Zoledronic acid was only modestly active as a stand-alone therapy for advanced malignant pleural mesothelioma in a small Phase 2 pilot clinical trial.
But researchers argue that its properties make it a suitable candidate for combo treatments of cancer, and called for further studies.
The research, “A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural Mesothelioma,” was published in the journal Lung Cancer: Targets and Therapy.
In their search for compounds that could extend mesothelioma patients’ survival, researchers at the University of Alabama at Birmingham homed in on a class of drugs that treat osteoporosis and other bone diseases.
Some of these therapies, called nitrogen-containing bisphosphonates, have cancer-suppressing properties. Zoledronic acid — sold as Reclast or Zometa for bone disease — prevented the growth and expansion of mesothelioma in lab-grown cells and in animals.
The drug reduced pleural effusions, or build-up of fluid in the lungs, in mesothelioma animal models. It also prevented the growth of new tumor blood vessels that help expand cancer.
Researchers believe Zoledronic acid’s action on the mevalonate cell signaling pathway is what gives it its anti-cancer properties. The energy-creating pathway is essential for cell growth and differentiation, and Zoledronic can inhibit a key enzyme in that process.
The Phase 2 clinical trial (NCT01204203) involved mesothelioma patients whose disease progressed after chemotherapy or whose condition was too poor to receive standard treatment.
The eight men in the study received intravenous infusions of Zoledronic acid. Researchers’ first assessment was that two men’s disease had become stable after treatment — the best results in the group. One of the two had a stable disease for 21 months.
When the team used positron emission tomography (PET) imaging to assess response, they discovered that one of the patients they had classified as having a stable disease had actually done better, achieving a partial response to treatment. PET imaging also showed that a patient initially classified as having a disease that was progressing actually had a stable disease.
The mean time between treatment and mesothelioma progressing was two months, with the range two to 21 months. Patients lived a median of seven months after treatment, with the range 24 days to 28 months.
Researchers also measured a number of factors in patients’ blood. One finding was that patients who failed to respond to Zoledronic acid had higher levels of VEGF and osteopontin before treatment began. Another was that those who responded or achieved a stable disease had lower levels of mesothelin and osteopontin after the therapy.
Zoledronic acid’s impact on cancer blood vessel formation and its low toxicity make it a possible mesothelioma therapy in combination with chemotherapy or other drugs, researchers concluded. They called for more studies to check on its effectiveness.