Ovarian cancer (OC) is the most lethal gynecologic cancer in the US. Unfortunately, the majority suffer relapse. Patients with recurrent platinum-resistant OC respond poorly to chemotherapy.
Immunotherapy with immune checkpoint inhibition (ICI) has emerged as a promising therapy in several cancers. Unfortunately, only small fraction (10-15%) of patients with OC do benefit from immunotherapy. Therefore, effective strategies are warranted to improve the overall benefit of immunotherapy in OC. Targeting immunosuppressive factors within the tumor immune microenvironment (TME) represents an attractive approach. Our focus in this proposal is on tumor-associated macrophages in OC.
Macrophages with a specific ‘suppressor’ phenotype (M2 subtype) within TME play a significant role in promoting an immunosuppressive environment and in mediating therapy resistance. These cells are the most prominent cells in OC. However, another phonotype (M1 subtype) provides a favorable pro-inflammatory TME and enhances the immune response. Targeting macrophages and switching their phenotype from M2 to M1 is potentially promising approach that has not been investigated thoroughly before. In this study, we propose to target them with two strategies: Targeted inhibition of the transforming growth factor-beta (TGF-beta) receptor and CD47 inhibition.
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.
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.
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.
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.
Lung cancer kills the most cancer patients in the world. Most of these patients are diagnosed late in their disease, and there is no cure. Having a chest CAT scan (CT scan) every year helps detect lung cancer early and reduces the chance of dying. When lung cancer is detected early, the patient has a higher chance to survive. Patients who are diagnosed with small lumps in their lungs, called lung nodules, have a higher chance of getting lung cancer. Having lung nodules can also require unnecessary, uncomfortable, and sometimes painful medical procedures that are not helpful for the patient. The purpose of our research is to help detect lung cancer earlier for patients with lung nodules, which could give them a better chance to beat cancer and survive. To do this, we propose to combine new medical test tests, from a blood draw and computer measurements from CAT scans. We will use simple blood draws to measure DNA materials in the blood that can help detect if lung cancer is present. We will also use computers to analyze hundreds of measurements from lung nodules in CAT scans that can tell us if the nodule is cancer. We will then combine the blood draw and computer measures from CAT scans using advanced math to detect lung cancer early more accurately without hurting the patient. Our goal is to improve early lung cancer detection so that it can be cured and help save patient lives.
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.
Mailing List
