R01CA263806

Targeting P38/JNK MAPK to ameliorate cisplatin-induced adverse sequelae on the nervous system - 1
Chemotherapy-related cognitive impairment (CRCI, chemo brain), chemotherapy-induced peripheral neuropathy 2 (CIPN), and gait changes are debilitating side-effects of cancer treatment with platinum agents (e.g., cisplatin), 3 taxanes, and vinca alkaloids.
Cisplatin is widely used as a chemotherapeutic agent to treat ovarian malignancies. 4
Over 70% of women report experiencing CRCI, CIPN, and/or falls during treatment or after completion, impairing 5 their quality of life.
These neurotoxic impairments can also compromise treatment with cisplatin, influencing 6 disease progression.
Currently, there are no FDA-approved clinical interventions for the treatment of CRCI and 7 CIPN.
Mechanistically, cisplatin-induced neuronal toxicity derives from nuclear and mitochondrial DNA damage, 8 and oxidative stress, which induce the activation of the mitogen-activated protein kinases (MAPK), P38MAPK 9 and C-JUN N-TERMINAL KINASE (JNK), leading to neuronal apoptosis.
Our preliminary data show that in vitro 10 pharmacological inhibition with small molecule inhibitors, i.e., NEFLAMAPIMOD for P38MAPK and SP600125 for 11 JNK, prevents cisplatin-induced reduction in dendritic spine branching and density.
Based on these data, we 12 hypothesize that inhibition of the P38MAPK/JNK pathways will prevent cisplatin-induced neuronal 13 apoptosis and damage, leading to attenuation of cognitive impairments, gait changes, and neuropathic 14 pain associated with CRCI and CIPN.
In this project, we propose to determine if: (1) cisplatin-induced P38 15 MAPK/JNK signaling underlies structural and functional neuronal damage, using in vitro pharmacological 16 inhibition and siRNA silencing; (2) NEFLAMAPIMOD and SP600125 prevent cisplatin-induced neuropathy and gait 17 alterations in the ID8 syngeneic epithelial ovarian cancer in C57BL/6 mice and the transgenic breast cancer 18 model C3TAG in FVBN mice; and (3) cisplatin-induced neurotoxicity is attenuated by P38MAPK/JNK inhibition 19 without compromising its anti-cancer activity.
Our approach includes in vitro analysis of 2 separate neuronal cell 20 lines, behavioral analysis using sensory testing for CIPN, testing of cognitive impairment, and novel 21 MouseWalker for gait changes in female mice using the two mouse cancer models.
The proposed studies will 22 demonstrate the role of the P38MAPK and JNK in cisplatin-induced CRCI/CIPN and translational potential for 23 novel strategies to treat CRCI and CIPN.
Due to health disparities, women suffer more disproportionately from 24 cancer and pain-related treatment than men.
Therefore, testing our hypothesis in female mice is expected to 25 significantly advance the understanding and treatment of cisplatin-induced neurotoxic side effects and improve 26 the quality of life for women with cancer.
Nevertheless, we expect that these findings may also apply to cisplatin- 27 induced neurotoxicity in males and to other cancers than ovarian and breast cancers. 28

Irvine University Of California

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

California United States

State-Wide

Clinical Characterization of Cancer Therapy-induced Adverse Sequelae and Mechanism-based Interventional Strategies (R01 Clinical Trial Optional) (PAR-19-325)

Amendment Since initial award the total obligations have increased 415% from $634,722 to $3,270,548.