New Bromodomain Inhibitor Shows Promise in Treating Malignant Pleural Mesothelioma

New Bromodomain Inhibitor Shows Promise in Treating Malignant Pleural Mesothelioma

A new bromodomain and extraterminal (BET) inhibitor, OTX015, may be a promising approach to treat malignant pleural mesothelioma (MPM), according to a recent study published in the International Journal of Cancer.

The study, “Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts,” shows that OTX015 significantly delays tumor growth in human MPM cell lines and animal models, showing an anti-tumor activity that is more marked than standard chemotherapy drugs for MPM, such as Platinol (cisplatin), Alimta (pemetrexed), or Gemzar (gemcitabine).

Since the majority of patients with malignant mesothelioma have diffuse growth of their tumors, surgery is often not an option, making chemotherapy the primary form of treatment. Currently, combined Alimta and Platinol constitute the backbone of most chemotherapy, while Gemzar is used to treat patients unable to take Alimta.

But despite increasing knowledge on mesothelioma molecular mechanisms, the prognosis of these patients is still poor, with median survival times that range from four to 12 months.

In recent years, researchers have shown that epigenetic modifications can contribute to the development of MPM, with several modulators of epigenetic processes showing activity against this cancer in both preclinical studies and clinical trials.

OTX015, in particular, is an inhibitor of the BET proteins, which are proteins that read the epigenetic code in the DNA and control the expression of a number of genes. OTX015 is currently in Phase 1 and Phase 2 clinical trials in hematologic malignancies and adult solid tumors (NCT01713582NCT02259114, and NCT02296476).

Since one of the genes controlled by BET proteins is c-Myc, a gene that is expressed at high levels in MPM cells, and that is known to drive the tumorigenic process in many other cancers, the researchers sought to investigate the effectiveness of OTX015 in MPM cell lines and animal models.

They developed four distinct cells lines derived from MPM patients with different histological types: epithelioid (MPM473 and MPM484); sarcomatoid (MPM60); and biphasic (MPM487), the three types of malignant mesothelioma that have been identified.

After treating the cells with OTX015, either in the lab or in mice implanted with the human MPM cells, the researchers found that OTX017 significantly decreased tumor growth both in the lab — in vitro — and in mice, or in vivo.

Compared to the other chemotherapy agents, OTX015 was the most effective drug in mice bearing epithelioid MPM473 cells, and showed a similar activity level as the most efficient treatment in the other two MPM cells tested in mice (Gemza in the biphasic MPM487 cell line and Platinol in the epithelioid MPM484 cell line).

The researchers believe this effect may be at least partly caused by the decreased levels of c-Myc, as OTX015 was found to decrease c-Myc expression in MPM473 and MPM487 cell lines.

The absence of toxic effects (assessed by lack of weight loss) in mice treated with active doses of OTX015 also makes this a potentially effective drug to treat mesothelioma patients.

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