PhD Scientific Days 2024

Theoretical and Translational Medicine I.

Enhancing therapeutic efficacy in triple‐negative breast cancer and melanoma: synergistic effects of modulated electrohyperthermia (mEHT) with NSAIDs especially COX‐2 inhibition in in vivo models

Text of the abstract

Introduction: Modulated electro-hyperthermia (mEHT) is a cancer treatment method, applying a 13.56 MHz radiofrequency electromagnetic current to induce tumor-specific damage. This study investigates the mEHT-induced molecular effect and the potential of a combination of non-steroid anti-inflammatory drugs (NSAIDs) to enhance its anti-tumor effects in 4T1 triple-negative breast cancer (TNBC) and B16F10 melanoma mouse models.

Methods: TNBC and B16F10 melanoma cells were injected into mice. They were treated with non-selective (Aspirin) or selective COX2 inhibitors (SC236) in combination with mEHT. Tumor volume was monitored by ultrasound and a digital caliper. Mice were euthanized and tumors were excised for molecular studies with Nanostring, qPCR, and immunohistochemistry.

Results: In this study, we report that mEHT monotherapy stimulated IL-1β (p=0.009) and IL-6 (p=0.07) expression, and consequently COX-2 (p=0,001), which may favor a cancer-promoting tumor microenvironment(TME). Thus, we combined mEHT with aspirin or SC236 in vivo. We demonstrate that NSAIDs synergistically increased the effect of mEHT in the 4T1 TNBC model. The strongest tumor destruction ratio(TDR) was observed in the combination SC236 + mEHT groups (p=0.004). TDR was accompanied by a significant increase in cleaved caspase-3, suggesting that apoptosis played an important role. IL-1β (p=0.002) and COX-2 (p=0.004) expression were significantly reduced by the combination therapies. Nanostring data demonstrated significant upregulation of genes participating in the formation of the extracellular matrix. Similarly, in the B16F10 melanoma model, mEHT and aspirin synergistically reduced the number of melanoma nodules in the lungs (p=0.02).

Conclusion: mEHT+NSAID therapy can inhibit tumor growth in TNBC and melanoma. The combination therapy reduces the stimulation of IL-1β and COX-2 induced by mEHT. SelCoxibs can regulate the extracellular matrix and cell membrane function in the TME, leading to the inhibition of cancer cell proliferation.
Funding: SE250+ excellence scholarship, Tempus Public Fundation