Glioblastoma multiforme is the most aggressive and malignant form of gliomas, a group of tumors arising from glial cells of the brain. Glioblastomas are very difficult to treat due to the diffused nature of the tumor itself. The tumor cells have a distinct invasive feature of spreading and diffusing into different parts of the brain. This characteristic feature of these tumors renders it difficult to treat.
Glioblastomas are one of the most chemo-resistant human cancers to treat clinically due to the activation of different cytoprotective mechanisms. One cytoprotective mechanism that has been gaining widespread attention is the unfolded protein endoplasmic reticulum stress response. Endoplasmic reticulum (ER) is the site where membrane and secreted protein are folded. Any disturbance of this process in the ER will cause ER stress and triggers a set of signaling pathway called the unfolded protein response (UPR). This pathway promotes cellular repair and maintains a productive ER protein folding environment. However, if the ER stress is excessive and exceeds the threshold of repair, then apoptosis (cell death) ensues. This mechanism has been target of research to develop chemotherapeutic agents that trigger apoptotic cell death in targeted cancer cells. Researchers have conducted studies using thapsigargin, an endoplasmic reticulum stress inducer, to evaluate its efficacy on glioblastoma cells.
GenSpera Inc. has developed a novel prodrug therapeutic agent mipsagargin, a thapsigargin analog prodrug for the treatment of cancer. Mipsagargin is in phase 2 clinical trials for treatment of glioblastoma multiforme. A two-stage, single-arm, open-label study led by neuro-oncologist Santosh Kesari, M.D., Ph.D., is being conducted at the UC San Diego Moores Cancer Center in La Jolla, California. The phase 2 results indicate mipsagargin to be very beneficial and well tolerated by advanced glioblastoma multiforme patients. The advantage mipsagargin has over other conventional chemotherapy drugs concerns overcoming the blood-brain barrier. While most conventional drugs are unable to cross the blood-brain barrier, Mipsagargin targets the prostate-specific membrane antigen (PSMA) expressing cells of the blood vessels associated tumor of which would not be accessible through other chemotherapy means.
Mipsigargin is a promising product for the future of cancer treatment. Brain cancers, such as glioblastoma multiforme, were previously difficult to treat due to the inaccessibility of the tumors caused by the blood-brain barrier. With mipsigargins capabilities of targeting the surrounding blood vessels of the tumor without harming nearby tissue due to its nature as a prodrug only pharmacologically activated in the presence of PSMA, targeted destruction specific to the tumor sites is now a possibility.
Quick QA, Faison MO. CHOP and Caspase 3 Induction Underlie Glioblastoma Cell Death in Response to Endoplasmic Reticulum Stress. Experimental and Therapeutic Medicine. 2012;3(3):487-492. doi:10.3892/etm.2011.422.
Holland EC. Glioblastoma Multiforme: The Terminator. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(12):6242â€“6244. doi:10.1073/pnas.97.12.6242.
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[Authored by Dilshad Rafi Ahmed]