A new form of treatment for cancer is to activate a patient’s own immune system to recognize and destroy tumor cells. Called cancer immunotherapy, this strategy has proven to have a remarkable impact on long-term survival for patients with a wide range of cancer types, but only a subset of individuals has sustained responses that can lead to a long-term cure. In order to advance cancer immunotherapy, it is critical to understand the immune signals responsible for robust tumor immunity.
One key part of the immune response to cancer is a cellular protein named STING (Stimulator of Interferon Genes) that allows immune cells to detect DNA derived from tumors. STING naturally responds to drug-like small molecules, and an exciting new area of study is the idea of “STINGing cancer” – using compounds that specifically activate STING to boost tumor recognition and patient responses to cancer immunotherapy. In spite of the clear role of STING in immune cell responses, STING signaling is poorly understood and we do not understand how signaling leads to improved patient responses.
Our research will determine how STING transmits signals to the immune system and which STING signal is critical for combating cancer. These experiments will provide the foundation for the design of next-generation drugs that target STING and, ultimately, will help us understand how to use cellular proteins like STING to better control human immune responses and treat cancer.
Scientists have recently made tremendous progress in treating cancers by activating the immune system to attack the tumor. However, these therapies are not effective against cancers with less DNA damage due to insufficient anti-tumor immune responses. The immune system is capable of attacking these tumors, but suppressive immune subtypes such as regulatory T cells (Tregs) are coopted by the tumor to protect itself. Tregs are associated with poor survival in many cancers, and show enrichment for particular T cell receptors (TCR). The TCR senses targets by binding to their peptide-MHC ligands, which display a cross-section of peptides expressed by a particular cell. Despite their important role in protecting tumors, the identity and specificity of tumor-resident Tregs is poorly studied. We are working to profile what T cells are enriched in low mutation rate cancers. We can then use approaches we have developed to find what these T cells as seeing in the tumor. This information will help us understand of one of the most important tumor-protective cell types, and may open the door to new cancer immunotherapies.
Funded by the Dick Vitale Gala, in memory of Benji Gilkey
T-cell acute lymphoblastic leukemia is an aggressive cancer that is most common in teenagers. Many patients cannot be cured, even with intensive chemotherapy. Our goals are to understand why chemotherapy does not cure some patients, and use this knowledge to improve treatment. We found that chemotherapy cannot cure patients whose leukemia cells are very difficult to kill in a test called BH3 profiling. This proposal is focused on mutations of a gene called JAK3 as a cause of death resistance of leukemia cells. This idea could be immediately translated into a clinical trial because JAK3-blocking drugs are already FDA-approved for clinical use. Here, we will ask the following questions: 1) Do JAK3 mutations block cell death in leukemia cells? 2) Will a JAK3-blocking drug improve the effectiveness of chemotherapy? 3) Is a JAK3-blocking drug safe and effective for the treatment of children with T-cell acute lymphoblastic leukemia? Successful completion of this project could lead to more effective treatment options for children with this particularly high-risk subset of T-cell leukemia.
2017 V Foundation Wine Celebration Vintner Grant in honor of David and Kary Duncan
Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) are blood cancers diagnosed in approximately 25,000 and 19,000 individuals each year in the US, respectively. Despite an enormous global effort, the treatments and outcomes for patients with MDS and AML have not improved significantly over the past 4 decades. The purpose of this study is to evaluate a new idea for MDS/AML therapy to see if there is sufficient promise to launch a clinical trial for patients at our center. By studying the genomes (the DNA blueprint in all cells) of patients with MDS/AML, the scientists involved in this proposal identified mutations (“mistakes”) in a structure called the spliceosome. These spliceosome mutations are very common in patients with MDS/AML. We recently found that the spliceosome-mutant cells are more readily killed in the laboratory by two drugs that are currently being tested in clinical trials for other cancers. In this project, we will test these two drugs alone and in combination using systems that we have developed in the laboratory. We will determine how, at the molecular level, these drugs kill the spliceosome-mutant cells and how they may become resistant to these treatments. Finally, we will develop tests to monitor the effects of these drugs when given to patients with MDS/AML. Since these drugs are already in clinical development for other indications, we expect that our work will rapidly help lay the foundation for clinical trials to see if these drugs offer new hope for patients with MDS and AML.
Myelodysplastic syndrome (MDS) is a group of clonal blood cell disorders characterized by abnormal-looking cells (cytologic dysplasia) and low cell count (refractory cytopenias) as a result of ineffective blood production (hematopoiesis). About 30-40 percent of MDS cases progress to acute myeloid leukemia (AML), a type of blood cancer, with poor prognosis and short survival time. We have discovered that a novel embryonic stem cell factor also a leukemic stem cell factor SALL4 is involved in the development of MDS and AML. We propose to study the SALL4 pathway in MDS and AML using murine models and test small molecule drugs that can block SALL4 function in MDS/AML. This study will provide new and critical insights and novel pathways in mediating MDS and its progression to AML which will enable us to develop innovative drugs in treating these patients in the near future.
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