Molecule shows potential to combat tumor treatment resistance
Mays Cancer Center Annual Report
Researchers are investigating multiple approaches to combat the deadliest form of brain cancer, giving patients and their families greater hope.
The highly devastating brain tumor glioblastoma multiforme (GBM) has long posed treatment challenges, as effective therapies have remained elusive. Despite responding initially to treatment, GBM patients often experience therapy resistance, leading to low long-term survival rates.
Researchers at Mays Cancer Center and from the Department of Obstetrics and Gynecology at The University of Texas Health Science Center at San Antonio have made significant progress in studying a promising new molecule that inhibits the ability of GBM tumors to repair themselves.
Published in the prestigious journal of Neuro-Oncology in January 2023, the study demonstrated that mice receiving this novel therapy in combination with chemotherapy showed extended survival compared to those receiving a single drug alone.
The molecule, known as NCD38, targets a specific subset of GBM cells called glioma stem cells. By disrupting their highly efficient DNA repair activity, NCD38 offers new possibilities for treatment.
“Glioma stem cells are notoriously difficult to treat,” said Gangadhara Sareddy, PhD, corresponding study author and a Mays Cancer Center investigator and associate professor of obstetrics and gynecology at the health science center.
Chemotherapy and radiation primarily damage the DNA of glioblastoma tumor cells, slowing tumor growth. However, glioma stem cells possess an elevated ability to repair this DNA damage, contributing to treatment resistance. NCD38 inhibits an enzyme called Lysine-Specific Histone Demethylase 1A (KDM1A), which plays a significant role in DNA repair within glioblastoma.
“While mice in the non-treatment group succumbed to GBM within two to three weeks of implantation, those in the combination therapy group — NCD38 with temozolomide — survived four to five weeks.”
– Gangadhara Sareddy, PhD, associate professor, Department of Obstetrics and Gynecology
“This enzyme is highly expressed in glioblastoma, and patients with elevated KDM1A expression tend to exhibit poorer overall survival,” Sareddy explained.
The study involved implanting GBM tumors into mice, followed by randomization into treatment groups. The mice in the treatment groups were assigned to receive either NCD38, the chemotherapy drug temozolomide or a combination of both. A control group received a nonactive placebo.
The mice receiving the combination of NCD38 and temozolomide demonstrated the longest survival rates. By inhibiting KDM1A activity and interfering with the cancer’s DNA repair, NCD38 enhanced the cancer-killing effects of temozolomide.
“While mice in the non-treatment group succumbed to GBM within two to three weeks of implantation, those in the combination therapy group — NCD38 with temozolomide — survived four to five weeks,” Sareddy said.
While the study is yet to be conducted in humans, the potential benefits observed in mice could translate into significant survival improvements of two to three years for patients.
“Identifying mechanisms that regulate DNA repair in glioma stem cells may unveil new paradigms to curb GBM growth and recurrence, ultimately improving patient outcomes,” noted lead author Salvador Alejo, a medical student in the South Texas Medical Scientist Training Program at the health science center. His research focused on this topic.
Further studies are needed to evaluate the safety and efficacy of this treatment strategy. Nonetheless, promising results from this study provide hope for developing new strategies to combat GBM treatment resistance and pave the way for enhanced patient care.
