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.
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.
|Gamo, Nao J; Birknow, Michelle R; Sullivan, Danielle et al. (2017) Valley of death: A proposal to build a ""translational bridge"" for the next generation. Neurosci Res 115:1-4|
|Date, Abhijit A; Rais, Rana; Babu, Taarika et al. (2017) Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease. J Control Release 263:132-138|
|Wozniak, Krystyna M; Vornov, James J; Wu, Ying et al. (2017) Peripheral neuropathy induced by microtubule-targeted chemotherapies: insights into acute injury and long-term recovery. Cancer Res :|
|Benbow, Sarah J; Wozniak, Krystyna M; Kulesh, Bridget et al. (2017) Microtubule-Targeting Agents Eribulin and Paclitaxel Differentially Affect Neuronal Cell Bodies in Chemotherapy-Induced Peripheral Neuropathy. Neurotox Res 32:151-162|
|Personius, Kirkwood E; Slusher, Barbara S; Udin, Susan B (2016) Neuromuscular NMDA Receptors Modulate Developmental Synapse Elimination. J Neurosci 36:8783-9|
|Zhang, Zhi; Bassam, Bassam; Thomas, Ajit G et al. (2016) Maternal inflammation leads to impaired glutamate homeostasis and up-regulation of glutamate carboxypeptidase II in activated microglia in the fetal/newborn rabbit brain. Neurobiol Dis 94:116-28|
|Majer, Pavel; Jan?a?ík, Andrej; Kre?merová, 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|
|Vornov, J J; Hollinger, K R; Jackson, P F et al. (2016) Still NAAG'ing After All These Years: The Continuing Pursuit of GCPII Inhibitors. Adv Pharmacol 76:215-55|
|Benbow, Sarah J; Cook, Brett M; Reifert, Jack et al. (2016) Effects of Paclitaxel and Eribulin in Mouse Sciatic Nerve: A Microtubule-Based Rationale for the Differential Induction of Chemotherapy-Induced Peripheral Neuropathy. Neurotox Res 29:299-313|
|Rais, Rana; Jiang, Weiwei; Zhai, Huihong et al. (2016) FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities. JCI Insight 1:|
Showing the most recent 10 out of 21 publications