Translational Archives - Page 14 of 31

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.

Kevin Krull, Ph.D.

Year one is partially funded by UNICO in memory of Toni Alongi

Survivors of childhood leukemia (ALL) who are treated with chemotherapy develop poor cognitive skills (e.g. attention, speed of thinking, reasoning). These poor cognitive skills cause problems with school, work and peer interactions. The survivors also display abnormalities on brain imaging. We demonstrated that fluid collected during a spinal tap (i.e. cerebrospinal fluid [CSF]) contained markers of brain injury. However, our initial study was too focused on specific brain cells. We could not identify the cause of the brain injury. Thus, we want to conduct another study to examine many more protein markers before and after chemotherapy treatment.

We will use an advanced process to identify over 4,000 proteins in the CSF. This will permit us to determine the cause of the brain injury. We will compare the proteins to sex and age of the survivors. We will also compare the proteins to the treatments the survivors got. Finally, we will compare the change in proteins to brain imaging and cognitive testing.

CSF samples from a recently completed trial have been collected and frozen at −80°C so they will not decay. The brain imaging and cognitive testing is currently being completed as part of an institutionally funded protocol. For the current project, we will process the CSF samples and link them to adverse events and clinical outcomes.

With this comprehensive approach, we will identify which survivors are at greatest risk, and identify targets to prevent brain injury in future clinical trials.

Norah Lynn Henry, M.D., Ph.D.

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

Aromatase inhibitors (AIs) are important drugs for treating breast cancer. These drugs lower estrogen levels and reduce the chance that a woman will die from cancer. However, about one in five patients stops taking the drug early because of aggravating muscle and joint pain. Stopping the drug too soon can increase her risk of her cancer coming back. We do not know why women develop this pain, but it might be due to very low estrogen levels. We also do not know how to prevent the pain. Oxylipins are fat particles in the body that can increase or decrease pain. We believe that when a woman is treated with medicine that lowers her estrogen levels, that leads to more fats that cause pain. By also taking omega-3 pills, we believe that women instead will have more fats that decrease pain. This will allow her to continue to take the AI medication. To address this question, women who are starting to take an AI will also take either omega-3 pills or olive oil pills. We will ask if they develop pain and also check the levels of fats in their blood. Through this study we will find out if omega-3 pills prevent this side effect, and will learn more about how the AI medicine causes the pain. Knowing more about why women get this bothersome pain and how to prevent it will allow doctors to better treat patients and will allow more women to continue taking this life saving medication.