Summary: Glioblastoma stem cells’ circadian clocks ramp up the cells’ metabolism, making them stronger, more resistant to treatment, and able to divide and multiply more rapidly. By targeting the stem cells with a small molecule drug, researchers found mice models lived longer and their tumors shrank.
Scientists at USC and UC San Diego have discovered a potential novel target for treating glioblastoma, the deadly brain cancer that took the life of Sen. John McCain and kills 15,000 Americans a year.
The target is the circadian “clock” found within the tumor stem cells, which governs how the tumor grows, multiplies and develops resistance to current treatments.
“We think this is opening the door to a whole new range of therapies,” said Steve Kay, Provost Professor of neurology, biomedical engineering and biological sciences at the Keck School of Medicine of USC, who is working with Jeremy Rich, a neuro-oncologist at University of California, San Diego who specializes in malignant brain tumors. “It’s a great example of collaboration and convergence.”
Kay and Rich report their findings today in Cancer Discovery.
Glioblastoma is rare but nearly always fatal, striking adults in their mid-60s. Average survival is only 15 months. That’s because this type of cancer infiltrates surrounding brain tissue, making it impossible to eradicate, even after surgery, radiation and chemotherapy. The tumor comes back, growing from stubborn cancer stem cells left behind.
Now scientists are focusing on a new potential vulnerability in those left-behind stem cells.
Kay is a pioneer in the study of circadian rhythms and the biochemical circadian clocks that regulate hundreds of activities, from sleep to digestion to body temperature.
Circadian clocks are comprised of specific protein molecules that interact in cells throughout the body, controlling how they grow, replicate and repair damage to their DNA. When circadian timing is off in cells, it can cause disease. Biological clocks that run fast or slow can result in disrupted or abnormal circadian rhythms, increasing the risk of developing cancer in some people.
When the team first examined the biological clocks of glioblastoma stem cells in the lab, Kay said the researchers found them “on steroids, on overdrive.” The cells’ circadian clock was ramping up the cells’ metabolism, making the cells stronger and more resistant to treatment and able to divide and multiply rapidly.
In collaboration with Synchronicity Pharma, a San Francisco-based biotechnology company, they used a small-molecule drug to target the proteins in the stem cells’ circadian clocks to disrupt their activity. The ramped-up metabolism abated, and the cells quickly died.
“This was a striking, amazing result nobody really predicted,” Kay said.
Small-molecule drugs can enter cells easily and in this case, cross the blood-brain barrier in mouse models of the disease.
Next, the researchers tested the small-molecule drug in an animal model of glioblastoma. They found the animal models lived longer and the tumor shrank in size.
“This lays the groundwork for us to explore this as a novel therapy for glioblastoma,” Kay said. “In the near future, we’re going to do more work with animal models of the tumor and compare our new drug with the current standard of care. Perhaps we can one day contribute towards meeting this terrible unmet medical need.”
In addition to Kay and Rich, other authors are Zhen Dong, Guoxin Zhang, Ryan Gimple, Qiulian Wu, Zhixin Qiu, Briana Prager, Xiuxing Wang, Leo Kim, Deobrat Dixit, Zhe Zhu and Lukas Chavez, all of UC San Diego; Meng Qu of Keck; Andrew Morton of Case Western Reserve University School of Medicine; Wenchao Zhou, Shideng Bao and Haidong Huang of Cleveland Clinic; Bin Li of the Ludwig Institute for Cancer Research; and Stephen Mack of Baylor College of Medicine;
Funding: The work was supported by NIH grants CA197718, CA154130, CA169117, CA171652, NS087913, NS089272, DK108087, CA184090, NS091080, NS099175, CA217066, CA217065, CA203101 and CA236313.
Kay has a financial interest in the company Synchronicity Pharma, which provided the drug molecules used in the experiments. Kay is a founder of the company and a member of its scientific advisory board.
Leigh Hopper – USC
The image is in the public domain.
Original Research: Closed access
“Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock”. Zhen Dong, Guoxin Zhang, Meng Qu, Ryan C Gimple, Qiulian Wu, Zhixin Qiu, Briana C Prager, Xiuxing Wang, Leo J.Y Kim, Andrew R Morton, Deobrat Dixit, Wenchao Zhou, Haidong Huang, Bin Li, Zhe Zhu, Shideng Bao, Stephen C. Mack, Lukas Chavez, Steve A. Kay and Jeremy N. Rich.
Cancer Discovery. doi:10.1158/2159-8290.CD-19-0215
Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock
Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSCs). Here, we show that GSCs, differentiated glioblastoma cells (DGCs), and non-malignant brain cultures all displayed robust circadian rhythms, yet GSCs alone displayed exquisite dependence on core clock transcription factors, BMAL1 and CLOCK, for optimal cell growth. Downregulation of BMAL1 or CLOCK in GSCs induced cell cycle arrest and apoptosis. Chromatin immunoprecipitation revealed BMAL1 preferentially bound at metabolic genes in GSCs, associated with differences in active chromatin regions compared to NSCs. Targeting BMAL1 or CLOCK attenuated mitochondrial metabolic function and reduced expression of the tricarboxylic acid (TCA) cycle enzymes. Small molecule agonists of two independent BMAL1::CLOCK negative regulators, the Cryptochromes and REV-ERBs, downregulated stem cell factors and reduced GSC growth. Combination of Cryptochrome and REV-ERB agonists induced synergistic anti-tumor efficacy. Collectively, GSCs coopt circadian regulators beyond canonical circadian circuitry to promote stemness maintenance and metabolism, offering novel therapeutic paradigms.