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.
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.
New cancer drugs are needed to improve quality of care, deliver cures, extend life and prevent relapse. We need to hunt in new places or in places that are not yet fully explored to come up with ideas for better drugs. We have focused on a previously overlooked area that is prime for exploitation, namely how DNA is packaged into cancer cells. DNA is the instruction manual of the cell and must be copied forward when cancer cells divide, a process called DNA replication. However, because DNA is so long it must be packaged correctly into the cell nucleus after it is copied. The cell makes a large number of DNA-packing proteins called histones to accomplish this task. We aim to find ways to attack a cancer cell’s ability to make histone proteins as a new cancer treatment strategy. We expect this be safer (less toxic) than targeting DNA replication itself, and hope to find ways to target it specifically to cancer cells. To do this, we are focused on the details of the DNA packing problem, by digging into the cellular components that control this process and asking molecular questions using the latest technologies. We want to understand how this process works better and how it goes awry in cancer cells so that we can exploit our findings for new drugs.
In the past decade, the incidence of pediatric IBD has doubled, and that of early-onset CRC has quadrupled in the United States. The aggressive clinical course of IBD and reduced overall survival of associated young-onset CRC represent an unmet clinical need. Notably, although the reasons for the upward trend of childhood IBD and early-onset CRC are poorly understood, food and nutrition that raises blood sugar have been identified as the major risk factor. Our research takes the nutrigenomic approach to investigate food-gene regulatory networks that can be exploited for harnessing tumor-initiating cells and pro-tumor inflammation. We anticipate that new mechanistic links and therapeutic targets identified in this study will inspire novel preventive and curative strategies to combat inflammatory diseases and cancer.
My research focuses on a class of proteins called chemokine receptors. Many types of cancers will express these receptors, and this can contribute to cancer metastasis. While many drugs have been developed to block chemokine receptors, very few of these drugs have been effective in clinical trials. This is largely because these drugs must hold these proteins in an “off” position 100% of the time to be effective, which is a tall order. We propose to develop a new class of drugs that turn on pathways in cells that will degrade these chemokine receptors—making them “disappear” from cells entirely. We anticipate that this will be a more effective way to prevent these proteins from promoting metastasis than previous drugs that just try to keep chemokine receptors from being turned “on.” This proposal is early stage validation of a new strategy to drug chemokine receptors. However, in the long term, we hope that this work will ultimately improve cancer treatments in two ways. First, it could inspire both new classes of drugs that will block cancer metastasis. Second, it could provide new strategies to discover drugs with these unique properties.
Therapies that recruit and reactivate a patient’s own immune system against cancer have shown a great deal of promise. However, not all patients benefit from these therapies. Thus, developing strategies to boost immune-based treatments is critical. One approach is to develop drugs that improve the function of immune cells. This can be done by targeting transcription factors, which are proteins that help regulate the expression of other proteins. However, transcription factors are very difficult to drug because they often do not have suitable binding sites for chemical compounds. Nevertheless, we recently developed compounds that target a transcription factor known to be important in certain immune cells. Our major goal is to see if targeting this transcription factor can boost the immune response against tumors in mice. We will also try to understand how these compounds reprogram immune cells. This is important because several companies are developing similar drugs, but how these drugs work is not fully understood. The experiments in this proposal will shed light on how this class of drugs work. This will be useful for evaluating how they are used in patients to improve patient outcomes like increased survival.
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.
The immune system provides critical protection against cancer. In fact, new patient therapies designed to boost immune defenses (immunotherapies) have greatly improved cancer treatment. T-cells are a key component of the immune system that can protect against tumor growth. Notably, T-cells can be harnessed for use in cancer therapies in the form of ‘adoptive cell therapy’ (ACT). ACT is an exciting approach in which T-cells are administered to a patient to help fight cancer. Encouragingly, ACTs have successfully cured certain cancer types.
However, ACT does not work well for most cancers. In our work supported by the V Foundation, we will test new strategies to improve ACTs against pancreatic cancer, one of the most lethal cancer types. Completion of this project will yield two important outcomes: 1) Increase our understanding of how the immune system fails to control cancer, and 2) Provide important insight into enhancing the effectiveness of ACT in patients with pancreatic cancer. Immune-based therapies offer hope and promise to cancer patients were traditional treatment approaches (such as chemotherapy or surgery) have failed. This project funded by the V Scholar Program explores new opportunities to enhance cancer immunotherapies.
Vintner Grant funded by the V Foundation Wine Celebration in honor of Leslie Rudd and Family
Cancer is one of the leading causes of death across the globe. Early cancer detection can facilitate effective treatment and fewer side effects to improve patient survival and quality of life. Therefore, there is tremendous interest in using recent technological advances in DNA sequencing, medical imaging, and machine learning methods to enable early detection efforts in cancer. Early detection efforts are likely most effective among individuals genetically predisposed to cancer. Moreover, DNA mutations during the aging process can also increase the risk of developing cancer. Therefore, we aim to use population-level sequencing data to build computational methods to assess individualized risk for developing cancer. We envision that the proposed approach will provide novel insights into the role of inherited and acquired DNA mutations toward tumor growth in high-risk individuals. These insights can be employed to facilitate early detection efforts in cancer.
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