Our bodies are constantly exposed to a multitude of challenges, such as microbes, toxins, and injuries, especially at barrier surfaces like the skin, lungs, and intestines. These tissues serve vital and complex functions in shielding us from environmental threats while also managing body moisture, oxygen levels, and nutrient absorption. For instance, the intestine must delicately balance the elimination of harmful microbes and toxins with the absorption of essential nutrients. This requires intricate cooperation between the intestinal lining cells and the intestinal immune system. Barrier tissues, like the intestine, are particularly prone to inflammation and cancer.
Inflammatory bowel diseases are chronic inflammatory conditions affecting the intestines. They result from an interplay of genetic and environmental factors, leading to dysregulated functioning of intestinal cells and immune system. These incurable diseases can significantly increase the risk of developing colon and rectal cancer. Yet, the mechanisms through which environmental factors and inflammation impact the immune system and cells of the intestine to drive the progression of chronic inflammatory diseases and cancer remain largely unknown.
Within the Niec lab, innovative tools have been developed to investigate how immune cells and the intestinal barrier cells respond to environmental challenges and interact in disease. Through this project, we aim to unravel the alterations occurring in the immune system and the intestine during inflammation. By understanding these processes, we aspire to develop strategies to prevent and treat cancer that arises from inflammatory bowel disease.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Malignant rhabdoid tumors and epithelioid sarcomas are rare cancers that can develop throughout the body. Sadly, these tumors are often deadly for patients who can’t have surgery or whose tumors don’t respond to chemotherapy. Recently, a new drug called tazemetostat has been approved to treat these cancers, but only about 15% of patients get better with it. Our new research project explores DNA damage repair and targeting its mediators in tumors cells to offer new treatments to patients. Our past research shows that a protein called ATR is important for the growth of tumor cells. It is possible that other similar proteins are necessary for tumor growth and is therefore important that we study them to understand if ES and MRT patients may benefit from other drugs that interfere with these processes. For example, we found that combinations of drugs, chosen logically based on research evidence, is more effective in controlling tumor cell expansion, when compared to using drugs alone. We plan to find the best combination of novel drug inhibitors to stop these tumors from growing. We also want to understand how these drugs work in the body so we can predict which patients will benefit the most. This research should lead to a new, safe, and effective treatment for many patients with RT and ES who currently have no cure. The findings might also help treat other types of childhood and young adult cancers, creating a roadmap for difficult to treat tumors.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Diffuse midline glioma (DMG) is a very aggressive brain tumor that occurs mostly in children. DMG treatment involves surgery, radiation, and chemotherapy, but most people with DMG don’t live longer than a year despite these treatments. We desperately need better therapies for this disease. Treating DMG is difficult because tumors aren’t the same in every person, so a drug that works for one person might not work for another. Therefore, we need treatments that are personalized for each patient. In addition, different parts of the tumor may not all respond to the same drugs, and we might need to use a mixture of drugs to eliminate the whole tumor. And even if we find drugs that do this in the lab, getting them into the tumor is tricky because of the “blood-brain barrier”, which prevents many drugs from getting from the bloodstream into the brain. We are proposing a new approach to DMG treatment that overcomes these challenges. To find individualized treatments, we will test many different drugs on tissue from surgery or biopsy to see which ones work best for each patient. We’ll also look at the effects of drugs on individual cells in the tumor and find the combinations of drugs that kill the most tumor cells. Finally, we’ll use a method called convection enhanced delivery (CED) to pump drugs directly into the tumor, bypassing the blood-brain barrier. By using these approaches, we will find better treatments for DMG and other brain tumors in kids.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Our research focuses on a type of leukemia called B-cell acute lymphoblastic leukemia (B-ALL), which is most commonly found in children and adolescents. Despite advancements in treatment, a significant number of young patients do not respond well to existing therapies and face high risks of relapse. Our project specifically addresses those cases caused by changes in a gene called CRLF2, which are associated with poor outcomes. To understand and combat this challenging disease, we are using a cutting-edge technique called CRISPR/Cas9 to create detailed models of human blood cells that carry the same genetic changes seen in patients with CRLF2-related leukemia. These models allow us to study the disease in a controlled environment and understand the step-by-step development from the initial genetic changes in a human blood cell to full-blown leukemia. By examining these models at a microscopic level, using technologies that analyze individual cells, we aim to uncover new details about how these leukemias develop and find weak points where new drugs could intervene. Our goal is to identify new treatments that could target these leukemias more precisely and to explore ways to detect and perhaps prevent the disease before it fully develops. This research could lead to better survival rates and less suffering for children affected by this aggressive type of leukemia, providing hope for families facing this diagnosis. The knowledge gained could also help in understanding other similar types of childhood leukemias, broadening the impact of our work beyond B-ALL.
Colorectal cancer is the second most common cause of cancer death. Immunotherapy is largely not effective in this disease. To work safely, it requires targets in tumors that are not also present in normal tissue. These are difficult to find. Our recent research shows that advanced colorectal cancers adopt a fetal-like state. This fetal-like state reactivates gene programs that are normally only expressed during early development. In normal adult tissues, these programs are turned off. This may make advanced cancer vulnerable. Reactivated fetal proteins could potentially be used as targets for new immunotherapies. Here we propose to study how these fetal proteins are recognized by the immune system. For this, we will use our unique and extensive biobank of organoids. Organoids are 3D cultures of cancer cells derived directly from patient tumors and normal cells. They are a more informative and realistic model of cancer than traditional cell cultures. We must first understand which molecules are shown to the immune system in cancer cells. We will then look for immune cells in the blood of colorectal cancer patients that can recognize the fetal molecules. This approach will ultimately lead to novel immunotherapies. These could help treat advanced colorectal cancer and related solid tumors.
Multiple myeloma (MM) is a type of bone marrow (BM) cancer that remains a significant challenge to treat, despite therapy advancements. In this study, we aim to explore a new approach to enhance the effectiveness of standard MM treatments. Our focus is on a specific type of immune cells called myeloid cells, that play a role in tumor growth and immune evasion in MM patients. We observed that MM patients have an increase of a particular type of myeloid cell that express on their surface, a molecule called CXCR2, in the BM and places where the cancer has spread to bone: (osteolytic lesions). The myeloid cells may contribute to MM resistance to treatment and to evasion of the body’s immune system. Based on these findings, we propose a clinical trial to test a drug called SX-682, which targets CXCR2-positive myeloid cells. We will investigate whether adding SX-682 to standard MM treatment will improve patient outcomes. Our trial will focus on MM patients whose cancer has come back after initial treatment. The primary goal of our study is to assess the safety and tolerability of SX-682 with standard MM treatment. Additionally, we aim to understand how SX-682 affects the immune environment within the tumor and in the blood. By targeting CXCR2-positive myeloid cells, we hope to enhance the body’s ability to fight MM, improving patient survival. Our study represents a promising step towards developing more effective therapies for MM by harnessing the body’s immune system to better combat this challenging cancer.
Immune cells are always patrolling our intestines, even when we are healthy. This includes B cells, which produce antibodies. Antibodies are floating molecular fire extinguishers which bind to and neutralize infections. In our intestines, huge amounts of antibodies are made every day. These bind to the ‘friendly’ bacteria that we live with to make sure they are well balanced, which keeps us healthy. In inflammatory bowel disease (IBD), the intestine becomes damaged by the immune system and antibodies change which bacteria they bind to. This turns the population of gut-bacteria from friendly to harmful, and can cause IBD to become colorectal cancer.
We do not know which B cells make cancer antibodies, or how antibodies make bacteria harmful. To understand this, we need to know how dangerous B cells become selected to produce the antibodies that turn IBD into cancer. This requires special tools to tell the helpful cells apart from the harmful ones. We built mice with multicolored B cells so we can follow the B cells that become hijacked during IBD and cancer. We may then understand where cancer-causing antibodies are made, and what they bind to. By doing this, we hope to compile a list of common antibodies that are always made before IBD becomes cancer, and look for them as warning signs in IBD patients. This could give doctors more time to treat high-risk patients before tumors form. In the future, we hope our findings help design new cancer drugs to delete harmful B cells.
Funded with support from Dave and Rhea Benson in honor of Angela Sbarra
The rates of rectal cancer are increasing in young adults. Treatment for rectal cancer includes chemotherapy, radiation, and surgery. These therapies can have a negative effect on the quality of life of survivors. Radiation can cause infertility and problems with bowel and bladder function, as well as sexual health. Up to one third of the patients need a permanent colostomy so they do not have normal bowel function. Due to these issues, there has been an interest in finding ways to improve treatment for rectal cancer so that radiation and/or surgery may not be necessary. One way we are trying to improve treatment of cancer, including rectal cancer, is with immunotherapy. Immunotherapy empowers the patient’s own immune system to fight cancer. When this happens, it is very effective. Funding from the V Foundation will support a clinical trial that will treat rectal cancer that is mismatch repair proficient with immunotherapy first. The project team believes that improved immunotherapies like Botensilimab (anti CTLA4) and Basltilimab (PD-1), and earlier treatment before the tumor has spread, will lead to responses. This research has the potential to change the treatment paradigm of all early-stage rectal cancers and omit radiation and surgery in those patients whose cancers disappear with immunotherapy and chemotherapy alone. This will be an important finding for patients’ quality of life. It will also teach us how to make the immune system work against cancers where it has not worked in the past.
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 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.