Four scientists from the University of Cincinnati (UC) Cancer Institute were recently awarded funding by local organizations to continue their research on ovarian, head and neck, and pancreatic cancers.
Ovarian Cancer Alliance of Greater Cincinnati ($47,500)
Principal Investigator, Chunying Du, PhD: Ovarian Cancer Chemoresistance
Du, associate professor in the Department of Cancer Biology, will use funding to look at a particular protein’s role (BRUCE) in resistance to chemotherapy for patients with ovarian cancer.
"Chemoresistance in ovarian cancer presents the biggest challenge for its treatment with poor outcomes for patients,” she says. "There are over 22,000 new cases and more than 14,000 deaths annually. New therapeutic approaches are needed to overcome this, and although many mechanisms can cause chemoresistance, the contribution of increased DNA repair capacity and reduced cell death in chemoresistance is understudied, considering most of the chemo drugs are actually DNA damaging agents.”
Du says current complementing therapies to platinum chemotherapy, known as Poly polymerase (PARP) inhibitors, target DNA repair pathways. However, which ovarian cancers are responsive to these types of therapies remains largely unknown in patients, in addition to patients with the BRCA1 genetic mutation. BRCA1 has been shown to be a precursor to a number of cancers, including breast and ovarian cancers.
"The protein known as BRUCE, the focus of this study, fills the gaps because of its roles, promoting DNA repair and inhibiting cell death, which open a new avenue for overcoming chemoresistance in ovarian cancer,” she says. "This study is important for both basic research and clinical association. First, this study is expected to provide insights to new molecular mechanisms that could cause chemoresistance mediated by high levels of the BRUCE protein in ovarian cancer. Second, it provides mechanism-based rationale for using BRUCE negativity as a determinant for platinum chemotherapy, radiation and PARP therapeutic responsiveness.
"These findings could be highly important in a clinical setting by developing BRUCE into a marker to help determine the best course of treatment for the patient—ovarian cancers with high levels of BRUCE could have platinum chemotherapy resistance, thereby necessitating alternative therapeutic regimes, and ovarian cancers without the BRUCE protein could mean response to chemo, radiation and PARP therapy.”
Steven Goldman Memorial Pancreatic Cancer Research Grant ($55,000)
Principal Investigator, Yana Zavros, PhD: New Models to Study Pancreatic Cancer
Zavros, professor in the Department of Pharmacology and Systems Physiology, will use this funding to develop organoid models of pancreatic ductal cancer to identify mechanisms that may cause pancreatic cancer stem cells to thrive.
An organoid is a miniaturized and simplified version of an organ within a system that shows realistic micro-anatomy.
"Gaining this knowledge is the first step in achieving our long-term goal to better understand the development and maintenance of pancreatic ductal adenocarcinoma (PDAC). This will allow us to develop an organoid-based platform for personalized medicine.” she says. "This cancer is very aggressive and patients can be resistant to most therapies. PDAC organoids may be used as a pre-clinical model to allow us to predict the efficacy of targeted therapies in individual patients.”
Zavros says PDAC is one of the most lethal cancers, with 1 to 5 percent five-year survival rates despite therapy.
"The poor response of PDAC to various existing treatments, which contributes to poor outcomes for patients, makes this disease a therapeutic challenge,” she adds. "Interactions between cancer stem cells and the tumor microenvironment can have a substantial impact on tumor characteristics and contribute to their diverse makeup. Given that cancer stem cells have a crucial role not only in tumor formation and progression, but also in drug resistance and recurrence of various cancer types, these cells are excellent targets for effective and new therapeutic approaches.”
Zavros says the mechanisms responsible for maintaining malignant cancer stem cells within the tumor microenvironment in PDAC are largely unknown. CD44 variable isoform 9 (CD44v9) (isoforms are members of a set of highly similar proteins that perform the same or similar biological roles) marks cancer stem cells and contributes to increased chemoresistance.
"Our evidence showing the selective expression of the programmed cell death 1 ligand (PD-L1) on CD44v9(+) cells is relevant to the mechanisms investigated in these studies,” she adds. "This is significant because tumors can avoid the immune response by expressing molecules such as PD-L1 that interact with PD-1 to stop T lymphocytes, the cells that play a central role in immunity. We want to use human-derived PDAC organoids to investigate these mechanisms, and this funding will help us develop this pre-clinical model.”
GIVEHOPE Pancreatic Cancer Research and Awareness Fund ($47,500)
Principal Investigator, Vladimir Bogdanov, PhD: Using a New Antibody to Target Pancreatic Cancer
Bogdanov, associate professor and director of the Hemostasis Research Program within the Division of Hematology Oncology at the UC College of Medicine, will continue his research focusing on targeting alternatively spliced Tissue Factor (asTF), a protein that promotes the formation of vascular networks that tumor cells often hijack to fuel their growth and spread.
"The overall objective of our proposal is to evaluate our recently developed humanized variants of the antibody targeting asTF, termed RabMab1, as a new therapeutic approach in treating pancreatic cancer,” says Bogdanov, who is also a member of the UC Cancer Institute and Cincinnati Cancer Consortium. "In addition, we hope to evaluate whether measuring asTF levels in the blood of pancreas cancer patients has predictive value and can serve as a tool for targeted therapies.”
He says that asTF expression and release into tissues is often increased in pancreatic cancer; asTF binds cell surface molecules, called beta1 integrins, in a specific region, triggering processes that drive cancer progression. Bogdanov adds that blocking asTF reduced growth of pancreatic cancer in animal models.
"We will perform preclinical studies in animal models to determine the most effective way to deliver RabMab1, ensuring that it is beneficial; these preclinical studies are needed in order to launch clinical trials,” he says. "We will also evaluate the relationship between baseline asTF levels and progression-free survival in patients with stage IV pancreas cancer.
"We will compare the expression of asTF at diagnosis, and at time of progression. We think that elevation of asTF post-chemotherapy may contribute to acquired resistance of pancreas cancer tumors that develops upon exposure to agents that cause cell death. Our primary objective is to evaluate asTF protein levels in plasma and tissue samples as predictors of progression-free survival.”
Bogdanov says that if his theories are true, this research will set the foundation for Phase I and II clinical trials evaluating RabMab1 in patients with advanced pancreas cancer.
"This is exciting as we are one step closer to testing a new therapy in patients to benefit outcomes; it could also help us determine if asTF can be used as a biomarker in patients with all stages of pancreas cancer,” he says. "About 53,670 people will be diagnosed with pancreatic cancer in 2017, and about 43,090 people will die from it. We’re thankful for this continued funding from GIVEHOPE which will hopefully help us come up with new and more effective treatments for this devastating disease.”
Brandon C. Gromada Head and Neck Cancer Foundation Research Grant ($20,000)
Principal Investigator, Nira Ben-Jonathan, PhD: New Treatments for Head and Neck Cancer Using FDA-Approved Drugs
Ben-Johnathan, professor in the Department of Cancer Biology, has discovered, in past studies, a tie between dopamine, a neurotransmitter, and various types of cancer, including breast and head and neck cancers.
"Activation of specific dopamine receptors, named D1R, located on the surface of cancer cells, were found to suppress cell growth and increase the ability of conventional anti-cancer drugs to kill the cells in head and neck cancers in animal models,” she says. "Patients with head and neck cancer are commonly treated with surgery, radiation and/or conventional chemotherapeutic drugs, but all of these treatments could cause debilitating side effects and a significant decrease in quality of life. Additionally, patients are often not responsive to current standard therapies, meaning there is a need for more targeted treatments.”
Ben-Jonathan says this study will help determine the occurrence of D1R in several hundred tumor samples and correlate D1R presence with advanced disease, responsiveness to treatment and overall patient survival.
"We will also use four dopamine/D1R-associated drugs, already approved by the FDA to treat unrelated health conditions,” she adds. "Head and neck cancer cells will be incubated with each anti-D1R drug alone, or together with cisplatin or taxol, which are common chemotherapy agents, and cell growth or death will be determined. We think that a combination treatment will be highly beneficial as a future treatment for head and neck cancer patients, possibly decreasing the severe side effects of conventional chemotherapeutic drugs while improving outcomes. This funding will help us prove our hypothesis.”