Targeting p38/JNK MAPK to ameliorate cisplatin-induced adverse sequelae on the nervous system

Chemotherapy-related cognitive impairment (CRCI, chemobrain), chemotherapy-induced peripheral neuropathy
(CIPN) and gait changes are debilitating side-effects of cancer treatment with platinum agents (e.g., cisplatin),
taxanes, and vinca alkaloids. Cisplatin is widely used as a chemotherapeutic agent to treat ovarian malignancies.
Over 70% of women report experiencing CRCI, CIPN and/or falls during treatment or after completion, impairing
their quality of life. These neurotoxic impairments can also compromise treatment with cisplatin, influencing
disease progression. Currently, there are no FDA-approved clinical interventions for the treatment of CRCI and
CIPN. Mechanistically, cisplatin-induced neuronal toxicity derives from nuclear and mitochondrial DNA damage,
and oxidative stress, which induce the activation of the mitogen-activated protein kinases (MAPK), p38MAPK
and c-Jun N-terminal kinase (JNK), leading to neuronal apoptosis. Our preliminary data show that in vitro
pharmacological inhibition with small molecule inhibitors, i.e., neflamapimod for p38MAPK and SP600125 for
JNK, prevents cisplatin-induced reduction in dendritic spine branching and density. Based on these data, we
hypothesize that inhibition of the p38MAPK/JNK pathways will prevent cisplatin-induced neuronal
apoptosis and damage, leading to attenuation of cognitive impairments, gait changes, and neuropathic
pain associated with CRCI and CIPN. In this project, we propose to determine if: (1) cisplatin-induced p38
MAPK/JNK signaling underlies structural and functional neuronal damage, using in vitro pharmacological
inhibition and siRNA silencing; (2) neflamapimod and SP600125 prevent cisplatin-induced neuropathy and gait
alterations in the ID8 syngeneic epithelial ovarian cancer in C57BL/6 mice and the transgenic breast cancer
model C3TAg in FVBN mice; and (3) cisplatin-induced neurotoxicity is attenuated by p38MAPK/JNK inhibition
without compromising its anti-cancer activity. Our Approach includes in vitro analysis of 2 separate neuronal cell
lines, behavioral analysis using sensory testing for CIPN, testing of cognitive impairment, and novel
MouseWalker for gait changes in female mice using the two mouse cancer models. The proposed studies will
demonstrate the role of the p38MAPK and JNK in cisplatin induced CRCI/CIPN, and translational potential for
novel strategies to treat CRCI and CIPN. Due to health disparities, women suffer more disproportionately from
cancer and pain-related treatment than men. Therefore, testing our hypothesis in female mice is expected to
significantly advance the understanding and treatment of cisplatin-induced neurotoxic side effects and improve
the quality of life for women with cancer. Nevertheless, we expect that these findings may also apply to cisplatin-
induced neurotoxicity in males and to other cancers than ovarian and breast cancers.

Grant Number: 3R01CA263806-05S2
NIH Institute/Center: NIH
Principal Investigator: Daniela Bota