Brain tumors are the number one cause of pediatric cancer deaths. And despite advances in treatment, children in remission have both the constant worry of their tumor returning, plus long term (often delibitating) treatment-induced side effects. . As new treatments are developed, there is an urgent need to better monitor treatment response.
Due to their location, the most common tool for monitoring pediatric brain tumors is recurrent imaging ( such as a series of MRI imaging scans over time). While imaging can provide some information about current disease status in brain tumor patients, it can’t provide details on how the tumor has changed in response to therapy. To address this gap in technological capacity, our team has developed a less invasive blood test that can remove rare tumor cells and particles released by the tumor in brain tumor patients. This test requires less than a teaspoon of blood, which makes it ideal for pediatric patients. For this study, we will use our test on 60 pediatric cancer patients with gliomas and medulloblastomas, in order to detect and monitor the these biomarkers in the blood, and watch for changes to their levels throughout treatment. At the end of this study, we then plan to test our techology in multi-center clinical trials. Our long-term goal is to use tumor biomarkers in blood to more rapidly identify when brain cancer patients need to be retreated, which we hope can in turn be used to accelerate and improve therapeutic interventions.
Co-funded by the Dick Vitale Gala, and WWE in honor of Connor’s Cure
Dr. Jun Qi is a synthetic organic chemist and chemical biologist who has developed small molecules and pioneered anovel chemical strategy in which small molecule therapeutics can be designed to destroy specific proteins within a cell, as opposed to suppressing enzymatic function.Dr. Mariella Filbin is a physician scientist specializing in pediatric neuro-oncology with clinical and scientific interests converging upon pediatric brain cancers, in particular, diffuse intrinsic protein glioma (DIPG) which is universally fatal. Dr. Filbin has used patient-derived modelsto identify a potential DIPG-specific target for Dr. Qi’s protein degrader technology. They will work together to overcome challenges in childhood brain cancer treatment, such as toxicity and blood-brain-barrier (BBB) penetration.This exciting study has two broad objectives:
To define the mechanism by whichthe cancer dependent proteinis driving DIPG formation and growth;
To yield optimized drug compounds suitable for preclinical study and translation to clinical trials in DIPG.
By working together as team, Drs. Qi and Filbin will cultivate a symmetrical relationship in whichchemistry will be used to clarify the biology; and biology will be used to guide the small molecule design and development. By combining their complementary skill sets in chemistry, chemical biology and cancer biology, their joint efforts will result in the preclinical validation of eliminating the target genes and ideally the development of a clinical trial using this novel strategy for DIPG to achieve the bench-to-bedside translation of their research.
RAS is a gene that plays a major role in cancer. The three members of the RAS family are HRAS, NRAS, and KRAS. One of these genes is mutated in about 15% of cancers. The mutant form is hyperactive.
In pediatric solid tumors, RAS is mutated in about 1-3% of cancers and more often in rhabdomyosarcoma.
Inhibiting RAS activity has been a difficult task in cancer drug development. One type of drug, the farnesyl transferase inhibitors (FTI), were developed twenty years ago. Clinical trials using these drugs were disappointing. We now have a better understanding of how to select patients that will best respond to FTI.
Only mutant HRAS is dependent on the farnesyl transferase enzyme. So, FTI should work best in patients with HRAS mutant cancers.
In a clinical trial of patients with HRAS mutant head and neck cancer, patients were treated with tipifarnib, an FTI. Trial outcomes showed that patients’ tumors got smaller (responded).
We are now studying FTI in pediatric solid tumors. We want to know what adaptive events occur in the cell and whether these changes only occur in mutant HRAS tumors. We also want to learn how tumors may escape the anti-cancer effects of FTI.
Studying these changes and paths of resistance can help us develop more complete and lasting responses. Our study aims to address these issues to find effective treatments for patients with HRAS mutant cancer.
Co-funded by the Dick Vitale Gala, and WWE in honor of Connor’s Cure
DIPG is a universally fatal brain tumor that occurs in children. Thanks to extensive research, we now understand the biologic causes of DIPG, but no one has found an effective way to treat the disease. Patients receive radiation to slow the disease and relieve symptoms, but they almost all die within two years of diagnosis. We have found that a target known as GD2 is highly expressed on DIPG. GD2 can be targeted with an antibody that is FDA approved to treat another type of cancer. When the antibody finds its target, it recruits immune cells to “eat” the cancer cells. Here, we propose combining anti-GD2 with another antibody that stimulates the immune system to “eat” cancer cells (anti-CD47). Because antibodies cannot reach the brain when given in the blood, we will deliver these two antibodies by direct injection into the tumor. Our main goal is to test this approach in mouse models of DIPG to see if it is safe and effective. This will hopefully serve as the basis for a clinical trial for children with DIPG. We will also explore alternative and complementary ways to attack the tumors.
Co-funded by the Dick Vitale Gala, and WWE in honor of Connor’s Cure
Years of cancer research have shown that combining therapies virtually always works better than when therapies are used alone. Recently, medications have been discovered that change the way genes are turned on and off. At the same time, treatments have been developed that use the body’s own cells to find and attack cancer cells. Each of these treatments have been shown to work alone on specific cancers. Each has known limits. However, the combination has not been studied. Our project explores whether combining these treatments will improveour treatments for childhood cancer. We are especially interested in if combining these therapies will increase the success of cellular therapies. Our proposal initially studies one specific medication that is already approved for use in children. We will also evaluate a large group of possible medications. We expect that our results will quickly result in a clinical trial for children. In addition, it may lead to a new treatment approaches for many cancers.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Fund
Scientists have given immune cells a detector forB-cell acute lymphoblastic leukemia (ALL).Theycalled these cells CAR T cells. In some patients, these CAR T cells disappear before they can clear the tumor. In others, these cells become too exhausted to work. We have recently identified the molecular code that prevents T cells from dying off or becoming exhausted. With the funding support, we will use this molecular code to make CAR T cells stay in cancer patients longer and clear B-cell ALL more effectively.We hope to use this strategyto cure a much larger population of pediatric cancer patients with B-cell ALL.
Funded by the Constellation Gold Network Distributors
Patients with pancreatic cancer are usually diagnosed with advanced disease and suffer from a very poor prognosis with limited treatment options. This is due to the lack of early detection tests and the largely asymptomatic onset of the disease. In the past decade, drugs that pit the body’s immune response against cancerous cells—also known as immunotherapeutics—have been used to treat a variety of cancers but seem to only benefit a limited number of patients. In particular, immunotherapeutics seem generally ineffectiveagainst pancreatic cancer, although it is unknown if there is a subset of pancreatic cancer patients who may benefit from this therapeutic approach. To understand why, we will use a new platform developed in our laboratory to study how different populations of cancerous and immune cells within the tumor interact with each otheras well as with the other cells in the tumor’s surroundings (i.e. tumor microenvironment). Additionally, the platform will track how these interactions change when the tumor is exposed to disturbances such as immunotherapeutics. Our study will allow usto understand how individual cell populations contribute to the pancreatic tumor’s response—or lack thereof—to immunotherapeutics as well as its ability to evade the immune response.Ultimately, our findings can be used to develop tests that can predict whether a patient with pancreatic cancer will benefit from a certain immunotherapeutic approach.
Funded by Mark and Cindy Pentecost in memory of Will DeGregorio
Ewing sarcoma relies on decades-old chemotherapy options, where aggressive treatments are met with poor disease outcomes. Ewing sarcoma is a devastating disease that affects mostly young adults age 10-16, but children under the age 10 can also develop this deadly illness. Due to the disease’s classification as a rare disease (less than 10,000 cases/year), it has not received the attention of the research community like other more common cancers; therefore, it is in desperate need of intense research and development of new therapeutic options. One of the key observations of Ewing sarcoma made back in the 1930’s is the accumulation of large amount of glycogen. Glycogen is a sugar molecule that our body uses to store energy; only specific organs such as the liver and muscle are capable of producing glycogen. The ability of Ewing sarcoma tumors to store large amount of glycogen has been forgotten until now. This proposal aims to understand the reason behind large glycogen accumulation in Ewing sarcoma and exploit the glycogen deposits as a possible drug target for the treatment of Ewing sarcoma.Dr. Sun has established ongoing collaborations with pediatric physicians to study the basis of glycogen targeting agents for the treatment of Ewing’s sarcoma, and to define early diagnostic biomarkersand evaluation of response to therapy.The long-term goal is to establish treatment options using one or multiple modalities as tailored therapies against Ewing’s sarcoma’s metabolic vulnerability.
Volunteer Grant funded by the V Foundation Wine Celebration in honor of Robert and Gail Sims
The advent of immunotherapy has dramatically changed the landscape of cancer treatments. The power of immunotherapy its potential toinduce long-lasting benefits for terminally ill patients, however only a minority of patients are currently responding to the treatment. We have previously shown that the composition of the immune cells found within the tumor is critically important for the therapeutic outcome, with two immune cell types being required for a strong and effective tumor elimination. These cell types are so-called killer T-cells, which recognize and eliminate tumor cells and dendritic cells, which are needed to “license” T cells to kill.
Killer T-cells are most effective when they are directed against targets only present on tumor cells and when all tumor cells have an evenly distributed expression of this target. However, in most tumors the targets are unevenly represented and only partially present representing ahurdle for successful tumor cell elimination. But more importantly this diffuse pattern directly weakens the strength of the killer T-cellresponse and changes the composition of immune cells in the tumor. To date we do not understand why a weaker T-cell response is observed and how we could overcome this shortcoming therapeutically. In the funded study, we aim to understand the dynamics of akiller T-cell responses against tumors with uneven target expression. In doing so we aim to understand which factors impact the expansion and function of killer T-cells and ultimately harness this knowledge to expand the fraction of patients benefiting from immunotherapy.
Funded through the Stuart Scott Memorial Cancer Research Fund by the Ayodele family in memory of Ade Ayodele
Colorectal cancer (CRC) is preventable when detected early. Because of effective screening, fewer Americans aged 50 and older are now being diagnosed with CRC or dying from it. Over the past 20 years, however, the number of Americans under age 50 who are diagnosed with CRC has doubled. Health experts estimate that the numbers of younger Americans with CRC will continue to increase rapidly over the next 10 years. The reasons for this increase are poorly understood. In addition, younger people are less likely to be diagnosed with CRC when the disease is still at an early stage. Also, of concern is that among men and women of all ages and all races, African-American men are the most likely to die of CRC.
The goal of this study is to better understand the reasons why people under age 50 in Utah are being diagnosed with CRC. As a first step, the researchers plan to identify the specific places in Utah where diagnoses of CRC among younger people are increasing the most. Next, they plan to conduct 1-hour recorded Zoom interviews over phone and/or video with 20 people who live in these places and were diagnosed with CRC when they were under age 50. Thirdly, the researchers plan to create and test a program that will raise Utahns’ awareness of the increasing risk of CRC among residents of the state who are aged under 50. This study is unique as CRC survivors are key to helping drive the study forward.
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