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From breast cancer to lung cancer
LONDON—While drug repurposing is often seen in terms of a drug approved for one indication being used to treat a completely different condition, in the case of recent work out of London, it's a short jump from one type of cancer to another.
In a new animal study from The Institute of Cancer Research, London, and the Francis Crick Institute, a class of drugs being advanced against breast cancers presenting with EGFR mutations was found to also have activity against lung cancers with the same mutations—specifically, those in patients whose lung cancer has developed treatment resistance. The work appeared in Cell Reports in a paper titled “Disruption of the Interaction of RAS with PI 3-Kinase Induces Regression of EGFR-Mutant-Driven Lung Cancer.”
The key to this work is a protein known as p110α. When the scientists blocked this protein, tumors with EGFR mutations shrunk noticeable. Specifically, the team focused on the interaction between p110α and the RAS protein. Like EGFR, RAS is a known oncogene, and is mutated in approximately one in five cancers. When the interaction between the two proteins was blocked, the researchers saw significant tumor shrinkage.
“At the moment, patients with EGFR-mutant lung cancers are given targeted treatments that are very effective for the first few years,” said Prof. Julian Downward, who led the study. “These drugs are improving, but unfortunately after a couple of years the cancer usually becomes resistant and starts to grow and spread again. The second line of treatment is currently conventional chemotherapy, which is not targeted and has substantial side-effects.
“Our new study suggests that it would be worth investigating whether p110α inhibitors could be used as a second-line therapy. As our research is at such an early stage, more research in mice and patient cells would be needed before even considering clinical trials, but it opens up a promising avenue of investigation.”
As the authors note in their paper, “EGFR acts upstream of both RAS and PI3K in lung tumorigenesis,” controlling the activation of downstream signaling pathways such as “RAS small GTPases and the RAF-MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. RAS is critical for the activation of the RAF pathway and also contributes directly to activation of the PI3K pathway through direct binding of RAS proteins to a RAS-binding domain (RBD) in the PI3K p110 catalytic subunit.”
“This interaction is needed for normal development; when the RBD in Pik3ca, the gene encoding p110α, is mutated in the mouse germline so that it cannot bind RAS, transient defects in normal lymphatic development occur as a result of impaired VEGF-C signaling via VEGFR3. Fibroblasts derived from these mice displayed attenuated epidermal growth factor (EGF)-induced signaling to PI3K,” they continued. “Most strikingly, endogenous RAS-mutant-driven tumorigenesis in the lung and the skin is abrogated in these mice with RBD-mutant p110α (Gupta et al., 2007). Moreover, disruption of the RAS-PI3K interaction in preexisting RAS-mutant-driven lung tumors causes partial regression and long-term stabilization (Castellano et al., 2013). This effect is not entirely tumor cell autonomous, as disruption of the interaction of RAS with PI3K p110α only in host tissue also reduces tumor growth and metastasis to some extent by mechanisms that include reduced tumor-induced angiogenesis and alterations in the tumor microenvironment.”
The authors added that “This approach could be effective not only in RAS-mutant-driven cancers but also those driven by mutations in EGFR, and, by extension, possibly in tumors driven by other upstream receptor tyrosine kinases, such as MET and ALK. As the scale of the problem of drug resistance to EGFR tyrosine kinase inhibitors becomes apparent, despite their initial effectiveness, it is likely that other additional approaches will be needed to block signaling though this pathway in order to reduce the likelihood of the evolution of drug resistance.”
There is some uncertainty still about the effectiveness of PI3K inhibitors in solid tumors, they cautioned, and Julian also noted that this research is very new. More work will need to be done to fully realize its potential.
“As we wanted to pinpoint the specific interaction responsible, we used a genetic technique that would not be practical in a patient treatment,” Julian explained in a press release. “We’re looking to develop ways to do this with drugs, as blocking this specific pathway would significantly reduce side effects, but this work is many years from the clinic. In the medium-term, investigating existing drugs that inhibit p110α will be the next step. While these have side effects, including temporary diabetes-like symptoms during treatment, they are still less toxic than chemotherapy.”
In other recent news from the ICR, a team is exploring how to turn ultrasound from detecting tumors to destroying it.
The approach is known as high-intensity focused ultrasound (HIFU), and works by using the targeted sound waves of ultrasound to heat cancer cells to the point of cell death—without damaging surrounding tissue. Prof. Gail ter Haar, professor of Therapeutic Ultrasound at the ICR, is leading the research. In recent years, the work has developed to include MRI. Given HIFU's ability to destroy cells, the HIFU beam needs to be very tightly targeted on cancer cells to avoid damaging healthy cells, but early HIFU machines couldn't operate the beam and use ultrasound imaging to guide it at the same time. ter Haar linked up with Prof. Nandita de Souza, Professor of Translational Imaging at the ICR and lead academic radiologist at the ICR and The Royal Marsden NHS Foundation Trust, in 2004 to adapt an MRI machine for HIFU.
Early use in late-stage cancer patients with bone metastases demonstrated proof of concept, and de Souza is now recruiting patients with recurrent gynecological cancer for a new trial.
“We’ve treated six patients so far, and we’ve already had some good results,” de Souza noted. “I’m hopeful the trial will show that HIFU can improve these patients’ quality of life.”