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.
Acute myeloid leukemia (AML) is an aggressive blood cancer that can recur after standard therapy. Although chemotherapy kills fast-growing AML cells, it often fails to destroy allcancer cells. As a result, the patient may appear to respond to therapy, but eventually the cancer returns. We found that the surviving cancer cells can overcome therapy by entering a senescence-like dormancy, allowing them to endure chemotherapy and resume cancerous activity after therapy has ended. The cancer cells become more aggressive than before treatment and showed changes in their epigenetic marks including DNA methylation. In this project, we will examine the mechanisms controlling the DNA methylation changes and their role in AML dormancy. Overall, this project will advance our understanding on the relevance of DNA methylation in cancer therapy and will define new therapeutic targets. Our long-term goal is to apply this information to develop new therapies to improve the survival of AML patients.
We study the response of the immune system to cancer. A type of immune cells, called T cells, play a central role in killing and clearing cancer cells. However, as cancer develops, these cells malfunction, leading to their inability to clear cancer cells, allowing for them to grow out of control. Many therapies used to treat cancer now target those cells, working to enhance their ability to fight cancer cells. One of them is called PD-1 blockade treatment. However, there is much we do not know about this treatment. Due to this, there are many individuals where this therapy does not show any therapeutic effect over traditional cancer treatments. We previously have found that the means by which the immune cells fuel their energy stores (called glucose metabolism) is central to their overall function during cancer development. Some tumors consume many resources to grow as quickly as possible, this prevents immune cells in the area from using these same resources to fuel energy from glucose. Our overarching goal is to determine the mechanism by which these immune cells malfunction due to a lack of resources and how this insufficient level of resources hinders the immune cell response to cancer. The research completed will be instrumental in our understanding of how T cells respond to cancer cells during the progression of disease and treatment.
Cancer is a problem of uncontrolled cell growth. Either too many new cells are being born or not enough old cells are dying. Cellular senescence is a normal aging process in which cells stop growing. However, these cells remain metabolically active and secrete factors to attract immune cells and increase inflammation. This process occurs naturally during aging due to different types of stress that build up over time. Senescence was first thought to protect against cancer since it prevents new cells from being made. In fact, many drugs currently used to treat human cancer patients block tumor growth by turning on senescence. However, more recent studies have shown that some tumor cells can eventually escape this process and start growing again. Cells that exit senescence may even grow faster and spread more easily than before. Given these new findings about the ‘dark side’ of senescence, there has been growing interest in using anti-aging drugs to treat cancer. However, this process is complex and has been difficult to study in the lab. We created a new mouse model of adrenocortical carcinoma (ACC), which is a deadly cancer that starts in the adrenal gland and has no effective treatments. Our model develops adrenal cancer, but only after an extended period of senescence. This model provides a unique opportunity to study the relationship between aging and cancer. Using this system, our goal is to (1) study the long-term effects of senescence on tumor growth, and (2) test anti-aging drugs as cancer therapy.
Funded by the Wine Celebration in honor of Carol Bornstein
Tumors are constantly growing and mutating – they are different from healthy cells, and thus should be able to be recognized by your immune system. However, immune cells respond to molecules that act as brakes, which can be used by tumor cells to escape being killed. While some of these immune brakes have been discovered, drugs blocking these do not work in most cancer patients, and many remain unknown. To improve survival for everyone, we need to figure out what the other important brakes are so we can reprogram your own immune system to fight cancer. We have recently discovered Siglec-15 as a new immune cell brake in tumors.Blocking Siglec-15 shows improved immune activity in studies involving human cells and mice. Based on these results, clinical trials targeting Siglec-15 are currently ongoing. Initial trial results show that targeting Siglec-15 is safe and slows down tumor growth in patients who have already failed other therapies. Thus, we need to understand the biology of Siglec-15 so we can design the best cancer therapy possible. Here, we will study how Siglec-15 suppresses tumor immunityand identify strategies to maximize its clinical response. Our proposal will improve our knowledge of cancer immunology and help patients in the fight against late-stage cancers.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Pediatric Cancer Research Fund
Acute myeloid leukemia is a cancer of the blood that affects hundreds of childreneach year in the USA. While the survival rate has improved, there is still a 30-35%chance of relapse within five years of diagnosis. We need better therapeutic options totreat this disease. Leukemia, in most cases, is caused by a breakdown in the bloodcells’ ability to regulate their genes. This leads to uncontrolled growth of partiallydeveloped blood cells that can overrun the host. While there are some drugs availableto treat this disease, most patients eventually will see their leukemia return. Ourresearch goal is to understand the mechanisms that break down when a healthy cellbecomes a leukemic cell. We want to develop better therapeutics to treat leukemia. Wehave found that excessive levels of the chromatin assembly gene CHAF1B is neededfor leukemic cells to stay cancerous. Turning down CHAF1B is enough to turn theleukemia tumor into normal cells. In fact, we think that CHAF1B is responsible fordriving therapy resistance in AML by repressing expression of differentiation genes. Ourwork over the next two years will enhance our understanding of how this processbreaks down in leukemia, and hopefully lead to better treatment options for patients.
Cancers of the brain and spine are hard to cure and are often lethal. Knowing if and when a cancer will recur has been challenging to predict. We do not have a good test to determine which cancers will return quickly and which will not. For this reason, nearly all patients are given the same treatment that often involves surgery, radiation, and drug therapy.
A holy grail in cancer research is to create a test that can predict cancer behavior. Our laboratory studies DNA structure and how it can be used to predict cancer behavior. One goal of our laboratory is to create a test based on DNA structure that can pick out the aggressive brain cancers from the less aggressive ones. A second goal is to create a test that can tell which cancers might respond to new drug treatments. To do this, we use a combination of cutting-edge experimental and computational approaches. We anticipate that such research will lead to the ability to create a treatment plan for each patient individually. We can treat aggressive cancers with tailored plans, whereas we can hold on treatments for cancers that are unlikely to need it.
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.
One of the biggest advances in cancer therapy in the past century has been the recognition that theimmune system can be targeted by drugs to trigger immunity against tumors. These drugs, called‘immunotherapies’ have improved survival for patients in a large and growing number of cancers.However, across cancer types, most patients do not durably benefit from treatment. The reasons forthis lack of benefit in particular tumor types and patient populations are unclear. We have developed an approach that leverages new technologies that give us insight into the states and activities of individual tumor and immune cells directly isolated from patient tumors. This approach allows us to dissect mechanisms of resistance to immunotherapy and cellular responses to novel treatments. We are applying our strategy in head and neck cancers, an under‐studied class of tumors that is diagnosed in more than 60,000 people in the US each year. Our preliminary studies have identified distinct immune suppressive pathways enriched in head and neck cancer. In the present project we will test whether drugs aimed at targeting these pathways can restore the anti‐tumor activation of immune cells. If successful, these studies aim to: i) validate the use of novel combination immunotherapies for head and neck cancer and ii) identify biomarkers of response that will allow us to select the patients who willmost benefit from these combinations.
Cancer treatments often fail to produce durable responses and resistant tumors eventually regrow. This process presents a major clinical challenge and results in significant patient mortality. The molecular details of this process, termed acquired resistance,are poorly understood and there are currently no therapeutic options to prevent it. For cancer immunotherapy, acquired resistance is emerging as a prevalent phenomenon affecting approximately half of patients who initially respond to treatment. Key to this process are the leftover tumor cells which remain alive and seed resistant tumors. We have observed a small subpopulation of cancer cells which survive directcytotoxic T cell attack over prolonged time periods. These cells, termed persister cells, survive through unknown mechanisms. In this proposal we will determine how persister cells survive despite undergoing T cell attackand also how a subset of persister cells eventually regrow and exhibit overt T cell resistance. If successful, our proposed work will shed light on acquired resistance to immunotherapy and may reveal new approaches to prevent tumors from recurring.
Pancreatic cancer will soon become the second biggest cause of death from cancer in the United States. Patients usually find out they have this disease after it is too late for surgery. This leaves treatment as the only option, and the ones in use only help patients live for a few months. To change this, we need to find new approaches to improve the survival of our patients.
Pancreatic cancer is hard to treat for many reasons. A key issue is that the tumors are made up of many cell types, not just cancer cells. Over the past few years, we have found ways these different cells can act together within a tumor to help cancers grow or avoid therapy. Most recently, we discovered that cancer growth can be slowed by blocking exchange of the amino acid asparagine when their mitochondria are stressed.
The goal of this project is to show how cancer cells make and share asparagine. Knowing this, we can better target this metabolism to kill the cancer cells. From our previous work, we also predict this strategy will help patients better respond to immunotherapy. The results from this project will show us how to improve pancreatic cancer treatment and provide data we need to start new clinical trials.
