Although cure rates in childhood acute lymphoblastic leukemia (ALL) have increased to over 85%, these cures are accompanied by a high rate of both acute and long term adverse effects. The intense use of both glucocorticoids (e.g. dexamethasone) and asparaginase contributes to both high cure rates and toxic effects. Our work has shown that asparaginase profoundly affects dexamethasone pharmacokinetics, and that interaction of these two drugs influences both efficacy and toxicity. In the prior funding period, we developed the first murine model of osteonecrosis (ON), showed that discontinuous dexamethasone is less osteonecrotic but not less antileukemic than continuous exposure to dexamethasone, that asparaginase increases the frequency of dexamethasone-induced ON, and that the proximal mechanism of ON is a drug-induced arteriopathy in the vessels supplying susceptible bone. Moreover, clinical data generated by our own group and others have identified treatment-related and inherited genomic risk factors for several adverse effects caused by asparaginase and dexamethasone, including ON and pancreatitis, as well as genetic risk factors for ALL relapse. We have shown that asparaginase systemic exposure affects not only dexamethasone pharmacokinetics but also the risk of ON and of ALL relapse, illustrating the interplay between asparaginase and dexamethasone on clinical outcomes. We found that genetic risk factors for ON involve glutamate receptor genomic variants, that proteomic analysis of plasma documented higher gamma glutamyl hydrolase in mice with vs without ON, and asparaginase treatment directly increases plasma concentrations of glutamate. However, the mechanisms whereby the glutamate pathway affects the risk of dexamethasone/asparaginase- induced adverse effects remain unclear, and likewise it is not known whether genomic variation that predisposes to one adverse effect (e.g. ON) may impact the risk of other adverse effects (e.g. pancreatitis) or the desired antileukemic effects. To address these questions experimentally, we are using findings from our extensive clinical studies of ON risk factors (funded via other mechanisms) to prioritize the study of host- and treatment-related risk factors for ON in our integrated murine models (developed during the past funding period) for assessing ON and antileukemic effects after dexamethasone combined with asparaginase.
In Aim 1, we will test the impact of treatment schedule on the frequency of ON, with secondary analyses of antileukemic effect and pancreatic toxicity.
In Aim 2, we will test the impact of biochemically perturbing the glutamate pathway (via glutamate supplementation and receptor antagonism) on dexamethasone- and asparaginase induced ON, with secondary analyses of antileukemic and adverse pancreatic effects.
In Aim 3, we will test the impact of specific germline genomic variation on the frequency of ON, with secondary analysis of antileukemic and pancreatic effects. Our long term goal is to improve the use of glucocorticoids and asparaginase to minimize adverse effects without compromising antileukemic effectiveness.
Glucocorticoids, such as prednisone and dexamethasone, are critical to cure the most common childhood cancer, a type of leukemia, and they are used even more commonly for other autoimmune diseases or as supportive care for cancer patients. However, they cause a serious side effect: avascular necrosis of bone or osteonecrosis, especially when combined with asparaginase. In this proposal, we will determine the best schedules of dexamethasone and asparaginase to decrease osteonecrosis without compromising desired therapeutic effects, and test how inherited genetic risk factors impact their toxicity and antileukemic effects.
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