Our lab works on finding new and better immunotherapies for cancer. To do this, we try to understand how cancer cells hide from the immune system. We also try to understand which proteins could be targeted with a drug to help the immune system find and kill cancer cells more effectively.
To accomplish this, we are studying ancient viruses that live in the DNA of all human cells. Usually, these viruses are kept quiet by “epigenetic repressors”. Our lab is studying how to turn on these viruses in cancer cells, with the goal of activating the immune system to kill the tumor.
We envision this approach leading to a new type of cancer therapy, which could be used in patients that don’t respond to standard immunotherapies.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Despite significant advances in the treatment of pediatric cancer, leukemia remains the second leading cause of cancer related death in children. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that affects both children and adults. When T-ALL does not respond to chemotherapy or returns after initial treatment (relapses), there are few treatment options. New treatments are needed for T-ALL. The way cancer cells use energy or develop building blocks for growth is different from normal cells. We are working to understand how these energy and building processes within T-ALL cells are altered, with the hope that we can use this as a vulnerability for developing new therapies. We are particularly interested in drugs that alter how the cells produce a building block called methionine, and we are testing how these drugs work in T-ALL. Our ultimate goal is to find effective and non-toxic treatments for T-ALL.
Colon cancer is a devastating disease. It is one of the leading causes of death from cancer, even after decades of research. Scientists have found that cancer changes the way cells use nutrients to grow rapidly and spread to other parts of the body. Inside cancers cells, specialized factors called enzymes help cancer do this. These enzymes help cancer cells use particular nutrients to keep growing and living. There is one kind of enzyme, called creatine kinases (CKs), that are extremely important for colon cancer cells but not for healthy ones. Because of this, we think we might be able to create a medicine that attacks CKs to treat colon cancer without affecting the rest of the body.
We have developed a new medicine that stops CKs and is effective at killing cancer cells that need CKs to live. Our plan is to develop this medicine to work in animals with colon cancer. This is the critical first step before we can try it in people. If we succeed, we could have a brand-new way to fight colon cancer by stopping the CK enzymes that cancer needs to grow and spread. We hope that this new treatment could be very strong against colon cancer that has spread to other parts of the body.
KRAS mutations are common driver mutations in cancer (ie a mutation that makes the cancer come to be) and particularly common in GI cancers. There are new drugs that target these KRAS mutations. Some drugs cover all KRAS and RAS mutations and some cover specific mutations but the drugs work for short periods of time, even when they work, and many patients still do not benefit at all from these drugs. We are trying to understand why the drugs do or do not work and ways to not only make the drugs work for more people, but when they work, make them work for longer periods of time.
Colorectal cancer (CRC) remains a major cause of cancer-related deaths, mostly due to the risk of cancer metastasis to the liver. This is because while we can detect and treat cancer that is limited to the primary location, we are, till date, unable to treat cancer that spreads to other parts of the body, creating the urgent need for new, life-saving treatments to fight cancer spread. Several studies have established that long-term use of aspirin, a common and inexpensive medicine, can help lower the risk of CRC. However, recent results from studying patients surprisingly showed that aspirin can increase the risk of cancer metastasis and death, especially among older adults. We further discovered that while aspirin may slow down how CRC starts, it can also help the growth of tumors after they have spread to the liver. We also found that this unexpected effect of aspirin on cancer spread is via suppressing the body’s immune system and its ability to fight cancer cells. This means drugs that counter the effect of aspirin may be able to help our immune system fight cancer spreading to the liver. We propose to understand how aspirin influences the immunity in the liver to fight cancer, as well as test whether drugs that oppose aspirin’s effects can inhibit cancer metastasis. We will also test the association of aspirin with metastasis within CRC patients. Ultimately, our new understanding of this process will help us build new treatments to fight cancer that spreads to the liver.
High-grade gliomas represent the leading cause of brain cancer-related death in both children and adults. A fundamental shift in our approach to glioma therapy is thus in dire need. Though much of cancer research has focused on attacking the malignant tumor cells, our focus here is to target the surrounding tissue that provides growth cues for the cancer to thrive. I recently discovered that one important cue for pediatric gliomas is the activity of neurons within the brain. We found that pediatric gliomas grow at a faster rate in response to elevated nervous system activity. Our work has led us to the discovery that these tumors directly communicate with electrically active neurons by plugging into the neuronal network to receive growth signals. These studies highlight the unexplored potential to target neuron-glioma circuit dynamics for therapy. We propose to take a unique new approach to treating these cancers by interrupting the electrical activity across these cancerous circuits. We aim to reframe our understanding of these tumors by investigating how they integrate electrical inputs and hijack normal mechanisms of brain development. A comprehensive understanding of these dynamic network interactions may lead to new therapeutic interventions aimed at normalizing the tumor microenvironment.
Uveal (ocular) melanoma (UM) is a rare type of eye cancer. When the cancer spreads to other sites in the body, outcomes are often poor. Unlike skin melanoma, UM does not respond well to new types of therapy focused on the immune system. Better treatments are urgently needed. Our lab has recently shown that UM tumors frequently lose a sex chromosome (Y in tumors from men, X in tumors from women). Loss of the male Y chromosome (LOY) in men and loss of one X chromosome (LOX) in women occurs in about half of tumors, thereby affecting many patients. We found that LOY is linked to worse survival, and that LOY and LOX can give clues whether a patient’s tumor will spread to other sites in the body. I now propose to study the exact role of LOY in UM with a combined approach. Using genome analysis, gene knock-outs and drug screens in uveal melanoma models, our team hopes to find the weaknesses of UM tumors with LOY. These weaknesses could suggest new treatments for patients. LOY is not limited to UM but also occurs frequently in other tumor types. Therefore, the proposed work has far-reaching implications for finding better treatments for many people living with cancer.
The immune system is your body’s resident doctor. Immune cells constantly examine the organs and tissues in your body. Most of the time, immune cells eliminate damaged or infected cells before they can make you sick. However, this process goes wrong in cancer. We now know that tumors use multiple strategies to hide from immune cells so that they can grow and spread throughout the body.
A new kind of medicine, called immunotherapy, teaches the immune system to recognize and destroy cancer. Some patients treated with immunotherapy cleared their tumors and remained in remission for decades – the closest we’ve come to a cancer cure. However, most patients with colorectal cancer, the second deadliest cancer in the US, do not benefit from existing immunotherapies. It is thought that these patients’ cancers have developed different or additional strategies to hide from immune cells – but how?
One way that immune cells examine cancer cells is by detecting the sugars, or glycans, they display on their surfaces. It was recently discovered that colorectal tumors decorate their surfaces with sugars that trick the immune system into thinking the tumor cells are healthy cells. Thus, glycans are emerging as a main strategy used by colorectal cancers to evade the immune system. This project will develop medicines that target these glycans as a new kind of immunotherapy. Our hope is that medicines targeting sugars can help improve outcomes for all patients with colorectal cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Children with muscle cancer commonly develop resistance to therapy. This is a major problem and most kids will die from resistant disease. Our group has developed a new combination of drugs to kill muscle cancers and is now being tested in kids and young adults. Yet, drug resistance to this same combination has been reported in other cancers and may develop in our patients. Our work will uncover how resistance develops and identify a new drug that can restore sensitivity to chemotherapy. This work is important because the new drugs we identify could be used to treat kids in the future.
Funded by the Dick Vitale Pediatric Cancer Research Fund with support from the Marc and Peg Hafer Family
Acute myeloid leukemia (AML) remains one of the most difficult leukemias to treat. Pediatric patients with AML have relied on standard toxic chemotherapy and bone marrow transplantation for the past few decades for treatment without any advancement in the development of targeted therapeutics for this disease. The development and clinical investigation of a new class of orally available drugs, called Menin inhibitors, has shown great promise in patients with specific, hard-to-treat subtypes of AML. However, we have recently described acquired resistance to Menin inhibitors through genetic mutation in the Menin gene during treatment. After characterizing and understanding the mutations in Menin, we now aim to try to overcome and possibly prevent resistance with the next generation of Menin inhibitors or with combinations with other drugs that show promise in treating AML. The experiments proposed here will guide the clinical implementation of Menin inhibitors into the standard of care in children with either newly diagnosed or refractory AML. We hope/expect that these approaches will, over time, supplant the need for chemotherapy much as has been the case for targeted therapy in APML, which previously required bone marrow transplantation, but is now cured with two oral therapies that have minimal toxicities.
