A drug used to treat bone disease and high blood calcium levels may carry benefits as part of a combination treatment for malignant pleural mesothelioma, a recent study concluded.
Researchers at the University of Alabama at Birmingham Comprehensive Cancer Center conducted a pilot study testing the effects of zoledronic acid — a bisphosphonate, or bone health drug, marketed as Reclast and Zometa — against a small group of patients with unresectable pleural mesothelioma.
The study, published in the June edition of Lung Cancer: Targets and Therapy journal, was a follow-up to preclinical research showing zoledronic acid’s antiangiogenic (substances that inhibit growth of new blood vessels) effect on mesothelioma cancer cells in vitro.
In the pilot study, zoledronic acid only showed a modest effect as a stand-alone therapy for patients with advanced pleural mesothelioma, with a composite response rate of 12.5 percent and a clinical benefit rate (response and stability of the disease) of 37.5 percent.
However, researchers believe the results warrant further investigation of the bone disease drug as a combination therapy for mesothelioma.
“Our findings suggest that zoledronic acid has single-agent activity in [malignant pleural mesothelioma] treatment,” lead author Muhammad Omer Jamil wrote in the study. “Zoledronic acid can mitigate angiogenesis at subcellular level by mevalonate pathway inhibition and is beneficial in antitumor therapy.”
How Bisphosphonates Inhibit Mesothelioma Cell Growth
Doctors have used bisphosphonates to treat osteoporosis and other bone conditions for decades, but the potential cancer-inhibiting effects of the drugs continue to be investigated.
Nitrogen-containing bisphosphonates, such as zoledronic acid, are known to effectively inhibit malignant pleural mesothelioma (MPM) tumor growth in vitro and in lab mice.
UAB researchers believe the drugs do this by inhibiting a linked series of chemical reactions known as the mevalonate pathway. Zoledronic acid also reduces experimental malignant pleural effusions.
“It demonstrates antiangiogenic effects and suppresses vascular endothelial growth factor (VEGF) blood levels,” Jamil wrote. “VEGF levels have been associated with MPM progression and poor survival in relation to high tumor microvessel density.”
Glycoproteins, such as mesothelin and osteopontin, are overexpressed in mesothelioma cancer cells and are associated with tumor progression.
“Our study reports that mesothelin and osteopontin levels decline in patients who have favorable therapy response and potentially may represent promising biomarkers of this disease,” Jamil wrote.
Currently, mesothelin is not used as a biomarker for mesothelioma diagnosis because of low sensitivity. Emerging immunotherapy drugs aim to target mesothelin.
The Need for Novel Approaches
Mesothelioma is a rare cancer with limited treatment options.
Patients receiving the standard chemotherapy combination of pemetrexed (Alimta) and cisplatin have a median overall survival of just over a year and a median time to progression of 5.7 months.
Researchers across the country are striving to find the best complimentary therapies or new stand-alone treatments to improve mesothelioma survival. These include clinical trials involving immunotherapy drugs, such as pembrolizumab (Keytruda), and immune suppression drugs such as fingolimod (FTY720).
The UAB study involved eight male patients with progressed pleural mesothelioma in three categories:
- Previously received one or more systemic therapies
- No prior therapy because of poor performance status, a score that estimates the patient’s ability to perform certain daily activities
- Those unwilling to receive systemic chemotherapy
The majority of patients had epithelioid mesothelioma, the most common cell type of the asbestos-related cancer. Only two patients reported a history of asbestos exposure.
Although the zoledronic acid study showed modest results, Dr. Francisco Robert of UAB’s division of hematology and oncology believes there are other treatment approaches that should take precedence.
“My feeling is that there are other exciting trials in mesothelioma, such as immunotherapy with checkpoint inhibitors with or without chemotherapy, antiangiogenic-based therapies, immune conjugates with anti-mesothelin, etc., that have priority in the clinical research for mesothelioma,” Robert told Asbestos.com. “At present, we do not have a plan to expand our study.”