Designed to identify, retain and further the careers of talented young investigators. Provides funds directly to scientists developing their own independent laboratory research projects. These grants enable talented young scientists to establish their laboratories and gain a competitive edge necessary to earn additional funding from other sources. The V Scholars determine how to best use the funds in their research projects. The grants are $200,000, two-year commitments.
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.
Myeloid neoplasms (MN), including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are fatal diseases because they are highly resistant to therapy. Ultimately, efforts at preventing MN might be the most successful way to eradicate this disease. Clonal hematopoiesis (CH) is thought to be the origin of MN. CH is a process whereby a hematopoietic stem or progenitor cell (HSPC) acquires a mutation (alteration in the nucleic acid sequence) that leads to a growth advantage compared to normal HSPCs. CH can be detected many years prior to a person developing MN but as of yet, there are no established therapies to prevent progression of CH to MN. We hypothesize that CDK4/6 inhibition might be a potential treatment to prevent MN through halting the progression of CH. Here we seek to: 1) further characterize the potential of CDK4/6 inhibitors to prevent CH expansion through analysis of pre-existing clinical trial data; and 2) using mouse modeling evaluate the potential of CDK4/6 inhibitors to inhibit CH independent of chemotherapy. If successful, this work will justify the development of clinical trials using CDK4/6 inhibitors to prevent CH from progressing to MN in high-risk populations. In the long term, we hope to use targeted approaches to eradicate high risk CH mutations to prevent the development of MN.
Acute myeloid leukemia (AML) is one of the most common and aggressive types of blood cancers. Even though we have made exciting progress and have stronger treatments available, around 30% of AML patients who receive treatment will experience a relapse and have a very low chance of survival. Therefore, we need to figure out how these diseases develop and become resistant to treatment. It has been proposed in AML, there are certain cells that have stem cell-like qualities, which allow them to evade therapy and cause the cancer to come back even after treatment. In this project, we will use advanced techniques to investigate how these cells acquire such characteristics by having specific chemical changes on messenger RNAs. Our ultimate goal is to develop new treatments that can improve the lives of people suffering from these deadly diseases.
Pancreatic cancer kills just about every patient that has it. Patients are first seen with advanced disease and rarely respond to current treatments. More advanced therapies are needed to save lives. Recent studies suggest that pancreatic cancer cells are especially reliant on cellular recycling processes for growth. Mouse models of pancreatic cancer show that blocking these recycling processes can decrease the growth of tumors. These results have led to the launch of several clinical trials. However, initial results from these clinical trials show that pancreatic cancer cells stop responding. The tumors become resistant to blocking recycling pathways. We have made pancreatic cancer cells resistant to these therapies in the lab. We will use these cells to uncover better therapies to prevent resistance and increase patient survival.
Previously, research showed that these recycling processes promote tumor growth. But, in some contexts these same recycling processes can block pancreatic tumor growth. Researchers still don’t know how or when this switch happens. This dual role could contribute to the therapeutic resistance seen in patients. To study this phenomenon, I will use mini-pancreatic organs, called organoids, that can be grown in the lab. For the first time, we will be able to study the mechanisms that regulate the dual roles of cellular recycling in pancreatic cancer. Together these studies will allow us to target the tumor promoting functions of the recycling pathways while preserving the tumor blocking functions. This will prevent resistance and increase patient survival.
Acute Myeloid Leukemia (AML) is the most common and deadliest blood cancer in adults. In 2022, over 11,000 AML patients sadly lost their lives in the USA. The treatment options for AML have stayed the same for many years. But in 2018, a new oral medication called Venetoclax was introduced as a potential breakthrough for AML treatment.
Normally, when our cells become damaged, they have a way of self-destructing called apoptosis. It helps stop any defects from spreading in our bodies. Unfortunately, cancer cells, including those in AML, don’t follow this program and become “immortal,” spreading and causing trouble. Venetoclax is designed to make those cancer cells self-destruct, specifically targeting and killing them.
At first, AML patients showed promising responses to Venetoclax. However, it’s disheartening that about 3 out of 10 patients don’t respond to the medication and in many other patients, AML comes back after treatment. That’s where our research comes in. We want to understand why some patients don’t respond to Venetoclax and how leukemia cells manage to escape apoptosis triggered by the medication.
Through our studies focusing on the molecular aspects of resistance to Venetoclax, we aim to identify potential targets for new and improved therapies for AML. Our studies will also propose combination treatments that could enhance the effectiveness of Venetoclax. Ultimately, with the knowledge gained from this research, we aspire to lay the groundwork for future clinical trials and develop better and safer treatments that will help AML patients live longer and have better lives.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Diffuse midline glioma (DMG) is a fatal pediatric brain tumor, striking 200-400 children in the U.S. each year. Most children with DMG survive <1 year and have no proven therapies beyond radiation. A series of new drugs are being tested in clinical trials of DMG patients, but we lack sufficient tools to track how well they work. Cancer is a rapidly moving target as it can mutate to evade the onslaught of anti-cancer drugs; thus, tumors must be analyzed repeatedly during treatment to assess therapy response. Today’s standard of care for DMG is limited to frequent imaging (MRI), which provides insufficient data to assess therapeutic response. By advancing a new blood-based assay specific to DMG, we aim to dramatically improve our ability to track the effects of treatment on this devastating disease. We will exploit extracellular vesicles (EVs) — small “bubbles” shed by cells — as surrogate markers of therapy response in DMG patients. EVs contain molecular contents (e.g., protein, RNA, DNA) from their mother cells. Tumors shed large quantities of EVs into the bloodstream, offering a potential new way to monitor treatment in DMG patients. We will develop a new assay platform that integrates cutting-edge developments in materials, optics, and deep learning AI into a single system for efficient EV analysis and test whether our platform reliably predicts drug response in DMG patients. Our approach has the potential to transform DMG therapeutic trials and clinical practice, and its flexibility may lend itself to other types of pediatric and adult cancers.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Primary brain tumors are the most common solid tumors in children. They are also the most frequent cause of cancer-related death in children and teens. Genetic profiling is an important tool in the treatment of these tumors. DNA sequencing provides information for proper diagnosis. It can also be used to understand how tumors change over time and to monitor response to treatment. However, performing biopsies is very challenging for brain tumors. Many tumors are in important areas of the brain and can’t be fully removed or repeatedly sampled.
“Liquid biopsy” is a new tool that can be used to diagnose cancer and track response for some systemic tumors. It works by detecting small pieces of DNA that break off from tumors. These can be found in the cerebrospinal fluid (CSF) and in blood (circulating tumor DNA, ctDNA). Accessing these “liquids” is usually easier and has fewer complications than surgery.
We previously showed that CSF ctDNA can be used to diagnose brain tumors and that ctDNA is associated with active disease. But there are instances where CSF ctDNA is not informative due to technical limitations. We propose to improve how these samples are analyzed so CSF liquid biopsies can help more patients. Our prior work was retrospective. For this project, CSF ctDNA monitoring will be added to a clinical trial. We will investigate whether there is a relationship between CSF ctDNA and disease burden. Validating CSF liquid biopsy could greatly improve how pediatric primary brain tumors are diagnosed and treated.
Funded by Friends and Family of Loie Conrad and Stacey Sanders
CAR-T cells are a new therapy where a patient’s own white blood cells are isolated, modified in a dish to better recognize their tumor, and infused back in. These engineered T cells have transformed the treatment of blood cancers and are being actively considered for solid tumors such as triple-negative breast cancer (TNBC) and ovarian cancer. Unfortunately, CAR-T cell treatment success has been limited partly because these cells eventually lose their ability to control tumors in a process called T cell exhaustion. Understanding why CAR-T cells become exhausted in solid tumors is absolutely required to improve patient outcomes and get better immune-targeted treatment responses. These dysfunctional T cells show many defects, including overproduction of a receptor known as PD-1 that inhibits T cells. It is not currently known why high levels of PD-1 are found on exhausted CAR-T cells and what the consequences of high PD-1 expression are. We hypothesize that by focusing on exhaustion-specific regulation, we can rewire CAR-T cells to prevent PD-1 mediated dysfunction in tumors while minimizing side-effects. These will be attractive targets for translation to early-phase CAR-T clinical trials in breast cancer, ovarian cancer, and other solid tumors, where there is intense interest in reducing T cell exhaustion.
Funded by Constellation Gold Network Distributors in honor of the Stuart Scott Memorial Cancer Research Fund
Humans are genetically diverse and exhibit variable susceptibility to developing diseases with a strong genetic component, leading to significant health disparities. The mechanisms by which certain genetic alterations differentially impact disease development and progression depending on the genetic background and the type of genetic lesion remain poorly understood. To tackle these problems, my group has developed sophisticated methods to rapidly engineer and probe endogenous gene function in primary cells and tissues of living animals in a manner that is agnostic to an individual’s genetic background. My lab is using these methods to elucidate the specific ways that different genetic alterations influence cancer development, progression, and therapy responses, with the goal of using this knowledge to better diagnose and devise novel strategies to target cancers in a more precise, personalized manner.
Funded by the Stuart Scott Memorial Cancer Research Fund
Adult midline gliomas are aggressive, unresectable tumors for which no curative treatments exist. These tumors are caused by faulty ‘epigenetics’ i.e. problems in the way cells switch certain genes ‘on’ or ‘off’. Our research is studying a protein complex called PRC1, which we have found these tumors use to keep certain genes switched off to promote growth. We aim to understand how PRC1 functions so that we can devise novel ways to target this pathway and develop new treatments for this disease.
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