Jianjun Wu, PhD

The human body’s immune system is a powerful weapon against cancer, but cancer can also create a complex environment that weakens immune system effectiveness. This environment, called the tumor microenvironment (TME), is made up of different cell types, including tumor cells and immune cells. Scientists have discovered a protein called STING that can change the TME and activate the immune system to fight cancer. However, STING therapy hasn’t worked well in clinical trials because tumors have become resistant to it. To activate STING, researchers use a small molecule called cGAMP. Treatment of cancer with cGAMP can activate STING in various cell types within the TME. When cGAMP is delivered to most immune cells in the TME, it activates STING and triggers an immune response against cancer. However, we found that cGAMP can also be delivered to T cells, which are important cells in killing cancer cells, it actually causes T cells to die. This weakens the immune system’s ability to fight cancer. Therefore, we think that the entry of cGAMP into T cells leads to their death, allowing tumor cells to escape being killed by T cells. Our goal is to identify the specific molecules responsible for cGAMP entry into T cells and develop new strategies to overcome tumor resistance to STING therapy by blocking the entry of cGAMP into T cells.

Priya Dedhia, MD, PhD

Adrenocortical carcinoma is a cancer of the adrenal glands that often kills the patient. Drugs to treat this cancer have failed because current research models, which use cell lines or mice, are too different from the cancer itself. Cell lines made from the cancer only have one type of cancer cell, while the original cancer has many types of cancer cells. Mice have many types of cancer cells, but the mouse cancer is too different from the human version to be helpful. To develop new treatments for this cancer, we need to make a model that includes many types of human cancer cells.

Organoids, or “mini-organs,” are a new research model that has many cell types and can be made from human tissues. They have been used to study other cancers that were previously difficult to study. We developed adrenocortical carcinoma organoids, which grew and made hormones just like the original cancer. Here, we use these organoids to study different types of cells in the cancer to determine which cells are more likely to cause worse disease. With this information, we can target weaknesses in the most dangerous cancer cells to stop the cancer from progressing, reduce treatment-related side effects, and improve survival and quality of life for patients with this terrible cancer. We also expect that our new methods can be used by scientists studying other cancers to figure out which cells are the most dangerous, so that patients with other cancers can benefit from this research.

LaQuita Jones, DO

Funded by the Dick Vitale Pediatric Cancer Research Fund and the V Foundation Wine Celebration in honor of Jon Batiste and Suleika Jaouad, and Christian and Ella Hoff

Leukemia is a cancer involving a type of blood cell. Some of these cancers can be especially difficult to treat because of their aggressive nature. My lab researches a type of blood cancer that causes death in nearly 4 out of 10 children who are diagnosed with this disease. Based on prior experience, we know that some characteristics of this cancer can lead to worse outcomes in children, but we don’t fully understand all of them. My research aims to discover a more detailed understanding of what causes these cancers to act aggressively, so we can then use this information to find new treatments to cure this type of cancer.

Margot Lazow, MD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Brain and spine tumors are the leading cause of cancer-related death in children, adolescents, and young adults. Outcomes for pediatric and young adult patients diagnosed with high-grade gliomas (HGG) remain dismal, with 5-year overall survival tragically <10%, despite intensive surgery, radiation, and/or chemotherapy. There is therefore a critical need to develop effective, well-tolerated therapies for children and young adults with HGGs. Recent scientific discoveries have provided valuable insight into the genomics of these aggressive diseases and identified genetic changes which can serve as targets for therapy. Research has helped develop less toxic medicines, usually oral drugs, which can directly target specific genetic alterations present in the tumor to slow or stop its growth and spare healthy organs. We propose an innovative multi-arm clinical trial offering a precision medicine approach to treat children and young adults newly diagnosed with HGGs. Detailed genetic sequencing using advanced technology will be performed on tumor tissue from all patients upfront, with return of results within 3-4 weeks. Patients will then be assigned to one of several unique molecularly-targeted treatment arms based on (and directly targeting) the genetic alterations identified in their tumor. We will also collect blood samples as well as cerebrospinal fluid and/or future tumor tissue throughout the study. Genomic and immune profiling analyses will be performed on these specimens over time that, in combination with imaging and patient-survey measures, can predict early response or recurrence to treatment (“liquid biopsy” tools) and improve the understanding of why some tumors become resistant to therapy.

Maria Mihaylova, PhD

Colorectal cancer is the second leading cause of cancer related deaths worldwide. Alarmingly, recent studies show that its incidence is increasing in younger adults. Certain environmental factors, such as diet, can have an impact on colorectal cancer. Calorie dense, western diets can lead to energy imbalance and excessive weight gain, which is associated with higher risk of colorectal cancer. Since diet is a modifiable risk factor, it is important to understand precisely how diet composition and particular nutrients within the diet can affect colon tumor cells directly and indirectly. We plan to systematically examine how colon cancer cells become dependent on certain nutrients that are necessary for rapid tumor growth and progression. We will also test how relevant dietary nutrients, such as sugars and fats, change the function of support cells found within the tumor and influence tumor growth. Our hope is to identify vulnerabilities in colon cancer cells that we can enhance through nutrition and develop new treatments that will improve survival and quality of life for cancer patients. 

Andrew Volk, PhD

Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Pediatric Cancer Research Fund

Acute myeloid leukemia is a cancer of the blood that affects hundreds of children each year in the USA. While the survival rate has improved, there is still a 30-35% chance of relapse within five years of diagnosis. We need better therapeutic options to treat this disease. Leukemia, in most cases, is caused by a breakdown in the blood cells’ ability to regulate their genes. This leads to uncontrolled growth of partially developed blood cells that can overrun the host. While there are some drugs available to treat this disease, most patients eventually will see their leukemia return. Our research goal is to understand the mechanisms that break down when a healthy cell becomes a leukemic cell. We want to develop better therapeutics to treat leukemia. We have found that excessive levels of the chromatin assembly gene CHAF1B is needed for leukemic cells to stay cancerous. Turning down CHAF1B is enough to turn the leukemia tumor into normal cells. In fact, we think that CHAF1B is responsible for driving therapy resistance in AML by repressing expression of differentiation genes. Our work over the next two years will enhance our understanding of how this process breaks down in leukemia, and hopefully lead to better treatment options for patients. 

Berkley Gryder, PhD

Funded by Matthew Ishbia and the Dick Vitale Pediatric Cancer Research Fund

DNA contains the story book of each human, written in our genome. Sometimes a single letter changes the meaning of a word, such as better to bitter.  Likewise, in some children a small DNA change encourages cancer to form and grow.  In childhood sarcoma, we recently discovered that certain DNA changes in cancer-causing proteins lead to errors in the rest of the genome’s ability to remember its cellular purpose. We found this was happening by formation of large “super-clusters” at cancer-causing genes.  The goal of our research is to discover why and how these super-clusters form.  We will explore the super-clusters using leading edge technologies including 3-dimensional genomic modeling, chemistry, cancer biology, and drug development focused on a deadly form of childhood cancer, called rhabdomyosarcoma.  We anticipate finding that the super-clusters are integral to rhabdomyosarcoma progression; and our work will illuminate potential new treatment targets and routes,  based on modifying the genetic error that is causing the cancer. For example, if we develop drugs that stop the formation of the super-clusters, will we also selectively kill the cancer cells?  This new work will provide the scientific data to support a new class of therapies for children with these deadly cancers. 

Genevieve Kendall, PhD

Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Fund

Alveolar rhabdomyosarcoma (ARMS) is an aggressive cancer of the muscle that occurs in young children and teenagers. Despite years of attempts to improve chemotherapy regimens, survival of patients with ARMS remains poor. This is especially true for patients who have advanced disease at the time of diagnosis. ARMS tumors typically possess a single and defining genetic mutation. A break in one specific chromosome will fuse with another chromosome, creating a fusion gene. These fusion genes can control hundreds or even thousands of other genes and transform a normal cell into a cancer cell. My project focuses on the PAX3-FOXO1 fusion. This fusion causes the most severe form of ARMS. However, there are no therapies that target PAX3-FOXO1 directly. Our goal is to understand how PAX3-FOXO1 transforms a normal cell into a cancer cell so that we can find new and precise therapies. To study this, we use zebrafish as a disease model because they are genetically similar to humans. We will integrate the human PAX3-FOXO1 fusion gene into the zebrafish genome to determine the steps required for ARMS tumor formation. For example, often normal development is hijacked by cancer genes. Our studies will determine if and how this happens in ARMS. Directly comparing zebrafish and human ARMS will pinpoint the most important drivers of disease and likely find new options for more targeted and specific therapies. 

Abhishek Chakraborty, PhD

Kidney cancer is among the ten most common forms of human cancer. While manageable in early stages, advanced kidney cancer remains incurable. Therefore, new drugs to treat this disease are urgently required. 

Kidney cancers emerge when normal kidney cells acquire changes in their genetic program. DNA, ouprimary genetic source-code, is like a thread that is compactly wrapped into a complex spool called “chromatin”. This wrapping protects DNA from environmental adversity and also allows precise control to switch genes on/offwhen desired. Importantly, many of the kidney cancer-causing genetic changes promote improper “chromatin” spooling, which possibly drives cancer growth by switching on the function of key tumor-promoting (onco)genes. Identifying and shutting off these misfiring oncogenes could thus block tumor growth, and be a means of therapy.   

Our laboratory has begun comprehensively probing this idea. Using cutting-edge technology, wfirst identified numerous genes that were associated with improper “chromatin” spooling and thus were erroneously switched on in cancerous kidney cellsAmong these genesour follow-up studies shortlisted ten candidate oncogenes that promoted tumor growth in mouse models. Many of these gene products rewire the cancer cell’s metabolismHere, we address which of these metabolic functions are indispensable for kidney cancer and how these changes fuel cancer growth. Cancer cells are perpetually hungry for nutrients to support their uncontrollable growth; therefore, starving kidney cancer cells of essential nutrients can be exploited for therapy. Together, our studies lay the foundations to establish such metabolic genes as clinically useful targets to treat kidney cancer. 

Pallavi Tiwari, Ph.D.

The most difficult challenge in treatment management of brain tumor patients is the need to accurately identify if a suspicious lesion on a post-treatment MRI scan is a benign treatment-effect or a “true” cancer recurrence. Both radiation effects and tumor recurrence have similar clinical symptoms and appearances on routine MRI scans. Currently, a highly invasive brain biopsy is the only option for confirmation of disease presence. Each biopsy procedure costs $20,000-$50,000/patient. Further, over 15% of patients who undergo biopsy will get an incorrect diagnosis due to difficulty in sampling of reliable locations of the tumor. There is hence a need for non-invasive image techniques to reliably differentiate benign treatment effects from tumor in brain tumor patients. Our team has developed new image-based biomarkers that use routine MRI scans to differentiate between these two conditions with an accuracy of 92% on n>200 studies. We propose to validate our image-based biomarkers in a limited clinical trial to reliably sample locations of tumor recurrence from benign radiation effects. The clinical trial will be based on creation of a “GPS” map of the locations of tumor and benign radiation necrosis in the tumor using MRI scans. This GPS map will assist neurosurgeons in reliably identifying locations to biopsy from during surgery. The proposed project, when successful, will thus have significant implications in personalizing treatment decisions in brain tumors.

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