Fast-growing and highly aggressive, glioblastoma (GBM) is the most common form of malignant brain tumor. It is also one of the most lethal cancers, with only 1 in 20 patients surviving for 5 years after diagnosis. This tumor is known to display a noticeable heterogeneity in cell composition and possesses incredible plasticity, thus switching to a reprogrammed cell population according to the selective pressure generated by the current therapeutic approaches. This feature makes it predisposed to resistance to therapy. Although this cancer is treated with a combination of radiotherapy and the chemotherapy drug temozolomide (TMZ), drug resistance develops in many patients. As such, there is a dire need for new GBM treatments. Many GBM and glioma tumors lack the DNA repair protein MGMT – an attribute implicated in their ability to gain drug resistance. A new class of glioma drugs exploits tumors that lack MGMT; the drugs lead to the generation of cytotoxic DNA and selectively kill tumor cells without the risk of resistance.
The new approach may lead to new glioma treatments and may represent a new paradigm for designing therapeutics that exploit specific DNA repair defects to combat drug-resistant tumors. Using a mechanism-based design approach, scientists developed TMZ analogs that create a dynamic primary DNA lesion, which can be repaired in healthy cells with intact MGMT-mediated DNA repair mechanisms. However, cancer cells lacking MGMT expression cannot repair the damage. In these cells, the primary lesions slowly evolve, creating more and more toxic secondary DNA lesions that result in the selective killing of MGMT-deficient tumor cells. The researchers found that, using a mouse model of TMZ-resistant human GBM, the drug-induced selective tumor-cell killing had an acceptable toxicity profile both in vitro and in vivo. HOwever, there is another road exploited by scientists to hit GBM: the drug repurposing, into the specific for psychodrugs.
Antipsychotics are a class of psychotropic drugs used for the treatment of bipolar disorder, psychosis, delirium, Huntington disease and Tourette syndrome. A role of antipsychotics in cancer therapy is supported by studies that demonstrate a reduced cancer incidence among patients affected by schizophrenia taking neuroleptic medications and which, in addition, report sporadic data showing a better course of GBM in psychiatric subjects taking neuroleptic drugs. For 20 years, Sanjay Srivastava, PhD and Chair in the Department of Immunotherapeutics and Biotechnology, at the Texas Tech University Health Sciences Center, has investigated existing drugs to determine if they can be repurposed to treat other conditions. For much of the last decade, his research has focused on investigating non-cancer drugs which can be repurposed to treat various cancers. His latest efforts led him and his team to obtain a patent for repurposing pimavanserin.
Srivastava began the research that led to the patent by investigating non-cancer drug candidates he hypothesized had the potential for treating brain cancer. The rationale behind repurposing drugs is that these drugs are already approved and are being used in clinical practice. Oncologists know that the primary hurdle to treating brain tumors is finding an effective drug that can pass through the blood-brain barrier. This semipermeable cellular-based barrier is responsible for protecting the brain from substances that could be harmful. This includes regulating or preventing the transfer of some drugs, chemicals and metabolites from the bloodstream to the brain. However, because antidepressant and antipsychotic drugs are able to cross the blood-brain barrier and reach to the brain, Srivastava and his team initially studied the old drug penfluridol as a potential treatment for brain cancer. Several years ago they found that pimavanserin suppressed the growth of some cancer cells, including pancreatic cancer cells.
His investigation eventually found that pimavanserin has the ability to suppress the growth of various other cancer cells, including those associated with pancreas and brain. To take their investigation to the next level, scientists implanted GBM cells into mice brains and the treated them with pimavanserin. The findings demonstrated that pimavanserin significantly suppressed the growth of brain tumors in animal models. What distinguishes pimavanserin from other antipsychotic drug candidates repurposed for cancer is its high selectivity toward the 5-HT2A (serotonin) receptor. This property enables pimavanserin to be one of the few second-generation antipsychotic drugs with potentially low toxicity. Beyond this, there are other potentially molecular aspects of this drug against cancerl cells. It looks like that pimavanserine may target the activated calcineurin, a cellular phosphatase needed for some aspects of gene expression and cellular proliferation under the Akt/Gli-1 signaling, which is often dysregulated in several forms of cancer.
A latest repurposing attempt concerns the association of TMZ with metformin, the widest and most employed drug to treat diabetes nowadays. Metformin can be cytotoxic for several cancer cells, either in vitro and in vivo, by stimulating apoptosis or autophagy or acting synergically woth other chemotherapeutics. Scientists started by treating glioblastoma cell lines U87MG, LNZ308 and LN229 with metformin, where they found a decreases cell viability, proliferation, migration and increased cell apoptosis in all three glioblastoma cell lines. Oxidative stress and hypoxia were both involved in the effects of the compound, in the metformin-treated glioblastoma cells. Metformin increased ROS production, impaired mitochondrial membrane potential, and reduced mitochondrial biogenesis. The combined treatment of metformin and TMZ had U87 as synergistic, LN229 as additive and LNZ308 as antagonistic. Metformin alone or with TMZ could suppressed MTFA and MGMT proteins in TMZ-resistant LN229 cells.
Metformin is known to mimic cellular starvation and induces ATP loss while activating signaling patways (AMPK-LKB1, for example) having tumor suppressing functions. One speculated target for metformin activity are mitochondria and, indeed, the ATP loss and the reduced MTFA mitochondrial transcriprion factor righteously corroborate the knowledge. Suppressing mitochondria biogenesis (driven by MTFA) means to steal energy to the malignant cells, whici is precisely what scientists aim for.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Feng SW, Chang PC et al. Int J Mol Sci. 2022 Jul 25; 23(15):8171.
Liu ZZ, Liu XN et al. Acta Pharmacol Sin. 2021; 42(11):1860-1874.
Ramachandran S et al. Cancers (Basel). 2021 Nov 12;13(22):5661.
Ramachandran S, Srivastava SK. Mol Ther Oncolyt 2020; 19:19-32
Dott. Gianfrancesco Cormaci
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