The most commonly used medications for osteoporosis worldwide, bisphosphonates, may also prevent certain kinds of lung, breast, and colon cancers, according to two studies published in the Proceedings of the National Academy of Sciences (PNAS; 2014; doi:10.1073/pnas.1421422111 and doi:10.1073/pnas.1421410111).
Bisphosphonates had been associated by past studies with slowed tumor growth in some patients but not others, and the mechanism behind these patterns was unknown. In these studies, the research team, led by researchers at the Icahn School of Medicine at Mount Sinai in New York, New York, showed that bisphosphonates block the abnormal growth signals passed through the human epidermal growth factor receptors (HER), including the forms of this protein family that make some tumors resistant to leading treatments.
The connection between bisphosphonates and HER receptors was detected first in a genetic database analysis and confirmed in studies of human cancer cells and in mice.
“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,” said 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, and a member of the Tisch Cancer Institute at Mount Sinai.
“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.”
The first study described evidence that bisphosphonates block abnormal growth signals through HER family receptors. Its results revolved around the HER/EGFR family, which consists of four types of transmembrane tyrosine kinase receptors: HER1, HER2, HER3, and HER4. HER family members occur on the surfaces of many cell types and regulate cell division and proliferation, processes closely linked to both normal tissue growth and the abnormal growth seen in cancer.
The second study examined the potential applications for this new mechanism: cancer prevention, combination with existing treatments, and use against treatment-resistant tumors.
Having seen that some people taking bisphosphonates have lower incidence of several cancers, the study authors analyzed the genes that become more or less active when a patient takes these medications using the Connectivity Map (cmap).
Combining bisphosphonates with the tyrosine kinase inhibitor not only stopped tumor growth in mice, but reversed it. In contrast, mice with colon cancer cells that do not signal for growth using HER receptors remained insensitive to bisphosphonate action.
“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,” said Zaidi. “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 nontraditional funding source, perhaps the federal government.”