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 with support from the Scott Hamilton CARES Foundation
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
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.
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.
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.
Cancer arises from alterations, termed mutations, of a cell’s genetic material (DNA). Understanding how different types of mutations promote cancer cell growth requires precise modeling of these mutations in tumor cells in order to discern how they specifically impact cell function. We propose to do this for two proteins that are frequently mutated in ovarian cancer. These proteins, CTCF and BORIS, bind to the DNA and can change the DNA’s structure to turn genes on or off. However, how their mutations affect the DNA binding for these two proteins and impact ovarian cancer cells is unclear. We propose to generate cellular models of BORIS and CTCF mutations and measure their impact on DNA structure and gene expression. From these data, we will discern the molecular alterations and functional consequences of their mutation. The goal is to define the mechanism by which these frequent mutations impact ovarian cancer cells, with the ultimate hope that such mechanistic insights can lead to novel therapeutic approaches to ovarian cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund in partnership with Mat Ishbia and Justin Ishbia
Childhood cancer remains the leading cause of death from disease in children in high-income countries. Our lab has used cutting-edge technologies to hunt for new drug targets in high-risk pediatric cancers. In neuroblastoma, a common pediatric solid tumor, we discovered a new potential therapeutic target. Drugs have been developed against this target, but they have not been tested in neuroblastoma. In this proposal, we will perform the critical testing of these drugs in high-risk neuroblastoma models in the lab. We will also determine why neuroblastoma cells depend on this target for survival. It is our long-term goal to develop clinical trials testing these drugs in children with high-risk neuroblastoma.
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