Pre-Clinical and Clinical Concepts Awardees

Current Awardee

Biomarkers of Health Improvements After Abstinence from E-cigarettes and Combustible Cigarettes

 

Principal Investigator: Amanda Palmer, Ph.D.

Cigarette smoking has been decreasing among adults and, at the same time, use of e-cigarettes (vaping) has dramatically increased. Therefore, e-cigarettes are forecasted to surpass cigarettes as the most popular tobacco product used in the US.

E-cigarettes are battery-operated devices containing a liquid solution with nicotine, flavors, and other chemicals. While cigarette smoking is detrimental to health and a known risk factor for cancer, e-cigarettes are thought to be less harmful but not entirely risk-free, and less is known about e-cigarette use and cancer risk. Importantly, negative health effects from cigarette smoking can be reduced or even reversed following quitting smoking.

The purpose of the present study is to evaluate changes in biomarkers of health, specifically related to cancer, respiratory, and cardiovascular risk, that may occur when people stop using e-cigarettes. In the present study, participants who use e-cigarettes (and who never smoked, smoked in the past, or currently smoke) will be recruited to participate in a laboratory session followed by a week of nicotine abstinence. Throughout the study, participants will provide biological samples for analysis of DNA damage, immune functioning, inflammation, and respiratory functioning. Results will provide insight into the health benefits of quitting vaping, which will help to support future research grants evaluating the effectiveness and health outcomes of new treatments to help people quit vaping.

Previous Awardees

Evaluation of a Proactive Identification and Digital Mental Health Intervention Approach to Address Unmet Psychosocial Needs of Individuals Living with Likely Incurable Cancer

Drs. Graboyes and Dahne's award is funded in part by LOWVELO, MUSC Hollings Cancer Center's fundraising bike ride that channels 100% of rider-raised dollars into cancer research.

Individuals living with likely incurable cancer lack feasible, accessible, and evidence-based treatment for depression. To address this need, we will conduct a pilot randomized clinical trial to 1) develop automated approaches to identify individuals with likely incurable cancer in the electronic medical record; and 2) compare a self-guided digital mental health intervention to manage depression among these patients versus standard existing treatments. Long term, this research has the potential to expand evidence-based mental health access to a growing population of individuals living with likely incurable cancer.

Fusobacterium Nucleatum Promotes Oncogenic Signaling through Disruption of the Epithelial Adherens Junction-Associated RNAi

Principal Investigator: Antonis Kourtidis, Ph.D.

Collaborators/Co-Investigators: Mindy Engevik, Ph.D., and Silvia Guglietta, Ph.D.

Dr. Kourtidis' award is funded in part by LOWVELO, MUSC Hollings Cancer Center's fundraising bike ride that channels 100% of rider-raised dollars into cancer research.

Colon cancer is the third most prevalent and second deadliest form of cancer. Although colonoscopies and public awareness helped reduce cases in ages 50 years and older, the incidence is alarmingly increasing in the younger population. Searching for causes for this increase, there has been particular interest on the microbes that exist in our gut. These microbes constantly interact with the lining tissue of the colon, called the epithelium, which forms a barrier that prevents their invasion into our body.

However, this barrier is compromised in colon cancer, whereas certain bacterial species, such as Fusobacterium nucleatum, are highly prevalent in colon tumors and have been associated with disease progression. Still, whether and how these bacteria promote the disease, is not well-established.

Work in our lab has shown that the proteins that are responsible for formation of the colon epithelial barrier also possess the ability to suppress colon cancer formation through regulating small molecules called microRNAs (miRNAs). We have also found that this mechanism is compromised in colon cancer. Since this mechanism associates disruption of the epithelial barrier with cancer, we wondered whether Fusobacterium nucleatum is promoting colon cancer by disrupting the function of these barrier-related miRNAs.

Our preliminary experiments support this idea, showing that this bacterium indeed disrupts miRNA-regulating proteins and promotes expression of oncogenes. We will fully examine this mechanism in this project, aiming for a better understanding of the causes of colon cancer and eventually developing antibiotic- or miRNA-based therapeutics that can suppress progression of the disease.

Using Implementation Mapping to Prepare for the Implementation of a Hereditary Cancer Clinic for Clinical Management of Patients at High Risk of Inherited Cancer

Principal Investigator: Caitlin Allen, Ph.D.

Dr. Allen's award is funded in part by LOWVELO, MUSC Hollings Cancer Center's fundraising bike ride that channels 100% of rider-raised dollars into cancer research.

This project will use implementation science strategies to support new clinical offerings through the Hereditary Cancer Clinic for individuals and families at high risk of developing cancer. We will use implementation mapping, a systematic, stakeholder-engaged approach to identify patient- and provider-level needs for cancer prevention, test strategies to address these needs, and develop an evaluation plan to assess the new care model. 

Sex Differences in Immune Responses to Non-Small Cell Lung Carcinoma (NSCLC) using Three Distinct Syngeneic Murine Models

Principal Investigator: Richard O'Neil, Ph.D.

Males and females exhibit differences in immune response to cancer which leads to significantly different outcomes — men are at twice the risk of dying from malignant tumors compared to women. Despite these observations, sex differences are rarely considered in pre-clinical models of cancer.

We propose that differences in tumor immune responses can be modeled in mice, and that these models will serve as valuable tools for exploring the mechanisms underlying this health disparity. This funding will be used to obtain mice and conduct single cell transcriptomic studies on tumor tissue from three distinct lung tumor lines in male, female, and ovariectomized mice in both subcutaneous and orthotopic models.

Regulation of PRMT1 by Amino Acids and CDK5

Principal Investigator: Wenjian Gan, Ph.D.

Post-translational modifications (PTMs), such as ubiquitination, phosphorylation and methylation, play a key role in maintaining signaling pathways in response to diverse environmental inputs. Aberrancies in key enzymes of these modifications may cause imbalanced signal transduction, contributing to human diseases including cancers. My lab is particularly interested in investigating the regulation and biological functions of protein arginine methyltransferases (PRMTs) in breast cancer and hepatocellular carcinoma progression.

Notably, PRMT1 is the main type I enzyme responsible for about 80% of arginine methylation. Previous studies showed that PRMT1 is upregulated in various cancers including breast cancer and hepatocellular carcinoma. This proposal will identify the upstream stimulus/regulator of PRMT1, providing a novel regulatory mechanism of PRMT1 biological function and a potential strategy targeting PRMT1 for cancer therapy.

A Novel Technology to Perform scRNA-Seq from Cryopreserved Human Tumors

Principal Investigator: Demetri Spyropoulos, Ph.D.

Collaborators: David Neskey, M.D., John Baatz, Ph.D., Martin Romeo, Ph.D., Denis Guttridge, Ph.D.

Tumors are often complex in nature, containing some cell types that are sensitive and some that are resistant to different therapies. Most cancers that relapse after treatment involve therapy-resistant subpopulations of such tumor cells. In order to know how to treat cancers so patients remain in long-term remission and don’t relapse, we need to understand the complexity of tumors.

New technologies now exist to determine tumor complexity, but they are very expensive and require immediate tumor processing before we can decide on which tumors to investigate. The research grant investigates a method for preserving and banking tumors live and intact for extended periods of time, so that informed decisions can be made on which sets of tumors to fully study and thereby develop the best therapeutic strategies.

Remodeling ER Morphology to Improve Tumor Immunotherapy

Principal Investigator: Jessica Thaxton, Ph.D.

Collaborator: Alex Andrews, Ph.D.

The tumor microenvironment (TME) presents extreme metabolic stress to tumor infiltrating lymphocytes (TILs) that debilitates their ability to control tumor growth. The endoplasmic reticulum (ER) is the central organelle through which cells experience stress. Our lab has shown that essential processes in the ER become dysregulated in the TME.

Our previous research led us to question whether the dynamic morphology of the ER becomes distorted in T cells in solid tumors. Our preliminary data indicate that ER morphology is compromised in CD8 TILs and that ER structure defines the capacity of T cells to control tumor growth.

This proposal will generate gene deletion tools in human T cells and a unique mouse model to study the role of ER shaping proteins to control T cell antitumor fate. New therapeutics that target ER architecture in TILs may extend across tumor types and to other dysmorphic tumor immune subsets, offering a panacea to reset immune homeostasis in tumors.

Overcoming Anti-Angiogenesis Therapy Induced Resistance in Recurrent Glioblastoma

Principal Investigators: Arabinda Das, Ph.D. and David Cachia, M.D.

Glioblastoma is a very aggressive brain tumor that to date we have no cure for. Treatments such as radiation and chemotherapy extend life, but unfortunately these tumors become resistant to treatment and grow back. One of the mechanisms by which they become resistant to a particular treatment used in clinic called bevacizumab is through a protein within the cell membrane called galectin 1. In this project we plan to inhibit galectin 1 with the hypothesis that this will make bevacizumab treatment more effective and prolong patient survival.

Combination of Autophagy Selective Therapeutics (COAST) in Serous Ovarian Cancer

Principal Investigator: Joe Delaney, Ph.D.

Ovarian cancer has routinely escaped attempts by scientists and doctors to treat and prevent long-term remission. One reason is that each and every ovarian cancer cell within a patient has an ability to shift its genes around — thousands at a time. Since genes enable a cancer cell to metastasize and resist drugs, this means ovarian cancer is uniquely able to evolve and evade many forms of chemotherapy. Delaney’s lab has developed drug treatments that work better in this type of cancer cell. They work by disrupting the “autophagy” pathway, a microscopic recycling system that this cancer type is unusually poor at performing and is easily clogged. These drugs are prescribed at a low cost in developing nations yet are able to combat some of the toughest forms of ovarian cancer. They are even prescribed to pregnant patients for other diseases due to their minimal side effects.

However, before using these drug combination treatments in people, researchers must investigate the safest, most efficient way of combining these drugs with a standard of care for ovarian cancer. This study will use mouse models of advanced ovarian cancer to evaluate how to use these drugs to achieve complete remission in the mice without harming essential organs. With these data, the researchers will be better able to move safely into human trials.

Philanthropic donor Matt Prisby funded Delaney’s project in its entirety. Prisby has been a strong supporter and proponent for furthering women’s cancer research at Hollings Cancer Center. Part of the funding came from the Sheryl Sirisky Prisby Endowed Scholarship, the first such scholarship dedicated exclusively to the advancement of Hollings’ work in women’s cancers.

Curcumin "Window Trial" of Anti-Tumor Effects on Breast Cancer Primary Tumors

Principal Investigator: Nancy Klauber-DeMore, M.D.

Dr. Klauber-DeMore proposed a prospective "window trial" to assess biologic effects of curcumin, a substance in turmeric, on breast cancer tumors. Some laboratories have reported that turmeric has anticancer properties on cells in culture. Her proposed study will assess for differences in tumor proliferation, apoptosis and angiogenesis of tumors between the core biopsy prior to treatment with curcumin and the resected surgical specimen post-treatment. She will assess these biologic markers of tumor growth using immunohistochemistry on paraffin-embedded tumor samples. This will determine whether turmeric affects breast cancer growth in humans.

Adoptive Transfer of Tumor Infiltrating Lymphocytes for the Treatment of Breast Cancer

Principal Investigator: Antonio Giordano, M.D., Ph.D.

There are few treatment options for patients with breast cancer that has spread outside the breast. The goal of this application is to develop a new treatment for these patients using a person's immune system to attack the cancer cells. Immune cells taken from tumors have shown the ability to kill cancer cells and, when used as a therapy, lead to remissions in patients with otherwise deadly forms of skin cancer. However, there is very limited research evaluating this concept in breast cancer. The objectives are to take a sample of a person's immune cells and make them grow in the lab, study what type of breast cancer is more susceptible to this type of treatment approach, and recruit expert scientists who can help validate the program and write a clinical protocol. The completion of these objectives would provide the opportunity to open and run this clinical trial at MUSC and to apply for more research funding to support the project.

Programming Metabolically Fit Tumor Infiltrating Lymphocytes (TILs) for Treating Urologic Cancer by Advanced Cell Technology

Principal Investigator: Shikhar Mehrotra, Ph.D.

Despite recent advances, T cell immunotherapy still remains inaccessible to a vast majority of the patients due to exorbitant costs and other difficult logistics associated with its generation at multiple centers. In addition, the availability of high affinity T cell receptors or novel Chimeric Antigen Receptors has been limited. Thus, TILs still present the best option for treating tumors that cannot be controlled using the conventional approaches. In this application, we propose to program prostate tumor infiltrating T cells with robust anti-tumor and glutaminolysis dependent phenotype that could help these TILs to compete for nutrients in highly glycolytic tumor microenvironment. Successful completion of this project will allow the use of this approach to treat cancer patients. 

Metabolic Remodeling of Protein Synthesis to Improve Cancer Immunotherapy

Principal Investigator: Jessica Thaxton, Ph.D.

T cells comprise a pool of endogenous immune cells with the power to regress solid tumors. However, in the hostile environment of tumors T cells undergo a response to stress that leaves them unable to combat tumor growth. We have found that modulation of T cell metabolism can prepare T cells to better survive and function in tumors and relieve their tumor-induced stress. This proposal will test the ability of the FDA-approved drug Omacetaxine to modulate T cell metabolism in tumors and to allow standard immunotherapy to work better.

Assessing CD8+ T Cell and NK Cell Responses versus MHC Class I Expression in Cancer Patients Treated with an IL-15 Superagonist during Progression on Anti-PD-1 mAb Therapy

Principal Investigator: Mark Rubinstein, Ph.D.