With a pair of RO1 grants from the National Institutes of Health, pain researcher Daniela Salvemini, Ph.D., will embark on two new research projects, studying chemotherapy-induced cognitive impairment, or "chemo brain," symptoms and unwanted side effects of opioids.
Salvemini, who is professor of pharmacology and physiology at Saint Louis University, has spent her career attempting to understand how pain happens in the body, including chronic pain, cancer pain and chemotherapy-induced pain. She studies pain pathways, the series of interactions between molecular-level components, to understand how pain occurs in order to develop new treatments.
With these awards, Salvemini will expand her work to seek answers to urgent questions surrounding pain and cancer drugs.
Chemotherapy-induced cognitive impairment, or "chemo-brain"
A $2,814,902 grant will allow Salvemini to study a common, debilitating side-effect of chemotherapy called chemotherapy-induced cognitive impairment. She is joined by co-investigators Timothy Doyle, Ph.D., Grant R. Kolar, Ph.D., and Susan Farr, Ph.D. from SLU as well as Jacoba (Cobi) Heijnen, Ph.D., and her team at MD Anderson Cancer Center.
Advances in cancer treatment have led to a sharp increase in the number of cancer survivors, reaching nearly 15 million people in the United States alone. However, in many cases, cancer treatment is associated with severe neurotoxic side effects that not only can disrupt social, educational and occupational functioning, but also decrease survival by interfering with adherence to medication and healthy behavior.
Chemotherapy-induced cognitive impairment (CICI), sometimes called "chemo-brain," is a major neurotoxic side effect of platinum-based (such as cisplatin) and anthracyclins (such as doxorubicin) chemotherapy drugs that are widely used as part of standard treatment for numerous cancers, including head and neck, testicular, colon, breast, ovarian and non-small cell lung cancers.
CICI is characterized by subtle to moderate cognitive deficits that include decreases in processing speed, memory, executive functioning and attention - side effects which can dramatically impact quality of life for patients, with symptoms persisting well after exposure. With nearly 40 percent of adults projected to be diagnosed with cancer in their lifetime and with CICI rates that are greater 50 percent in cancer patients and survivors, CICI represents a growing public health concern.
Little is known about the mechanisms underlying CICI, and there are no FDA-approved drugs to prevent or cure the condition.
"It is imperative that we understand the underlying causes of this serious adverse drug reaction and identify novel therapeutic approaches with the potential for rapid translation to the clinic," Salvemini said.
In previous work, Salvemini and her team found that chemotherapy dysregulates endogenous adenosine signaling at one of its receptors, A3AR, leading to neuroinflammatory processes and mitochondrial dysfunction in the central nervous system that contribute to the development and continuation of cognitive impairment.
This grant will explore the use of highly selective A3AR agonists - chemicals that activate the nuclear receptor - as a therapeutic approach to mitigate chemo-brain, providing new molecular insights that will advance our understanding of how chemo-brain occurs.
The researchers also hope their study will show whether CICI can be reversed or turned down once symptoms have appeared by turning on the A3AR receptor. This finding would offer hope that cognitive function could be restored in those cancer survivors who have been already developed CICI.
The team expects that this work will lead to expedited "proof-of-concept" studies, opening the door to a new translational effort in the treatment of chemo-brain to find solutions for this highly unmet medical need.
"We hope that the combination of an A3AR agonist with chemo will prevent dose limiting toxicities, therefore enabling the patient to undergo their full cycle of chemo," Salvemini said. "More excitingly, we hope that we can reverse the toxicity that has already established thus making a big difference to the quality of life of patients who are cancer free but who are still affected by CICI.
"Imagine patients being able to lead normal lives, putting a shirt or a sock on without feeling pain or the ability to perform a simple daily task because their cognitive impairment is improved or at least not worsened. This is our mission: to make an impact on human suffering. I have dedicated over 25 years to this and I am more motivated than ever.
"I am so grateful to my collaborators and team for their dedication to these efforts."
Opioids and Pain, Tolerance and Dependence
A $1,722,666 NIH grant will allow Salvemini to study another alarming problem: opioid pain killers that are capable of quelling terrible pain also carry debilitating side effects and significant risk of addiction. She is joined by co-investigators who include Timothy Doyle, Ph.D. and Grant R. Kolar, Ph.D., from SLU as well as Todd Vanderah, Ph.D., and his team at the University of Arizona.
This pain problem sets up a discouraging dilemma for patients and doctors. Opioid pain killers, like hydrocodone and morphine, can ease unbearable pain for those who are suffering. The price, however, can be side effects like nausea, vomiting, drowsiness or sedation, and psychological effects like euphoria, hallucinations or delirium. They also can lead to addiction and cause withdrawal symptoms once halted.
As she searches for new ways to mitigate the side effects of these drugs while preserving their pain killing ability, Salvemini will build on previous work that studied alterations in sphingolipid signaling in the brain.
Salvemini found that these alterations cause the development of several opioid side effects, including pain caused by the chronic use of opioids, called opioid-induced hyperalgesia (OIH), and tolerance, which happens when opioids lose their effects over time, called antinociceptive tolerance, which can lead to increased doses which in turn can contribute to dependence.
Salvemini and her team have identified the molecular cause that drives these unwanted opioid effects. With this grant, they will explore the mechanisms at the cellular and molecular levels that cause OIH, tolerance and dependence.
Salvemini hopes this work will lead to a drug that could be taken together with opioids.
"The idea is to combine a drug that blocks sphingolipid signaling with opioids in order to preserve opioids' pain-killing properties, but minus their side effects," Salvemini said.
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