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.
Funded by Lloyd Family Clinical Scholar Fund
Some cancers grow because of an abnormality (or “mutation”) in a gene called ALK. Currently, there are FDA-approved pills that shut down this abnormal ALK protein and cause cancers to shrink down. However, over time, cancer can develop resistance to these treatments and start to regrow and spread, and once that happens, there are few effective treatment options for these cancers. We are working to develop a cancer “vaccine” to treat patients with ALK-mutated cancer. Similar to how vaccines against COVID-19 or influenza help the body fight off these viral infections, our new cancer vaccine is designed to cause a patient’s immune system to attack cancer cells and shrink down tumors. Hopefully these treatments will help our patients to feel better and live longer with their cancer.
Abeloff V Scholar*
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.
*The research project that receives the highest rating by the Scientific Advisory Committee is annually designated as the Abeloff V Scholar. This award is in honor of the late Martin D. Abeloff, MD, a beloved member of the Scientific Advisory Committee.
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.
There are many types of kidney cancer and most current treatments were designed for the commonest type, called “clear-cell kidney cancer.” However, these therapies work less well in other types of kidney cancer. Unfortunately, because the different kinds of kidney cancer can look similar under the microscope, many kidney cancers are misdiagnosed.
One such cancer is “translocation renal cell carcinoma” (tRCC), which makes up about 5% of all kidney cancers in adults and over half of kidney cancers in children. Early and accurate diagnosis of tRCC is important for two reasons. First, this kidney cancer has a poor prognosis and it is vital that patients are accurately informed of their diagnosis. Moreover, an early diagnosis may give a patient the opportunity to cure the cancer through surgery before it spreads. Second, an accurate diagnosis can inform which is the best treatment for a patient to receive.
Although tRCC is frequently misdiagnosed under the microscope, it is unique in terms of the genes it expresses. In this project, we will develop methods to diagnose tRCC based on its distinctive pattern of gene expression. We will apply these methods to both biopsies of tumor tissue and so-called “liquid biopsies,” in which DNA from tumor cells is extracted from a routine blood draw. This work will advance the accuracy and ease with which kidney cancer is diagnosed and may lead to new ways to diagnose tRCC earlier – when it can be caught and cured before it spreads.
Pancreatic cancer remains a devastating diagnosis that is incurable in most patients, killing ~50,000 Americans per year. Treatment options including newer immunotherapy approaches are notoriously ineffective. These grim numbers motivate the search for a new strategy called “interception” that might prevent pancreatic cancer altogether. Interception seeks to target the earliest events in the progression of normal pancreas cells into invasive cancer. While this progression spans over a decade, no interception options currently exist.
We have identified a compelling target for interception. This protein is responsible for maintaining the normal identity of pancreas cells, and its activity diminishes as cells progress to cancer. Furthermore, studies comparing thousands of individuals with or without pancreatic cancer have found that this protein impacts risk of developing pancreatic cancer. Lastly, our team has developed potent drugs that can modulate the activity of this protein.
Our goal in this proposal is to pioneer an interception strategy by pharmacologically boosting activity of this protein to prevent progression of normal pancreas cells into cancer. We will characterize the mechanisms and impacts of these new drugs in mouse models of pancreatic cancer as well as in human specimens. Our studies will lay groundwork for clinical trials of interception to prevent pancreatic cancer altogether. Pancreatic cancer interception can also help address issues of psychological trauma associated with diagnosis and unequal access to treatment. Like taking aspirin to prevent heart disease before it happens, we envision these new drugs will be transformative in the fight to end pancreatic cancer.
Lung cancer is the leading cause of cancer death in both the US and the world. There is an effective screening tool called low dose computed tomography (CT) scans of the lungs, which can find lung cancers earlier while curative surgery is still an option. These screening CT scans are recommended once to year for heavy current and former smokers, but only a tiny fraction of those who should be getting lung screening are receiving it, in part because of the high false positive rate with screening CT scans. When lung screening identifies an abnormal area (called a nodule) within the lung, the chances are much greater that it will turn out to be benign rather than cancer. However, to prove the nodule is benign a battery of tests and procedures are often ordered, leading to cost, inconvenience, possible complications, and worry. Our project aims to cut the obstacle of false positive results on lung cancer screening in half by developing a blood test that can be drawn in a doctor’s office after a patient is found to have a lung nodule on a screening CT scan and can help predict whether the nodule is benign or cancerous. The test is built upon a cutting-edge technology called multiplexed mass spectrometry-based plasma proteomics, which can detect the signature spectrum of hundreds of proteins within a patient’s blood plasma using just a small sample. Our test will look at the pattern of proteins to see if the pattern matches those seen in cancer patients. Our long-term goal is to develop an accessible test that will promote increased lung cancer screening uptake and lead to more lives saved.
Bob Bast Translational Research Grant*
Most women from families that have the greatest risk for breast and ovarian cancers are not aware that they are at higher risk. Even among women who are aware of this risk, no tests are available for ovarian cancer, and no tests for breast or ovarian cancer can predict when a cancer is most likely to occur. The current tests typically detect cancer when it has already spread and is very difficult to cure. There is a great need to have a test that can accurately identify women who are at higher risk for breast and ovarian cancer and can detect cancer early. Our project will develop a blood test which can predict which women are most at risk for ovarian and breast cancer. Following that, we will study whether the same blood test can predict when cancer among these women is most likely to develop, increasing the chances that a cancer is found early and significantly improving the odds of survival. The novelty of our test is that we are looking at a new class of molecules in blood using cutting-edge strategies that have never been used for cancer detection.
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.