Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with anticancer treatment which can lead to early discontinuation of therapy and/or severely affect quality of life. Little is known about the mechanisms responsible for CIPN, and despite many CIPN therapeutic clinical trials, no standard evidence-based treatment exists. Excessive glutamate transmission has been implicated in the pathogenesis of peripheral neuropathy and neuropathic pain. Inhibition of the glial enzyme glutamate carboxypeptidase II (GCPII) has been shown to selectively dampen excessive glutamate transmission and alleviate neuropathic pain and protect peripheral nerves from the functional and histological deficits induced by chemotherapeutic agents. Based on these data, an orally bioavailable, thiol-based GCPII inhibitor was taken into clinical studies. Although the inhibitor was well-tolerated in Phase 1, subsequent immunological toxicities observed in GLP primate studies halted its development. Importantly the toxicity was not due to the GCPII mechanism, but rather due to the thiol moiety in the compound. As a class, thiol drugs have a risk of inducing hypersensitivity reactions. We now outline an iterative drug discovery plan to identify clinically viable non thiol GCPII inhibitors to test the hypothesis that this mechanism will provide therapeutic benefit to CIPN patients. Our iterative drug discovery plan includes a systematic zinc binding group replacement strategy, extensive in vitro drug-ability assessments, drug metabolism, in vivo pharmacokinetics, biomarker strategies, and evaluation of compounds in paclitaxel- and oxaliplatin-induced neuropathy and nerve crush efficacy experiments. Active compounds emerging from these efforts will be ready for IND enabling studies and ultimately clinical investigation in CIPN patients.

Public Health Relevance

Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and common side effect of chemotherapy treatment rated by cancer survivors as one of the most disabling. Little is known about the mechanisms responsible for CIPN, and despite many CIPN therapeutic clinical trials, no standard evidence-based treatment exists. In several animal models, inhibitors of the glial enzyme glutamate carboxypeptidase II (GCPII) have been shown to protect peripheral nerves from chemotherapy-induced injury and prevent neuropathic pain symptoms, without affecting chemotherapy efficacy. We propose to synthesize potent, selective, orally available, and tissue penetrable GCPII inhibitors that when dosed concurrently with chemotherapy will attenuate CIPN severity. Drugs emerging from these efforts will be ready for IND enabling studies and ultimately clinical investigation in CIPN patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA161056-02
Application #
8468134
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (91))
Program Officer
Alley, Michael C
Project Start
2012-05-09
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$342,087
Indirect Cost
$130,922
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Majer, Pavel; Jančařík, Andrej; Krečmerová, Marcela et al. (2016) Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA). J Med Chem 59:2810-9
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Rais, Rana; Rojas, Camilo; Wozniak, Krystyna et al. (2014) Bioanalytical method for evaluating the pharmacokinetics of the GCP-II inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA). J Pharm Biomed Anal 88:162-9
Alt, Jesse; Stathis, Marigo; Rojas, Camilo et al. (2013) Glutamate carboxypeptidase II is not an amyloid peptide-degrading enzyme. FASEB J 27:2620-5
Vornov, James J; Wozniak, Krystyna M; Wu, Ying et al. (2013) Pharmacokinetics and pharmacodynamics of the glutamate carboxypeptidase II inhibitor 2-MPPA show prolonged alleviation of neuropathic pain through an indirect mechanism. J Pharmacol Exp Ther 346:406-13

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