Chemotherapy-induced peripheral neuropathy (CIPN) is a devastating and often lifelong adverse drug reaction associated with standard of care chemotherapy for many pediatric and adult cancers. Acute vincristine-induced peripheral neuropathy is common (~25-40% of patients), often disrupting curative therapy, whereas chronic neuropathy causes long-term morbidity that compromises quality of life. In part because of a paucity of genetically diverse human models of CIPN, there are no preventive measures or effective treatments for this devastating adverse drug effect. Our multi-disciplinary team comprising three established programs based at the University of Chicago, St. Jude Children's Research Hospital (SJCRH), and Boston Children's Hospital/Harvard Medical School capitalizes on novel stem cell technology to create patient-derived human neurons, through differentiation of induced pluripotent stem cells (iPSCs) created from the blood of adult survivors of childhood acute lymphocytic leukemia (ALL) treated with vincristine. We are taking a bedside to bench strategy by using blood from cancer survivors with severe, persistent neuropathy and matched survivors with no neuropathy (controls) to create an in vitro model that will allow mechanistic studies of CIPN and provide a means to screen compounds for the prevention or treatment of CIPN. The adult survivors of childhood cancer have extensive genetic and phenotypic information to determine extent of motor and sensory neuropathy including nerve conduction studies to determine axonal integrity, and tests of manual dexterity, balance and gait speed to determine physical function (all part of SJCRH-SJLIFE with existing IRB approved protocols). We are choosing those at the extremes of the phenotypic spectrum (severe neuropathy or no neuropathy), allowing us an unprecedented opportunity to use a combination of morphological and functional studies to test whether the iPSC-derived neurons recapitulate the phenotypes of the individuals from which the neurons were derived (i.e., significantly more chemotherapeutic damage to neurons from patients with severe toxicity compared to neurons from controls following in vitro treatment with vincristine). If the phenotypes prove to be significantly divergent, the patient-derived neurons can be used in high throughput screening to identify drugs that reverse the effect of chemotherapeutic damage. The impact is high because, to our knowledge, this will be the first effort to evaluate chemotherapeutic toxicity in neurons from well-phenotyped patients.
Our aims are: 1) To identify an in vitro toxicity readout in patient-derived neurons that parallels the clinical phenotype from well-phenotyped cancer survivors following treatment as children with vincristine; 2) To determine the effect of a SNP (rs924607) in the promoter of CEP72 on its mRNA expression and its effects on sensitivity to vincristine in motor neurons, which our preliminary data indicate increases sensitivity to vincristine. We will gain insights on the underlying mechanism for inter-individual variation in CIPN and establish a new paradigm of using stem cells to study adverse drug reactions.
This proposal will focus on creating a state of the art, human patient cellular model to study chemotherapy- induced peripheral neuropathy, a common drug-induced disability associated with the treatment of many cancers. Neurons will be created from the blood of adult survivors of childhood cancer living with severe, persistent neuropathy, and from control patients who have developed minimal symptoms of neuropathy, thereby providing a framework for mechanistic studies and the discovery of novel agents to prevent or treat this adverse drug reaction.
