Increase the effectiveness of current cancer chemotherapy or immunotherapy treatments

A new drug could increase the vulnerability of cancer cells to existing chemotherapy or immunotherapy treatments.

Survival after a cancer diagnosis has increased in recent years. However, the prognosis remains serious in cases detected in advanced stages, with metastasis, or in those in which there is resistance to standard therapies. In this sense, a collaborative work led by the Translational Molecular Pathology group of the Vall d’Hebron Research Institute (VHIR) in Barcelona and the Pharmaceutical Chemistry group (GQF) of the School of Engineering at the Ramon Llull University of Barcelona, 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 current treatments with chemotherapy or immunotherapy. The work in this line of research is in the preclinical development phase and has been carried out in collaboration with the VHIR Biomedical Research in Urology group and the Cancer Network Biomedical Research Center (CIBERONC) in Spain.

In previous studies, it was possible to identify the MNK1 protein as a possible therapeutic target for the treatment of cancer. MNK1 is responsible for activating the eIF4E factor, which is considered to have a poor prognosis for many types of tumors because it allows tumor cells to survive treatments and, therefore, is related to resistance to conventional therapies.

In the new study, initiated with the doctoral thesis of Elisabeth Bou and published in the academic journal Journal of Medicinal Chemistry, a drug (known as EB1) that blocks MNK1 and, therefore, also the activation of the eIF4E factor has been studied. “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 group of Translational Molecular Pathology of VHIR and CIBERONC. It should also be noted that the pathway activated by MNK1 does not have essential functions for healthy cells, therefore, its elimination would not produce other unwanted side effects.

VHIR investigation team. (Photo: VHIR / CIBERONC)

This is not the first time drugs have been tested against this cellular pathway. However, the EB1 drug has a novel mechanism of action that would reduce the side effects produced by other types of MNK1 inhibitors. Generally, inhibitors of this protein bind to the same place as ATP, a molecule necessary to carry out the main function of activating eIF4E. “The usual inhibitors prevent the main function of MNK1, but they can cause the unwanted activation of secondary functions. On the other hand, in this study carried out in cells, we have verified that EB1 inactivates MNK1 completely and thus prevents unwanted effects from being caused”, says Dr. José I. Borrell, director of the Pharmaceutical Chemistry group (GQF) of the School of Engineering at Ramon Llull University. The EB1 drug would also have the capacity to inhibit the growth of tumor cells by itself, while the rest of the existing inhibitors do not offer this possibility.

The authors of the study highlight above all the low toxicity of the drug, which would not have secondary 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, also reduce the side effects of primary therapy.

With the aim of reaching clinical practice, it is currently being studied 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 have good results. The authors of the study are beginning to study its efficacy in breast and prostate cancer, but they think that it is possible to apply it to any type of tumor because the mechanisms of resistance to most treatments are similar. (Source: CIBERONC)