SLU investigator aims to reduce chemotherapy-induced peripheral neuropathy

Saint Louis UniversityFeb 27 2012

A Saint Louis University investigator noted for her pain research is working to reduce a painful chemotherapy side effect, thanks to a $126,500 grant from the Mayday Fund, an organization dedicated to alleviating the incidence, degree and consequence of human physical pain. Researchers believe that a solution to the problem of chemotherapy-induced peripheral neuropathy (CIPN) not only would dramatically improve quality of life for sufferers, but also would save lives by allowing cancer treatment to continue at optimal levels.

Daniela Salvemini, Ph.D., associate professor of pharmacological and physiological science at SLU, will examine the way in which two particular molecules are involved in the development of pain caused by chemotherapy drugs. Salvemini's work lays the groundwork to manage or prevent CIPN and to develop new therapies to eliminate or limit symptoms. CIPN is one of most common causes of dose reduction and discontinuation of what is otherwise a life-saving therapy.

Chemotherapy-induced peripheral neuropathy is a side effect experienced by many who are taking anti-tumor chemotherapy drugs. It can appear as tingling or numbness in the hands and feet, shooting or burning pain in the limbs, or can feel like hot or cold temperature extremes. Symptoms may resolve within weeks or months of stopping the chemotherapy treatment or may last for years.

Accompanied by chronic neuropathic pain, CIPN is an effect of widely used antitumoral agents in several classes of drugs, including the taxane (e.g., paclitaxel), platinum-complex (e.g., oxaliplatin), vinca alkaloids (e.g., vincristine) and proteasome-inhibitor (e.g., bortezomib) classes. Because oncologists may be forced to limit doses to manage side effects, CIPN reduces the success of chemotherapy drugs. The pain also can cause psychological distress, fatigue, sleep disorders, cognitive deficit and diminished activity, all of which decrease quality of life for patients under treatment, as well as those in remission.

"Until recently, we haven't had a strong understanding of how anti-tumor drugs are causing this pain, and so we haven't been able to develop effective therapies to stop it," Salvemini said. "Now, however, we have discovered that two critical pathways are involved in the development of chemotherapy induced pain, the peroxynitrite pathway and the ceramide to sphingosine-1- metabolic pathway."

Blocking CIPN may allow for more lives to be saved by permitting the administration of larger, potentially more effective doses of cytotoxic drugs to cancer patients. Furthermore, the impact on quality of life would be enormous, says Salvemini.

The ability to reduce or eliminate this symptom amongst cancer survivors also would lower the huge costs associated with narcotic and neuropathic medication needed to manage the chronic pain. In addition, many patients with CIPN are unable to work because they cannot drive a vehicle or they suffer the side effects of drugs needed to control the symptoms, which can impede their judgment and occupational performance. For this reason, work place productivity would be improved, as well.

In past research, Salvemini discovered peroxynitrite, a molecule that is very important in the development of pain and inflammation. More recently, she and her colleagues found that both peroxynitrite and sphingolipids such as sphingosine-1-phosphate are involved in the development of pain caused by common chemotherapy drugs, including paclitaxel, oxaliplatin and bortezomib.

Now, funded by the Mayday grant, Salvemini will study the two molecules to see if they can be used as biomarkers for CIPN. A biomarker, the term for any substance that can be measured to determine a particular biological state, would allow doctors to know when to begin and discontinue drugs for CIPN pain. In effect, the molecules would serve as an objective measuring tool.

"Because the pain can be so debilitating, many patients are treated with chronic pain medications, like neurontin and narcotics," Salvemini said. "One of the most useful aspects of a reliable biomarker is that it would allow doctors to initiate an intervention before the symptoms develop and to continue it until the patient no longer needs it."

Perhaps more importantly, though, is the potential to target peroxynitrite and sphingosine-1-phosphate as a way to develop new therapies. If researchers can block the production, metabolism or actions of these two molecules, Salvemini theorizes, with some evidence from her earlier research, the pain may be halted, as well.

Should initial stages of the current study prove successful, Salvemini will conduct a proof-of-concept study in partnership with the Saint Louis University Cancer Center.

"This is a serious clinical problem because it significantly reduces the quality of life of affected patients and limits further use of the chemotherapy drugs which have this side effect," said Friedrich Schuening M.D., director of hematology and oncology at Saint Louis University Cancer Center. "If this side effect could be prevented or at least delayed, this would allow continued use of otherwise effective chemotherapy and improve quality of life."

Because anti- sphingosine-1-phosphate therapies are already clinically available, this research has the potential of making a significant impact in alleviating human suffering soon, Salvemini says.