Research We Fund

A key feature of the MPNs is aberrant megakaryopoiesis, including increased numbers of platelet-producing megakaryocytes in essential thrombocythemia and atypical megakaryocytes that drive fibrosis in myelofibrosis (MF). Recent studies have found that increased activity of the chromosome 21 kinase DYRK1A, which is a feature of the MPNs, enhances megakaryocyte growth while its loss suppresses their expansion. This effect appears to be mediated, at least in part, by DYRK1A’s control of NFAT2 phosphorylation and subcellular localization. The goals of this research are to determine whether DYRK1A is a therapeutic target in chronic phase MPNs and to define the contributions of NFAT2 phosphorylation to the disease.

Development of a strong anti-cancer immune response requires coordinated action of the innate and adaptive parts of the immune system, but cancer cells alter their environment to suppress virtually every step in this process, which promotes cancer progression and treatment resistance. One promising strategy could be to target Heat shock protein 70 (HSP70), which plays an important role in both innate and adaptive immunity, and we therefore developed a series of novel antibodies to HSP70, one of which cured mice of multiple myeloma. Based on strong preliminary data, we propose additional studies to better understand how this antibody activates various types of immune cells, how it works against both cancer cells and modifies the immune environment in mouse models, and how it could work even better in combination with other agents against myeloma. Since this antibody is already being developed into a drug for phase I clinical trials, these studies will directly inform its use in the clinic against multiple myeloma, and possibly against other blood-related cancers such as B-cell lymphomas.

Because acute leukemias are very sensitive to radiation, radioisotopes are ideal payloads to arm antibodies against these difficult-to-cure, aggressive blood cancers. Here, we will develop fully human anti-CD123 antibodies carrying the highly potent alpha-emitter astatine-211 (211At) as a new therapy for acute leukemia. CD123 is broadly displayed on acute leukemia cells in most patients and overexpressed on leukemic stem cells but is only found on a small subset of normal blood cells, enabling the use of 211At-CD123 radioimmunotherapy in the transplant and non-transplant setting with limited toxicities to normal tissues.

We have investigated the consequences of p53 loss on stem cell properties, namely clonogenic growth, self-renewal, and drug resistance in multiple myeloma. We have found that both the level of Notch signaling and BCMA impact these properties, and we will explore novel strategies to improve outcomes in p53 mutant multiple myeloma.