Researchers at Virginia Tech’s Fralin Biomedical Research Institute at VTC have developed an encouraging three-pronged approach to treating glioblastoma, an aggressive brain cancer with an average survival time of approximately 15 months. Their findings published this week in Oncogenesis.

“By using a combinational therapeutic strategy, we’ve created a promising approach to combat chemoresistance in the most lethal brain cancer,” said Zhi Sheng, assistant professor at the Fralin Biomedical Research Institute, who led the study.

Glioblastoma often resists front-line chemotherapies, including temozolomide, a drug that damages DNA and triggers tumor cell death. Nearly half of glioblastoma patients resist the treatment by producing a DNA-repairing enzyme, MGMT, but until recently it wasn’t clear why temozolomide wasn’t working for patients who lacked the MGMT enzyme.

Sheng’s research team used glioblastoma cell lines and primary glioblastoma cells derived from patient tumor specimens to discover that inhibiting two specific proteins when combined with temozolomide, produced an effective “triple combinational therapy” that overcame chemoresistance. The findings could significantly delay tumor recurrence resulting from chemoresistance and prolong survival in glioblastoma patients, according to Sheng.

Their new study, in combination with the Sheng Lab’s 2015 study published in Cancer Research, is the first to depict a specific channel protein and its enzymatic interactions with signaling molecules driving tumor growth that may underlie chemotherapy resistance in glioblastomas that don’t express the DNA-repairing protein MGMT – as well as a novel therapeutic approach.

“Further studies are needed, but this may be the kill switch for glioblastoma that we’ve been searching for – a potential way to prolong cancer survival time with strong translational potential,” said Robert Gourdie, the study’s co-corresponding author, Commonwealth Research Commercialization Fund Eminent Scholar in Heart Reparative Medicine Research, and director of the Center for Vascular and Heart Research at the institute.

In previous studies of gliomas, increased levels of the connexin 43 protein suppressed tumor growth. But in more aggressive glioblastomas, Sheng’s research team previously showed that more connexin-43 inversely promotes cancer growth and chemoresistance.

A decade ago, Gourdie and his lab developed the study’s connexin 43-targeting molecule, alphaCT1. Subsequently, they discovered useful effects of the peptide on wound healing with his former postdoctoral associate, Gautam Ghatnekar. Together they formed a biopharmaceutical company, FirstString Research, to bring the drug through clinical testing and to the market.

The researchers described the positive effects of inhibiting connexin 43 activity in their 2015 study. They found the right target, but their studies in canine glioma patients revealed difficulties in delivery of effective alphaCT1 doses to brain tumors in these companion animals.

In the new study, Sheng and his colleagues identify other enzymatic targets that complement the alphaCT1 molecule – with a potentially more efficacious combinational approach.

“To me, the most novel finding in this study is that we discovered connexin 43 selectively binds to the PIK3CB/p110beta protein, enabling certain glioblastoma cells to gain chemoresistant traits,” Sheng said.

Previous cancer research has shown that a specific signaling pathway – PI3K/Akt controlled by the enzyme PIK3CB/p110beta – is faulty in aggressive cancers. While this pathway is well-described in the literature, Sheng said they are the first to identify connexin 43’s role in activating it.

Sheng’s team applied two molecules that blocked downstream chemical reactions, curbing the production of Akt – a key protein kinase that the cancer cells need to metabolize food, move, proliferate, and survive.

alphaCT11 molecule binding to PI3K
For the first time, Sheng and his research team identified connexin 43’s role in activating the PI3K/Akt signaling pathway that becomes faulty in aggressive forms of cancer, including glioblastomas. They successfully interrupted this pathway by applying alphaCT11 – a connexin 43 agonist molecule – to selectively bind to PI3K, as rendered above. Rendering provided by Sheng Lab at Virginia Tech.

“If we’re successful in translating this discovery, we will have a chance to overcome drug resistance in glioblastomas expressing high levels of connexin 43 and PIK3CB/p110beta, which account for 25 percent of all cases,” Sheng said.

The study’s first author, Kevin Pridham, was a postdoctoral associate in Sheng’s lab during the study. Other members in the Sheng lab who contributed to this study included Sujuan Guo, former research associate; Min Liu, former research assistant; Virginia Tech Carilion School of Medicine (VTCSOM) graduates, Farah Shah and Pratik Kanabur; Kasen Hutchings, a second-year VTCSOM student; Virginia Tech undergraduate students, Gabrielle Lewis and Marc Morales. Other research contributors included Jane Jourdan, research associate in the Gourdie lab; Ghatnaker and Christina Grek of FirstString Research; Robin Varghese, assistant professor at the Edward Via College of Osteopathic Medicine; Kevin Sheng, Duke University undergraduate who worked in the Varghese lab; Samy Lamouille, assistant professor at the Fralin Biomedical Research Institute; and Deborah Kelly, professor of biomedical engineering at Penn State.

Sheng said that mentoring undergraduate, graduate, and medical students is a key priority for his lab.

“As a biomedical researcher at Virginia Tech, I have a unique opportunity to teach a wide range of students – from high school through medical school. I design research projects that are intentionally clinically relevant so they’ll gain skills necessary to pursue careers in medicine or translational research, making significant contributions to human health,” Sheng said.

This research was supported by the National Cancer Institute and National Heart, Lung, and Blood Institute, both part of the National Institutes of Health, as well as summer undergraduate student fellowships supported by the Fralin Biomedical Research Institute, Virginia Tech Carilion School of Medicine, and St. Baldrick’s Foundation.

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