Funded Research

Principal Investigator: Hanwen Zhang, PhD

Goal: Advance a next generation theranostic pair with a novel compound, 89Zr/227Th-Lumi-PSMAUrea, for targeting imaging and alpha particle therapy of metastatic prostate cancer.

Description: Prostate cancer (PCa) is the most common non-cutaneous malignancy diagnosed in men and is their second leading cause of cancer death. Over 90 percent of these cancer cells overexpress a cell-surface protein, prostate specific membrane antigen (PSMA). Radiopharmaceuticals that target PSMA can be used to sensitively detect and characterize PCa, as well as direct cancer-specific radiation to sites throughout the body. The FDA has recently approved several PSMA-agents for imaging and targeted therapy. However, the overall survival extension of Lutetium-177 labeled therapeutics is only four months, due to the low absorbed dose at sites of disease from this low energy beta particle emitter. By developing a next generation theranostic pair with a novel compound, 89Zr/227Th-Lumi-PSMAUrea, which enables sensitive and high contrast PET imaging with 89Zr and exquisitely potent high-absorbed dose alpha particle therapy with 227Th, we seek to generate further safety and efficacy data in order to translate 89Zr-Lumi-PSMAUrea for first-in-man studies. 89Zr-Lumi-PSMAUrea PET imaging will precisely guide and predict 227Th-Lumi-PSMAUrea therapy to eradicate prostate malignancy.

Principal Investigator: Elizabeth Salerno, PhD, MPH

Goal: Determine the feasibility and preliminary efficacy of a physical therapist-delivered prehabilitation physical activity intervention to prevent cognitive decline in breast cancer patients undergoing chemotherapy, hopefully leading to a significant paradigm shift in the way we implement standard of care rehabilitation during cancer survivorship.

Description: Despite chemotherapy’s effectiveness at treating breast cancer, many patients experience severe declines in cognitive function during treatment that can persist for years. Our team’s previous research suggests that regular physical activity may help, but randomized controlled trials are necessary to confirm these findings. Our research also suggests that physical activity should begin as soon as possible after a cancer diagnosis, but most targeted physical activity interventions are designed to begin after chemotherapy completion, once cognition has already declined. Interventions delivered before or during treatment (e.g., prehabilitation) may be better suited to prevent treatment-related impairments and improve prognosis; however, these trials are difficult in practice. Oncologists have limited (if any) time to systematically advise patients on physical activity behavior, and patients are overwhelmed by a new cancer diagnosis and hesitant to begin activity on their own without proper support. Ideal models of cancer care should be pragmatic, which includes referral to physical activity programs through existing healthcare pathways to support enrollment, adherence, and long-term behavioral maintenance. To address these gaps, we propose to conduct a pilot randomized controlled trial exploring both the preliminary efficacy and feasibility of a remote, physical therapist-delivered prehabilitation physical activity intervention to prevent cognitive decline in breast cancer patients undergoing chemotherapy, compared with a wait-list control condition. Findings from this study will provide critical preliminary data for scaling our intervention to confirm the role of physical activity on cognitive function and implement pragmatic approaches to prehabilitation during treatment for breast cancer.

Principal Investigator: Jason Held, PhD

Goal: Address critical knowledge gaps in our functional and mechanistic understanding of how silencing the enzyme GSTP1 re-wires cysteine oxidation of the proteome in breast cancer, hopefully providing new ways to inhibit breast cancer growth and transformation.

Description: Glutathione S-transferase Pi 1 (GSTP1) is an enzyme that we find is uniquely and dramatically downregulated in luminal and some Her2-positive breast cancers, as well as liver and prostate cancers. This proposal will investigate how GSTP1 acts as a tumor suppressor via regulation of cysteine oxidation in proteins. This is a novel function for GTP1, so we will characterize its structure and role in cancer signaling.

Principal Investigator: Christopher Maher, PhD

Goal: Understand how our recently discovered lncRNA, RAMS11, interacts with a pioneering transcription factor to promote tumor growth and metastasis in non-small cell lung cancer patients.

Description: Lung cancer is the most common malignancy and has the highest mortality worldwide, with approximately 80-85 percent of all lung cancer patients categorized as being non-small cell lung cancer (NSCLC). Despite improvements in diagnosis and treatment options, currently only five percent of NSCLC patients with aggressive disease survive five years or longer. This represents an unmet clinical need to improve the current treatments. To address this, NSCLC research has primarily focused on understanding which genes that produce proteins, also known as protein-coding genes, have altered activity in tumor cells compared to normal cells. However, our lab recently discovered a novel class of genes that eluded researchers because, contrary to central dogma, they enable a cell to function without generating a protein (we refer to as long non-coding RNA [lncRNA] genes). Building on this discovery, our lab is focusing on how these understudied lncRNA genes enable a lung tumor to develop and eventually spread throughout the body (also known as metastases). More specifically, we recently discovered a lncRNA that becomes more active in lung cancer patients that have more aggressive disease. The current proposal will study how this lncRNA acts as a “master regulator” by interacting with specific proteins to alter their normal function and cause the original tumor to grow and spread. In the longer-term we intend to “drug” this lncRNA, ultimately leading to the development of novel therapeutics for improving outcomes in this deadly disease.

Principal Investigator: Roberto Galletto, PhD

Goal: Define the role of Pif1 in telomere maintenance in cancer cells and to identify small molecule inhibitors to test the functional outcome of Pif1 inhibition.

Description: One hallmark of cancer cells is their ability to maintain the ends of their chromosomes, in a special DNA structure called telomeres. This gives cancer cells the ability to replicate indefinitely. In general, telomere maintenance in cancer cells occurs via reactivation of a protein called telomerase, a specialized enzyme that extends the DNA length of telomeres. However, in about 10-15 percent of tumors, telomeres are maintained by a telomerase-independent pathway, termed Alternative Lengthening of Telomeres (ALT). As neither normal cells nor majority of tumors rely on ALT, specific inhibition of this pathway provides an attractive target for therapeutic intervention specifically tailored to ALT+ cancers. However, the mechanisms of ALT in human tumors and suitable targets for small molecule inhibition have remained elusive. To this end, we identify human Pif1, an enzyme that unwinds the DNA double helix and facilitates DNA replication at hard-to-replicate sites, as a candidate to be targeted for inhibition in ALT.

Principal Investigator: Ben Major, PhD

Goal: Test the pyrimenthamine drug as an inhibitor of the NRF2 protein in head and neck squamous cell carcinoma, which if proven true could result in the ability to sensitize NRF2-active cancers to standard of care chemotherapy, radiation therapy, and immune inhibition therapy.

Description: Patients suffering advanced head and neck squamous cell carcinoma (HNSCC) face poor prognoses and limited treatment options. Massive DNA sequencing efforts have revealed genes, that when mutated, contribute to HNSCC progression and resistance to chemotherapy and radiation therapy. Principle among these is the NRF2 gene, which for decades has been known to protect normal cells from stress and environmental toxins like air pollution and sun exposure. The evolution of a normal cell to a cancer cell is exceedingly stressful to cellular life, and as such, mutation and activation of NRF2 provides the growing cancer with critical survival capabilities. Moreover, HNSCC cancers with NRF2 mutations and activation have been shown to be resistant to front line chemotherapy, radiation therapy and immune-directed therapy. We recently discovered that the drug Pyrimethamine has an inhibitory effect on NRF2 activity in cell culture models and in mouse models. Mechanistically, we found that Pyrimethamine inhibits the dihydrofolate reductase (DHFR) enzyme, and that this results in inhibition of NRF2. Pyrimethamine is an FDA approved drug that has been used for decades for treatment of protozoan infections and malaria. A growing body of research shows that it has potential antitumor activity, however it has not been previously studied in HNSCC or specifically in the context of NRF2-active tumors. In this study of HNSCC patients with advanced disease, we will determine if Pyrimethamine treatment for two weeks results in loss of activity of DHFR and NRF2. If proven true, these data will support a near-future Phase 2 clinical study wherein we test whether Pyrimethamine sensitizes NRF2-active cancers to standard of care chemotherapy, radiation therapy, and immune inhibition therapy.

Principal Investigator: Aimilia Gastounioti, PhD

Goal: Our goal is to discover novel imaging phenotypes of breast cancer risk from mammography and bring effective personalized breast cancer risk models to more racially diverse screening populations.

Description: This is a study to learn whether a woman’s risk of developing breast cancer can be predicted by using computers to evaluate changes in her mammograms over time. Breast cancer risk is related to several factors, including having family members with breast cancer, certain changes in genes (mutations), and reproductive history (like number of children and breastfeeding history). Some previous studies have shown that a woman’s risk is associated with what her mammogram looks like when analyzed by a computer – looking at features of the image before a cancer is visible. However, most of these mammograms were from White women, and it is not known whether these same features can predict breast cancer risk in Black women. Because Black women are affected by more aggressive cancers that show up at younger ages, it would be particularly helpful to be able to predict breast cancer risk in this group of women. The previous studies have also looked only at features from a single mammogram. This study will look at changes in mammograms from year to year to find out whether risk can be better predicted from these changes. We will retrospectively analyze mammograms of both White and Black women in order to develop a computer program that will give a more accurate estimate of each woman’s individual risk of breast cancer, regardless of race. The ultimate goal is to improve our use of screening mammograms and lower risk of dying from breast cancer.

Principal Investigator: Ben Major, PhD

Goal: Test the pyrimenthamine drug as an inhibitor of the NRF2 protein in head and neck squamous cell carcinoma, which if proven true could result in the ability to sensitize NRF2-active cancers to standard of care chemotherapy, radiation therapy, and immune inhibition therapy.

Description: Patients suffering advanced head and neck squamous cell carcinoma (HNSCC) face poor prognoses and limited treatment options. Massive DNA sequencing efforts have revealed genes, that when mutated, contribute to HNSCC progression and resistance to chemotherapy and radiation therapy. Principle among these is the NRF2 gene, which for decades has been known to protect normal cells from stress and environmental toxins like air pollution and sun exposure. The evolution of a normal cell to a cancer cell is exceedingly stressful to cellular life, and as such, mutation and activation of NRF2 provides the growing cancer with critical survival capabilities. Moreover, HNSCC cancers with NRF2 mutations and activation have been shown to be resistant to front line chemotherapy, radiation therapy and immune-directed therapy. In this study of HNSCC patients with advanced disease, we will determine if Pyrimethamine treatment for two weeks results in loss of activity of DHFR and NRF2. If proven true, these data will support a near-future Phase 2 clinical study wherein we test whether Pyrimethamine sensitizes NRF2-active cancers to standard of care chemotherapy, radiation therapy, and immune inhibition therapy.

Principal Investigator: Ting Wang, PhD

Goal: Exploring Precision Oncology Opportunities Contributed by Transposable Elements

Description: We recently discovered that the drug Pyrimethamine has an inhibitory effect on NRF2 activity in cell culture models and in mouse models. Mechanistically, we found that Pyrimethamine inhibits the dihydrofolate reductase (DHFR) enzyme, and that this results in inhibition of NRF2. Pyrimethamine is an FDA approved drug that has been used for decades for treatment of protozoan infections and malaria. A growing body of research shows that it has potential antitumor activity, however it has not been previously studied in HNSCC or specifically in the context of NRF2-active tumors.

Principal Investigator: Hanwen Zhang, PhD

Goal: Advance a next generation theranostic pair with a novel compound, 89Zr/227Th-Lumi-PSMAUrea, for targeting imaging and alpha particle therapy of metastatic prostate cancer.

Description: Prostate cancer (PCa) is the most common non-cutaneous malignancy diagnosed in men and is their second leading cause of cancer death. Over 90 percent of these cancer cells overexpress a cell-surface protein, prostate specific membrane antigen (PSMA). Radiopharmaceuticals that target PSMA can be used to sensitively detect and characterize PCa, as well as direct cancer-specific radiation to sites throughout the body. The FDA has recently approved several PSMA-agents for imaging and targeted therapy. However, the overall survival extension of Lutetium-177 labeled therapeutics is only four months, due to the low absorbed dose at sites of disease from this low energy beta particle emitter. By developing a next generation theranostic pair with a novel compound, 89Zr/227Th-Lumi-PSMAUrea, which enables sensitive and high contrast PET imaging with 89Zr and exquisitely potent high-absorbed dose alpha particle therapy with 227Th, we seek to generate further safety and efficacy data in order to translate 89Zr-Lumi-PSMAUrea for first-in-man studies. 89Zr-Lumi-PSMAUrea PET imaging will precisely guide and predict 227Th-Lumi-PSMAUrea therapy to eradicate prostate malignancy.

Principal Investigator: Armin Ghobadi, MD

Goal: Our goal is to determine if adding the targeted oral drug duvelisib to standard treatment with genetically modified immune cells (chimeric antigen receptor or “CAR” T cells) will decrease cellular immunotherapy-related side effects and help CAR T cells to more effectively kill non-Hodgkin lymphoma.

Description: Non-Hodgkin lymphoma is the most common blood cancer in adults. It develops from the lymphatic glands, which form an important part of the immune system. Currently, the first treatment patients receive for this cancer is high doses of chemotherapy, which can cure about half of patients. However, if the lymphoma does not disappear after chemotherapy or comes back after treatment, additional chemotherapy treatments are unlikely to provide a cure. Physicians are increasingly interested in harnessing the body’s own immune system to help fight cancer, including lymphoma. One promising approach is the collection and modification of the patient’s own immune cells to make a special type of anti-cancer treatment called chimeric antigen receptor T cells or “CAR T cells”. These cells are specifically designed to find and destroy lymphoma cells after recognizing a specific protein on their surface. In prior studies, the use of CAR T cells has been shown to cure about a third of patients with NHL who were not cured by chemotherapy. Unfortunately, this therapy can have significant side effects that require hospitalization or admission to the intensive care unit, including fevers, confusion, difficulty breathing and low blood pressure. Further, the majority of patients are still not cured by this approach and most treatments are ineffective if the lymphoma comes back after receiving CAR T cell therapy. Consequently, our study proposes to use duvelisib, a medicine that can be taken by mouth, to improve the function of CAR T cells during treatment. Based on work in the laboratory, we believe it will decrease the side effects of CAR T cell treatment while helping CAR T cells to last longer and kill cancer cells better. With this approach, we hope to increase the number of patients who can safely receive CAR T cells and provide better control of the cancer, ultimately leading to more patients with lymphoma being cured.

Principal Investigator: Kian-Huat Lim, MD, PhD

Goal: Our goal is to improve the efficacy of treatment for patients with metastatic gastric and esophageal cancers by combining a new drug called CA-4948 with current chemo-immunotherapy treatments to activate killer T cells.

Description: Chronic inflammation is an important risk factor that leads to the development of gastrointestinal cancers including gastric, esophageal, pancreatic, and colon cancers. Under the microscope, we can easily observe that these cancers are heavily surrounded by inflammatory cells. These inflammatory cells secrete soluble factors that not only fuel cancer cell growth, but also block our bodies’ main immune defense mechanism, particularly the killer T cells. We have recently identified IRAK4, an enzyme within cancer cells, as a key target that drives chronic inflammation in gastrointestinal cancers. We found that blocking IRAK4 using a new drug called CA-4948 can dramatically decrease inflammatory cells inside the cancer of experimental mouse models, causing the killer T cells to be partly activated. When we added an immunotherapy agent called anti-PD1 antibody, we observed a further boost in killer T cell activity and number, which led to complete elimination of cancers in more than half of the experimental mice. This is an exciting finding that led us to open a new clinical trial for patients with metastatic gastric and esophageal cancers, in which chemotherapy and immunotherapy are already part of the regimen. Our hope is that adding CA-4948 will make these therapies more effective and last longer in patients. To our best knowledge, this is the first clinical trial that combines CA-4948 with chemo-immunotherapy in cancer patients. If shown to be effective from this study, we will proceed to open this clinical trial in a larger scale in collaboration with other cancer centers in the future.

Principal Investigator: Roberto Galletto, PhD

Goal: Define the role of Pif1 in telomere maintenance in cancer cells and to identify small molecule inhibitors to test the functional outcome of Pif1 inhibition.

Description: One hallmark of cancer cells is their ability to maintain the ends of their chromosomes, in a special DNA structure called telomeres. This gives cancer cells the ability to replicate indefinitely. In general, telomere maintenance in cancer cells occurs via reactivation of a protein called telomerase, a specialized enzyme that extends the DNA length of telomeres. However, in about 10-15 percent of tumors, telomeres are maintained by a telomerase-independent pathway, termed Alternative Lengthening of Telomeres (ALT).

Principal Investigator: Elizabeth Salerno, PhD, MPH

Goal: Determine the feasibility and preliminary efficacy of a physical therapist-delivered prehabilitation physical activity intervention to prevent cognitive decline in breast cancer patients undergoing chemotherapy, hopefully leading to a significant paradigm shift in the way we implement standard of care rehabilitation during cancer survivorship.

Description: Despite chemotherapy’s effectiveness at treating breast cancer, many patients experience severe declines in cognitive function during treatment that can persist for years. Our team’s previous research suggests that regular physical activity may help, but randomized controlled trials are necessary to confirm these findings. Our research also suggests that physical activity should begin as soon as possible after a cancer diagnosis, but most targeted physical activity interventions are designed to begin after chemotherapy completion, once cognition has already declined. Interventions delivered before or during treatment (e.g., prehabilitation) may be better suited to prevent treatment-related impairments and improve prognosis; however, these trials are difficult in practice. Oncologists have limited (if any) time to systematically advise patients on physical activity behavior, and patients are overwhelmed by a new cancer diagnosis and hesitant to begin activity on their own without proper support. Ideal models of cancer care should be pragmatic, which includes referral to physical activity programs through existing healthcare pathways to support enrollment, adherence, and long-term behavioral maintenance. To address these gaps, we propose to conduct a pilot randomized controlled trial exploring both the preliminary efficacy and feasibility of a remote, physical therapist-delivered prehabilitation physical activity intervention to prevent cognitive decline in breast cancer patients undergoing chemotherapy, compared with a wait-list control condition. Findings from this study will provide critical preliminary data for scaling our intervention to confirm the role of physical activity on cognitive function and implement pragmatic approaches to prehabilitation during treatment for breast cancer.

Principal Investigator: Sheila Stewart, PhD

Goal: Our goal is to develop smarter breast cancer therapies that have a more potent effect at limiting disease progression by interrogating how age-related changes in non-tumor cells contribute to increases in breast cancer.

Description: As neither normal cells nor majority of tumors rely on ALT, specific inhibition of this pathway provides an attractive target for therapeutic intervention specifically tailored to ALT+ cancers. However, the mechanisms of ALT in human tumors and suitable targets for small molecule inhibition have remained elusive. To this end, we identify human Pif1, an enzyme that unwinds the DNA double helix and facilitates DNA replication at hard-to-replicate sites, as a candidate to be targeted for inhibition in ALT.

Principal Investigator: Patricia Ribeiro Pereira, PhD

Goal: Our goal is to enhance the efficacy of immunotherapy treatments in gastric tumors. We aim to use molecular imaging techniques to investigate the mechanisms of cancer-cell surface protein regulation to enhance immune checkpoint blockade efficacy in gastric tumors.

Description: Cancer cells can become invisible to monoclonal antibody drugs (i.e., a form of immunotherapy) by decreasing the availability of cancer-cell surface proteins, which are the ones targeted by these drugs. We have recently shown that proteins present in high quantities in gastric cancer cells are not always available at the cell surface for the effective binding of antibody drugs. The processes by which proteins are distributed throughout the cancer cell and internalized from the cell membrane could explain why immunotherapies only work in 30% of patients with gastric cancer. Thus, there is a critical need to understand the biological mechanisms of cancer-cell surface protein regulation and develop approaches that allow effective control of these processes. The Disease Imaging and Therapy lab uses cutting-edge imaging technologies to visualize in the whole body and in real-time the biological processes by which proteins are internalized into the gastric cancer cell and away from the membrane where antibody drugs bind to them. We then develop pharmacologic approaches to control these processes in ways that enable the conversion of non-responder gastric cancers into responders. This proposal aims to use our imaging methodologies to discover the membrane trafficking mechanisms of PD-L1—an important membrane protein that prevents immune cells from destroying cancer cells—and determine whether PD-L1 trafficking can be modulated to enhance the efficacy of antibody drugs targeting PD-L1 in gastric cancers. These approaches will enhance antibody therapies targeting cell-surface receptors and increase the number of patients that benefit from them.

Principal Investigator: Chris Maher, PhD

Goal: Understand how our recently discovered lncRNA, RAMS11, interacts with a pioneering transcription factor to promote tumor growth and metastasis in non-small cell lung cancer patients.

Description: Lung cancer is the most common malignancy and has the highest mortality worldwide, with approximately 80-85 percent of all lung cancer patients categorized as being non-small cell lung cancer (NSCLC). Despite improvements in diagnosis and treatment options, currently only five percent of NSCLC patients with aggressive disease survive five years or longer. This represents an unmet clinical need to improve the current treatments. To address this, NSCLC research has primarily focused on understanding which genes that produce proteins, also known as protein-coding genes, have altered activity in tumor cells compared to normal cells. However, our lab recently discovered a novel class of genes that eluded researchers because, contrary to central dogma, they enable a cell to function without generating a protein (we refer to as long non-coding RNA [lncRNA] genes). Building on this discovery, our lab is focusing on how these understudied lncRNA genes enable a lung tumor to develop and eventually spread throughout the body (also known as metastases). More specifically, we recently discovered a lncRNA that becomes more active in lung cancer patients that have more aggressive disease. The current proposal will study how this lncRNA acts as a “master regulator” by interacting with specific proteins to alter their normal function and cause the original tumor to grow and spread. In the longer-term we intend to “drug” this lncRNA, ultimately leading to the development of novel therapeutics for improving outcomes in this deadly disease.