2021 Spring Idea Grants
Targeting CD40 for Cancer Therapy Beyond an Immune Response
Investigators: Xue-Feng Bai, MD, PhD, Translational Therapeutics (TT); Naduparambil Jacob, PhD (TT); Zaibo Li, MD, PhD, Cancer Biology (CB); Junran Zhang, MD (CB); and Xiaoli Zhang, PhD
Despite advances in targeted therapies and immunotherapy, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Even among NSCLC patients who initially respond to therapy, most will eventually develop resistance and relapse. Therefore, more novel treatment strategies are urgently needed. Cluster of differentiation 40 (CD40) is important for the immune response through its binding to the ligand CD154 (CD40L). However, our preliminary data suggest that CD40 might function in the DNA damage response (DDR) outside its role in the immune response. We found that CD40 inhibition slows cell growth and sensitizes NSCLC to inhibitors targeting the DDR protein kinase ATR and its downstream effector CHK1, which are required for cell survival during replication stress (RS). Thus, the goal of this application is to identify previously unrecognized functions of CD40 in DDR and explore its inhibition as a new therapeutic approach against CD40-expressing NSCLC. The success of our proposed study will yield fundamental insights into a novel role for CD40 in DDR and potential new therapies targeting a subset of lung tumors (CD40+) that normally have a poor prognosis. Using CD40 antagonists for treating NSCLC is a paradigm shift. Given that anti CD40/CD40L drugs and antibodies are currently being investigated for the treatment of autoimmune disease, our anticipated results could lead to the repurposing of already existing anti-CD40 drugs for oncology.
Targeting Immune Inhibitory Molecule SUSD2 to Rejuvenate CD8+ T Cell Antitumor Immunity
Investigators: Kai He, MD, PhD (TT), and Haitao Wen, MD, PhD*, Molecular Carcinogenesis and Chemoprevention (MCC)
A key advancement in the treatment of lung cancers is utilizing the immune system to attack cancer cells. However, a majority of lung cancer patients rapidly become resistant to immune based therapeutic approaches. We have identified a new molecule called SUSD2 (sushi domain containing 2) that can cause immune cell less functional in killing cancer cells. It is our hope that inhibiting this molecule can help with increasing immune attack against cancer cells and treating lung cancer more effectively.
Establishing the Importance of the CTLH Complex in NSCLC
Investigators: Vincenzo Coppola, MD* (CB), and Lianbo Yu, PhD
The fight to cure lung cancer has made incredible progress by using drugs directed at specific genetic alterations (targeted therapy) and by harnessing the patient immunological response (immuno-therapy). However, these types of therapy have their own limitations including the fact that they cannot be used for all patients and might only have temporary effects in most of the patients. This proposal studies molecules, called CTLH proteins, that might be excellent targets for novel therapies. When finished, this study will open new avenues of treatment for lung cancer patients that cannot be treated with existing therapies.
CD74 CAR-T Cell Therapy in Mantle Cell Lymphoma
Investigators: Lapo Alinari, MD, PhD*, Leukemia Research (LR); Wing Chan, PhD*; Natarajan Muthusamy, PhD, DVM (LR); Yiping Yang, MD, PhD (LR); and Xiaoli Zhang, PhD
Mantle cell lymphoma (MCL) is an aggressive and incurable blood cancer. Despite the development of targeted drugs, we have not made significant breakthroughs into overcoming drug resistance and preventing relapse in this disease. CD74, a protein expressed on MCL cell surface, mediates a pro-survival signal and drives tumor cell growth. With this project we aim to develop a novel cell-based strategy using MCL patients’ own normal (autologous) T cells engineered to bind to CD74 (CD74 CAR-T cells) and efficiently kill MCL cells. Our study will provide relevant data for future studies towards developing a novel, effective therapy for MCL patients.
Cardiac OCT3 Biomarker Identification and Validation
Investigators: Daniel Addison, MD, Cancer Control (CC), and Alex Sparreboom, PhD* (TT)
Doxorubicin is an effective anticancer agent that can cause severe damage to the heart (cardiotoxicity). Using unique genetic mouse models, we recently found that this form of toxicity is dependent on an uptake process in the heart that is mediated by a protein called OCT3. The proposed studies are a continuation of this prior work and will test the hypothesis that the activity of OCT3 in the heart can be determined before initiation of doxorubicin treatment in order to improve the use OCT3 inhibitors can mitigate the incidence and severity of this debilitating side effect.
Project Limb Rescue: A Pilot Study Evaluating the Feasibility of Transcutaneous Sensors for the Detection of Cancer-Related Lymphedema
Investigator: Carlo Contreras, MD* (TT) Lynne Brophy, MSN, RN-BC, APRN-CNS, AOCN; Emre Ertin, PhD
Millions of cancer survivors have lymphedema, which is long-term arm swelling after completing their cancer therapy. For many patients, lymphedema is painful, unsightly and debilitating. The early signs of lymphedema are subtle, and sometimes it’s only diagnosed by hospital equipment. The goal of this study is to use new, adhesive-based sensors to detect lymphedema and to develop this method into a way for patients to check for lymphedema at home. We will use our sensors to make measurements in 70 subjects. We will also evaluate a few commercially available devices to detect lymphedema, using new software that we are developing.
Identification of Molecular Treatment Response Predictors and Associated Genomic Response Patterns in AML Patients With IDH Mutations
Investigators: Ann-Kathrin Eisfeld, MD (LR), and Alice Mims, MD* (LR)
Acute myeloid leukemia (AML) is an aggressive blood cancer, of which only ~25% of patients are currently cured despite modern therapies. It became clear over the past years that the cancer cells of leukemia patients respond differently to available treatments based on differences in the molecular underpinnings of the cells. Our proposal focuses on the subtype of AML patients that harbor mutations in the isocitrate dehydrogenase (IDH) genes in their leukemia cells, which comprise ~20% of all AML patients. Based on a cohort of 840 patients collected from several large Cancer Centers throughout the US we will determine which of the various different treatments works best for patients based on additional gene mutations that are present in the cells. The information derived from this part of the study will be used to design a clinical trial specifically tailored for IDH-mutated AML patients. In the second part of the study we will track the cancer cells over time, from time of diagnosis, during chemotherapy, and compare how the molecular underpinnings change when they are exposed to different treatments. To do this, we will look at samples that were collected throughout the disease journeys of 90AML patients treated here at The James Cancer Hospital. We are hopeful that both study parts together will enable us in the future to give the best therapy to each individual patient, based on the genes that are driving their leukemia.
Development of a Risk Assessment Tool to Identify Triple-Negative Breast Cancer Patients at Risk of Rapid Relapse
Investigators: Barbara Andersen, PhD (CC); Samilla Obeng-Gyasi, MD, MPH* (CC); Saurabh Arun Rahurkar, PhD; and Daniel Stover, MD (TT)
Triple-negative breast cancer has worse outcomes than other breast cancer subtypes and there is a subset characterized by rapid relapse, recurrence and/or death within 24 months of diagnosis. The purpose of this study is to create a risk assessment tool that will identify triple negative breast cancer patients at risk for rapid relapse and to pilot an intervention that addresses psychosocial drivers of rapid relapse. The goal of this risk assessment tool is to increase health equity for patients with aggressive breast cancer.
(NOTE: The above study is funded by the Stefanie Spielman Fund for Breast Cancer Research at the OSUCCC – James.)
The Pulmonary Effects of a Standardized Research Electronic Cigarettes: Protonated Nicotine Effects
Investigators: Peter Shields, MD (CC), and Min-Ae Song, PhD* (CC)
The long-term health effects of electronic cigarettes (EC) remain unknown. The most popular e-cig devices on the market predominantly contain nicotine salts, which make them much less irritating, much less harsh to inhale and may lead to much higher nicotine content. This study will evaluate the lung toxicity of EC by switching from cigarettes to EC with and without nicotine. This data is critical to inform policies across the U.S. reducing the amount of nicotine in EC with the intent of reducing addictiveness and toxicity, but this has not been tested.
(NOTE: The above study is funded by the Urban and Shelley Meyer Fund for Cancer Research.)
2021 Fall Idea Grants
Targeting CD56 Signaling to Improve Response to Therapy and NK Cell-Mediated Cytotoxicity
Investigators: Don Benson, MD, PhD (MCC), and Francesca Cottini, MD* (TT)
Multiple myeloma (MM) is an incurable disease that affects vulnerable elderly adults and minorities, causing morbidity and poor quality of life. We identified the protein CD56 as a key player able to support MM growth and escape from the immune system. We propose to study how CD56 affects responses to therapies and block its activity to benefit patients with this deadly disease.
Development of Alternating Electromagnetic Fields as an Effective and Non-Invasive Anti-Metastasis Therapy
Investigators: Dinesh Ahirwar, PhD; Ramesh Ganju, PhD (CB); Jonathan Song, PhD* (CB); and Vish Subramaniam, PhD (CB)
Current clinical strategies fall short both in accurately identifying patients at high risk of metastasis and in successfully treating patients with metastatic disease. We have shown that non-contact and very weak alternating electric fields, called induced electric fields (iEFs), hinder the escape of metastatic breast cancer cells in culture and formation of distant metastases from aggressive breast tumors in mice. These findings suggest that the mechanism of action of iEFs is linked to the inhibition of cancer cell migration leading to metastasis. In the proposed work, we will test and optimize the intensity of iEF treatment that demonstrates maximum efficacy in curbing metastasis. Our studies will be facilitated by a novel and interdisciplinary experimental framework that will describe multiple biomarkers and key endpoints for metastasis-suppression and response to iEF therapy. Therefore, our enhanced knowledge of iEF treatments will point to novel therapeutic strategies that specifically target metastasis, which are critically needed when so few treatment options for metastatic breast cancer currently exist.
Targeting GPR84 to Overcome Macrophage Mediated Resistance to Immunotherapy for Breast Cancer
Investigators: William Carson, MD (TT); Qin Ma, PhD (CB); and Gang Xin, PhD* (TT)
Immune checkpoint blockade (ICB) produces extraordinary clinical responses in more than 25 types of tumor, but only a small number of patients benefit from this therapy. Our data support a provocative model that G Protein-Coupled Receptor 84 (GPR84) pathway can be pharmacologically activated to shape macrophages toward the anti-tumorigenic phenotype to overcome ICB therapy resistance. Results will inform the development of promising treatments to reshape the immunosuppressive tumor microenvironment through manipulation of metabolic signaling, and thereby restore responsiveness to PD-1 blockade for breast cancer patients.
(NOTE: This project was funded by IRP money from the Stefanie Spielman Fund for Breast Cancer Research at the OSUCCC – James.)
Role of MUC5AC in Predicting the Treatment Response in Pancreatic Ductal Adenocarcinoma
Investigators: Ashwini Esnakula, MBBS; John Hays, MD, PhD (TT); Ashish Manne, MBBS* (TT); Pravin Mishra, PhD (TT); and Lianbo Yu, PhD
Pancreatic cancer is one of the most lethal cancers, and there are no effective ways to determine the best chemotherapy treatment option for each patient. MUC5AC is a protein found in the normal mucous of the lung and stomach, but only in abnormal pancreatic tissue. This project will measure the abundance of different MUC5AC subtypes, as well as their location within the pancreatic tumor cells. We will correlate the MUC5AC signature in tumor and/or blood with clinical outcomes. We expect that the MUC5AC signature may become a new way for doctors to select pancreatic cancer treatments better.
Integrating Biomimetic Tissue Engineering and Multi-Omics Systems Analysis to Overcome CTCL Drug Resistance
Investigators: Catherine Chung, MD; Walter Hanel, MD, PhD; Qin Ma, PhD (CB); and Anna Vilgelm, MD, PhD* (TT)
Cutaneous T-cell lymphoma (CTCL) is a rare malignancy where cancerous T cells expand within the skin causing patches, plaques and tumors that are often resistant to treatment. This project will investigate whether non-malignant cells of the skin protect malignant T cells from therapies and, therefore, should be targeted to overcome resistance. To achieve this goal, we will develop a reliable laboratory model of CTCL and its microenvironment using skin samples from CTCL patients and utilize it to uncover how malignant and non-malignant cells interact, and how these interactions affect therapeutic responses.
Characterizing the Development of Secondary Myelodysplastic Syndrome from Chronic Lymphocytic Leukemia (CLL) in the Era of Small Molecule Inhibitors for the Treatment of CLL
Investigators: James Blachly, MD (LR); Adam Kittai, MD (LR); and Kristin Koenig, MD*
Secondary myelodysplastic syndrome (t-MDS) is a bone marrow failure disorder caused by cancer treatment or other medications that patients received in the past. It occurs in about 0.5% of all patients treated for any cancer but occurs more commonly in chronic lymphocytic leukemia (CLL) patients treated with certain chemotherapies. Little is known about the development of t-MDS in CLL patients receiving the newer non-chemotherapy treatments for their CLL. We plan to figure out when and why these CLL patients develop t-MDS.
Adipose Tissue Tregs and Potential for Immunotherapy for ER(+) HER2(-) Breast Cancer
Investigators: Willa Hsueh, MD* (CB), and Robert Wesolowski, MD (TT)
The form of breast cancer, ER+ Her2-, afflicts 70% of women with breast cancer and is commonly associated with increased weight and postmenopausal status. Drugs that have recently revolutionized cancer treatment regulate immune checkpoint blockade (ICB) but have shown very little effect in ER+ Her2- cancers. While overall survival rates of patients with metastatic ER+HER2- breast cancer have increased significantly since the advent of CDK 4/6 inhibitor plus endocrine therapy, virtually all patients will experience disease progression and endocrine therapy resistance. Currently, there are no FDA-approved ICB approaches for ER+HER2- cancer, so there is a critical need to better understand why this cancer is unresponsive and how to improve its responsivity in order to develop new targeted therapeutic options for metastatic ER+HER2- breast cancer. Our data suggests there are changes in the immune cell composition in adipose tissue in obesity in humans and mice. The changes also occur in breast tissue and likely have a profound effect on breast cancer development, growth and metastasis. Our goal is to comprehensively analyze changes in immune cells in breast and subcutaneous adipose tissue in lean and obese women undergoing mastectomy and immediate reconstruction for ER+HER2- breast cancer, and to develop a mouse model that recapitulates this cancer in order to test combination agents that impact ICB. Based on our current data, we propose a novel combination that has potential to be effective in treatment of ER+HER2- breast cancer.
(NOTE: This project was funded by IRP money from the Stefanie Spielman Fund for Breast Cancer Research at the OSUCCC – James.)
Intralesional Influenza Vaccine for Patients With Melanoma
Investigator: Carlo Contreras, MD* (TT)
Traditional chemotherapy is not very effective for patients with advanced melanoma. Instead, medications that boost a patient’s own immune system (called “immunotherapy”) has shown great promise over the last 10 years. Researchers are looking to find other immunotherapy medications that can do an even better job at killing melanoma tumors. One promising way to boost the immune system is to inject a specific type of influenza vaccine directly into the melanoma tumor. The influenza vaccine is the shot we typically receive once a year to reduce the risk of getting sick with the “flu." Based on published research, we are most interested in a specific influenza vaccine product called Flucelvax. We propose a clinical trial where we are evaluating the safety and tolerability of receiving intralesional Flucelvax in patients with melanoma. We will enroll a total of 36 patients with melanoma. Group #1 will include patients with early-stage melanoma. These patients will receive a standard Flucelvax dose in their arm muscle, followed by two doses of Flucelvax directly into the melanoma skin cancer site. These Flucelvax doses will be given on Days 2 and 14, and then the patients in Group #1 will have their standard melanoma removal operation on Day 28. Group #2 will include patients with advanced melanoma who have a melanoma lump underneath the skin and who will be starting standard immunotherapy medication. These patients will also receive a standard Flucelvax dose in their arm muscle, followed by eight doses of Flucelvax directly into one of the melanoma tumors underneath the skin. The Flucelvax doses given underneath the skin will occur every two weeks while the patient continues to receive standard immunotherapy medication. In order to understand the possible effects of Flucelvax, we will check for changes in blood samples. In Group #1, we will also compare the appearance of the melanoma in the original skin sample before Flucelvax therapy and compare it to the melanoma skin site at the time of the surgical removal. For one year after the last Flucelvax dose, we will also collect information regarding whether or not the melanoma has grown back. The U.S. Food & Drug administration has reviewed our proposal and has provided clearance to carry out this clinical trial.
Accelerated Aging in Hematopoietic Stem Cell Transplant Patients
Investigators: Janice Kiecolt-Glaser, PhD* (CC), and Ashley Rosko, MD (CC)
Multiple myeloma is a blood cancer that is diagnosed more commonly among older adults, men and African-Americans. Multiple myeloma is a highly treatable cancer but remains incurable. An autologous stem cell transplant is an important part of the treatment regimen for patients who are newly diagnosed. An auto-transplant can result in longer remission but is also a highly intensive therapy associated with more toxicities. Patients are required to have a caregiver during the transplant process to aid in recovery and are an integral part of cancer journey. Caregivers most commonly are spouses or partners. After transplant, most myeloma patients will require indefinite therapy, of different intensities, over time. The distress of a myeloma diagnosis, transplant and long-term therapy can result in high levels of depression and anxiety in both the patient and the spouse/partner. Depression in patients with myeloma has been associated with worse outcomes. Functional recovery and frailty can also accelerate among this older adult population. Understanding the global health of the patient, physically, emotionally and biologically before and after transplant is imperative. Importantly, the relationship of these changes to the spouse/partner is unexplored. In this proposal, we will contrast the patient and spouse/partner health trajectories before and after transplant using a comprehensive frailty assessment, evaluation of depression and anxiety, and blood biomarkers of aging. We will also evaluate these changes in relationship to marital quality and gender. Understanding the impact of an intensive therapy globally on the individual will help us improve long-term quality of life with myeloma survivorship.
Dietary Interventions to Modify Response to Immunotherapy: A Companion Assessment Within the NutriCare Study
Investigators: Daniel Spakowicz, PhD* (MCC), and Jiangjiang Zhu, PhD (MCC)
Immunotherapy has improved outcomes for lung cancer patients, but only about 20% of patients respond to treatments. One strategy for improving treatment response is via the microbiome. Which microbes drive response in different populations, and how best to modify the microbiome, are areas of active research. Here, we leverage a national dietary intervention clinical trial to study to assess the changes to the microbiome and determine the causal role of the microbiome in response to immunotherapy using mouse models. This will help to establish the extent to which the diet can be modified to promote immunotherapy outcomes.
Understanding Mechanisms Related to the Obesity Paradox in Pancreatic Cancer
Investigator: Kaylin Chasser*
Obesity is a known risk factor for pancreatic cancer but can contribute to improved outcomes through the obesity paradox. The obesity paradox is a contradictory idea wherein obesity can result in slower cancer progression and the improved survival of cancer patients. Since obesity is associated with increased visceral adipose tissue, we intend to study visceral adipose tissue in the context of obesity-associated pancreatic cancer. By understanding how changes in visceral adipose tissue gene expression and immune environment influence pancreatic cancer, we could reveal processes involved in the obesity paradox and use them to slow tumor growth and increase survival.
Supporting Black Breast Cancer Survivors: Feasibility Trial of Health Coaching-Based Navigation at the Conclusion of Treatment
Investigator: Bridget Oppong, MD* (CC)
After breast cancer treatment is complete, patients enter survivorship which comes with new concerns as women resume their normal lives. There can be stress from the physical side effects of treatment but also mental burdens. To support patients, programs are available in areas including coping, mindfulness and nutrition in addition to provider-based care. These resources can be limited, and studies show black women may suffer from higher stress and yet are less likely to get support. This study will evaluate a form of navigation using health coaching to identify individual needs and then direct black women to appropriate support programs.