Facilitate the transition of projects from the laboratory to the clinic. Translational researchers seek to apply basic knowledge of cancer and bring the benefits of the new basic-level understandings to patients more quickly and efficiently. These grants are $600,000, three-year commitments
Most cancer treatments — such as chemotherapy, radiation therapy and targeted therapy — work by direct killing of cancer cells. Some of the recent and most powerful therapies work by stimulating the patient’s own immune system to kill cancer cells. While these new immune-based therapies work better than most previous therapies and are now approved for treating 13 cancer types, they do not work for all patients. To understand why these treatments works for some patients and not others, we need better tools to investigate how the immune system interacts with cancer. We have developed a new way of growing tumors outside patients’ bodies to study how tumor cells and immune cells interact with each other. Our goal is to study how different types of immune cells stop cancer growth. We use our new method for growing tumors outside of the body to test out new treatments designed to steer the immune response towards tumor cells more effectively. If initial tests are successful, we will aim to try these new treatments in patients with melanoma and potentially other types of cancer.
Stomach cancer, the third-leading cause of cancer death world-wide, is classically divided into two primary types, one of which is called Diffuse Stomach Cancer (DSC). DSC is a very aggressive and rapidly-lethal disease where we lack effective therapies. Additionally, DSC also impacts a relatively unique group of patients. DSC is increasingly common in young females, often women in their 30’s-40’s and is also highly prevalent in the Latin American and Native American populations. Unfortunately, although DSC patients are in tremendous need of therapies, there has been relatively little laboratory research seeking to understand biology of these cancers or to develop new, more effective therapies. At our cancer center, we have established a new collaborative research programaiming to address this critical unmet medical need. We have built off of the progress we have made by studying the specific genes that are abnormally turned on in these cancers. Over the past years we have specifically studied the biology of DSC and have defined new highly promising candidate therapeutic approaches. Additionally, our collaborative team has developed new cancer models (cancer cells we can grow and study in the laboratory) from Latin American patients’ (and young females’) cancers. We now propose to bring together our new candidate therapies and this new collection of patient models to prepare optimal therapeutic approaches for DSC into clinical trials. This work will enable us to rapidly bring the most promising new therapeutic approaches into patients, including under-represented minorities whose cancers are often not adequately studied.
Pancreatic cancer is the 3rd leading cause of cancer-related death in the United States, with a five-year survival rate of less than 9 percent. Activation of the immune response in the microenvironment is associated with better outcomes in pancreatic cancer patients. The tumor and gut microbiota has recently been shown to influence tumor progression by modulating the tumor microenvironment.
We have recently demonstrated that the composition of the gut microbiome may determine tumor behavior and outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. We have identified specific bacteria signatures in the tumors of long-term survivors (LTS) compared to the stage-matched- short-term survivors (STS). We have also shown that transplantation of fecal microbiome from LTS or healthy controls of pancreatic cancer patients into a mouse model of PDAC significantly reduces pancreatic cancer growth. These important findings prompted us to target tumor microbiome as a therapeutic approach in pancreatic cancer patients. Here, we propose to transplant stools from PDAC long term survivals or healthy controls into PDAC patient to change their immune suppressive behavior to immunoactivated one. To this end, we will first analyze the changes in microbiome of PDAC patients after the transplantation of gut microbiome from long term survivals or health controls. Next, we will evaluate the tissue obtained from biopsy and surgical specimen for the changes in tumor microbiome of PDAC patients. Finally, we will characterize the tumor immune infiltrates from tissues obtained from PDAC patients to see if we can switch PDAC immunosuppressive TME into immunoactivated by fecal microbial transplantation. This proposal would be the stepping stone to move forward efficacy trials in PDAC patients combining FMT with standard treatment or immunotherapy.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. CLL starts in the bone marrow in a type of white blood cells called B-lymphocytes. Standard chemotherapy has been successful in treating most patients, but drugs often are not effective when a small group of leukemia cells have specific changes in their DNA. In our earlier work, we used advanced DNA sequencing and found mutations that were present in only a few leukemia cells. These mutations, which were not found by common approaches in the clinic, changed the function of a gene called TP53. The cells that had these mutations became the major leukemia population when CLL came back. To treat such high-risk patients, new drugs have been developed, which disrupt the processes that leukemia cells use to interact with their environment. Similar to resistance against chemotherapy, some cells, which may have alterations that stop the drug from working, are not killed and can result in CLL’s return. In this project, Rutgers Cancer Institute of New Jersey and the Institute of Oncology Research will work together to analyze patient samples collected during treatment in a clinical trial, and apply highly sensitive experimental approaches to thousands of single leukemia cells to develop models that help us understand how CLL cells behave and change under new therapies. We will test our results in independent groups of patients who are being treated with the same drug, with the goal of finding new ways for doctors to diagnose and treat patients.
The proposed studies will address two major issues in treating two hematological cancers, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML): limited new and effective treatments for the last 30 years; treatments that are optimal on a patient-specific basis. MDS and AML cells arise in the bone marrow from healthy hematopoietic stem cells. Accumulation of several mutations is involved in this process. In addition, other cells in the bone marrow can affect MDS or AML development or progression: stroma cells that give rise to bone, fat and other cell types. We have identified a new pathway of communication between MDS or AML cells and stromal cells. At least 35% of MDS and AML patients express high levels of JAGGED1 in their bone cells. Our studies in mice show that JAGGED overexpression leads to MDS/AML development. Conversely, blocking JAGGED1 in mice treats MDS and AML and prevents lethality. We generated human antibodies that block JAGGED1 activity and can be used in treating MDS and AML patients. Our purpose is to test efficacy of the most active human antibodies in all subtypes of MDS and AML using mouse models and cells from patients. We have developed a robust and simple screening test for identifying the patients who have the JAGGED1 pathway active using cells from their bone marrow. Our studies will benefit patients by screening and identifying the ones with pathway activity that can be treated with the antibody. This patient-specific approach should increase the precision and efficacy of treatment.
Partially funded by the Stuart Scott Memorial Cancer Research Fund and the V Wine Celebration in honor of First Responders
Nick Valvano Translational Research Grant*
Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) originate from abnormal blood stem cells which have acquired multiple molecular aberrations over time and generate the bulk tumor cells that are diagnosed in patients in the clinic. Conventional therapies inhibit the bulk tumor cells; however, they do not eliminate the early blood stem cells that are the true root of the disease. Recent work has uncovered unexpected diversity of stem cells in patients with MDS, detected through a new methodology which we recently developed. Cancer/leukemia development is, at least in part, promoted by exposure to environmental toxins. The terrorist attacks on the World Trade Center created an unprecedented environmental exposure to aerosolized dust and gases that contained many carcinogens, and over the past few years we have built a large repository of samples from 9/11 first responder fire fighters, and non-exposed fire fighters as a control. We will leverage this unique sample repository and our newly developed methodology to study over time blood stem cells of individuals who have donate samples to this repository. Our study will be instrumental to improve diagnostic assessment, including at blood the stem cell level, and this may help to improve treatment selection focused on the true root of the disease. In addition, our study may be helpful for the development of treatment strategies for the prevention of leukemia in the future.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Sarcomas are cancers of connective tissues in the human body. It affects children and teenagers more than adults. Cancers that spread to other parts of the body are difficult to treat and are not often curable. A new treatment approach called immunotherapy uses the body’s own immune system to fight cancer. Our approach uses immune cells of the body, namely T cells, to find and kill tumor cells after introducing an artificial molecule called chimeric antigen receptor (CAR). These CAR-enhanced T cells developed in our laboratory recognize a protein on the surface of the cancer cell, namely HER2. Patients with advanced sarcoma received these HER2-specific CAR T cells in our ongoing clinical trial. The CAR T cells did not cause severe adverse reactions in any of the treated patients. More than half of the 10 patients who received the cell treatment benefited from it, with 2 patients achieving tumor elimination and 4 others achieving cancer stabilization. We will now test if larger dose of T cells can be tolerated or increase the chances of benefit. We will also study immune responses in these patients to identify mechanisms, if any, that can lead to improved treatments. Finally, we will evaluate a new molecule that can help CAR T cells overcome tumor signals that turns them off. The insights gained from this study will help design and develop targeted treatments for sarcoma.
Immunotherapy has revolutionized our ability to care for cancer patients, and works by enabling one’s own immune system to detect and kill cancer cells. Unfortunately, immunotherapy has not yet been broadly effective against the most common type of breast cancer, which is driven by the estrogen hormone (ER-positive or “Luminal” breast cancer). This project aims to overcome this challenge. We will investigate whether radiation treatment in combination with other targeted therapies can overcome resistance to immunotherapy in Luminal breast cancer. We will use clinically relevant breast cancer models to better understand how radiation and immunotherapy work together to stimulate anti-tumor immunity. We will use genetic tests to identify biomarkers of an effective immune response, as well as biomarkers of treatment failure. Finally, we will apply these tests to a clinical trial of radiation and immunotherapy in breast cancer patients. Our goal for this project is to determine whether radiation-immunotherapy combinations can potentially improve the lives of patients with breast cancer. We anticipate that results from this project will inform the optimal design of clinical trials investigating radiation-immunotherapy combinations in breast cancer patients.
The immune system removes transformed cells that give rise to cancer. For many years, the process that tumors use for shielding against the immune system was poorly defined. Now the factors that prevent tumors from being destroyed are being discovered. This is spurring new drugs to be made that kick-start immune cells to reject tumors. These new drugs, named immune ‘checkpoint’ inhibitors, are having a major impact on the treatment of patients with different cancers. These drugs disrupt tumor shielding to revive immune cells for combat and inspire hope that one-day patients may no longer need toxic chemotherapy. Although many patients respond well to immune therapy drugs, with time, the tumor can adapt and develop new tactics to outsmart immune cells. Now that more than 40% of cancer patients are candidates for immune therapy, drug resistance is becoming a key problem.
With colleagues at Vanderbilt University, we recently studied how resistance may develop in patients with melanoma, breast, and lung cancer. We found new factors that could cause tumor resistance, but might also be novel targets for immune therapy. In this proposal, we first plan to study these new targets in tumor samples from patients with resistance. Secondly, we will learn how they bind to tumor shielding factors and screen drugs that could block them. Finally, we will study these new immune therapy drugs in mouse models of cancer. We expect that this proof of concept study will introduce a new target for next stage development in early clinical trials.
Funded by the Stuart Scott Memorial Cancer Research Fund
Immunotherapy has been one of the most remarkable advances in our fight against cancer. Its transformative impact on patients has been recognized with the 2018 Nobel Prize in Medicine. Immunotherapy, unlike other treatments for advanced tumors, can result in long term remissions and cures. Unfortunately, only a subset of patients benefit from immunotherapy. The majority of patients experience unremitting progression of cancer and a significant number suffer serious side-effects, which are sometimes life threatening. In those patients, immunotherapy could end up delaying or preventing other useful treatments. Cancer patients and their doctors badly need tests called ‘predictive biomarkers’ to determine whether a particular patient will benefit or be harmed by immunotherapy. Here, we propose to discover such biomarkers by analyzing tumor tissue samples from a large group of patients treated with immunotherapy. We have established a database (MIRIE) which includes all University of Michigan patients who received cancer immunotherapy since 2011. We have also developed a novel molecular assay (TAGTILE) to identify gene changes and gene expression patterns in their tumor tissues obtained before immunotherapy. By using TAGTILE to compare tumors from patients who did benefit from the therapy to tumors from patients who did not, we will be able to identify molecular characteristics of responding tumors. This information will be used to create a diagnostic test (e.g. a decision chart) to help oncologists and patients decide whether to choose immunotherapy. When routinely implemented, such a test can improve results in patients and avoid unnecessary side-effects.
