Assistant Professor of Radiology and Cancer Biology
Purpose: Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer mortality in the United States. We recently established the potential value of lactate dehydrogenase (LDH) inhibition as a therapy for HCC, further highlighting this disease’s enhanced relative dependence on LDH for growth and survival . Recognizing the importance of optimizing drug delivery, we hypothesized that local delivery of this metabolic inhibitor would enhance its therapeutic efficacy. By comparing the effects of intravenous and intraarterial delivery of an LDH inhibitor, the purpose of this study was to examine whether local delivery would enhance therapeutic efficacy.
Materials and Methods: Diethylnitrosamine (0.01%) was supplemented to the drinking water of male Wistar rats for 12 weeks to induce autochthonous HCC formation . Animals with tumors measuring 100 mm3 on T2-weighted MRI received a single dose of an LDH inhibitor (10 mg/kg; 737 – NCI) either intravenously (n=6) or intraarterially (n=7). Treatment efficacy was compared in the two groups according to the change in tumor growth rate, which was quantified using an exponential growth model fit to tumor measurements taken before and after drug administration. This model is summarized by the formula: Volume=Sizet=0*(A)t. The fold-change in the model parameter A was used as a test statistic (TS) for all comparisons reported.
Results: Intraarterial delivery of LDH inhibitor significantly slowed tumor growth (TSavg=0.989, TSsd=0.00761, p< 0.01). Consistent with prior reports, intravenous LDH inhibitor delivery also slowed tumor growth (TSavg=0.997, TSsd=0.00210, p< 0.05) . The therapeutic effect of intraarterial delivery was statistically superior to that observed with intravenous delivery (p< 0.05). Of note, tumor regression was observed in 3 of 7 animals in the intraarterial group, while this was never observed in the intravenous group.
Conclusion: These data demonstrate the superiority of intraarterial delivery for an LDH inhibitor previously shown to slow tumor growth in a rodent model of HCC. Future work will examine the potential synergistic effects of multiple injections and/or use of embolics on treatment response. More broadly, these findings highlight the benefit of locoregional administration of cancer therapies by Interventional Radiologists as a means of improving therapeutic efficacy.
References:  NR Perkons, O Johnson, G Pilla, E Profka, M Mercadante, D Ackerman, TPF Gade. “Functional genetic screening enables theranostic molecular imaging in cancer.” Clinical Cancer Research. 2020.