Two studies from Icahn School of Medicine at Mount Sinai researchers, published in the Proceedings of the National Academy of Sciences (PNAS), have shown that drugs commonly used to treat osteoporosis, bisphosphonates, can also prevent certain types of cancers, including lung cancer.
Previous studies had already linked bisphosphonates to decreased tumor growth, however the reason behind this observation was unknown.
These two new studies show that bisphosphonates are able to stop growth signals sent via EGF receptors (HER), including mutant forms of this protein that can render some cancers resistant to common therapies.
“Our study reveals a newfound mechanism that may enable the use of bisphosphonates in the future treatment and prevention of the many lung, breast and colon cancers driven by the HER family of receptors,” lead study author Mone Zaidi, MD, Professor of Medicine and of Structural and Chemical Biology within the Icahn School of Medicine at Mount Sinai, Director of the Mount Sinai Bone Program, said in a press release. “Having already been approved by the FDA as effective at preventing bone loss, and having a long track record of safety, these drugs could be quickly applied to cancer if we can confirm in clinical trials that this drug class also reduces cancer growth in people. It would be much more efficient than starting drug design from scratch.”
In the study titled “Bisphosphonates inactivate human EGFRs to exert antitumor actions”, the team observed that bisphosphonates were able to block abnormal growth signals via the human epidermal growth factor receptor (HER/EGFR) family. Proteins from the HER family are present on the surface of different types of cells and have the capacity to regulate cellular proliferation, which is a fundamental event in the excessive growth associated with tumor progression.
A big percentage of non-small cell lung cancers (30%) are driven by genetic changes in the HER1 receptor, which results in an intensive abnormal growth.
Dr. Zaidi and his team found that bisphosphonates could attach themselves to the kinase domains of HER proteins, blocking growth signals. This seems to be the reason why tyrosine kinase inhibitors, such as trastuzumab, erlotinib and gefitinib have significantly improved cancer patients’ survival. However, therapy longer than 3 years usually results in resistance to these drugs.
In the second study, titled “Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer”, the team analyzed the genetic profile of patients upon bisphosphonate therapy, registering which genes become more or less activated. Using the Connectivity Map (cmap), a database developed by The Broad Institute at MIT, researchers were able to understand the connections between drugs, diseases and genes.
The team was able to discover a link between bisphosphonates and the HER receptor, therefore designing experimental procedures to validate the potential of treating HER-driven cancers with bisphosphonates alone or as an adjuvant with the tyrosine kinase inhibitor iritinib.
The results showed that early bisphosphonate treatment (in mice models) prevented the development of HER-driven tumors. Additionally, combination therapy managed to stop tumor growth and ultimately reverse it.
“While this finding is exciting, there is no business model for conducting the costly clinical trials that would be needed to repurpose bisphosphonates for cancer,” Dr. Zaidi explained. “Pharmaceutical companies are unlikely to pay for research to develop generic drugs where there is no chance of patent protection or profit, so we will be looking for a non-traditional funding source, perhaps the federal government.”
