Discovering a Novel Immunophilin to Lower the Toxicity of Cancer Therapeutics

DESCRIPTION (provided by applicant): Chemotherapy induced peripheral neuropathy (CIPN) is a frequent and often dose limiting side effect of mainstay chemotherapeutics including taxanes, bortezomib, vinca alkaloids, platinum complexes, and newly approved therapeutics such as Eribulin. Initial symptoms of CIPN include sensory loss and pain in the extremities, and can later progress to uncontrolled bladder emptying, respiratory dysfunction, and paralysis. These symptoms generally become worse during combination therapeutic regimens, dose-dense regimens, and for pretreated patients. In addition to further lowering the quality of life fo cancer patients, neurotoxicities may cause over 33% of patients to reduce dosages or halt chemotherapy for certain regimens (oxaliplatin, leucovorin, fluorouracil, e.g.), leading to worse therapeutic outcomes. Current approaches to treating CIPN have focused on alleviating specific symptoms as opposed to the root causes. Recently, there has been great progress in understanding the mechanistic underpinnings of peripheral neuropathies including CIPN and the role of nerve growth factor (NGF). In particular, NGF has been shown to prevent the onset of CIPN caused by a wide variety of chemotherapeutics including taxanes, platinum complexes, and vincristine. However, clinical trials to prevent peripheral neuropathy using human NGF have failed due to poor pharmacokinetics. Using recently developed chemistry to build novel small molecules called neuroimmunophilins that bind to the chaperonin FKBP52 and directly potentiate NGF, we have demonstrated that neuroimmunophilins can prevent the onset of neurotoxicity without compromising anti-cancer activity both in vitro and in vivo. In this proposal we wish to screen and select additional FKBP52 binding moieties in the presence of anti-cancer agents to select a lead candidate for further development as a therapeutic to prevent CIPN caused by taxanes and platinum complexes. We propose the following aims: Aim 1. Design and synthesize and a focused library of neuroimmunophilin moieties to inhibit FKBP52. Aim 2. Screen and select library compounds for the ability to bind to FKBP52, a neurotrophic target, and assess in vitro pk/pd. Aim 3. Perform in vitro screens for neurotrophic activity in the presenceof anti-cancer agents in primary nerve cells and peripheral nerve cell lines and select compounds. PUBLIC HEALTH RELEVANCE: Severe toxicity caused by drugs used to treat cancer remains a critical, worldwide problem. Among the numerous challengesin this area, the severe toxicity of chemotherapeutics causes early termination of therapeutic regimens, thereby lowering the efficacy of these regimens. In addition, toxic chemotherapeutics endanger the health of cancer patients and lower the quality ofpatient life. Amplyx proposes a fundamentally new method for lowering the toxicity of chemotherapeutics. Our strategy employs immunophilin compounds which can protect healthy cells from the neurotoxic side effects of chemotherapeutics.