Targeted Hyperactivation of PI3K/AKT in B-cell malignancies
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. It affects certain cells in the immune system, called B cells and T cells. Multiple enzymes, known as kinases, are necessary to regulate signaling in B cells. One of these kinases, called PI3K, is involved in normal B cell development. Deleting inhibitors of PI3K activity in immature B cells leads to cell death. PI3K works in concert with another kinase called AKT, which together help regulate the growth and survival of B lymphocytes. Under- or over-activating this PI3K/AKT pathway triggers cell death. Current therapies for B-cell leukemia are focused on inhibiting these types of kinases.
We propose an innovative new approach, targeting hyperactivation of signaling B cells to trigger cell death in leukemia cells and kill drug-resistant cells. We will explore agents that activate the PI3K/AKT pathway, as well as drugs called small molecule inhibitors, in combination with CAR T antibodies. CAR T cell therapy is a promising new form of immunotherapy that uses the patient’s own immune system to fight cancer with less toxic side effects. Our research will determine whether overactivation of PI3/AKT signaling will enhance the effectiveness of CAR T cell treatment, offering a better therapy for children with cancer.