Cancer remains the leading cause of death by disease in US children, despite major advances in the last 20 years. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and optimizing treatment has improved cure rates to >85%. As cure rates improve, there is a compelling need to mitigate the acute and chronic toxicities of ALL therapy, because substantial morbidity with current treatment can persist into adulthood, compromising quality of life and longevity. Although targeted agents hold promise for someday reducing treatment morbidity, there are very few promising targeted agents for childhood ALL and they are always given with chemotherapy, thus conventional chemotherapy will remain the mainstay of curative treatment for decades to come (1, 2). Research supported by this grant, funded as 3 consecutive MERIT awards, has focused on elucidating genomic determinants of drug efficacy and toxicity in children with ALL, leading to a number of treatment modifications (1), exemplified by our work identifying inherited polymorphisms in the TPMT gene and its association with hematopoietic toxicity (3), which has now been widely translated to clinical practice (4). Our new aims are logical extensions of research conducted during the current funding period, focusing on genetic predisposition to acute and persistent neuropathy from vincristine (VCR), a medication given 20-30 times to every child with ALL. Acute VCR-induced neuropathy is a common toxicity (~25-40% of patients), often disrupting curative therapy, whereas chronic neuropathy causes long-term morbidity that compromises quality of life. We will extend our recent discovery of a genetic polymorphism in CEP72 (essential for microtubule assembly), that causes lower CEP72 expression and increases sensitivity to VCR (a microtubule inhibitor), increasing the risk & severity of acute VCR-induced peripheral neuropathy. We will determine whether this polymorphism is also related to persistent neuropathy in adults cured of ALL and whether neuropathy can be mitigated by reducing the dosage of VCR in patients homozygous for the CEP72 risk allele or by using a liposomal formulation that produces lower peak VCR concentrations. Specifically, this grant will support a prospective single-institution clinical tril of children with newly diagnosed ALL to determine whether reducing VCR dosage in patients homozygous for the CEP72 risk allele (~16% of patients) mitigates neuropathy without compromising efficacy (Aim 1); we will also determine in a double-blind randomized study if treatment with liposomal VCR mitigates neuropathy in these patients (Aim 2).
In Aim 3, we will capitalize on our unique St. Jude Life cohort studies of adverse health consequences in adult survivors of childhood cancer, to determine if the inherited CEP72 promoter SNP predisposes to VCR-induced peripheral neuropathy that persists in adults cured of childhood ALL, compromising their quality of life.
Our final aim (Aim 4) uses next generation sequencing to identify additional variants in CEP72 and GWAS to identify additional common variants that predispose to VCR-neuropathy, and interrogates their effects in iPSC neurons and ALL cells.
Acute lymphoblastic leukemia (ALL), the most common cancer in children, serves as a paradigm for disseminated cancers that are curable with chemotherapy, in both children and adults. This grant extends advances made in the prior funding period, during which we identified a genetic polymorphism in CEP72 (encoding a centrosomal protein essential for microtubule assembly) that leads to lower expression, enhanced sensitivity to vincristine (VCR, a microtubule inhibitor), and increased incidence and severity of VCR-induced peripheral neuropathy. Our new aims will determine whether one can mitigate this toxicity without compromising efficacy by reducing the dosage of VCR in patients homozygous for the CEP72 risk allele (T/T at rs924607) or by using a liposomal formulation of VCR, and whether genetic polymorphisms in CEP72 or other genetic loci influence the risk and/or severity of VCR-induced peripheral neuropathy that persists in some patients decades after curative treatment has been completed, compromising quality of life of adults cured of childhood ALL.
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