Patients with relapsed blood cancers after allogeneic stem cell transplant are often treated with donor lymphocyte infusion (DLI), a type of immunotherapy that boosts the anti-tumor response and aims to induce cancer remission. The success of DLI varies from patient to patient. Dr. Bachireddy aims to investigate the determinants of DLI success and failure by studying the leukemic and immune cells during response to immunotherapy. Careful study of successful anti-tumor immune responses may reveal insights into tumor-immune interactions that may be relevant to predicting patient response to novel immunotherapies in other tumors.

Dr. Bendall is using novel single-cell analysis techniques to investigate how normal regulatory cell signaling networks are rewired, allowing cancer to grow unchecked.  He has applied this technology to examine healthy human blood cells, measuring multiple parameters simultaneously in single cells.  Collectively, such single-cell analyses provide an unprecedented opportunity to identify novel regulators (such as drugs, genes, and protein modifications) of cell development and identity, as well as provide insight into how these regulators interact with genes and mutations that promote cancer cell transformation.  His goal is to use these studies to contribute to the development of more effective diagnostics and treatments to improve clinical outcomes. 

Dr. Bowman focuses on acute myeloid leukemia (AML), which can be characterized by successive development of genetic mutations. While some mutations are found in nearly every cell of the disease, others are found in sub-populations and are thought to arise at later stages of disease development. It remains unclear if these late mutations are necessary for leukemic progression and are actionable therapeutic targets. He aims to develop models to test the oncogenic dependency of one of the most commonly mutated genes in AML, FLT3. Further models will be developed to understand the role of mutation order in disease development.

Dr. Brooks is analyzing cancer genome sequence data to identify DNA mutations that affect RNA splicing, a form of gene processing and regulation. By characterizing these mutations, her work will provide further understanding of the role of splicing alterations in cancer as well as insight into the functional consequences of cancer mutations.

Dr. Brown studies acute lymphoblastic leukemia (ALL), an aggressive leukemia and one of the most common malignancies in children and adolescents. Despite significant progress, relapse is associated with high rates of drug resistance and poor prognosis. As a result, relapsed ALL is the leading cause of cancer-related death in children. Dr. Brown will use large-scale genetic (DNA) and transcriptomic (RNA) data and leukemia animal models to dissect how a small number of ALL cells are able to escape the cytotoxic effects of chemotherapy. These cells then undergo genetic and epigenetic changes that allow them to generate resistance to chemotherapy and proliferate, causing relapse of this devastating childhood disease. Understanding this process may lead to novel therapeutic approaches for relapsed ALL.

Cutaneous T cell lymphoma (CTCL) is an incurable cancer of the immune T cells in the skin. In advanced disease, the cells escape into the blood, the lymph nodes, and at times the visceral organs. Patients with advanced disease eventually succumb to a combination of tumor burden and disease-related immunosuppression. Dr. Choi [Doris Duke-Damon Runyon Clinical Investigator] has recently used next generation sequencing to identify gene mutations that he hypothesizes are important for CTCL pathogenesis. He will molecularly dissect how these gene mutations alter signaling pathways in CTCL, using human models and patient samples. His ultimate goal is to identify novel therapeutic strategies that selectively target CTCL cancer cells, hastening the development of a cure for this intractable disease.

Dr. Daniels aims to improve the ability of engineered T cells to kill cancer. Specifically, his goal is to understand how signaling events during T cell activation determine the therapeutic properties of activated T cells. He uses synthetic immunology techniques and computational methods to search for synthetic receptors that confer desired functions upon T cells. Ultimately, he hopes to design and create receptors that improve the ability of T cells to proliferate, persist, recruit other immune cells, and kill cancer cells.

We share our bodies with trillions of microorganisms: the microbiota. The microbiota interacts with our bodies to affect health and disease, including cancer development and response to therapies. For example, in patients receiving hematopoietic stem cell transplantation as treatment for leukemias, lymphomas, and other blood cancers, disruptions in the microbiota have been linked to disease relapse, infections, treatment complications, and survival. Given these serious effects, it is important to understand how to manipulate the microbiota through therapies like prebiotics: carbohydrates that can be ingested to stimulate the growth and maintenance of various bacteria. The challenge is that different people have different microbiotas and therefore may respond differently to the same prebiotic. To address this challenge, Drs. David and Sung have developed a novel microfluidic platform to isolate individual bacteria from a patient’s stool sample and grow them against selected prebiotics, allowing an understanding of how a given patient’s microbiota may respond to different prebiotics. To do this using conventional techniques would take a stack of petri dishes as tall as the Empire State Building and months of work; their innovative system can do it in a single day. They believe that by using this novel system, they will be able to predict the best prebiotic for a given patient, thereby manipulating their microbiota and improving cancer outcomes. They will test this strategy using patient samples in their artificial gut “bioreactor” as well as in mouse models. The success of this project would lead to clinical trials of personalized prebiotics.

Dr. Didychuk is investigating the mechanism by which the Kaposi’s sarcoma herpesvirus (KSHV) co-opts the cellular host machinery to produce its own gene products in a manner distinct from other viruses and host cells. This research should reveal insights into this unique mode of transcriptional control. KHSV is an oncogenic virus that causes various cancers including, Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease, in immunocompromised individuals.

Leukemia is, for some patients, an inherited disease that may affect multiple individuals within a single family. Similar to other diseases such as inherited breast cancer, we now understand that specific genes may increase an individual's risk for developing leukemia over the course of his or her lifetime. While an increasing number of genes involved in inherited leukemia have been identified, the underlying molecular mechanisms that contribute to the development of leukemia and other blood cancers are less well understood. Some individuals with inherited blood cancers develop abnormal blood conditions years before actually developing overt leukemia. Dr. Drazer aims to better understand the molecular mechanisms that cause these abnormal blood conditions to transition into leukemia. The goal of this work is to apply these findings to inform future therapies for patients with blood cancers.