Elucidating Molecular Mechanisms Underlying Exceptionally Wide Therapeutic Window for Small Molecule Allosteric Activators of Protein Phosphatase 2A
Project Goal: Provide critical cell biology and biochemical insight into the complex biology of PP2A phosphatases, forming the basis for future clinical effort to apply this class of compounds for the treatment of pediatric cancer patients, as a nontoxic chemotherapy.
Institution: Dana-Farber Cancer Institute, Harvard Medical School
Researchers: Ken Morita, MD, PhD
Year Awarded: 2020
Type of Childhood Cancer: T Cell Acute Lymphoblastic Leukemia
Several years ago, our team has identified perphenazine (PPZ) as an FDA-approved antipsychotic drug that unexpectedly kills T cell acute lymphoblastic leukemia (T-ALL) cells through its activation of protein phosphatase 2A (PP2A), a critical phosphatase and a tumor suppressor that removes phosphates from a key regulatory molecule that mediates the proliferation of tumor cells. Yet, because of its other activity as an antagonist dopamine in the central nervous system, PPZ can cause serious movement disorders, limiting its usefulness as an antileukemic agent. By using detailed biochemical reporter assays, I have recently identified and reported a new class of compound, which is designated as iHAP1 (improved Heterocyclic Activators of PP2A), as a highly specific and potent small molecule that potently reactivates the phosphatase activity of PP2A and kills T-ALL cells without interfering the dopamine receptor signaling (Morita K. et al. Cell. 2020). iHAP1 is highly effective as an antitumor agent in T-ALL xenograft mice models, and significantly extends overall survival of the treated mice. In addition, iHAP1 is surprisingly tolerable in these preclinical mice models up to 80 mg/kg/day without affecting the maintenance and proliferation of normal cells such as the bone marrow cells. Besides, iHAP1 treatment effectively suppresses the growth of not only T-ALL cells but also other pediatric cancers such as acute myeloid leukemia (AML) and neuroblastoma cells at a dosage that the proliferation of normal bone marrow cells is not inhibited. Stimulated by these findings, in the proposed research, I will ask the molecular mechanisms of how iHAP1 creates this exceptionally wide therapeutic window. Addressing such mechanisms is of paramount importance to advance a clinical candidate drug of this class into Phase I clinical trials in patients with childhood malignancies. Thus, the insights generated in the proposed research will provide critical cell biology and biochemical insight into the complex biology of PP2A phosphatases, forming the basis for future clinical effort to apply this class of compounds for the treatment of pediatric cancer patients, as a nontoxic chemotherapy.