Research Article: Strategies in regulating glioblastoma signaling pathways and anti-invasion therapy

Date Published: April 22, 2019

Publisher: Public Library of Science

Author(s): Eunok Jung, Aurelio A. de los Reyes V, Kurt Jan A. Pumares, Yangjin Kim, Joseph Najbauer.


Glioblastoma multiforme is one of the most invasive type of glial tumors, which rapidly grows and commonly spreads into nearby brain tissue. It is a devastating brain cancer that often results in death within approximately 12 to 15 months after diagnosis. In this work, optimal control theory was applied to regulate intracellular signaling pathways of miR-451–AMPK–mTOR–cell cycle dynamics via glucose and drug intravenous administration infusions. Glucose level is controlled to activate miR-451 in the up-stream pathway of the model. A potential drug blocking the inhibitory pathway of mTOR by AMPK complex is incorporated to explore regulation of the down-stream pathway to the cell cycle. Both miR-451 and mTOR levels are up-regulated inducing cell proliferation and reducing invasion in the neighboring tissues. Concomitant and alternating glucose and drug infusions are explored under various circumstances to predict best clinical outcomes with least administration costs.

Partial Text

Glioblastoma multiforme (GBM) is the most common and the most aggressive type of brain cancer. The median length of survival time is approximately 12 to 15 months following diagnosis. GBM is characterized by anaplasia, nuclear atypia, cellular pleomorphism, mitotic activity, and more importantly, alternating phases of rapid proliferation and aggressive invasion into the surrounding brain tissue. This leads to an inevitably critical recurrence even after the surgical resection of the main tumor mass [1, 2]. The mainstay of treatment for GBM is surgery, followed by radiotherapy and chemotherapy. Despite advances in these approaches, glioma cells can still invade the neighboring tissues beyond detection leading to tumor recurrence. High probability of main treatment failure also encourages researchers to investigate the use of innovative treatments when the first line of therapy has failed, in order to improve clinical outcomes [3].

The periodic switching behavior of glioblastoma cells between proliferation and invasion phases is highly influenced by fluctuating glucose levels [14, 17]. In response to high glucose supply, miR-451 and mTOR are up-regulated and AMPK complex is down-regulated inducing cell growth. On the contrary, low glucose level up-regulates AMPK complex, down-regulating miR-451 and mTOR, promoting cell migration [15]. The mutual antagonistic mechanism between miR-451 (mTOR) and AMPK complex and the cell’s strategic metabolic adaptation support the survival of cancer cells even in a nutrient-deprived microenvironment [14, 55].




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