Research we fund

Children with Down syndrome (Trisomy 21) have an increased risk of childhood leukemia and, in these cases, the initiating genetic alterations already occur during the development of the fetus. In 30% of newborns with Down syndrome, a pre-leukemia disease occurs, which in some cases can progress to acute myeloid leukemia. I am planning to determine why children with Down syndrome have an increased risk of developing leukemia with the goal to identify potential therapeutic targets.

Project Term: April 1, 2021 - March 31, 2023

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

The goal of our program aims to understanding the general roles of DNA methylation machineries in epigenetic regulation and cancerous transformation seen in hematological cancers. Routinely, we take a set of integrated biochemical, genomics, oncology, and medicinal chemistry approaches to tackle the broad and critical questions in this field. Our findings shall not only promote current understanding of how hematological malignancies occur but also help develop novel therapeutic approaches.

Project Term: July 1, 2018 - June 30, 2023

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

Coming soon.

Project Term: April 1, 2021 - March 21, 2026

The processes that control the progression of myeloproliferative neoplasms to leukemic transformation remain largely unknown. We have developed genetic mouse models that recapitulate leukemia progression in humans. We aim to discover new regulators and pathways controlling the propagation of leukemia stem cells as targetable vulnerabilities. Our study promises to provide critical insights into developing new and generalizable therapies to selectively eliminate leukemia stem cells.

Project Term: July 1, 2019 - June 30, 2024

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.

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

This project focuses on designing new immunotherapy approaches for the treatment of patients with follicular lymphoma. It is based on a clincal trial that tests combinations of antibodies, with the goal of making the patients’ own immune systems more effective at attacking their lymphoma. Through analysis of tumor and blood samples from the patients on the trial, we hope to gain a deeper understanding of the biology of follicular lymphoma and its vulnerability to immune attack, which will help to design the next generation of trials. The trial and sample collection are currently ongoing.

Project Term: July 1, 2018 - June 30, 2023

We are testing whether the immune checkpoint inhibitor pembrolizumab can improve outcomes of patients. In MDS, we showed that entinostat reduces the number and activity of immune suppressive cells, thereby making the cancer susceptible to the killing effect of pembrolizumab. We are now testing this combination in a clinical trial. In CML, many patients cannot completely clear the disease despite tyrosine kinase inhibitor (TKI) therapy due to inability of their immune system to eradicate all CML cells. We therefore designed a clinical trial to augment the TKI impact on CML cells by adding pembrolizumab.

Project Term: July 1, 2018 - June 30, 2023