Funded with support from the Scott Hamilton CARES Foundation
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.
Funded by the V Foundation Chicago Epicurean in honor of Marc Silverman and in memory of Jeff Dickerson
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.
Lung cancer is the deadliest cancer in the United States and lung adenocarcinoma is the most common type of lung cancer. While genetic mutations contribute to the development of cancer, cancer cells also activate gene programs over time that allow the cancer cells to become more aggressive and harder to treat. Advanced lung cancer cells evade current treatments such as chemotherapy or therapies that target the immune system. In our work, we have found that late-stage lung cancer cells expressed a unique transcription factor that activates gene programs which permit cancer cells to spread throughout the body. Of note is that these cancer cells also release molecules which we believe signal myeloid cells to enter the tumor. In doing so, the myeloid cells cause the immune system’s T-cells to be less effective and reduce how well current treatment strategies work. We seek to understand how late-stage cancer cells facilitate disease progression and how they limit response to current therapies. We have generated new mouse models which will allow us to investigate the gene programs that are active in these advanced cancer cells and to determine how these cells become resistant to therapy. Overall, our goal is to identify new options for targeting late-stage cancer cells which could be combined with, or used in place of, current treatment strategies so that we can increase how long patients with lung cancer live and improve their quality of life.
In just over the past 10 years, new drugs that improve our own immune system’s ability to clear tumor cells have become an incredibly powerful class of cancer treatments. These therapies known as immune checkpoint inhibitors or ICIs work broadly against many different tumors, providing hope for many patients to better fight off their cancer. However, each patient is unique, and ICIs can work better for some patients than others. There are many reasons for these differences, including a person’s genetics, their type of cancer, and their environment. Recently, studies including our own have shown that microbes in our bodies also affect how well ICIs stop the growth of tumors. In our lab, we aim to understand how these microbes function during cancer treatment. We focus on how microbes make molecules that stimulate our immune system, which work with ICIs to fully activate tumor-fighting cells. In our work sponsored by The V Foundation, we will find new enzymes to make these active molecules. Using these enzymes, we will build better probiotics and test whether they can help to clear ICI-resistant tumors. Together, these studies will advance our long-term goals to understand how gut microbes affect cancer treatment and to generate new bio-based therapies that improve outcomes for cancer patients.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Asparaginase is an important drug for the treatment of childhood leukemias. However, some leukemias become resistant to asparaginase, and this makes them very difficult to treat successfully. We discovered that by blocking a protein called GSK3α, we can make drug-resistant leukemia cells sensitive to asparaginase again. Although this finding is promising in the lab, there are currently no drugs known to block GSK3α that can be used to treat patients.
This proposal is focused on overcoming this problem by testing two different but related ideas. First, we will test the hypothesis that some existing drugs, which have already been developed for other purposes, also possess the ability to block GSK3α. Because these drugs are already approved for use in patients, we would be able to quickly start testing these in patients with leukemia. Second, we have engineered several new compounds that are specifically designed to target GSK3α. Fortunately, these have shown early promise in the lab, and we are ready to evaluate whether these newly engineered compounds fit the criteria as candidates for new drug development. If this line of research is successful, we expect it will lead to two different treatment strategies combining asparaginase with a drug that blocks GSK3α.
With support from the V Foundation for Cancer Research, we are optimistic that our work has the potential to lead to the development of potent new treatment strategies for some of the most difficult-to-treat forms of childhood leukemia.
In patients with hormone positive breast cancer that has spread to other parts of the body eventually the cancer can stop responding to hormone blocking pills and their cancer starts to grow again. In this project we will develop vaccines that eliminate breast cancer cells that no longer respond to hormone blocking pills. This will cause the remaining breast cancer cells start responding again to hormone blockers. The result of these vaccines would be that those patients with hormone positive breast cancer will have a much longer time where that the hormone blocking medication would work. The immune response would also help to kill more of the breast cancer cells. This should mean that patients will live much longer with hormone positive breast cancer that has spread. This research will be tested first in mice and then in patients with hormone positive breast cancer that has spread to other parts of the body.
We are testing a drug, tucatinib with a form of focused radiation called stereotactic radiosurgery for a type of breast cancer (HER2-positive) that affects 20-25% of breast cancer cases when it spreads to the brain.
This study will help find out if the combination of tucatinib and radiation is safe and if patients can tolerate it well without too many side effects.
About 40 patients with this type of breast cancer that has spread to the brain will be part of the study. First, they will receive the drug tucatinib along with the focused radiation treatment. After that, they will continue taking tucatinib along with two other medicines called capecitabine and trastuzumab. These three medicines are already used as the standard treatment and have been effective for patients like these. Patients will receive this combination until their tumor grows back or if there are serious side effects.
This study will also help find out the correct dose of tucatinib to use. Additionally, the study will answer how well the treatment works and how it affects brain function.
