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.
Funded by the Dick Vitale Pediatric Cancer Research Fund
KMT2A acute lymphoblastic leukemia (KMT2A ALL) is the most common ALL subtype in infants and common in older children with ALL. It is a deadly disease that does not respond well to chemotherapy treatments and often returns. Our goal is to identify new medicines that can improve the health of patients with this disease. Our studies show that KMT2A ALL need the signaling molecule DYRK1A to multiply and grow, a process called cell proliferation. DYRK1A regulates cell proliferation by transmitting information to other signaling molecules. Using a specific DYRK1A inhibitor slowed down cell proliferation but did not kill KMT2A ALL cells. Our study showed that one molecule is important for protecting KMT2A ALL cells against DYRK1A inhibition. This molecule is called BCL2. We are now testing using a two-medicine treatment approach if inhibition of DYRK1A and BCL2 can kill KMT2A ALL cells. If this new treatment approach proves to be better than current chemotherapy treatments, we aim to test this new strategy in patients.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Neuroblastoma is a common and deadly childhood tumor. Even with our best treatments, the disease may return. If this happens, our best treatments are not always effective and most patients will pass away. This motivated us to study how neuroblastoma becomes resistant to treatment. Neuroblastoma tumors are made up of different kinds of cancer cells, some of which are sensitive to chemotherapy, and some of which are resistant. Importantly, these different populations can switch between each other, causing sensitive cells to become resistant. How cells do this is not well understood, but may be related to proteins called “transcription factors.” Understanding how resistance occurs may allow us to create new treatments. These treatments could change resistant cells into sensitive cells or stop sensitive cells from becoming resistant. In this proposal, we will use new tools to understand how neuroblastoma cells switch between sensitivity and resistance. We will also use these tools to identify the controllers of these switches. We hope these studies will lead to new ways to treat children with neuroblastoma by targeting resistant cells. We believe this will create new ways to stop this terrible childhood cancer.
Funded by the Scott Hamilton CARES Foundation in partnership with the Dick Vitale Pediatric Cancer Research Fund
Brain tumors are the leading cause of childhood cancer mortality. Two types of these brain tumors, both with mutations in different parts of the histone 3 protein, are both aggressive and deadly. Although these tumors are so awful for the child that has one in their brain, when the tumor is removed with surgery, it is very hard to grow in a dish. For this reason, many scientists take these patient tumor cells and grow them in a mouse. Yet, we and others have seen that although this way of growing the tumors is better than nothing as it allows us to research the tumor cells, the tumor changes a lot in the mouse brain. For this reason, we have generated new models, using transplantation to a cortical organoid. A cortical organoid is a three-dimensional model of the developing human brain made from stem cells. Our work shows this system mimics more aspects of the original tumor, and also provides an opportunity to see how the tumor cells interact with the human brain. We will further optimize this system to study these pediatric brain tumor and we will now begin to ask, which cell types actually cause the tumor to recur after surgery? Which cell types are most invasive, and thus most dangers? Finally, we will also try to identify the cause of these tumors so that we can either prevent them from emerging in children in the first place, or detect them early to prevent tumor progression.
Lung cancer is the leading cancer killer in both men and women in the U.S. Early detection is the most effective way to fight against this deadly disease. In recent years, an imaging method known as low-dose CT (LDCT) scan has been studied in people at higher risk of getting lung cancer. LDCT scans can help find nodules in the lungs that may be cancer. However, majority of those nodules are actually benign, yet exposing many of those patients to a needle biopsy or other invasive procedures. Hence, there is an urgent and unmet need for an accurate and non-invasive approach to distinguish those nodules that are malignant from those that are not. In this proposal, we will develop and validate a novel method to integrate a blood test and the LDCT imaging for the early detection of lung cancer. Specifically, from blood we extract cell-free DNA, from which we develop an ultra-sensitive assay to profiles the epigenome of cell-free DNA, therefore to detect even a trace amount of tumor DNA. Using advanced machine learning algorithms on the integrated genomics and imaging data, we aim to significantly improve the accuracy of the cancer detection. For those patients with nodules identified from LDCT, we will integrate the two sources of information to determine whether the nodules are malignant or benign.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Osteosarcoma (OSA) is a bone cancer that mostly affects young people. Surgery and chemotherapy are the most common forms of treatment but can cause serious side-effects that make patients very ill. When a patient’s OSA has spread from the bone to the lungs it is much harder to treat. Recent research has shown that immune cells can be engineered to improve their ability to fight cancer. This approach has cured patients with certain blood cancers when all other previous therapies failed. However, this approach is less effective in “solid” cancers like OSA. We are pursuing a new approach where immune cells that naturally recognize mutated proteins in a patient’s tumor (TIL) are collected and grown to large numbers before returning them to the patient. This approach has achieved cures in several solid cancers, including those that have spread to other areas of the body including the lungs, but it is not always effective. In previous work, we found that disabling a gene called CISH allows TIL to kill cancer cells more effectively. We are currently testing this in a clinical trial in patients with gastrointestinal cancer. In the current proposal, our goal is to see if this approach can also be used to treat OSA. If successful, our approach may offer a curative option with far fewer side-effects compared to current therapies.
Renal medullary carcinoma (RMC) is a rare but deadly kidney cancer that mainly occurs in young individuals of African descent that carry a blood disorder called sickle cell trait. Most people carrying the sickle cell trait never develop any symptoms. Many do not even know that they have it. Approximately 1 in 14 African Americans have the sickle cell trait and are at risk for developing RMC at an average age of 28 years old. RMC is also an under-recognized global health challenge because the sickle cell trait is found in ~300 million individuals around the world, mainly in Africa. Almost every patient with RMC is diagnosed late, when the cancer has already spread to other organs. Less than 5% of these patients survive beyond 3 years. Furthermore, many patients with RMC are initially misdiagnosed and lose precious time while being treated with the wrong therapies. The chances of a cure considerably increase when RMC is diagnosed and treated early. With the help of our patient advocates, we have established the largest collection of blood and tissue samples from patients with RMC worldwide. Using these samples, we have found evidence that patients with RMC have antibodies against unique proteins found only in cancer. We have developed a novel technology that allows the detection of more than 400,000 of these antibodies using only a drop of blood, quickly (within 3 days) and affordably. Our proposal aims to investigate and develop this new approach for the early diagnosis of RMC.
Basal (BCC) and squamous cell (SCC) carcinomas are the most common form of skin cancer. If diagnosis is delayed, the tumors may require surgery that is more extensive. These tumors may be superficial, which are slow-growing, confined to the outer skin layers, and can usually be treated without surgery. Alternatively, they may be invasive, penetrating the deeper skin layers to destroy these tissues, often requiring surgery that can be costly and painful. While these skin cancers often may be diagnosed with the naked eye, it is difficult to tell whether they are superficial or invasive. Thus, there is a clear need for a new diagnostic approach that can inform patients and their physicians whether a particular lesion should be biopsied, and whether evaluation is urgent if the lesion is likely to be invasive. Currently there is no non-invasive (without biopsy) to accomplish this. Here, we propose to develop a new test based on micro-RNAs (miRNAs) that can be recovered simply on adhesive tape from suspicious skin lesions. We believe these miRNAs can be used to identify non-melanoma skin cancers and their subtypes as a new non-invasive way to decide whether (and how urgent) a biopsy needs to be performed. First, we will determine which miRNAs are most associated with superficial and invasive skin cancers by analyzing miRNAs in previously biopsied tissues. Second, we will validate this technique on a group of patients who come to clinic with a suspicious skin lesion.
Liver cancer is one of the deadliest cancers in the world and it is becoming more common in the United States due to liver disease or liver scarring. Patients with liver problems are at risk of developing liver cancer, and if the cancer is found at an early stage, it can be cured. Therefore, patients with liver problems should be screened regularly so that the cancer can be found early. Unfortunately, current screening techniques are not very sensitive and require trips to special imaging centers twice a year. Our work will create a new and better screening tool for early detection of liver cancer that can be used anywhere. By improving the quality and access to better imaging, screening will be more effective and can be done wherever patients need it most, without the need to travel to a hospital or specialized imaging center. We believe that by improving both the quality and access to screening, patients with liver cancer will be found at an earlier stage, allowing for better patient care. Further, easier access to this new screening tool will allow more people to access the healthcare they need.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Brain tumors are the leading cause of cancer related deaths and long term side effects in children. Treatments that are specifically directed to tumors, while sparing normal brain cells, are desperately required to increase the effectiveness of treatments and to reduce side effects. This project is focused on trying to find ways to inhibit specific mutations in a group of genes that are found across common childhood gliomas. Our hope is that our work will help us find ways to use medications that target these mutations specifically to allow precision medicine approaches.
