Pancreatic cancer remains a lethal illness with limited treatment options. While harnessing the immune system has demonstrated dramatic results in controlling other cancers, it has so far failed in pancreas cancer. The development of effective immunotherapy for pancreatic cancer requires the activation and expansion of immune cells that recognize and kill the cancer. We have developed a cancer vaccine by fusing malignant cells with powerful immune stimulating cells known as dendritic cells that are capable of inducing anti-tumor immunity. This strategy allows the immune system to see cancer antigens so that they can be recognized and attacked. This vaccine showed excellent results in clinical trials in patients with blood cancers. One challenge to developing a vaccine for pancreatic cancer involves obtaining adequate tumor tissue needed to create a personalize vaccine. We have solved this problem by developing a culture system that allows for growth of a patient’s tumor tissue in vitro known as organoids that can subsequently be fused with patient’s own dendritic cells created personalize vaccine. In our first aim, we will conduct a clinical trial in patients with pancreatic cancer to show the feasibility, safety, ability to stimulate a immune response and preliminary efficacy of the vaccine product. While we expect that this strategy will be feasible and work in some patients, it is likely that it will not be enough for all patients. For that reason, in the second aim, we will work with mouse models to combine the vaccine with strategies that could make it better.
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.
In recent years, doctors and scientists have recognized that a person’s genetic make-up helps determine their risk for developing particular bone marrow derived cancers. The bone marrow produces all of our blood cells, and the white blood cells that fight infection can be broken down roughly into two classes, myeloid cells and lymphoid cells. Between these two main groups, the DNA changes that confer risk for developing cancers are best defined for myeloid blood cancers, whereas DNA changes associated with lymphoid blood cancers largely remain to be discovered. Drs. Godley, Leavitt, and Wiemels have formed an interdisciplinary team to fill this void. Drs. Godley and Leavitt are hematologists who work directly with patients and families with clustering of lymphoid cancers, and Dr. Wiemels is an epidemiologist who works with large population-based data sets and blood samples to understand factors that put groups of people at risk for disease. Collectively, their work has shown that Hispanic patients are particularly susceptible to developing lymphoid cancers and are more likely to suffer poor outcomes. Drs. Godley and Leavitt have already identified variants in several genes that appear to confer particular risk for developing lymphoid cancers, and these provide a starting point for the proposed studies. The team will be focused in Chicago and California, areas with large Hispanic populations, with the ultimate goal of using genetic risk factors to optimize therapy for patients and to develop preventive strategies to avoid cancer development in high-risk individuals.
Most patients with acute myeloid leukemia (AML) have a poor prognosis, and a “bone marrow” or hematopoietic cell transplant (HCT) is the only chance for a cure. The new immune system that develops in the patient is the active part of the therapy, including natural killer (NK) cells. A major obstacle for HCT in AML patients are the complications that occur due to high doses of chemotherapy. Newer transplant types referred to as “mini” transplants are more tolerable with fewer side effects, but have a high relapse chance. We developed a new method to activate donor NK cells, which result in a long-lived, highly potent memory-like NK cell. These are made from donor immune cells by purifying the NK cells, activating overnight cytokines, and then infusion into the patient. This new NK cell therapy approach has been tested in a phase 1 study at WUSM for patients with AML with promising clinical results and no major side effects. However, without a “matched” immune system, the AML patient’s immune cells reject the donor NK cells after 2-3 weeks, and thus the memory-like NK cells have only a few week “window of opportunity” to eliminate the AML. Here, we combine the “mini” HCT transplant with memory-like NK cell infusion from the same donor to leverage the strengths of each individual approach. We expect that the donor memory-like NK cells will result in a complete remission, allowing time for the new immune system to develop and safely provide a long term cure.
Acute leukemias (acute myeloid leukemia—AML and acute lymphoid leukemia—ALL) are lifethreatening cancers of the blood responsible for 40% of all childhood cancer deaths. For those who survive, life-altering side effects from conventional therapy are common. Despite progressively improved survival, these circumstances are far from ideal. To achieve better outcomes with fewer side effects, we need new treatments that target mechanisms of leukemia cell survival. By focusing on these adaptations we have discovered an “Achilles heel” in leukemia cell survival. We discovered that leukemia cells depend upon a partnership between two proteins, Growth Factor Independence-1 (GFI1) and Lysine Specific Demethylase-1 (LSD1) in order to survive. The GFI1—LSD1 complex promotes leukemia cell survival by blocking genes that cause cell death. Leukemia cells cannot survive without GFI1, even if LSD1 is present, nor can they survive without LSD1 even if GFI1 is present. This suggests that inhibitors of the GFI1—LSD1 axis can trigger leukemia cell death. To this end, we developed a new drug (SP-2577) that selectively inhibits LSD1, overriding pro-survival effects of the GFI1—LSD1 axis and triggering death of AML and ALL cells. Notably, SP-2577 causes death of leukemia cells that are resistant to other drugs currently used to treat leukemia, and thus may provide a treatment for patients with relapsed disease. Our proposal tests the addition of SP-2577 to established treatment regimens for patients with relapsed AML or ALL and validates markers of SP-2577 “on target” activity for future multi-institutional clinical trials.
Acute myeloid leukemia (AML) has the most dismal prognosis of all blood cancers, and >70% of AML patients will succumb to their disease. Therapy is still based on a chemotherapy regimen developed more than three decades ago and what little progress has been made is attributable to improvements in supportive care. Although most patients initially respond to therapy, leukemia stem cells survive in sanctuary sites of the bone marrow and eventually cause relapse and death. Intense research has identified the major DNA mutations in AML, but this knowledge has not led to therapeutic breakthroughs. To overcome this stalemate, our translational medicine research team has taken a function-first approach to identify vulnerabilities in AML cells that are independent of genetic mutations and continue despite protection afforded by the bone marrow. We discovered that cells from most AML patients are highly dependent on SIRT5, an enzyme that regulates energy metabolism, while normal controls are not dependent on SIRT5. As no clinical SIRT5 inhibitors exist, these results prompted us to conduct a search for new SIRT5 inhibitors. We identified a highly promising candidate (HCI-0250) as the starting point for the development of a clinical SIRT5 inhibitor. We will validate SIRT5 as a therapy target in AML using mouse models reflecting key aspects of the clinical disease. In parallel, we will develop a potent and selective SIRT5 inhibitor as a candidate for clinical trials in AML. If successful, our work may lead to a new treatment paradigm applicable to a majority of AML patients.
Funded by the Stuart Scott Memorial Cancer Research Fund
Antibody treatments that block ‘immune checkpoints’ which prevent the immune system from fighting cancer, have resulted in impressive tumor shrinkage and long term survival in many patients with cancer. Results from studies in metastatic triple-negative breast cancer (TNBC) indicate promising activity but not yet the exceptional results seen in tumors known to be highly “immunogenic” or responsive to alterations in the immune system. Strategies to make TNBC “immunogenic” are therefore of great interest as they may result in long term control of TNBC. This is of particular relevance to minority groups such as the African American population, who often present with an aggressive TNBC with limited treatment options available.
Our collaborators at Johns Hopkins have laboratory data, suggesting that combining the histone deacetylase (HDAC) inhibitor entinostat with immune-checkpoint blockade (nivolumab and ipilimumab) led to eradication of breast tumors and long term cures. Research suggests that entinostat may alter the tumor environment by affecting the regulatory immune cells which can prevent immune-checkpoint agents from fighting cancer. This combination may thus be able to convert these traditionally “non-immunogenic” tumors into tumors which can respond to immune therapy.
We are thus conducting a phase I clinical trial of entinostat, nivolumab +/- ipilimumab in advanced solid tumors and patients with TNBC. We anticipate that the collection of blood and tumor specimens during the study will allow us to determine how these drugs are working in patients so we can develop future trials with the hope of significantly improving outcomes for patients with TNBC.
Funded by the Stuart Scott Memorial Cancer Research Fund
Obesity and diabetes are associated with increased risk and worse outcomes for endometrial cancer (EC). African American (AA) women suffer a higher mortality from EC than Caucasian (CAU) women, and this may be in part due to greater rates of both obesity and diabetes among AA versus CAU patients. Metformin is a drug used in the treatment of type 2 diabetes. Our preliminary data finds that metformin has anti-cancer activity, due to its indirect effects within the body (decreased insulin/glucose) and direct effects on EC cells through inhibiting signaling pathways involved in metabolism, including suppression of fatty acid/lipid biosynthesis. Thus, it is logical that metformin may break the link between obesity and EC and emerge as a new targeted agent for the treatment of this cancer.
Our overall goal is to assess the contribution of indirect effects (via decreasing insulin and glucose levels) and direct effects (via inhibition of metabolic pathways and blunting of fatty acid/lipid biosynthesis) of metformin to its overall anti-cancer efficacy in (i) a clinically relevant EC mouse (obese/lean) model and (ii) an ongoing randomized phase 2/3 clinical trial evaluating metformin versus placebo, in combination with standard of care paclitaxel/carboplatin for the treatment of EC. We hypothesize that predictors of metformin response will include both molecular and metabolic biomarkers, specifically obesity, insulin resistance, upregulation of insulin/glucose signaling and heightened fatty acid/lipid biosynthesis, and this response may differ according to race. From this work, we hope to validate metformin as an innovative treatment strategy for obesity-driven EC.
Immune targeted therapies, which stimulate the immune system to attach cancer have revolutionized cancer treatment strategies. These successes have offered new therapeutic avenues for cancer patients, especially for those with lung cancer. Despite the impressive clinical efficacy and duration of responses observed, the fraction of patients with durable responses remains in the order of 20% and there is therefore an unmet need to maximize efficacy of these treatments as well as identify the patients more likely to respond. We propose to use clinical samples from 2 novel clinical trials that combine immune targeted therapy with a different class of medicines, called epigenetic therapy. We have shown that epigenetic therapy may attract immune cells to the cancer site therefore “priming” an anti-tumor immune response. We propose to pinpoint the mechanisms that mediate response and resistance to these therapies by looking at the genetic make-up of cancer cells as well as by studying the tumor microenvironment. We believe our comprehensive, cutting-edge scientific approach linked with ongoing or soon to start clinical trials will result in immediate clinical intervention initiatives and is consistent with our mission to deliver improved treatments to patients with lung cancer.
