Funded by the Dick Vitale Pediatric Cancer Research Fund
Chromatin is the normal form of our genomes and it is formed by DNA and proteins. Chemical changes of these building-blocks, and the factors that control these epigenetic events play essential roles in maintaining the integrity of cells, tissues, and ultimately entire organisms. Recent advances in genomics have uncovered that chromatin and epigenetic regulators are broadly altered in human diseases, particularly in pediatric cancers. This project focuses on understanding how the chromatin regulator Menin helps decipher the chemical language of chromatin, and how it can control or impair gene expression in childhood leukemia. These studies will improve our fundamental knowledge of how protein complexes come together on chromatin and how obstruction of these processes result in the very devastating development of pediatric blood cancers. We use an interdisciplinary approach to provide mechanistic insights into these important questions. This work will shed light into the biology of how Menin regulates chromatin and gene expression, and will pave the way for the development of novel drugs that target these factors in pediatric blood cancers.
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.
Funded by the Dick Vitale Pediatric Cancer Research Fund and the V Foundation Wine Celebration in honor of Bob McClenahan
Leukemia is a blood cancer that can be fully treated with anti-cancer drugs in most people. However, many people with leukemia do not respond to these drugs and are at risk of dying. It is not known why some leukemias respond to treatment while others do not. We believe that the type of normal blood cell that becomes leukemic impacts the behavior of individual leukemias. We believe that if a normal blood cell possessing the ability to form many other types of blood cells (in other words, it is a blood ‘stem cell’) turns into leukemia, this leukemia will be hard to treat. On the other hand, if the normal blood cell does not possess such properties – it is a more mature blood cell – this leads to treatable leukemia. In this proposal, we will apply our experience in engineering different types of blood cells (stem cells and more mature blood cells) to become leukemic. We will ask how the type of healthy blood cell impacts the behavior of the resulting leukemia. We will use genetics to understand how the properties of normal blood stem cells are transferred to leukemia cells to impact aggressiveness. We expect that successful completion of this study will improve our understanding as to why some forms of leukemia are treatable and why some are not treatable. We hope that these conclusions can lead to better understanding of individual patient leukemias and improved treatments.
The goal of this project is to make new drugs against ovarian cancer genes using a new drug discovery method. Ovarian cancer (OC) remains a deadly disease. OC will be diagnosed in over 21,000 women in the United States this year and 13,770 patients are expected to pass away during this time. While initial responses to the best anti-cancer drugs are frequent, most patients with OC will experience disease again after 24 months of treatment, and most women will unfortunately pass away from this disease within five years. Thus, there is an urgent need to make new drugs to treat ovarian cancer. The classic approach to drug discovery is both time intense and costly, and most cancer drug discovery is focused on making drugs against cancer proteins whose shape is considered readily ‘druggable’. Our central premise is that many ovarian cancer proteins can be drugged. To test our idea, we will use a new tool that finds druggable proteins by detecting drug binding to cancer causing proteins in OC cell lines and patient tumors. If successful, this program should develop a new class of anti-cancer drugs to help women suffering from OC.
Brain tumors are now the most common cause of cancer-related death in children. Most affected children undergo surgery and receive extensive therapy with toxic substances, yet many will succumb to their disease. It has been a major interest of the research community and pharmaceutical companies to develop more effective drugs that target specific cancer-causing proteins. However, identifying suitable protein targets is often challenging. We question if we can target a different class of molecules called microRNAs. Our work will answer which microRNAs are the most promising targets across different types of childhood brain tumors and how to target them most effectively.
We are developing a novel experimental system that allows us to collectively study the effects of all microRNAs in the human genome. Our system is based on modern genomic and computational techniques that are only recently feasible. This will enable us to identify and test the most promising targets.
We are hopeful that our findings will result in a better understanding of how microRNAs cause brain tumors and will lead to better treatments that help young patients. Better treatments will result in higher survival rates and lower side effects. In the short-term, our basic research study provides molecular rationale and pre-clinical results to further pursue developments. Over the long-term, we hope that our results will lead to novel drugs that will help affected children.
Cancer occurs when cells grow in an uncontrolled manner. These cells spread to other tissues and form metastatic tumors. Unlike normal cells, cancer cells can survive within a tumor environment that has low amounts of nutrients and does not have a normal oxygen supply. This is because cancer cells contain a different set of factors called “proteins,” which are the principal machinery for work in a cell. These changes in protein are what drive increased cell growth. Proteins are made through a process called “translation,” where the cellular genetic material is converted from RNA into protein. We seek to block the translation of cancer-promoting proteins, and to determine if this will stop the formation of tumors.
To address this goal, our research is focused on understanding how translation is regulated in cancer cells. Here, we are studying a regulator of translation called eIF3. eIF3 is increased in cancers, including those of the breast, lung, stomach, cervix, and prostate. Furthermore, eIF3 overexpression is linked to poor prognosis. In this proposal, we will determine how eIF3 contributes to translation of cancer-promoting proteins and evaluate the potential of eIF3 as a therapeutic target. Ultimately, the long-term goal of this research is to define how protein production is regulated in cancer cells, to allow for rational design of cancer treatment therapeutics that target translation.
Funded by the Stuart Scott Memorial Cancer Research Fund
We believe that the immune system in patients witha precursor condition to multiple myeloma (a cancer in the bone marrow) allows the disease to progress (worsen) into more serious disease. Our project aims to find immune biomarkers that predict disease progression and identify patients who will likely progress early to treat the most at-risk patients before they become symptomatic. These markers may include changes in the number or type of immune cells or changes in the way those cells work. We will also examine how patients’ immune systems change in response to a new treatment that targets immune cells. We will use DNA and RNA sequencing and spatial imaging to investigate single cells from the bone marrow. We will gain a detailed picture of how the immune system supports or fights the tumor. This work will support the development of new treatments that may slow or stop disease progression.
This application focuses upon the need to develop new therapies for stomach cancer, which is the 3rd leading cause of cancer mortality in the world. In our laboratory’s prior studies, we described the patterns of disruptions in the genome (or DNA of the cell) that develop in the stomach cells which become cancerous. The overall hope for this work is that finding the genetic causes of cancer can be a source of development of new targets for guiding cancer therapy. The primary way to try to use genomic understanding of cancer to guide therapy has been to find specific genes which are aberrantly activated in cancer. However, to date, approaches to use this approach to guide therapy for stomach cancer has been largely disappointing despite individual successes. Therefore, this new research program supported by the V Foundation and the Gastric Cancer Foundation aims to develop alternative approaches to use our understanding of the gastric cancer genome to guide development of new therapies. Instead of focusing on the genomic alterations that impact individual genes, we are now pivoting to more broadly evaluating the patterns of genomic alterations and the classes of instability or genomic disruptions that occur in cells. We have developed new approaches to classify the types of genomic disruptions that are characteristic of gastric cancer and then directly connecting these patterns to possible new therapeutic targets. We believe that this work may serve as a critical foundation for novel development of therapies for these deadly cancers.
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.
