Research we fund

Myeloproliferative neoplasms (MPNs) carry JAK2(V617F), MPL(W515L) and mutations in calreticulin (CALRmut) often accompanied by mutations in TET2, ASXL1, DNMT3A, EZH2, and other genes. We will develop a strategy based on gene mutation profiling to identify MPNs displaying specific defects in DNA repair. These defects will be then explored by specific DNA repair inhibitors to eliminate quiescent and proliferating MPN stem and progenitor cells without affecting normal cells and tissues.

Refractory pediatric B- and T- lymphoid cancers exhibit hyperactivation of MYC and its downstream pathways. Experimentally, MYC inactivation sustains tumor regression. However, MYC’s requirement in normal B/T-cells has hampered the development of MYC inhibitors. Recently, we showed that MYC-High B/T-Lymphoid Neoplasms (B/T-MLN) evade Natural Killer (NK) cell surveillance. Hence, we propose to develop targeted off-the-shelf NK therapies as an alternative to MYC inhibition for treating B/T-MLN.

Dr Tasian’s scientific passion is successful development of precision medicine therapies for high-risk childhood leukemia. Her translational laboratory research program focuses upon investigation of kinase inhibitors and chimeric antigen receptor (CAR) T cell immunotherapies in childhood ALL and AML using primary patient specimens and patient-derived xenograft models. Through her laboratory and clinical research, she aspires to improve cure rates and minimize toxicities for children with leukemia.

Hairy cell leukemia (HCL) is very sensitive to chemotherapy, whose toxicity to the bone marrow and the immune system is however concerning. We have established vemurafenib plus rituximab as a very effective chemotherapy-free regimen in relapsed/refractory HCL (NEJM, in press). Here, we will test it in a clinical trial against a chemotherapy-based standard of care represented by cladribine plus rituximab, aiming at lower toxicity and similar efficacy.

My research focuses on why and how risk of acute myeloid leukemia (AML) increases with aging. Studying naturally aged mouse models in combination with mice engineered to express mutations commonly found in human blood stem cells with aging, we are investigating whether certain inflammatory factors that increase during aging increase the risk of leukemia. My goal is to identify biomarkers to assess risk of AML development in aging individuals and define new therapeutic targets to prevent AML.

This proposal aims to understand the molecular mechanisms underlying response to AZA therapy in MDS, as a basis for developing more effective therapies. A ribonucleotide, AZA’s effects on RNA remain unknown. Here, we will investigate the impact of in vivo AZA therapy on RNA alternative splicing and DNA demethylation in MDS patients. Secondly, we will investigate whether AZA treatment exposes neoepitopes in the dysplastic cells of patients, which could be exploited for cancer immunotherapy in MDS

Adoptive T cell therapies for acute myeloid leukemia face numerous hurdles such as limited target antigens, immunosuppressive tumor environment as well as the loss of efficacy due to downregulation of the targeted antigen. The goal of our project is to address some of these challenges with a single T cell product targeting multiple tumor associated antigens that have limited expression on healthy tissues via a novel combination of native T cell receptor and gene engineered CAR targeting.

Drug resistance in AML can develop via a non-genetic process which remains poorly understood. Using our novel cellular barcoding technology that can trace the growth of thousands of cancer cells, our research will identify genes that are switched on or off in AML cells that lead to drug resistance and relapse. This work will reveal the factors underpinning non-genetic drug resistance that may be targeted with new drugs to prevent relapse and ultimately improve quality of life and survival.

Blocking the progression of smoldering multiple myeloma (SMM) to active MM is an unmet clinical need. In primary mouse models of MM, we aim at demonstrating that modulation of the gut microbiota by vaccination against the commensal Prevotella heparinolytica and/or colonization by P. melaninogenica, also in combination with anti-PD-L1 antibodies, inhibit the progression of asymptomatic MM to full-blown disease. Our findings are expected to provide the ground for clinical trials in SMM patients.

Coming soon.

The project builds on evidence that mutations leading to persistent EZH2 activation drive germinal center B-cell lymphomagenesis by disrupting T-cell surveillance, and will test the hypothesis that EZH2 inhibition synergizes with immune checkpoint blockade and/or co-stimulation to eradicate these diseases. These results will provide the rationale for clinical development of precision-medicine immune-epigenetic combination therapies for lymphomas where these mechanisms are specifically altered.

We propose to the hypothesis that patients with LCH who fail initial chemotherapy will respond to a targeted strategy of blocking MAPK signaling through MEK inhibition. This trial is a Phase 2 study to evaluate the safety and efficacy of cobimetinib in patients with refractory LCH.  Exploratory aims will evaluate response of lesions with specific mutations, ability of peripheral blood mononuclear cells to determine disease burden, and development of somatic mutations in patients who relapse.