Justin Wahlstrom, MD
Mechanisms of Chemotherapy Resistance in Childhood T-ALL
Acute leukemia is the most common type of childhood cancer. T-cell acute lymphoblastic leukemia (T-ALL) is a type of childhood leukemia, and in up to 25% of these patients, they cannot be cured with standard chemotherapy. The reasons for this are unclear, but are thought to involve the manner in which biochemical signals activate and deactivate certain proteins that cause cell death. In T-ALL, these biochemical signals are altered. We are testing whether two biochemical signaling pathways (RAS and PI3K) are more active in T-ALL patients who do not respond well to standard chemotherapy. We are also testing the ways in which these signals change in response to chemotherapy. Our proposal aims:
1) To determine whether hyperactive biochemical signaling and decreased levels of cell death proteins are found in chemotherapy-resistant T-ALL cells, and 2) To determine whether a newer class of drugs that inhibits this signaling can restore the activity of cell death proteins, and overcome resistance to conventional chemotherapy.
We predict that higher RAS and PI3K signaling activities in chemotherapy-resistant T-ALL patients cause a decreased ability of chemotherapy to activate the cell death proteins needed to kill the cancer cell. We also predict that we might be able to use newer, non-chemotherapy drugs in combination with standard chemotherapy in order to inhibit these hyperactive signals, and that this will make these cells easier to kill. If this is true, then we will be able to target these hyperactive signals in order to more effectively treat pediatric T-ALL, which will result in better cure rates for this disease.
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