Acute myeloid leukemia (AML) is a common and deadly blood cancer caused by the abnormal proliferation of malignant myeloid progenitor cells. The 5-year survival rate for patients with de novo AML is only 30%, and it falls to under 10% in patients over 65 years of age, in large part because these older patients cannot tolerate the intensive chemotherapy regimens that are typically required in order to achieve a cure. In this study, a team of researchers led by Justine Rutter and Kevin Lin from the Wood Lab discovered that a major signaling pathway required for survival and drug resistance in AML cells is controlled by a protein complex known as PI3K(gamma) which is only expressed in hematopoietic cells, and in particular those from the myeloid compartment. Teaming up with co-first author Lois Kelly and her mentor Dr. Alexandre Puissant from the St. Louis Hospital in Paris and Dr. Anthony Martin from the University of Montpellier, the team went on to define the downstream mechanism driving PI3K(gamma) dependence, assess its relevance as a therapeutic target in advanced human and mouse model systems, and create a selective heterobifunctional degrader molecule to efficiently target PI3K(gamma). Together, these findings suggest that drugs targeting PI3K(gamma) may have exciting activity and reduced toxicity in patients with AML. Through a partnership with a pharmaceutical company, the researchers hope to begin translating these findings to human clinical trials in the next two years.
The paper can be accessed here.