Assessment of efflux transport, pharmacokinetics and systems pharmacology impact on MMAE induced neurotoxicity

About This Grant

ABSTRACT Exposure to Monomethyl Auristatin E (MMAE), following antibody-drug conjugate (ADC) treatment, has been linked to neurotoxicity in approximately 50% of patients that is commonly irreversible and can have substantial impact on cancer survivor quality of life or prompt discontinuation of life-saving therapy. Therefore, the long- term goal associated with this proposal is to improve therapeutic outcome by abolishing ADC-mediated peripheral neuropathy. The overall objective of this proposal is to uncover novel signaling pathways that influence the development of MMAE-induced peripheral neuropathy, as well as assess the role membrane transporters in regulating this adverse event. The central hypothesis is that analysis of interactions following peripheral nervous system drug exposure using a network-based systems pharmacology model will reveal a combination of targets that can mitigate neurological side-effects of MMAE-based therapy, and that P-gp regulates the severity of MMAE-induced neuropathy. The rationale for this project is that identification of proteins that regulate MMAE-induced neuropathy would provide a pharmacological target to abolish a devastating adverse event or predict interpatient variability through genetic variation or drug-interactions associated with these proteins. The central hypothesis will be tested by pursuing two specific aims: i) Evaluate P-gp as a factor that regulates MMAE pharmacokinetics and disposition into peripheral nerves along with peripheral neuropathy; and ii) Identify signaling changes in peripheral nerves by MMAE using a systems pharmacology network-based model. Under the first aim, in vivo and ex vivo P-gp genetic knockout mouse models will be used to measure the ability of this transporter to modulate MMAE disposition and neuropathy. Additionally, we will evaluate the role of other transporters in regulating MMAE DRG sensitivity. Under the second aim, drug pharmacokinetics, along with signaling network changes coupled with patterns of differentially expressed genes in peripheral nerves exposed to MMAE will be used to develop a systems pharmacology network-based model. Simulations and analyses of the model will identify interventions in the network that would provide protection from MMAE neurotoxicity. The research proposed in this application is innovative because it represents a substantive departure from the status quo by measuring the involvement of a drug transporter in regulating MMAE toxicity instead of efficacy, along with establishing multiple signaling events or potential molecular targets that could predict or ameliorate this adverse event. The proposed research is significant because it is expected to identify P-gp as a transporter that is genetically variable among patients and susceptible to drug interactions, and could therefore be assessed to predict the severity of, or prevent, MMAE neurotoxicity. Additionally, our systems pharmacology model is expected to identify protein networks that can be manipulated to ameliorate this adverse event. Ultimately, such knowledge is predicted to reduce the number of patients who would experience a toxicity that can impact quality of life or become life threatening through dose reduction or cessation of cancer therapy.