Cancer patients treated with many widely used chemotherapeutic agents, including paclitaxel (PAC) and oxaliplatin (OXA), frequently develop chemotherapy-induced peripheral neuropathy (CIPN) that may lead to dose reduction, dosing schedule changes and termination of treatment. In some patients, acute peripheral neuropathy (PN) can transition into chronic PN lasting well beyond termination of chemotherapy. Currently, there are no drugs to prevent CIPN and the therapeutic ?off-label? use of existing analgesics is not effective. Recent evidence suggests that a member of the thermo-sensitive TRP ion channel family is responsible for pain generation arising from the affected sensory neurons. We have identified the transient receptor potential, subfamily A, member 1 (TRPA1), as a promising target for novel analgesic drugs to treat or prevent CIPN. TRPA1 is activated by noxious cold and ROS, consistent with rapidly induced cold allodynia symptoms found in CIPN patients. The goal of this proposal is to develop a novel therapeutic approach based a new molecular mechanism that targets this key molecule involved in acute and chronic responses to CIPN. We propose to develop a novel, therapeutic small molecule functional antagonist of TRPA1 for the treatment of CIPN. TRPA1 receptor-channels serve a highly specific function on sensory nerve fiber endings that detect and transmit the sensations of pain and hyperalgesia in response to nerve injury. PAC or OXA treatment induces upregulation and sensitization of TRPA1. Our preliminary in vivo data shows that TRPA1 antagonists reverse neuropathic pain behaviors in a translational paclitaxel-CIPN model. The overall goal is to develop a TRPA1 antagonist delivered in combination with either PAC or OXA that is effective in blocking TRPA1 activation during CIPN. Our studies will first determine the potency and efficacy of TRPA1 antagonists to inhibit PAC- and OXA- induced activation in cultured DRG neurons. Second, the pharmacokinetics of three TRPA1 antagonists will be determined to enable dose selection for in vivo efficacy studies. Third, dose-response profiles for TRPA1 antagonists will be determined in translational rat PAC- and OXA-CIPN models using acute and chronic dosing.
The final aim i s to determine if a TRPA1 antagonist administered before and during PAC or OXA dosing can prevent induction of CIPN. The final Phase 1 milestone is to deliver an advanced preclinical candidate having pharmacological properties necessary for a full development program in Phase 2.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of chemotherapy occurring in 70-90% of patients receiving paclitaxel, oxaliplatin and other chemotherapeutic drugs for cancer treatment. CIPN may lead to dose reduction, dosing schedule changes and termination of treatment. Acute symptoms arising from neurotoxicity can appear rapidly upon infusion and transition to chronic peripheral neuropathy after termination of chemotherapy. Currently, there are no drugs that can prevent induction of CIPN and existing analgesic drugs are ineffective for the treatment of CIPN symptoms. Emerging evidence suggests that TRPA1 channels represent a new molecular target for discovery of a therapeutic agent which may be used in combination with taxanes or platinum-based drugs to effectively mitigate or prevent induction of CIPN. Algomedix has discovered a novel structural series of potent and selective small molecule TRPA1 antagonists having excellent drug-like features. Importantly, these compounds are active in rat models of neuropathic pain, including the paclitaxel-induced CIPN model. In this proposal, will use a combination of in vitro and in vivo studies to establish the efficacy of TRPA1 antagonists to reverse and/or prevent both acute and chronic pain behaviors in rodent paclitaxel and oxaliplatin models of CIPN. The overall goal of this study is to identify and optimize a novel TRPA1 antagonist as a therapeutic agent that can mitigate or prevent CIPN induced by many chemotherapeutic drugs.
