Liron Bar-Peled, PhD

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. 

Volker Hovestadt, PhD

Funded by WWE in honor of Connor’s Cure

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. 

Amy Lee, PhD

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. 

Irene Ghobrial, MD

Funded by the Stuart Scott Memorial Cancer Research Fund

We believe that the immune system in patients with a 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.

Adam Bass, MD

Funded by Gastric Cancer Foundation

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. 

Shannon Stott, PhD

Nick Valvano Translational Research Grant *

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. 

Jun Qi, PhD

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 a novel 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 models to 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 which the cancer dependent protein is 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 which chemistry 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.

Stefani Spranger, PhD

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 to induce 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 a hurdle for successful tumor cell elimination. But more importantly this diffuse pattern directly weakens the strength of the killer T-cell response 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 a killer 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. 

Sahand Hormoz, Ph.D.

Abeloff V Scholar * (Three-way Tie for Top Rank)

Funded by the Constellation Gold Network Distributors

The human body generates hundreds of billions of new blood cells every day to replace old and dying cells. These new cells come from stems cells that live in the bone marrow. Sometimes the genetic material inside one of the stem cells is altered in a way that changes its behavior. The altered stem cells produce too many blood cells and slowly take over the bone marrow. In the clinic, we diagnose this as a type of blood cancer (called myeloproliferative neoplasm or MPN). Intriguingly, the same genetic alteration in different patients can result in very different forms of the disease. The disease outcome is just as unpredictable. Some patients show no symptoms for decades whereas others rapidly deteriorate. To understand this disease, for each patient, we would like to know where and when the disease originated and how the cancer cells expanded over decades. To answer these questions, we have developed technologies that allow us to measure molecular profiles of individual cells. To reconstruct the history of the disease, we will use the genomes of individual cancer cells in the same way that the evolutionary history of species is reconstructed from their presentday genomes. Our preliminary work has shown that cancer first occurs decades before diagnosis. Finally, to test therapies, we will engineer mice in which individual cells record their lineage histories in their own DNA. Together, our measurement will provide the most comprehensive molecular history of how cancers originate and progress in individual patients. 

Zuzana Tothova, M.D., Ph.D.

Abeloff V Scholar* (Tied for Top Rank)

Funded by the Constellation Gold Network Distributors

Use of a new DNA sequencing technology called next generation sequencing (NGS) has significantly improved our ability to describe the genetic basis of human cancers, including blood cancers like leukemia. However, we do not fully understand how most of the genes that cause leukemia play a role in this disease and how to target them with therapy. We know that mutations in a protein complex called the cohesin complex, which normally helps genes turn on and off, frequently occur in patients with blood cancers. These mutations usually occur during the process of disease progression from pre-cancerous states to highly aggressive cancer types. Cohesin mutations are found in 10-20% of patients with blood cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) and are associated with poor survival. With this grant, we will focus on exploring how DNA changes mediated by the cohesin complex play a role in disease progression. Specifically, we will examine folding of DNA into loops and organization of chromatin during the steps of disease progression. Treatment options for patients with blood cancers are limited, and by expanding our understanding of the mechanisms by which leukemia causing genes contribute to disease development, we aim to inform the design of urgently needed therapies for patients. The impact of this work is far reaching and may extend to patients with other blood cancers, including chronic myelomonocytic leukemia (CMML) and chronic myeloid leukemia (CML), as well as patients with bladder cancer, glioblastoma, Ewing sarcoma and breast cancer.

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