Tuesday, April 4, 2017

Imiquimod and Mebendazole...drugs repurposed for mousie melanoma

Folks in melanoma world tend to go nuts when reports like these hit the news stand.  Partly out of desperation for an effective treatment, but also because sometimes such reports fail to make it clear that these great strides were attained in mousies rather than ratties.  Despite the skepticism my first sentence may convey, mice ARE the first step toward ratties and if they can find a treatment that works for more of my melanoma peeps, I'll take it!!!

First up is imiquimod, a cream that is usually used topically to treat venereal warts, basal cell carcinoma, and actinic keratosis.  These little mice seem to have had it applied topically (??? I think) as well as having it injected in their tail veins (not sure which vein that would be in ratties!!!) followed by radiation and it seemed to make melanoma lesions more responsive to that treatment.

Next there's mebendazole, an old, cheap, oral drug most often used to treat pin worms in kids...but also infestations of many other wormy critters as well as giardia.  Generally, it is safe to use, though in large doses can cause bone marrow suppression.  As an aside, I had a good many doses of this as a child because my mother seemed to have been of the persuasion that an ounce of prevention was worth a pound of cure....not that this med works like that for worms nor melanoma, as I sit here today as a Stage IV melanoma rattie!!!

At any rate, here you go.....

The TLR7 agonist imiquimod induces anti-cancer effects via autophagic cell death and enhances anti-tumoral and systemic immunity during radiotherapy for melanoma. Cho, Lee, Ko, et al. Oncotarget. 2017 Feb 15.

Toll-like receptor (TLR) ligands are strongly considered immune-adjuvants for cancer immunotherapy and have been shown to exert direct anti-cancer effects. This study was performed to evaluate the synergistic anti-cancer and anti-metastatic effects of the TLR7 agonist imiquimod (IMQ) during radiotherapy for melanoma. The pretreatment of B16F10 or B16F1 cells with IMQ combined with γ-ionizing radiation (IR) led to enhanced cell death via autophagy, as demonstrated by increased expression levels of autophagy-related genes, and an increased number of autophagosomes in both cell lines. The results also confirmed that the autophagy process was accelerated via the reactive oxygen species (ROS)-mediated MAPK and NF-κB signaling pathway in the cells pretreated with IMQ combined with IR. Mice subcutaneously injected with melanoma cells showed a reduced tumor growth rate after treatment with IMQ and IR. Treatment with 3-methyladenine (3-MA), ameliorated the anti-cancer effect of IMQ combined with IR. Additionally, the combination therapy enhanced anti-cancer immunity, as demonstrated by an increased number of CD8+ T cells and decreased numbers of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) in the tumor lesions. Moreover, the combination therapy decreased the number of metastatic nodules in the lungs of mice that were injected with B16F10 cells via the tail vein. In addition, the combination therapy enhanced systemic anti-cancer immunity by increasing the abundances of T cell populations expressing IFN-γ and TNF-α. Therefore, these findings suggest that IMQ could serve as a radiosensitizer and immune booster during radiotherapy for melanoma patients.

The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma.  Simulam-Rosenthal, Dakshanamurthy, Gaur, et al. Oncotarget. 2017 Feb 2.

Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes. Downstream ERK targets for cell cycle, including cMYC, were down-regulated, consistent with S- phase suppression by MBZ+trametinib, while apoptosis markers, including cleaved caspase-3, cleaved PARP and a sub-G1 population, were all increased with time. These data suggest that MBZ, a well-tolerated off-patent approved drug, should be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mut or other non-V600E BRAF mutant melanomas.  

Thanks to all the dear mousies!! love, rattie

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