Tumor Treating Fields’ Potential in Mesothelioma

Tumor treating fields (TTFields) are an emerging treatment modality where low intensity, intermediate frequency, alternating electric fields are delivered through arrays placed around the anatomic region of the tumor. Their use concomitant with pemetrexed and platinum-based chemotherapy was approved by the FDA for first-line treatment of unresectable, locally advanced or metastatic pleural mesothelioma (MPM), in light of significant patient benefit in a phase II clinical trial (STELLAR clinical trial; NCT02397928) (1). Despite observed improvements in overall survival, there is lack of clarity on the mechanisms behind TTFields’ efficacy in this patient population.

One of the 2021 AACR-Novocure Tumor Treating Fields Research Grant recipients, Maurizio D’Incalci, MD, Professor and Laboratory Head of Group of Cancer Pharmacology at Humanitas University, Italy seeks to elucidate the molecular mechanisms behind the combinatorial efficacy of TTFields/chemotherapy in mesothelioma. The STELLAR trial showed that both overall survival and progression-free survival were longer in patients with epithelioid histology than in patients with other subtypes. Professor D’Incalci and his colleagues leveraged the availability of patient-derived mesothelioma cell lines to help explain this observed histotype-specific effect of TTFields.

In a recent paper in Cell Death and Disease, they confirmed that a sarcomatoid cell line, CD60, was only slightly affected by TTFields (2). In contrast, an epithelioid cell line, CD473, was susceptible to TTFields, even after only 24 hours of exposure. Cell cycle analyses showed that these TTFields-sensitive cells were blocked in G2M phase. This block was associated with an increase in Chk1 protein levels. Even when TTFields were no longer applied to these cells, G2M block and TTFields-induced polyploidy persisted. Sarcomatoid cells, on the other hand, resumed growth, albeit at a slower rate, upon TTFields discontinuation.

To further interrogate the histotype-specific effects, RNA seq analyses were conducted on epithelioid and sarcomatoid cells exposed to 1.12 V/cm TTFields (conditions used in the clinic). Baseline analyses confirmed that the transcriptional profiles of the cell lines were comparable to those of patient biopsies of the same histotype. The authors found 1329 differentially expressed genes (DEGs) in TTFields-sensitive epithelioid cells. Pathway analyses indicated that the DEGs were associated with pathways mainly related to cell cycle checkpoints, SUMOylation, nuclear pore complex, and RHO GTPases. The putative importance of Rho GTPases in the TTFields response in mesothelioma is similar to the observed role of the Rho-associated coiled-coil kinase signaling pathway in TTFields’ effects in glioblastoma (3).

Professor D’Incalci noted, “There are still gaps in our understanding of the antineoplastic mechanisms engaged by TTFields in mesothelioma. In this study, we tried to address some unresolved clinically pertinent issues, such as which factors influence mesothelioma susceptibility towards TTFields. Even though further experiments need to be performed in order to confirm our findings, we showed convincingly that TTFields inhibits mesothelioma cell proliferation and provided a mechanistic rationale for future therapies and combinations with anticancer drugs.”

Commenting on the importance of the AACR-Novocure Tumor Treating Fields Research Grant on his research, Professor D’Incalci shared, “The grant supports my efforts to find new therapeutic strategies against MPM and to train new postdoctoral researchers. Moreover, this grant has laid the groundwork for a promising collaboration between preclinical and clinical researchers focused on the care of mesothelioma patients.”

Applications are currently being accepted from early-career investigators for the 2022 AACR-Novocure Career Development Award for Tumor Treating Fields Research in Ovarian Cancer. The deadline for submission is September 20, 2022. Please visit the AACR’s funding page for more information.

Reference:

¹ Ceresoli GL, Aerts JG, Dziadziuszko R, Ramlau R, Cedres S, van Meerbeeck JP, et al. 2019. Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial. Lancet Oncology 2019; 20:1702-9.

2. Mannarino L, Mirimao F, Panini N, Paracchini L, Marchini S, Beltrame, et al. Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations. Cell Death Dis 2022; 13:612

3. Voloshin T, Schneiderman RS, Volodin A, Shamir RR, Kaynan N, Zeevi E, et al. Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Acting Dynamics. Cancers (Basel) 2020; 12:3016.