According to the researchers, if their Phase II clinicaltrial efforts prove successful, their findings could have a game-changingimpact on the way we treat prostate cancer and potentially otherdifficult-to-treat types of cancer.
Prostate cancer, which is the second-most frequentlydiagnosed cancer and the sixth-leading cause of cancer death in men worldwide,is in most cases slow-growing and symptom-free, and often metastasizes from theprostate to other parts of the body, particularly the bones and lymph nodes.Depending on a patient's age and overall health, stage of disease and geneticfactors, treatment options are radiation therapy and/or a
radical prostatectomy.
In 2009, Queens University scientists Drs. Robert Siemensand Charles Graham published the results of the first-ever clinical trial inwhich low doses of nitroglycerin were used to treat prostate cancer. The studyshowed that nitric oxide-mimicking agents such as nitroglycerin were effectivein overcoming cancer cells' resistance to immune attack. This initial studyalso showed that the use of nitroglycerin significantly slowed the progressionof the disease in men with recurrence after their original treatment.
Now, Siemens and Graham, who work for the university'sDepartment of Biomedical and Molecular Sciences, hope to build on their earlierwork by conducting a Phase II trial that will specifically study theeffectiveness of nitroglycerin on prostate cancer.
Nitroglycerin is converted to nitric oxide in the body bymitochondrial aldehyde dehydrogenase, and nitric oxide is a naturalvasodilator.
"In many ways, nitric oxide behaves like oxygen," explainsGraham. "We have been interested in studying hypoxia and how low levels ofoxygen contributes to the malignant progression of tumor cells, metastasis andtherapy resistance. If you put oxygen back into this equation, you can stop thismalignant behavior. We came up with a new concept in which nitric oxideinterferes with the way that tumor cells interfere with cell signaling."
The researchers are currently recruiting 60 patients withprostate cancer to participate in a randomized, double-blind,placebo-controlled trial. Graham says prostate cancer is a good choice forstudying the effects of nitroglycerin because the only indication the diseaseis recurring is a patient's level of prostate-specific antigen (PSA), a proteinproduced by cells of the prostate gland.
"Other than that, there are no other overt signs ofdisease," says Graham. "For that reason, these patients don't get any otherkind of therapy. This makes them an ideal group to look at. By comparison, inbreast cancer, for example, patients are usually treated aggressively."
In the study, which will be conducted at the Centre forApplied Urological Research at Queen's University, some patients will get aplacebo patch; some will get a low-dose nitroglycerin patch; and another groupwill get a higher-dose nitroglycerin patch. Fourteen patents have been issuedto Queen's research discoveries in the use of nitroglycerin and similarcompounds for the treatment of cancer. PARTEQ Innovations, the technologytransfer office of Queen's, has already licensed some of this intellectualproperty to Nometics Inc., a spinoff pharmaceutical company that is developingproducts and therapies based on this and related research.
"For the next phase of the clinical trials, we hope to havea commercially made patch with the right dose," says Graham.
The findings could have applications for other conditions,including pregnancy complications and inflammatory diseases. Graham adds thatnitroglycerin also has a high safety profile, "and the main side effect is aheadache."
Graham concedes that using a century-old, inexpensive drugto treat prostate cancer and other diseases is "not a blockbuster enterprise,"but he notes, "there are so many men in this situation that can benefit fromthis treatment. If we can come up with something that is an alternative toaggressive therapies, this will give them better quality of life."
"The problem with Big Pharma is they are often notinterested in finding new uses for old drugs because their business model isbased on creating new blockbuster drugs," he says. "But even thoughnitroglycerin is inexpensive, we think that by producing a lot of thesepatches, there is opportunity for profit."
The study is being funded by Ontario's Academic HealthScience Centre Alternative Funding Plan Innovation Fund, with additionalsupport from Nometics. The ongoing preclinical research that led to this studyis funded by the Canadian Institutes of Health Research.
