Latest research published in Clinical Cancer Research by the Vall d´Hebron Institute of Oncology´s (VHIO) Stem Cells & Cancer Group has established the efficacy of a novel therapeutic strategy aimed at reverting resistance to PI3K/AKT pathway inhibitors in the treatment of colorectal cancer for the very first time. By simultaneously inhibiting the Wnt/β-catenin pathway, in parallel with the use of PI3K/AKT pathway inhibitors, VHIO scientists have succeeded in reverting resistance to these inhibitors. Their research also proposes a new predictive avenue to gauge the efficacy of this novel combinatorial therapy in patients with colorectal cancer (CRC), thus facilitating a more precise selection of patients to be treated with these agents.
The oncogenic mutations that spontaneously occur in the KRAS/PI3K/AKT pathway are some of the most common alterations in cancer. Those in the colon and rectum, unlike other tumor types, show high levels of resistance to treatment with PI3K- or AKT-specific inhibitors resulting in continued tumour growth in the majority of cases. Such resistance is due to abnormal Wnt/β-catenin pathway activation which triggers an accumulation of β-catenin in the nucleus of cells and therefore prevents the FOXO3a protein from inducing cell death.
Héctor G. Palmer, Principal Investigator of VHIO´s Stem Cells and Cancer Group and co-author of the study observes, “The simultaneous pharmacological inhibition of the Wnt/β-catenin and PI3K/AKT pathways reduces tumour growth”. He continues, "Using β-catenin and FOXO3a levels as predictive biomarkers of response to treatment with PI3K, AKT, and Wnt/β-catenin inhibitors represents an important first step in potentiating therapy against this type of cancer".
Since high levels of nuclear β-catenin block FOXO3a activity the use of PI3K/AKT inhibitors in colorectal cancer patients may also cause the treated cells to escape and produce metastases. Due to the vast complexity of colorectal cancer, this tumor type currently ranks third in the leading causes of death by cancer worldwide, with some 1,400,000 cases per year according to figures reported by the World Health Organization (WHO).
To study the novel Wnt/β-catenin pathway inhibitor, a tankyrase inhibitor, cell cultures were used and patient-derived tumour cells were injected into experimental laboratory mice. These so-called "xenopatient" animal models are optimal since they faithfully recapitulate human disease by preserving the same original genetic and clinicopathological alterations of each patient. The study showed that the simultaneous inhibition of the Wnt/β-catenin and PI3K/AKT signal prevents resistance to these pathways and halts tumour growth. In addition, a surprise effect was observed; in some colorectal tumours, it is enough to simply inhibit the Wnt pathway in order to decelerate cancer growth.
Research into the Wnt/β-catenin signalling pathway is nothing new – it has been the focus of intense study for many years. Despite such exhaustive efforts, the first effective drugs for blocking the oncogenic activity of this pathway were only designed five years ago. Palmer's group´s pioneering research into better understanding of this signalling pathway in cancer is demonstrating the potential of novel anti-Wnt/β-catenin therapies as well as leading to a more precise selection of therapy to match the specificities of each patient.
In parallel, clinical studies at VHIO are currently underway to establish the toxicity and efficacy of a novel Wnt/β-catenin pathway inhibitor drug. The results obtained from this present research represent a catalyst for future clinical trials using this promising anti-cancer therapy.
Photo: VHIO´s Stem Cells & Cancer Group
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