Research we fund

We will test if Gene Expression and Mutation Analysis (GEMA) could be applied as personalized medicine tool to identify individual patients with AML displaying specific preferences for repairing spontaneous and drug-induced DNA damage. These preferences will predispose leukemia stem and progenitor cells to synthetic lethality triggered by already approved as well as novel DNA repair inhibitors.

Project Term: July 1, 2018 - June 30, 2021

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.

Project Term: July 1, 2021 - June 30, 2024

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

Project Term: July 1, 2019 - June 30, 2022

The oncoprotein eIF4E is dysregulated in many cancers including AML. We show that eIF4E drives production of the glycosaminoglycan hyaluronan (HA). Further, HA elevation alters the surface architecture of high-eIF4E AML cells and this is required for eIF4E’s oncogenic activity. We will explore HA’s involvement in AML and the efficacy of depleting HA in patients using hyaluronidase in a Phase I trial in AML.

Project Term: July 1, 2019 - June 30, 2021

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.

Project Term: October 1, 2021 - September 30, 2024

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.

Project Term: July 1, 2021 - June 30, 2024

Follicular lymphomas (FL) depend on stromal cells for survival and proliferation and evade T-cell immune surveillance. Although indolent, most FLs eventually undergo either progression or transformation to an aggressive lymphoma. Effective treatments to prevent this remain a critical unmet need. This proposal will develop novel, mechanism-based therapeutic regimens for FL that overcome defective immune surveillance, prevent FLs from receiving stromal support and prevent disease progression.

Project Term: October 1, 2021 - September 30, 2024

Pediatric leukemia cells hijack the BCL-2 family signaling network to overexpress a range of anti-apoptotic proteins, including BFL-1 and MCL-1, and thereby enforce cellular immortality and cause treatment resistance. Here, we will harness novel and unique stapled peptides with the capacity to selectively target BFL-1, MCL-1, and importantly, both targets simultaneously, in order to reactivate the cell death pathway in MCL-1 and BFL-1 dependent pediatric leukemias.

Project Term: July 1, 2019 - June 30, 2022

Past studies of protein-coding regions have extensively characterized the genome of multiple myeloma (MM), but there has been little information on the prognostic impact of non-coding variants that may affect gene expression and regulation. Using a well-defined set of patient samples at different stages of disease progression we will define non-coding mutational hotspots in MM that contribute to progression and poor prognosis, identifying novel targets for alternative treatment strategies.

Project Term: July 1, 2019 - June 30, 2022

We found that immune checkpoint protein B7-H3 is overexpressed in Acute Myeloid Leukemia (AML) cells compared to normal hematopoietic cells. We have developed four monoclonal antibodies (mAbs) which successfully block B7-H3 and activate NK cells to induce apoptosis in AML cells. In this proposal we propose to generate therapeutically relevant anti-B7-H3 chimeric recombinant mAbs and test their activity in vivo. In addition, we will identify the receptor for B7-H3 expressed on NK cells.

Project Term: July 1, 2019 - June 30, 2022

GATA-3 identifies high-risk subtypes of mature T-cell lymphomas (MTCL), as its target genes, which we have systematically identified, have significant cell-autonomous and non-cell-autonomous (by regulating constituents of the tumor microenvironment) roles in these MTCL. As our preliminary data suggests that XPO-1 inhibition is a novel, and largely unexplored, therapeutic strategy in these MTCL, we will examine its cell-autonomous (Aim #1) and non-cell-autonomous (Aim #2) role in GATA-3+ MTCL.

Project Term: October 1, 2021 - September 30, 2024

We propose to develop a novel personalized immunotherapy to treat patients with refractory acute myeloid leukemia. We have shown that tumor-specific T cells (TAA-T) can diminish leukemia disease burden after allogeneic stem cell transplant. We now propose to augment the efficacy of the TAA-T products in the autologous setting using IL-15 backpacks to enhance TAA-T function and enhance efficacy without increased toxicity in vivo.

Project Term: July 1, 2018 - June 30, 2022