Summary: MP-Pt(IV), a second generation prodrug appears to have curative properties against glioblastoma when coupled with chemotherapy in mouse models.
Source: Houston Methodist
Houston Methodist researchers found that mice harboring human glioblastoma tumors in their brains had greatly enhanced survival and weight gain when given a newly developed prodrug.
This mitochondrial-targeted prodrug – an inactive compound that cancer cells selectively metabolize to produce an active toxic drug – also greatly improves outcomes when coupled with standard therapies of radiation and/or chemotherapy. The drug selectively targets and destroys the DNA inside the glioblastoma cell mitochondria (the energy factory of the cancer cell) leaving normal cells intact.
In an Oct. 8 study published online in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research, investigators used a second-generation prodrug called MP-Pt(IV) to target the deadly cells of glioblastoma tumors, a brain cancer that is almost always fatal and has no cure. Life expectancy in humans with glioblastoma ranges from a few months to two years.
Human glioma cells were removed from patients during surgical excision and isolated within 10 minutes after removal. The glioblastoma cells were injected into the brains of 48 female mice for a 300-day study. The prodrug was well tolerated, and, when given on its own, extended survival by more than a factor of three.
However, when combined with standard chemotherapy and radiotherapy, the drug was curative in nature, allowing 90% of mice to survive, thrive and gain weight during the 10 months of observation.
“This study tells us that adding MP-Pt(IV) to a chemoradiotherapy protocol could address a critical need in glioblastoma treatment,” said David S. Baskin, M.D., FACS, FAANS, corresponding author and director of the Kenneth R. Peak Center for Brain and Pituitary Tumor Treatment in the Department of Neurosurgery at Houston Methodist.
“We now know that MP-Pt(IV) is an excellent candidate for preclinical development.”
Funding: Co-authored by medicinal chemist Sudhir Raghavan, Ph.D., and senior brain cancer researcher Martyn A. Sharpe, Ph.D., the study, entitled “MP-Pt(IV): A MAOB-sensitive mitochondrial-specific prodrug for treating glioblastoma,” was supported by Donna and Kenneth Peak, The Kenneth R. Peak Foundation, The John S. Dunn Foundation, The Taub Foundation, The Blanche Green Fund of the Pauline Sterne Wolff Memorial Foundation, The Kelly Kicking Cancer Foundation, The Gary and Marlee Schwarz Foundation, The Methodist Hospital Foundation and The Veralan Foundation. Sharpe is funded by the John S. “Steve” Dunn Jr. Distinguished Professorship in Brain Tumor Research.
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Source:Houston Methodist Contact: Patti Muck – Houston Methodist Image: The image is in the public domain.
MP-Pt(IV): A MAOB-sensitive mitochondrial-specific prodrug for treating glioblastoma
We previously reported the in vitro and in vivo efficacy of N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propenamide, a prodrug that targeted the mitochondria of glioblastoma (GBM). The mitochondrial enzyme monoamine oxidase B (MAOB) is highly expressed in GBM and oxidizes an uncharged methyl-tetrahydropyridine (MP-) moiety into the mitochondrially-targeted cationic form, methyl-pyridinium (P+-). Coupling this MAOB-sensitive group to a nitrogen mustard produced a prodrug that damaged GBM mitochondria and killed GBM cells. Unfortunately, the intrinsic reactivity of the nitrogen-mustard group and low solubility of MP-MUS precluded clinical development. In our second generation prodrug, MP-Pt(IV) we coupled the MP-group to an unreactive cisplatin precursor. The enzymatic conversion of MP-Pt(IV) to P+-Pt(IV) was tested using recombinant human MAOA and rhMAOB. The generation of cisplatin from Pt(IV) by ascorbate was studied optically and using mass-spectroscopy. Efficacy toward primary GBM cells and tumors was studied in vitro and in an intracranial patient-derived xenograft mice GBM model. Our studies demonstrate that MP-Pt(IV) is selectively activated by MAOB. MP-Pt(IV) is highly toxic toward GBM cells in vitro. MP-Pt(IV) toxicity against GBM is potentiated by elevating mitochondrial ascorbate and can be arrested by MAOB inhibition. In in vitro studies, sub-lethal MP-Pt(IV) doses elevated mitochondrial MAOB levels in surviving GBM cells. MP-Pt(IV) is a potent chemotherapeutic in intracranial patient-derived xenograft mouse models of primary GBM and potentiates both temozolomide (TMZ) and TMZ-chemoradiation therapies. MP-Pt(IV) was well tolerated and is highly effective against GBM in both in vitro and in vivo models.