR and KLHDC8 in order to curb the growth of cancer.

“If you could treat with an EGFR receptor inhibitor, and you can treat with something that prevented the relapse, you might have a longer response [to tumor growth],” Webster Cavenee, professor of medicine at the UCSD School of Medicine, said.

If it can be proved that other types of cancer use KLHDC8 as a replacement for the EGFR removed by current cancer treatments, then Cavenee and Furnari’s discovery can be used to study other tumors.

Currently, the research lab is looking to see how KLHDC8 is working with other genes to cause tumor growth without the help of EGFR, and how these other genes are individually contributing to tumor growth. They will also be looking at possible chemical compounds that can tackle these genes.

“What we found really leaves the groundwork for new ways to approach therapy, and to get around this problem of resistance to targeted drugs and brain tumors,” said Jill Wykosky, a postdoctoral fellow who worked on the experiment along with Akitake Mukasa.

This would be an improvement from current methods of tackling cancer, where doctors are forced to increase treatments — such as chemotherapy and radiation therapy — as their effectiveness decreases over time. However, these treatments can be toxic at high levels and have adverse effects on the patients.

Researchers began looking at why patients responded to drugs and then relapsed by taking away the known fuel for cancer growth, a protein called EGFR — epidermal growth factor receptor — in experiments on mice.

“When you’re looking at cancer and you want to target the cancer with a therapeutic [drug], you really need to know if the molecule that you’re targeting is required by the tumor to continue to grow,” said Frank Furnari, associate adjunct professor of medicine at the UCSD School of Medicine.

By removing EGFR, scientists found that the protein is one of the main factors that start, develop and maintain gliomas. However, they discovered that though the tumor would stop at first, and the mice appeared to recover, the cancer would continue growing without the help of EGFR. They concluded there had to be another factor causing tumor growth.

The second factor was found to be KLHDC8, which was present in high volumes in gliomas when EGFR was gone. This showed that the gene was deactivating the drugs that were trying to prevent tumor growth.
Glioma treatment would thus need to target both EGFR and KLHDC8 in order to curb the growth of cancer.

“If you could treat with an EGF receptor inhibitor and you can treat with something that prevented the relapse, you might have a longer response [to tumor growth],” said Webster Cavenee, professor of medicine at the UCSD School of Medicine.

If other types of cancer are using the same strategies to get around the need for EGFR, then Cavenee and Furnari’s discovery can be used to study other tumors.

Currently, the research lab is looking to see how KLHDC8 is working with other genes to cause tumor growth without the help of EGFR, and how these other genes are individually contributing to tumor growth. They will also be looking at possible chemical compounds that can tackle these genes.

“What we found really leaves the groundwork for new ways to approach therapy and to get around this problem of resistance to targeted drugs and brain tumors,” said Jill Wykosky, a postdoctoral fellow who worked on the experiment along with Akitake Mukasa.

Readers can contact Regina Ip at [email protected].

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