Small molecule drug may improve cancer-killing efficacy of oncolytic virus [PreClinical]

1. A small molecule screen identified that microtubule-destabilizing (MD) drugs enhanced the cancer-killing activity of oncolytic vesicular stomatitis virus.

2. In several mouse tumor models, combination therapy of virus and the MD drug colchicine led to increased viral titres and improved survival outcomes when compared to either monotherapy. 

Evidence Rating Level: 2 (Good)

Study Rundown: Oncolytic viruses (OVs) are engineered to specifically target and kill cancer cells. Because their performance in clinical trials has varied widely and subsets of cancers do not respond to OV therapy, researchers look to improve OV efficacy. In this study, the authors showed a potential approach is to complement OV treatment with a pharmacological agent. In a screen the authors identified several small molecules that enhance the cell-killing activity of the oncolytic vesicular stomatitis virus strain VSVΔ51. Nearly half of these identified compounds demonstrated MD activity, in which the drugs targeted microtubules, the filament network inside cells that supports cell structure and intracellular transport.

When paired with VSVΔ51 and administered to a human renal carcinoma cell line, the anti-inflammatory MD drug colchicine was particularly effective in decreasing cell viability. Colchicine improved viral spread and expression of viral proteins in cancer cell lines but not in a normal human fibroblast cell line. VSVΔ51 and colchicine combination therapy was tested in a variety of aggressive, virus-resistant mouse tumor models. Compared to either monotherapy, combination therapy (MD drug + OV) resulted in significantly increased virus levels and improved animal survival.

While colchicine enhancement of viral activity was specific to cancer cells, colchicine itself is considered to be nonspecifically toxic. Indeed, the study data showed that colchicine had microtubule-destabilizing and cytotoxic activity in both normal and cancer cell lines. Overall, this study demonstrated the efficacy of VSVΔ51 and colchicine combination therapy; however, further studies to show the safety of the therapeutic approach are needed.

Click to read the study in Nature Communications

Relevant Reading: VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents

In-Depth [animal study]: This study identified and examined the efficacy of MD compounds paired with OVs for the improvement of cancer therapy. A screen of small molecule drugs that enhanced VSVΔ51 activity identified several classes of MD drugs: colchicinoids, vinka alkaloids, and benzimidazoles. Representative members of the drug classes were tested in a viability assay of human renal carcinoma cells. Compared to VSVΔ51 alone or MD drug alone, combination treatment with an MD drug and VSVΔ51 resulted in the great reduction in cancer cell viability, across a number of drug concentrations (0.12 to 10µM). The toxic effects of the combination therapy were not observed in normal human fibroblast cells (nHFCs). Combination treatment resulted in increased viral titer in a number of cancer cell lines, but not in nHFCs.

Combination treatment was tested against both monotherapies in a number of mouse models. First, in mice with subcutaneous human HT29 colon tumor xenografts, 10⁸ plaque-forming units of MG-1 (a virus strain closely related to VSVΔ51) were delivered intratumorally and 2mg/kg of colchicine was delivered intraperitoneally. Within 6 days post treatment, tumor volume was lowest in the animals that received combination therapy. This trend continued for the duration of the ~ 2 week study. Second, a similar therapy regimen was applied to mice with subcutaneous mouse 4T1 breast tumors. Twenty four hours post treatment, in vivo imaging showed that viral spread at the tumor site was higher for animals that received combination treatment compared to those that received virus alone. Correspondingly, viral titers were significantly higher in the animals that received combination treatment (p=0.008). Animal survival was significantly higher for animals with combination therapy than virus alone (p=0.024) or colchicine alone (p=0.0082). Finally, in a highly treatment-resistant ovarian cancer mouse model, animal survival was significant higher for animals with combination therapy than granulocyte-macrophage colony-stimulating factor-enhanced virus alone (p=0.0007) or colchicine alone (p=0.0082).

Image: PD

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