Designed to identify, retain and further the careers of talented young investigators. Provides funds directly to scientists developing their own independent laboratory research projects. These grants enable talented young scientists to establish their laboratories and gain a competitive edge necessary to earn additional funding from other sources. The V Scholars determine how to best use the funds in their research projects. The grants are $200,000, two-year commitments.
Funded by the Dick Vitale Pediatric Cancer Research Fund
We study a set of bone cancers that affect children and young adults. The treatment for these cancers has remained the same for the last 40 years – combinations of toxic medicines known as chemotherapy, followed by surgery or radiation to remove what is left of the cancer. While this strategy cures some patients, far too many children continue to die from these cancers. We believe we have found two specific weaknesses in these tumors: problems in their ability to repair damage to their DNA and a survival signal in a special pool of cancer cells known as “residual disease”. Through this research, we hope to bring new therapies to patients and cure more children with these bone tumors.
Funded by the Dick Vitale Pediatric Cancer Research Fund
One major challenge in treating any type of cancer is resistance, or when a cancer stops responding to a certain type of drug or therapy. Some cancer cells may become resistant my changing the way they read and write their DNA, or the genetic blueprint in the cell nucleus. Other cells may change the way proteins are expressed on the surface, which can change their shape or ‘stickiness’ and ability to move in the body. When doctors can understand exactly how cancer cells become resistant to a certain drug, they can sometimes combine two or more drugs together to overcome this.
For some new classes of drugs, we have not even begun to explore how cancer cells might become resistant. One of these classes is nanoparticle drugs, which usually involves bringing together molecules like fats or polymers to help delivery drugs into certain cells. The goal of this research project is to identify the ways that pediatric cancer cells can become resistant to nanoparticle drugs, and find new drug combinations that are more effective and less toxic to children with cancer. Many lab-based studies of nanoparticles are performed in common cancers of adulthood such as breast cancer, and this has led to new treatments in the clinic, but there have been very few studies of nanoparticle drugs in childhood cancer. Currently, there is only one nanoparticle drug approved for use in children. By studying resistance to nanoparticle drugs in a deadly childhood brain tumor, we can take the first step towards a new clinical treatment for these children.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Neuroblastoma is a childhood cancer that develops from nerves outside of the brain. Half of these cancers spread and cause high rates of death despite treatment. Many researchers study how proteins impact cancer growth and spread. Proteins work differently when sugars are attached to them. Sugars are added to proteins through a process called glycosylation, and the way that sugars are added is different in adult cancers. Few people have studied how glycosylation changes the behavior of childhood cancers. We have applied new technology to studying neuroblastomas and found that a certain sugar, fucose, is decreased in advanced tumors. We will extend our work and look at how sugars change when cancer cells are treated with chemotherapy. We found that decreased levels of fucose increases the ability of certain immune cells to find neuroblastoma cells. We have proposed studies to determine how proteins joined to fucose change how neuroblastomas are recognized by white blood cells. The proposed work will be the first use of this technology to define how cancers cells change their sugar patterns to avoid death when treated with chemotherapy.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Neuroblastoma (NB) is a type of childhood cancer that is difficult to treat after it has spread throughout the body. Using animals that develop aggressive NB, we found different types of tumor cells that may lead to cancer spread. We are proposing to look very closely at these different tumor cells and determine how they may lead to NB spread and drug resistance in patients. We will also test new targeted drugs for their effects on NB spread and through our studies, new ways to treat aggressive childhood cancer may be found.
T cell therapy, like CAR-T, utilizes our body’s own immune defense to fight against cancer. While CAR-T therapy has worked well for some types of blood cancers, it faces challenges in solid tumors like breast cancer. One problem is that CAR-T cells don’t kill cancer cells effectively in the suppressive environment of solid tumors although they can target them. They can also cause harmful side effects by over-releasing cytokines in the body. Another challenge is that making CAR-T cells from a patient’s blood takes a lot of time and money. To overcome these challenges, my lab is developing programmable viral particles that can target tumor like CAR-T cells while bypassing the limitations of CAR-T therapy. In this project, we will engineer CAR-T mimic viruses that can target breast cancer cells and deliver gene circuits to them. These gene circuits can make cancer cells suicide or reprogram them to turn “cold” tumor “hot”. The unique feature of these viral particles lies in their ability to target and rewire tumor environment, their ease of manufacturing, and compatibility with evolving gene circuit technologies. We hope that these innovative anti-tumor viruses will become a versatile and accessible treatment that can synergize with other therapies to enhance cancer treatment.
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.
Funded with support from Carrie Collins in memory of Marty Collins
Immunotherapy helps the immune system recognize and kill cancer and it can cure patients where other treatments fail. Unfortunately, it still does not work for most patients. It is the goal of our research to understand why. Without a clear understanding of how cancer talks with the immune system, and how this conversation changes as cancer progresses, it is difficult to identify the root causes of why immunotherapy fails. Studying cancer evolution in patients is also challenging, as we rarely have the full history of tumor development and there is huge variability between tumors from one patient to the next. Through innovative genetic engineering, we are developing new mouse models of cancer that allow us to carefully study cancer development at all stages of the disease, especially at the moment when tumors acquire the ability to invade into other tissues—the reason cancer is so deadly. Why and how the immune system fails to stop cancer invasion and metastasis is not well understood and is a question of great importance. We will use the models we developed to study this question in creative and powerful new ways. We will also test exciting new immunotherapies, like cancer vaccines, in our models and determine why some tumors respond to treatment and others do not. Through this work, we hope to help match patients with the right immunotherapies and develop better immunotherapies that will be effective for many more patients.
Colorectal cancer is the third leading cause of cancer-related deaths in both men and women. Most people that get colorectal cancer are not genetically predisposed and while the causes are not clear there are three key players in the intestine: 1) immune cells, 2) microbes, and 3) environmental factors such as diet. How these players interact to determine cancer risk needs to be understood. We recently found that mothers can shape intestinal microbes and immune cells for multiple generations by influencing diet in early life (breastmilk). Our big question is, Can mothers protect their offspring from developing colorectal cancer by shaping their immune system? We will use mouse models to address maternal influence on multigenerational colorectal cancer susceptibility. Using a multi-omics approach, we will study the mechanisms of how breastmilk factors shape intestinal microbes and immune cells and protect from colorectal cancer. Our studies will provide the much-needed insight into immune cell-microbe-diet interactions and their role in cancer initiation and progression, and in the future we could harness protective factors in breastmilk to prevent or treat colorectal cancer.
Cells require nutrients to fuel their metabolism to sustain life. Healthy tissues are fed nutrients by blood vessels in a process called perfusion. In contrast, cancers have dysfunctional blood vessels. Compared to normal tissues, blood vessels dysfunction in tumors limits perfusion. This limited perfusion results in abnormal nutrient levels in tumors. We have found that abnormal nutrients in pancreatic tumors blocks the ability of chemotherapeutic drugs to kill pancreatic cancer cells. This is an important finding as pancreatic tumors are resistant to chemotherapeutics, which causes high mortality in this disease. We propose that: (1) identifying the nutrients in pancreatic tumors and (2) how these nutrients lead to chemotherapeutic resistance could lead to new treatments to improve patient chemotherapy outcomes. These are the two critical goals of the proposed project.
To identify the metabolic stresses in tumors that cause chemotherapeutic resistance, we searched for nutrients in tumors that cause chemotherapy resistance. We found that certain amino acids accumulate to high levels in tumors and cause chemotherapy resistance. We will determine if blocking tumor accumulation of these amino acids can improve the chemotherapeutic treatment of pancreatic tumors. Toward the second goal of identifying how amino acid accumulation causes therapy resistance, we will use advanced biochemical and genetic tools to determine how the amino acids accumulating in tumors enable pancreatic cancer cells to survive chemotherapy treatment. Completing aims will provide new insight into how nutrients in pancreatic tumors cause chemotherapy resistance and provide clinically actionable approaches to improve chemotherapy response in patients.
CAR T cell therapy is an exciting new cancer therapy where immune cells from a patient, called T cells, are reprogrammed outside the body to seek out and kill tumor cells. While this approach has been highly effective for some types of cancer such as lymphoma and leukemia, it has not yet been effective for solid tumors such as ovarian cancer and pancreatic cancer. One reason for this failure is that many tumor cells have found ways to hide from the engineered immune cells and avoid being killed. We call the genes that enable tumors to hide “immune evasion genes.” Our lab has identified one of the key immune evasion genes, called NKG2A-HLA-E. We believe that blocking this gene could make tumor cells more visible to CAR T cells and greatly increase their cancer killing abilities. This would result in more effective therapies for patients that could lead to longer survival. Additionally, our lab has also developed new ways to identify all the evasion genes used by tumors to hide from CAR T cells. This exciting new approach could reveal several additional genes that tumors use to escape CAR T cells, and we identify these genes and attempt to block them to determine if this also improves the ability of CAR T cells to kill tumors. This work could help to identify the ways tumors escape from the immune system and could provide researchers and clinicians with the information required to build more effective cancer therapies using the immune system.
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