Survival after a cancer diagnosis has increased in recent years. However, the prognosis remains serious when it is diagnosed in advanced stages, with metastasis, or in those which are resistant to the usual therapies. In this sense, a collaborative work led by the Translational Molecular Pathology group of the Vall d'Hebron Research Institute (VHIR) and the Pharmaceutical Chemistry group (GQF) of the IQS School of Engineering (Universitat Ramon Llull), has studied an inhibitor of a pathway related to resistance to chemotherapy and immunotherapy. Blocking these mechanisms of tumor malignancy would increase the efficacy of these treatments. The work, published in the Journal of Medicinal Chemistry, is now in preclinical development stages, and has been carried out in collaboration with the Biomedical Research in Urology group at VHIR and CIBER of Cancer (CIBERONC).
Previous studies led by Dr. Santiago Ramon y Cajal, head of the Translational Molecular Pathology group at VHIR, head of the Pathological Anatomy Service at Vall d'Hebron University Hospital and CIBERONC group leader, had identified the MNK1 protein as a possible therapeutic target for cancer treatment. MNK1 is responsible for activating the eIF4E factor, which is considered a poor prognostic factor in many types of tumors because it allows tumor cells to survive treatment and, therefore, is related to resistance to conventional therapies.
In this work, initiated with the doctoral thesis of Dr. Elisabeth Bou, a new drug (known as EB1) has been studied to block MNK1 and, therefore, also the activation of the eIF4E factor. "The inhibition of this pathway does not have an antitumor effect by itself, but if it were administered together with chemotherapy or immunotherapy we would prevent tumor cells from surviving and improve the results obtained with these treatments", explains Dr. Stefan Hümmer, researcher of the Translational Molecular Pathology group at VHIR and CIBERONC. Also, MNK1-activated pathway does not have essential functions for healthy cells, so its elimination would not produce other unwanted side effects.
This is not the first time that drugs have been tested against this cellular pathway. However, the EB1 drug presents a novel mechanism of action that would reduce the side effects produced by other types of MNK1 inhibitors. Generally, inhibitors of this protein bind at the same site as ATP, a molecule necessary to carry out the main function of eIF4E activation. "The usual inhibitors prevent the main function of MNK1, but can lead to unwanted activation of secondary functions. In contrast, in this study carried out in cells, we have found that EB1 completely inactivates MNK1 and thus prevents unwanted effects", says Dr. José I. Borrell, coordinator of the Pharmaceutical Chemistry group (GQF) of the IQS School of Engineering (Universitat Ramon Llull).
The researchers highlight the low toxicity of the drug, which has no side effects on healthy cells. In addition, the fact of sensitizing tumor cells to standard treatments would make it possible to reduce the dose of chemotherapy and, therefore, reduce the side effects of primary therapy.
With the aim of reaching clinical practice, researchers are currently studying which combinations with existing treatments, both chemotherapy and immunotherapy, allow greater benefits for patients. In the case of immunotherapy, EB1 could prevent tumor cells from escaping recognition by the immune system, one of the reasons why these treatment strategies may not work well. "We are beginning to study its efficacy in breast and prostate cancer, but we think it is possible to apply it to any type of tumor because the mechanisms of resistance to most treatments are similar", concludes Dr. Santiago Ramon y Cajal.