Translational Archives - Page 13 of 30

Stavroula Kousteni, Ph.D. & Azra Raza, M.D.

Bob Bast Translational Research Grant*

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.

Ulrich Steidl, MD, PhD

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.

Meenakshi Hegde, M.D.

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.

Gaorav Gupta, M.D., Ph.D. & Benjamin Vincent, M.D.

Funded by Hooters of America, LLC

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.

Randall Davis, M.D.

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.

Marcin Cieslik, Ph.D. & Ajjai Alva, M.D.

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.

David Carbone, M.D., Ph.D.

Lung cancer is the leading cause of cancer death in the US and worldwide, and non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. A subset of these cancers has a “driver” gene mutation the epidermal growth factor receptor (EGFR) for which targeted agents are highly effective in causing tumors to shrink. However, it never cures patients and the tumor always grows back. This proposal focuses on why the cancer is not completely killed even though all of the tumor cells have this mutation, and how to overcome this problem and kill the cancer more thoroughly. Our published and preliminary data have demonstrated that targeted therapy rapidly induces drug persistent cancer stem cells (DPCs) within days of starting therapy, and these DPCs don’t die with the drug. We show that this therapy specifically activates other genes called Notch3 and β-catenin that are essential for this effect. We show in animal experiments that targeting both EGFR and β-catenin result in reduced numbers of DPCs, and improved depth and duration of response and overall survival. This is a completely different approach than trying to target drug “resistance” pathways that develop months after initiation of therapy due to the “persistence” of tumor in the early days of therapy. Our goal is to eliminate tumor persistence so that it doesn’t have the chance to develop resistance, resulting in the cure of these patients. In this application, we propose to study how this persistence happens and attempt to move toward curing these patients by targeting β-catenin in combination with EGFR in a pilot human clinical trial. Successful completion of the proposed research will increase our understanding of why tumor cells are not eradicated with EGFR targeted therapy and test a novel drug combination that we hope will improve the survival of these patients.

Leonard Zon, M.D.

Funded in partnership with Adenoid Cystic Carcinoma Research Foundation (ACCRF)

We recently found that retinoic acid treatment reduces the growth of a salivary gland tumor.  The retinoic acid has the ability to shut down the cause of the cancer which is due to the overactivity of a gene called c-myb.  Retinoic Acid has been successfully given to patients with a rare type of leukemia and we plan to use the same doses as the leukemia patients.  We will examine whether the retinoic acid is active in the tumor and whether the growth of the tumor is reduced.  Our studies have the possibility of finding the first treatment for this metastatic tumor.

Ann Partridge, M.D.

Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund

People who have been treated for cancer are not only at risk of cancer returning, but also at risk of long term side effects of their treatments some of which may threaten their life, including heart disease and other cancers. Medical teams are always searching for new ways to identify and reduce these risks. Some people will develop changes in their blood cells called “Clonal Hematopoiesis” (CH) and people with these changes have recently been found to be at higher risk of developing serious problems such as cancer and heart attacks and dying. CH is found more in older than younger people and more commonly in people who have been treated for cancer. We don’t know how common CH is in cancer survivors, who is at risk, when it develops and when and if we should be looking for it. But we are finding it more commonly with genetic tests that are being done as a part of their care. Our team hopes to provide answers to these questions by looking for CH in a group of women who were treated for breast cancer at a young age and agreed to give us blood samples and let us follow them over time. We will do special testing to find CH in their stored blood and see how it is different in different women, and changes over time. We will also ask them how they might feel about learning about CH results if they had CH, how learning about these risks that might affect them, and what they might need to support them best to help them to manage these risks. We hope this research leads to findings that can be used to understand this problem better and to improve how we take care of cancer survivors both now and in the future.

Elli Papaemmanuil, Ph.D.

Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund

Leukemias represent cancers of the blood and are caused by genetic changes (mutations) in our blood cell that drive uncontrolled cell growth. Cancer survivors are more likely to develop leukemia than the general population. Traditionally this was thought to be a consequence of toxicity from the treatments used to fight their cancer, which leads to the development of therapy-related myeloid neoplasm (tMN) one of the most deadly and challenging to treat cancers. However recent studies show that leukemia associated mutations can be found many years before cancer diagnosis and interestingly, these blood mutations can also be seen in healthy people who never develop leukemia. This is phenomenon is called clonal hematopoiesis (CH). Our group has shown that CH is frequent in cancer patients and we find that cancer treatment may promote growth of cells carrying such mutations. To understand the effects of cancer treatment in patients that carry such mutations and how this dictates subsequent progression to leukemia, we propose to study a total of 45,000 cancer patients at time of cancer diagnosis. This will identify individuals with CH at time of diagnosis. We will then follow up patients and study the effects of oncologic therapy to analyzed for the presence of CH and study the effects of distinct cancer treatments on CH. Our study will help us understand tMN and guide the development of interventions to prevent tMN.