Targeted Hyperactivation of PI3K/AKT in B-cell malignancies
Background: 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.
Project Goal: 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.
Project Update 2023: We found that targeting one of the isoforms of PI3K called Pik3c2b induced hyperactivation of signaling in B cells triggering cell death in leukemia cells and killed drug-resistant cells. Similarly, deleting inhibitors of PI3K activity in immature B cells induced cell death. PI3K works in concert with another kinase called AKT, which together help regulate the growth and survival of B lymphocytes. We are currently exploring 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. Also, using genome-wide loss of function screen, we will determine whether molecules that are central to drive oncogenic signaling at the cell membrane will enhance the effectiveness of immunotherapy. Over activation of AIC’s represents similar mechanism on which current CD19 CAR-T cell therapy is based. Altogether, we believe that our results provide new therapeutic approach to improve current regimen of immuno-therapy for patients with cancer which can be tested for its success in the clinic.
