2023-10-26 10:49:19
A new joint work of the Sea Hospital Research Institute, el Hebron Valley Institute of Oncology (VHIO), IDIBEL and the Catalan Institute of Oncologywith researchers from the Cancer CIBER (CYBERONC), opens the door to a new way to avoid the tumor proliferation.
It is a combination of different existing treatments for attack on three fronts at cells cancerous and stop its progression. The study is published in the magazine EMBO Journal.
Attacking the IKKa protein – which acts to allow tumor cells to multiply – is currently not viable, as it can cause toxicity to patients.
Researchers have focused on the role of one protein in particular, IKKαwhich is known to act on other proteins to allow tumor cells to multiply and escape the action of treatments.
Attack this protein not currently viablesince general IKKα inhibitors can cause a lot of toxicity to patients.
Therefore, researchers have looked for other ways to act on it and have been able to verify how IKKα regulates two pathways related to tumor proliferation and resistance to chemotherapy.
“In tumors, IKKα is capable of regulating, activating, different pathways linked to proliferation and tumor survival; Consequently, identifying these pathways is essential to design new therapeutic targets for the treatment of cancer patients,” explains the Luis Espinosacoordinator of the Research Group on Molecular Mechanisms of Cancer and Stem Cells at the Hospital del Mar Research Institute and main coordinator of the work.
The pathways identified in this study involve the BRD4 protein and the signaling pathway HOW/STAT and there are drugs that can inhibit its activity.
New features IKKa
Until now there were no clues about the ability of IKKα to act on tumors through these two ways. By activating them, cancer cells are able to proliferate and, at the same time, cell death induced by chemotherapy treatments is inhibited.
The inhibition of both pathways enhances the death of tumor cells in response to chemotherapy. This role has been verified both in animal models and in organoids generated from cells from patients with colon and rectal canceralthough the conclusions can spread to other tumors with these mechanisms activated. It has been possible to certify that “in tumors that present combined activation of the two pathways by IKKα, inhibit them together with chemotherapy It is much more effective than individual treatments”says Espinosa.
Performing screening to identify tumors with these activated mechanisms could allow the identification of patients who are candidates for new therapeutic approaches.
This may allow us to select combinations of treatments that act together with chemotherapy to stop the cancer. At the same time, using more than one drug also makes it easier reduce doses and the toxicity of the treatments.
Therefore, do screened to identify tumors with these mechanisms activated, could allow the patient identification, candidates for new therapeutic approaches. Researchers have also been able to identify the levels of both IKKα and another protein, the leukemia inhibitory factor (LIF).
“The LIF protein is involved in various physiological processes and pathologies related to embryonic development promoting, on the one hand, a immunosuppressive environment and, on the other, the stem cell proliferation during embryo development,” explains Go to SeoICREA professor and head of the Gene Expression and Cancer Group of the Vall d’Hebron Institut d’Oncologia (VHIO).
“In some types of cancer LIF levels are alteredso that the tumor appropriates the functions of this protein to turn off the immune system against tumor cells and increase the number of tumor stem cells, boosting tumor growth and progression”.
In this study, the researchers describe that IKKα with BRD4 can induce LIF and promote chemoresistance of colon cancer tumor cells.
“He goal of chemotherapy es damage DNA to cause the tumor cell death. We have discovered that LIF may be involved in repair these damages in the DNA, allowing the tumor cell to continue dividing and proliferating. That is, LIF generates chemoresistance.”
The researchers have proven that the inhibition of LIF in tumor cells of colon cancer It prevents DNA damage caused by chemotherapy from being repaired and the tumor cell dies, making the therapy effective.
In this context, the laboratory led by Seoane has developed an antibody capable of blocking LIF protein which is being tested in a phase II clinical trial in pancreatic cancer and that it could be useful in combination with chemotherapy as a therapeutic strategy against colon cancer.
Reference:
Espinosa, Ll. et al. “IKKα kinase coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy”. EMBO Journal (2023)
Rights: Creative Commons.
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