Marlene Harris-Ride Cincinnati Gives $200,000 for Breast Cancer Research

Marlene Harris-Ride Cincinnati has continued its support of University of Cincinnati (UC) Cancer Institute scientists with the annual award of five grants, totaling $200,000, to continue promising breast cancer research.

Ride Cincinnati, a cycling event for all ages and abilities, was founded in 2007 by Harvey Harris, DDS, his family and two friends in memory of his late wife, Marlene Harris.  

Ride Cincinnati has contributed over $1 million directly to the university since August 2007. In addition, the Western & Southern Foundation has earmarked funds from its gifts to the Barrett Center to support the Ride Cincinnati annual cycling event. The efforts to date have resulted in over $1 million for cancer research.

The 2016 winning research projects include:

Drug Co-Delivery Using Nanoparticles for Metastatic and Drug-Resistant Breast Cancer

Joo-Youp Lee, PhD, associate professor in the Department of Biomedical, Chemical and Environmental Engineering in UC's College of Engineering and Applied Science, is continuing his research on the use of nanoparticle drug delivery for treatment of metastatic and drug-resistant breast cancer.  

"The development of nano-scaled carriers as a drug delivery system has made a tremendous difference in the fight against cancer," Lee says. "Among these tiny carriers, various nanoparticles made of biocompatible and biodegradable materials have been the focus. Significant progress has been made in improving nanoparticle formulas, targeting and drug potency. However, despite these advancements, metastases and drug resistance remain major challenges."

"Our project has made a significant progress since last year," he continues. "The original nanoparticle system proposed was successfully created and evaluated for delivery of microRNA inhibitors, stopping the protein transformation that promotes cancer progression as well as drug resistance and sensitizing the cancer cells to chemotherapeutic drugs, such as doxorubicin and paclitaxel."

Lee says about 10 to 20 percent of breast cancer cells do not express various biomarkers and are referred to as triple negative breast cancer. 

"It is very difficult to detect and target and has high potential for metastases," he says "Drug resistance is another major challenge in developing effective chemotherapy. Due to gradually developed resistance of traditional anti-cancer drugs, new drugs that can target specific carcinogenic pathways are being sought based on molecular biology, such as microRNA inhibitors."

Lee says during the early study, researchers learned that the original nanoparticle structure released the targets out of order. 

"Since the microRNA inhibitor is supposed to be released first to suppress the protein function involved in drug resistance before the chemotherapeutic drug, the order of the releases should be reversed," he says, adding that various chemotherapeutic drugs can now be used in conjunction with microRNA inhibitor. "We have re-designed the nanoparticle system that releases the microRNA inhibitor followed by conventional chemotherapeutic drugs with a desired time delay. In addition to a controlled release feature, the new system is responsive to a pH change, which suppresses drug resistance. Also, and more importantly, this new system will be connected with anti-epidermal growth factor receptor to target triple negative breast cancer. Our hopes with this model are to be able to effectively treat these types of breast cancer while maximizing the efficacy of both agents through optimal delivery and minimal dosing of chemotherapy to greatly reduce side effects."

Development of a Small Molecule Inhibitor for GTP-Energy Sensor to Eliminate Breast Cancer

Atsuo Sasaki, PhD, assistant professor in the Division of Hematology Oncology at the UC College of

Medicine and a researcher at the Brain Tumor Center at the UC Neuroscience Institute and UC Cancer Institute, has been challenged to target breast cancer with p53 mutation, which occurs in more than 30 percent of breast cancer patients, promotes high resistance to chemotherapy and predisposes patients for recurrence—the major cause of breast cancer deaths.

"There's a desperate need to develop new therapeutics to improve outcomes for p53-mutated breast cancer patients," he says. "Recently, our team found, for the first time, that a specific enzyme, PI5P4Kβ, is responsible for sensing the available supply of GTP, an energy source that fuels the uncontrolled growth of cancer cells. Importantly, enzyme activity of PI5P4Kβ is critical in p53-mutated breast cancer growth. Through chemical library screening with new technology, we have identified both new and FDA-approved compounds that hinder PI5P4Kβ activity.

"The goal of this project is to target the GTP energy sensor—PI5P4K—by our identified inhibitors to suppress p53-mutated breast cancer cells."

Sasaki adds that while results have suggested pharmacologic blocking of PI5P4Kβ activity could potentially eliminate the formation of p53-mutated breast cancer, there have been no commercially available PI5P4K inhibitors.

"Through national and international collaborations with the National Institutes of Health's Chemical Genomics Group and with the National Institute of Advanced Industrial Science and Technology and the High Energy Accelerator Research Organization in Japan, we have developed a screening system and conducted newly developed nuclear magnetic resonance-based screening, identifying selective compounds to inhibit PI5P4K activity," he says. "One of these compounds turned out to be a FDA-approved NSAID—non steroidal anti-inflammatory drug. In this pilot grant, we will test whether the identified PI5P4K inhibitors and NSAID-PI5P4K inhibitor could be a new and beneficial approach to inhibit breast cancer progression."

Pencil Beam Scanning Proton Therapy for Patients With Early Stage Breast Cancer

A research team led by Teresa Meier, MD, a resident physician within the Department of Radiation Oncology at UC Medical Center, and Vinita Takiar, MD, PhD, assistant professor in the College of Medicine and a radiation oncologist within the UC Cancer Institute, are looking at the use of pencil beam scanning proton therapy (PBSPT), the most advanced and sophisticated means of proton delivery developed so far, for patients with early stage breast cancer.

There has been no organized study of this type of therapy in the delivery of accelerated partial breast irradiation (APBI) to date. APBI is a more targeted radiation that minimizes radiation exposure to the normal breast tissue. 

"Breast cancer will affect one in eight women during their lifetime," says Meier. "Nearly two-thirds of women present with early stage, limited disease, with most living many years beyond their diagnosis with the side effects of their cancer treatments. For these patients, treatment has evolved from mastectomy to breast conservation therapy, which consists of a smaller surgery followed by daily radiation to the entire breast over four to six weeks. However, about one-third of women will experience significant skin toxicity related to radiation."

She says that as a majority of the recurrences occur close to where the surgery took place, APBI has been introduced to target the specific area and spare a significant portion of normal breast. 

"While there are multiple APBI techniques, none of them are perfect—some are invasive and others affect the normal breast tissue and organs like the lung, heart or other breast," she says. "PBSPT has the advantage of skin sparing, as the beam essentially paints the targeted area spot-by-spot."

"Considering the opening of the UC Health Proton Therapy Center this year, we believe that this is an ideal environment to test our hypothesis. So in this study, we will investigate whether PBSPT could serve as an alternative, feasible and potentially better treatment option for patients with early stage breast cancer following surgery."

Mechanisms Connecting Ron Receptor Signaling to the Breast Tumor Microenvironment

Susan Waltz, PhD, professor in the Department of Cancer Biology and a member of both the UC Cancer Institute and Cincinnati Cancer Center, is continuing research studying Ron receptor signaling in hopes of understanding its role in the development and spread of breast cancer. A goal of the proposal is to understand the 'crosstalk' between Ron in tumor cells and the non-tumor cells (immune cells and other support cells) and how this crosstalk supports a robust environment for tumor growth.

"Metastatic disease is the major cause of death from many cancers, including breast cancer and traditional therapies like chemotherapy have had limited success in blocking disease progression," she says. "Recent data suggests that tumors can influence the behavior of the cells surrounding it by promoting the development of a 'tumor-friendly' microenvironment that protects tumor cells from surveillance by the immune system and dramatically limits the effectiveness of therapy. 

"Tumor infiltrating immune cells and support cells help promote each stage of tumor development and metastatic spread and therefore can be new targets for therapy. However, while we understand many features of the 'crosstalk' between tumor cells and the tumor microenvironment, we still don't know who the major players are that activate this 'crosstalk,' and new studies in this area offer new opportunities to identify targets that can inhibit tumor spread and resistance to treatment."

Waltz says prior studies have shown that the expression of the Ron receptor tyrosine kinase, a protein that is found on the surface of cells and plays a role in regulating cell growth and migration, is increased in human breast cancers and breast cancer cell lines as well as being correlated with aggressive and metastatic disease. 

"We have data that shows Ron is expressed in both breast cancer epithelial cells and in myeloid/immune cells; however, we don't know how Ron expression in each of these cell types specifically contributes to aggressive breast cancer phenotypes," she says. "Preliminary data suggests that expression of Ron in both cell types is important for the formation of tumors but that each cell type contributes in a different way to create a supportive 'tumor friendly' microenvironment.

"This study will examine if the expression of Ron in both tumor epithelial cells and myeloid/immune cells functions independently to promote tumor growth and cancer spread in part by creating a conducive tumor microenvironment. These data will provide the basis for approaching national funding agencies for additional support and will allow us to suggest new combination therapies that may provide better outcomes for women with breast cancer."

Molecular Profiling of Primary and Metastatic Breast Cancers

Like snowflakes, no two breast cancers are exactly alike.

That's the premise behind research that Elyse Lower, MD, professor in the Division of Hematology Oncology, Department of Internal Medicine at the UC College of Medicine and director of the Breast Cancer Center for the UC Cancer Institute, and her team are conducting to further understand tumor gene progression and potentially find new genetic targets and treatments for each cancer.

"Traditional pathologic evaluation of invasive breast cancer has included genetic biomarker testing for estrogen receptors, progesterone receptors and HER-2, human epidermal growth factor receptor 2, which promotes the growth of cancer cells on the primary tumor," Lower says. "This evaluation is extremely limited and fails to capture more complete primary gene expressions as well as changes that can occur when tumors return. Our research group and others have shown discordance between hormone receptors and HER-2 expression between primary, meaning the original tumor, and metastatic, or tumor cells that have spread, disease. This 'disagreement' can be associated with changes in outcome and potential treatments for advanced breast cancer. 

"Our team is interested in the genetic analysis of breast tumors for a variety of genes including MED-1, Ron and osteospondin."

Lower says researchers will use a variety of molecular techniques to provide in depth analysis of matched primary and metastatic breast cancer samples.

"This evaluation should increase our understanding of tumor gene progression and may provide additional genetic targets for new treatment strategies," she says. "We will analyze breast cancers from patients with metastatic breast cancer—spread to another organ such as lung, liver, bone. The genetic findings at the time of diagnosis will be compared to those seen in the metastatic tumor."