The study led by VHIO also benefited from the collaboration with Professor Alberto Muñoz´s laboratory at the Instituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de Investigaciones Científicas (IIB-CSIC-Madrid).
Published today in Nature Medicine, this work identifies biomarkers that predict response to treatment and proposes therapeutic solutions for patients who do not respond well. These advances will guide better selection of treatments and avoid the risk of administering ineffective drugs.
Colon cancer is a disease caused by a malignant tumour in the large intestine. When detected early the tumor is removed through surgery and patients are treated with adjuvant chemotherapy, eliminating the disease in the majority of cases. However, in advanced stages, colon tumours are resistant to a broad spectrum of anti-tumour drugs and cancerous cells escape treatment and disseminate around the body, giving rise to metastasis. Currently there are no effective treatments to halt the progression of colon cancer in these later stages and most patients die as a result of disease progression.
Over recent years new drugs have been designed to target and block the activity of certain molecules responsible for promoting tumor growth and metastasis. Some of these, which are currently in clinical trials, are showing promising results in certain patients, while others show no improvement at all. This study headed by the VHIO examines the differential response to treatment and was supported by the Olga Torres Foundation (FOT), the Scientific Foundation of the Spanish Association Against Cancer (AECC), and the Carlos III Institute of Health (ISCIII).
New clinical horizons
Dr Héctor G. Palmer´s team has described for the first time the molecular mechanisms through which the interaction between the oncogenic pathways of Wnt/beta-catenin and RAS/PI3K/AKT determines the response to treatments with pharmacological PI3K or AKT inhibitors. Although both pathways are genetically altered in colon cancer, it is the over-accumulation of beta-catenin in the nucleus of cancer cells that makes them resistant to cell death induced by these anti-tumoral drugs.
Activation of the PI3K/AKT pathway retains the FOXO3a protein outside the cell nucleus, inhibiting its ability to act as a tumour suppressor that induces cell death. Therefore, "Targeting PI3K or AKT activity with these novel inhibitors allows relocation of FOXO3a in the nucleus promoting cell death. These drugs are being tested in clinical trials worldwide providing promising initial results in certain tumour types", explains Héctor G. Palmer, Head of VHIO´s Stem Cells and Cancer Group.
However, many colon cancer patients do not show any benefit. The reason for this is explained by Dr Palmer: "If the patients treated with these inhibitors show very high levels of nuclear beta-catenin, FOXO3a cannot induce cell death but promotes the opposite effect by escaping treatment and causing metastasis." According to Héctor Palmer, this finding has tremendous clinical value, since "the identification of nuclear beta-catenin as a biomarker to predict response guides the selection of patients who will benefit from treatment with PI3K or AKT inhibitors and discard their use in candidates who would provoke an adverse response."
Furthermore, Dr Héctor Palmer and his collaborators have discovered a solution for those patients for whom treatment with PI3K or AKT inhibitors would be contraindicated. They used an experimental drug that reduces the levels of nuclear beta-catenin, allowing the cell death induced PI3K or AKT inhibitors. These findings propose the combination of both types of inhibitors in the future for a more effective target-directed therapy in colon cancer.
Delivering on the promise of personalized medicine
VHIO pioneers pre-clinical functional studies and clinical trials in the fight against cancer. Importantly, Dr. Palmer´s team has developed in vivo models that accurately recapitulate disease progression in colon cancer patients. They inoculate the animals with cells derived from the patient's tumour, creating a "xenopatient" model. These cells regenerate the the disease in the animals with the same distinctive characteristics as in the individual patient, retaining its original genetic, clinical and pathological alterations. The xenopatients represent a parallel reality of each patient in the laboratory. This approach allows the study of disease progression and response to experimental medicines before subjecting the patient to new treatments. This model could soon form the basis of future functional, predictive and personalized cancer treatments.For further information:
Amanda Wren | EurekAlert!
Research offers clues for improved influenza vaccine design
09.04.2018 | NIH/National Institute of Allergy and Infectious Diseases
Injecting gene cocktail into mouse pancreas leads to humanlike tumors
06.04.2018 | University of Texas Health Science Center at San Antonio
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
In an article that appears in the journal “Review of Modern Physics”, researchers at the Laboratory for Attosecond Physics (LAP) assess the current state of the field of ultrafast physics and consider its implications for future technologies.
Physicists can now control light in both time and space with hitherto unimagined precision. This is particularly true for the ability to generate ultrashort...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
19.04.2018 | Materials Sciences
19.04.2018 | Physics and Astronomy
19.04.2018 | Physics and Astronomy