Haider Mahdi, MD

Funded by Lloyd Family Clinical Scholar Fund

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. 

Mark Awad, MD, PhD

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.

Debattama Sen, PhD

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.

Francisco Sánchez-Rivera, PhD

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.

Richard Phillips, MD, PhD

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.

Joshua Gruber, MD, PhD

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.

Chia-Wei Cheng, PhD

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.

Despina Kontos, PhD

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.

Hatem Soliman, MD

Funded by Hooters of America, LLC

The goal of this project is to understand experiences of racial and ethnic minority patients with cancer with clinical trials. This is an important topic because racial and ethnic diversity in cancer clinical trials is low. This project will help us to understand difficulties patients have in joining clinical trials. It will also help us to understand reasons that make participating in a trial easier for patients. This project will allow patients to share their views on steps we can take to improve diversity in our trials. We will also compare feedback from medical oncologists and trial coordinators. This project will lead to the creation of an intervention to address to issues identified in this study. If successful, our goal will be to test out intervention in other settings.

Ronny Bell, PhD

Funded by the 2021 Victory Ride to Cure Cancer

Dr. Ronny Bell is a Professor in the Department of Social Sciences and Health Policy at the Wake Forest School of Medicine and Director of the Office of Cancer Health Equity at Atrium Health Wake Forest Baptist Comprehensive Cancer Center. Dr. Bell’s research focuses on disparities that impact health outcomes and health care access for racial/ethnic minority and underserved populations.

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