Chemotherapy-induced peripheral neuropathy (CIPN) is one of the major causes for dose reduction and treatment cessation. CIPN is mainly reported in the hands and feet and includes both persistent pain and sensory loss (numbness). In 25%–30% of affected patients, CIPN does not resolve after completion of cancer treatment. Damage to peripheral nerves, loss of intra-epidermal nerve fibers, and sensitization of remaining fibers are thought to be at the origin of the numbness, tingling, and pain that are characteristic of CIPN.
There is critical need for development of novel mechanism-based interventions to prevent and treat CIPN, as no FDA-approved treatment exists for this condition.
Current CIPN Studies
Principal Investigators: Heijnen and Dantzer ● Funding: NIH R21
Damage to mitochondria in peripheral sensory neurons contributes to mechanical allodynia in rodent models of chemotherapy-induced peripheral neuropathy. Chemotherapeutic agents induce structurally abnormal, swollen, and vacuolated mitochondria in axons and cell bodies of peripheral nerves. These structural abnormalities are associated with functional deficits, including impaired respiration and reduced ATP production. Such mitochondrial dysfunction results in oxidative stress that further aggravates neural damage.
We have reported that protecting mitochondrial integrity prevents neuronal loss in a model of ischemic brain damage. Protection of brain mitochondria was achieved using compounds that prevent mitochondrial accumulation of p53 and/or activation of mitochondrial JNK, thereby maintaining ATP production and reducing oxidative stress.
Using in vivo and in vitro approaches, we are now testing the hypothesis that targeting these pathways also prevents chemotherapy-induced neuronal damage and neuropathic pain.
Principal Investigators: Kavelaars, Heijnen
The aim of this project is to determine the contribution of peripheral T cells to chemotherapy-induced peripheral neuropathy (CIPN). Our hypothesis is that peripheral immune cells, and in particular T cells, contribute to CIPN through infiltration into dorsal root ganglia, where these cells promote resolution from CIPN. Using RAG1 knockout mice and transplantation of a specific subset of T cells, we are investigating the contribution of these cells to development of and recovery from CIPN.
Preliminary data indicate a key role for local production of the anti-inflammatory cytokine interleukin (IL)-10. We are now investigating the source and target of IL-10 and how T cells regulate IL-10 production in the spinal cord and/or dorsal root ganglia of mice with CIPN.
Principal Investigators: Heijnen, Kavelaars ● Funding: Acetylon Pharmaceuticals
HDAC6 is cytoplasmic deacetylase with a substrate specificity for non-histone proteins. HDAC6 has been described as influencing multiple intracellular processes, such as deacetylation of tau, transport of ubiquinated proteins to the aggressome, mitochondrial axonal transport, and cell spreading and motility.
In this project, we are examining the effect of an HDAC6 inhibitor and its underlying mechanisms in a mouse model of cisplatin-induced neuropathy.
Principal Investigator: Kavelaars ● Funding: NIH R01
The long-term goal of this project is to investigate the mechanism via which G protein-coupled receptor kinase 2 (GRK2) and its downstream molecular pathways prevent transition from acute to chronic pain. We have shown that low-nociceptor GRK2 causes transition from acute to chronic pain and that this is associated with a switch in cAMP signaling from a PKA-mediated pathway to an Epac1-mediated pathway. We are now aiming at investigating the molecular mechanisms via which GRK2 regulates cAMP to Epac1 signaling.
In addition, we are investigating the changes in the nociceptor that occur in response to Epac1 activation during the transition to chronic pain. In this project we are applying molecular, biochemical, and in vivo studies.
Principal Investigators: Kavelaars, Dantzer, Kelley ● Funding: NIH R01
The goal of this project is to determine the biological basis underlying comorbid pain and depression. This knowledge is crucial for the development of novel therapeutic strategies.
We have demonstrated that activation of indoleamine 2, 3 dioxygenase and a downstream enzyme in the same pathway, KMO, is necessary for the development of depression-like behavior, but not pain, in a murine model of nerve injury. We have also identified key roles for peripheral macrophages and interleukin-10 production in resolution of pain, and we are investigating their roles in depression-like behavior. We are also investigating the role of the adaptive immune system, and in particular T cells, in recovery from pain and depression.