Zuzana Tothova, M.D., Ph.D.

Abeloff V Scholar* (Tied for Top Rank)

Funded by the Constellation Gold Network Distributors

Use of a new DNA sequencing technology called next generation sequencing (NGS) has significantly improved our ability to describe the genetic basis of human cancers, including blood cancers like leukemia. However, we do not fully understand how most of the genes that cause leukemia play a role in this disease and how to target them with therapy. We know that mutations in a protein complex called the cohesin complex, which normally helps genes turn on and off, frequently occur in patients with blood cancers. These mutations usually occur during the process of disease progression from pre-cancerous states to highly aggressive cancer types. Cohesin mutations are found in 10-20% of patients with blood cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) and are associated with poor survival. With this grant, we will focus on exploring how DNA changes mediated by the cohesin complex play a role in disease progression. Specifically, we will examine folding of DNA into loops and organization of chromatin during the steps of disease progression. Treatment options for patients with blood cancers are limited, and by expanding our understanding of the mechanisms by which leukemia causing genes contribute to disease development, we aim to inform the design of urgently needed therapies for patients. The impact of this work is far reaching and may extend to patients with other blood cancers, including chronic myelomonocytic leukemia (CMML) and chronic myeloid leukemia (CML), as well as patients with bladder cancer, glioblastoma, Ewing sarcoma and breast cancer.

Stephanie Correa, Ph.D.

V Scholar Plus Award – extended funding for exceptional V Scholars

Tamoxifen is an extremely effective drug for patients with estrogen sensitive breast cancer but it comes with a variety of side effects, including hot flashes. We use mice to test if symptoms similar to hot flashes are mediated by the effects of tamoxifen on the brain. We study a region of the brain that is very sensitive to estrogen and controls body temperature. We have identified differences in this region that are associated with changes in body temperature during tamoxifen treatment. Our immediate goal is to test if we can use this knowledge to block temperature changes in mice receiving tamoxifen. Our hope is that these studies could one day help us reduce hot flashes and improve the lives of breast cancer patients and survivors.

Francine Garrett-Bakelman, M.D., Ph.D.

V Scholar Plus Award – extended funding for exceptional V Scholars

Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults. The majority of patients diagnosed are over the age of sixty and individuals in this age range experience poor response to treatment and worse clinical outcomes compared to younger patients. Despite advances in the field, clinical outcomes for AML patients over the age of sixty remain poor. To improve upon current treatment options for AML patients over the age of sixty, it is essential to better understand the mechanisms that drive the disease in these patients. The project proposed utilized data generated from AML patients older than 60 to identify RBM47 as a potential biomarker and driver of the disease. We will utilize data from another set of patients to confirm the association between the level of RBM47 in AML cells and clinical outcomes in these patients. Furthermore, in order to identify how RBM47 may contribute to the disease, we will determine what aspect(s) of AML biology RBM47 may regulate. Collectively, these findings will contribute to a body of knowledge for a long-term goal of identifying potential targetable mechanisms of disease that could be used to develop new and more effective treatments for AML patients over the age of sixty.

Janet Patterson-Kane, BVSc, Ph.D., FRCVS

Funded in partnership with the Morris Animal Foundation and the Wine Celebration Fund-A-Need

In 2012, Morris Animal Foundation launched its Golden Retriever Lifetime Study primarily to explore the risk factors related to cancer in golden retrievers. The Study has been following 3,044 dogs throughout their lives, collecting wide-ranging data on each animal each year, including environmental exposures, behavior, medical diagnoses, medications, diet and more. Golden retrievers were selected for this study because they are diagnosed with cancer at a much higher rate than most other breeds of dogs, and some of the most common cancers in golden retrievers are closely related to common human cancers.

This grant relates to genomics of our enrolled Study dogs. We will first test DNA samples from all of the dogs. We will be looking for small variations in hundreds of thousands of places along the DNA strands. Some variations may imply that a dog has a greater risk of a certain cancer type or one of the other diseases we are documenting. Similar studies are done for humans, but the advantage in dogs is that such information might ultimately be used in breeding programs to reduce the occurrence of cancer in the first place.

A second aspect of the grant will focus on biopsy specimens. We receive biopsy specimens from many of the cancers diagnosed in our Study dogs. We will be conducting a very detailed analysis of DNA, called sequencing, in these cancer tissues. Cancers occur due to changes in the DNA, called mutations. This study will allow us to determine which mutations are occurring in certain cancers that have similarity with those occurring in human patients. These include lymphoma (a cancer of white blood cells), osteosarcoma (bone cancer), and hemangiosarcoma (cancer of blood vessels). This information may lead to further studies on how to prevent and treat these cancers in both dogs and humans.

Michael Cinkoskey

Funded in partnership with the Morris Animal Foundation and the Wine Celebration Fund-A-Need

In 2012, Morris Animal Foundation launched the Golden Retriever Lifetime Study primarily to explore the risk factors related to cancer in golden retrievers. The Study has been following 3,044 dogs throughout their lives, collecting wide-ranging data on each animal each year, including environmental exposures, behavior, medical diagnoses, medications, diet and more. Golden retrievers were selected for this study because they are diagnosed with cancer at a much higher rate than most other breeds of dogs, and some of the most common cancers in golden retrievers are closely related to common human cancers.

The data being collected by the Golden Retriever Lifetime Study is freely available for academic research via the Morris Animal Foundation Data Commons. The goal of the current project is to augment the Data Commons with high-resolution genotype data on each of the dogs and, eventually, complete DNA sequence data on all of the dogs diagnosed with cancer, along with a suitable number of other dogs as controls. As the genotyping and sequencing is completed, Morris Animal Foundation will perform preliminary data validation and analysis, and then incorporate the data into the Data Commons, where it will be available to everyone with an account. This will enable researchers from institutions around the world to participate with us in the effort better understand canine cancer as well as inform human cancer research.

Morris Animal Foundation Data Commons accounts can be requested by anyone involved in academic research by completing the registration form on the Data Commons website.

Marjory Charlot, M.D.

Funded by the Victory Ride to Cure Cancer

All cancer patients should have the opportunity to get very good care through research studies. Research studies are important to make cancer treatments and survival from cancer better but very few people of color are treated on cancer research studies called clinical trials. One way to solve this problem is to use specially trained staff to help cancer patients better understand clinical trials.  These staff are called patient navigators. In this project, we will use patient navigators to teach and support patients asked to be in a cancer research study.  These navigators will work as a team to make sure that all African Americans who receive care at the Cancer Center are considered for a clinical trial.  In order for the patient navigator to know which patients may be fit to participate in research, we will use information from the medical record to create a list of patients that could be asked about their interest to get treatment with a clinical trial. The patient navigator will use this list to contact patients and will teach patients about clinical trials and connect patients to finance counselors, social workers and other helpful community services as needed. To understand if the project is a success, we will compare the total number of patients, by race, treated on a cancer research study before and after the project.

Anne Avery, VMD, Ph.D.

Funded in partnership with The Leukemia & Lymphoma Society’s PedAL Initiative and the Wine Celebration Fund-A-Need

Acute myeloid leukemia is a cancer of bone marrow cells. It can be difficult to treat, particularly in young patients. The disease can differ from one patient to another, depending on the kinds of mutations that are found in the cancer cell. Different mutations may respond to different treatments.

Dogs also develop acute leukemia. In this species the outcomes are dismal, with most dogs being euthanized within days of the diagnosis because of poor quality of life. Currently available chemotherapy is ineffective in this species.

In this project we will sequence DNA and RNA from 100 cases of naturally occurring acute leukemias in pet dogs. Our goal is to find mutations and gene expression patterns shared between dogs and people. Once these shared features are identified, new treatments can be devised which can be tested first in dogs, and if successful, translated to humans. This approach offers a chance at better therapies in both species.

Jihye Yun, Ph.D.

Colon cancer is the second leading cause of cancer-related deaths in the United States. An increasing number of human studies have highlighted the association among the consumption of sugary drinks, obesity, and the risk of colon cancer. It is currently thought that sugar is harmful to our health mainly because consuming too much can lead to obesity. It is well known that obesity increases the risk of many types of cancer, including colon cancer. However, whether a direct, causal link exists between sugar consumption and colon cancer has remained unknown.

Our group recently showed that consuming a modest amount of refined sugar every day—the equivalent of a human drinking about 12 ounces of a sugar-sweetened beverage daily—accelerates colon tumor development in mice, and it does so independently of causing obesity. The proposed project will identify the molecular mechanisms by which sugar enhance colon tumor development. In particular, we will focus on how sugary drinks alter the bacteria living in the gut and how these altered gut bacteria contribute to tumor development. To this end, we hope to identify bacteria that increase specifically in response to sugar consumption that could serve as new targets for prevention and treatment for colon cancer patients. Given that more than half of American young adults consume at least one sugar-sweetened beverage daily, and that young-onset colon cancer is on the rise for unknown reasons, any positive findings from this project will be of immense significance.

Vivian Weiss, M.D., Ph.D.

Funded by the Tyler Trent Fund and the Dick Vitale Pediatric Cancer Research Fund

A critical failure in the field of pediatric thyroid cancer care is the use of adult treatments for a childhood disease that has distinct genetics and tumor behavior. With thyroid cancer incidence rapidly increasing, we need to develop personalized treatments for this population to ensure their long and productive lives. There is currently no way to predict which children will go on to develop recurrent or aggressive disease at the time of biopsy and thyroid surgery. While thyroid cancer is generally curable, adolescents and young adults present with more frequent local and metastatic disease when compared to older adults. Adult treatment protocols lead to high cure rates, but adolescents and young adults have many years of potential recurrence, radioactivity-induced side effects, and secondary malignancies ahead. Precision medicine is becoming the standard of care for many diseases except pediatric thyroid cancer.

To develop more individualized pediatric thyroid cancer care, the scientific community must first strive to better understand the mutations and abnormal cellular signaling responsible for thyroid cancer behavior. Our research program utilizes a large cohort of adolescent and young adult human thyroid tumors in order to study the signaling pathways responsible for the unique growth and spread of each tumor. The funds from the Pediatric Cancer V Scholar Award will lead to an improved understanding of thyroid cancer development in this population and innovative therapies for children with this disease. These treatment strategies can then be applied to a wide range of pediatric cancers with reliance on similar signaling pathways.

Tuomas Tammela, M.D., Ph.D.

Lung cancer is the leading cause of cancer-related death worldwide, killing more than breast, prostate, colon, kidney, and liver cancer combined. Lung adenocarcinoma (LUAD), the most common type of lung cancer, alone kills ~60,000 Americans every year. Therefore, preventing lung cancer would have a large impact on society. Preventing lung cancer altogether would also address the problem of worse outcomes for patients who, for social and economic reasons, have unequal access to cutting-edge cancer treatment. Even patients who are cured of cancer experience psychological trauma, so prevention would also mean that no one would have to go through such a traumatic experience. Our initial results show that early lung cancers are less complex and therefore should be easier to eliminate compared to advanced disease that has spread from the lung to other parts of the body. We propose to study the earliest steps, when a normal lung cell becomes a cancer cell. To do this, we have developed a way to study lung cancer cells in the lab that closely resembles how tumors grow in humans. In addition to studying features of early lung tumor cells, we will also study the surroundings of these cells, a method that has not been used before to study lung cancer. We aim to discover molecular processes that are essential for the formation of lung cancer. Drugs could then be developed to block these processes and stop lung cancer at its earliest stages – preventing the disease altogether.

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