3735 - MCT Inhibition Targets Cervical Cancer in Lactate Enriched Microenvironments

Purpose/Objective(s): We have previously shown that lactobacilli dominated cervical microbiomes were associated with non-response to chemoradiation and reduced recurrence free overall survival. Lactobacilli in the tumor microenvironment leads to elevated lactate levels which provide metabolic fuel for cancer cells and lead to radiation resistance. Cells shuttle lactate through monocarboxylate transporters (MCTs) 1 and 4, a possible target to blunt lactate’s effects. While multiple MCT inhibiting drugs exist, no MCT inhibitor has been FDA approved as a treatment method for cancer Our goal is to develop a lactate exposure model to investigate lactate-driven tumor growth and target it using MCT inhibitors.

Materials/Methods: We grew SiHa cells in L-Latic acid supplemented media and exposed them to Syrosingopine (MCT1 and 4 inhibitor) and Bay-8002 (MCT 1 inhibitor with dose dependent 4 activity). We then collected the cell cultures 5-days post treatment and evaluated cell viability via Cell Titer Glo. We subcutaneously injected MEER cells into the flanks of C57BL/6 mice to determine the effect of lactate exposure on tumor growth. Once palpable, we administered weekly injections of sodium lactate into tumors followed by a radiation dose of 6 Gy per day x 3 days. Tumor volume was measured with a caliper. To determine the effects of MCT inhibition on in vivo tumor growth, we administered Syrosingopine to our tumor-bearing mice. We administered Syrosingopine via intraperitoneal injection every other day for two weeks. Tumor volume was measured with a caliper.

Results: In vitro testing on SiHa cells revealed lactate supplemented cells have a greater sensitivity to MCT treatment than control cells. 10µM Syrosingopine treatment showed a 5-fold decrease in viability in lactate treated cells compared to control cells (p<0.001). 80µM Bay-8002 revealed a 2-fold decrease in cell viability in the lactate enriched cells compared to control cells (p<0.001). In vivo Lactate supplemented tumors show a greater rate of growth compared to vehicle alone (mean size 93mm³ vs 56mm³, respectively; p<0.001; n=6). With the addition of radiation treatment, lactate supplemented tumors continue to outgrow non-lactate tumors (mean size 74 mm³ vs 48mm³; p<0.001; n=11). Our synergetic mouse model with the addition of Syrosingopine shows a reduction in tumor volume in lactate tumor group which was not seen in the control group given the same treatment (mean size 85mm³ vs 132mm³; p=0.0047; n=5).

Conclusion: Our data shows that lactate fueled tumors exhibit more aggressive growth in vivo and are radiation resistant. In addition, our data supports that MCT 1 and 4 inhibitor, syrosingopine, reduces cell viability and tumor volume in lactate supplemented models. As we learn more about the interactions between Lactobacilli and tumors this data may provide an avenue to target treatment resistant cervical cancers.