Funded by Lloyd Family Clinical Scholar Fund
About 5% of non-small cell lung cancers (NSCLCs) have DNA mutations in the anaplasticlymphoma kinase (ALK) gene, and patients with this “ALK-positive” subtype of lung cancer are typically young and have never, or only lightly, smoked. For ALK-positive NSCLC, there are a number of FDA approved oral ALK inhibitor pills, including alectinib, lorlatinib, and brigatinib. While these targeted therapies are initially very effective, the benefit of each of these drugs is usually limited to only a few years because ALK-positive lung cancers almost always develop drug resistance through a variety of complex mechanisms. Although PD-1 inhibitors such as pembrolizumab (Keytruda) have revolutionized the treatment of lung cancer in general, particularly in smoking-associated cancers, most patients with ALK-positive lung cancer do not respond to existing immunotherapies.
We developed an ALK vaccine immunotherapy, composed of small pieces of the ALK protein, which is an effective treatment in animal models of ALK-positive lung cancer. We now plan to launch a first-in-human clinical trial to test this ALK vaccine in patients whose cancer is growing despite treatment with an ALK inhibitor. The vaccine will be tested in combination with an approved ALK inhibitor or with an approved immunotherapy (nivolumab). We will also study immune cells in the blood and in tumor biopsies both before and after vaccination to ensure that this novel therapy is generating a proper anti-ALK immunologic response as we would expect. Our goal is to develop a safe and potent ALK vaccine to improve outcomes for our patients.
Abeloff V Scholar*
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 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.
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.
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