Healthcare, Singapore (Commonwealth Union) – Glioblastoma, a particularly deadly form of brain cancer, typically has a low survival rate among patients within five years of diagnosis due to its resistance to treatment. Despite efforts, recurrence of glioblastoma is almost certain, compounding the challenge of managing this disease.
Yet, a glimmer of hope emerges from a collaborative effort between researchers at the Nanyang Technological University, Lee Kong Chian School of Medicine (LKCMedicine) and the National Neuroscience Institute (NNI). Their recent study offers promising prospects for glioblastoma patients, potentially revolutionizing treatment strategies to combat recurrence.
Researchers of the study pointed out that presently, the primary chemotherapy drug employed against glioblastoma is temozolomide (TMZ), which disrupts cancer cell DNA, impeding their ability to proliferate. However, the relentless nature of glioblastoma manifests as resistance to TMZ over time, attributed to the genetic diversity within tumor cell populations. This genetic heterogeneity enables some cells to withstand and adapt to treatment, evading its effects.
The researchers further indicated that compounding the challenge is the limited arsenal of drugs effective against resistant glioblastoma, exacerbated by the blood-brain barrier’s restrictive nature, hindering drug delivery to the brain.
In a bid to unravel the mechanisms underpinning drug resistance and identify potential targets for combating resistant glioblastoma, the researchers conducted a comparative analysis of protein kinase activity. These enzymes play pivotal roles in cellular signaling pathways associated with cancer progression and dissemination, offering insights into the distinctive behavior of mesenchymal glioblastoma (ME) and proneural glioblastoma (PN) cells obtained from patients.
Glioblastoma manifests in various forms, with the ME subtype being notably aggressive and resistant to treatment, in contrast to the more promising prognosis associated with PN. Complicating matters, PN glioblastoma can evolve into a ME variant, exacerbating cancer recurrence.
Researchers have identified key differences between these subtypes, notably in the activation of a protein kinase group known as mitogen-activated protein kinases (MAPK). Within the ME subtype, two MAPK members, p38MAPK and MEK/ERK, exhibit heightened activity.
The researchers pointed out that for ME glioblastoma, p38MAPK signaling enhances the function of drug-efflux transporter proteins, facilitating the removal of therapeutic agents from cells. Additionally, this signaling pathway aids in the repair of DNA damage inflicted by treatments like TMZ, bolstering the cancer cells’ resilience and bolstering ME’s intrinsic resistance to therapy.
Alternatively, MEK/ERK signaling pathways kick into gear as glioblastoma develops resistance to drug treatments—a phenomenon termed adaptive resistance. Researchers noted that inhibiting p38MAPK led to a decrease in intracellular pH and an increase in calcium levels, setting off MEK/ERK signaling and bolstering the survival of glioblastoma cells. This pH shift also interfered with the conversion of TMZ into its active form, diminishing its efficacy.
Repurposing drugs for personalized cancer care, researchers transplanted patient-derived ME cells into mice. They discovered that mice treated with a combination of the p38MAPK inhibitor ralimetinib, MEK inhibitor binimetinib, and TMZ exhibited the longest survival, reaching 72.5 days compared to mice treated solely with TMZ, who survived only 63 days.
Binimetinib, also known as Mektovi, has gained FDA approval for treating melanoma, while ralimetinib underwent Phase 1 trials for glioblastoma treatment. Ralimetinib and binimetinib’s actions in inhibiting p38MAPK and MEK/ERK pathways, respectively, bought back TMZ’s effectiveness against ME. Additionally, p38MAPK inhibition reduced the expression of various drug transporter proteins, augmenting TMZ retention within cells.
Associate Professor Andrew Tan of LKCMedicine, who is the co-lead of the study says “Our study has shown that glioblastoma acquires drug resistance through multiple pathways, highlighting the need for more precise treatments of the disease.”
“Instead of using a single drug, therapies that target the innate and adaptive mechanisms of drug resistance simultaneously could be feasible treatments for resistant glioblastoma tumours,” added the Dean’s Postdoctoral Fellow at LKCMedicine Dr Hong Sheng Cheng, who is the 1st author for ]the study.
“We have demonstrated that the repurposing of existing drugs is a key strategy to maximise the implementation of precision medicine in cancer, especially when treating highly recurrent tumours like glioblastoma,” explained Associate Professor Ang Beng Ti, who is a senior consultant at the Department of Neurosurgery as well as a co-Principal Investigator at the Neuro-Oncology Lab in NNI, one of the co-lead investigators.
The researchers aim to initiate clinical trials, advancing the treatment towards practical application in the clinic. Additionally, they plan to leverage state-of-the-art molecular profiling methods and artificial intelligence technologies like machine learning.
