Marlene Harris-Ride Cincinnati has continued its support of 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 UC Health Barrett Cancer Center to support the Ride Cincinnati annual cycling event. The efforts to date have resulted in over $1 million for cancer research.
This year’s research projects include:
CALCOCO1—A Novel Autophagy Receptor and Therapeutic Target in Breast Cancer: Carol Mercer, PhD, research assistant professor in the Department of Internal Medicine, Division of Hematology Oncology
About the study: Autophagy, literally self-eating, is an important cellular stress response involving the engulfment of cell "cargo” in vesicles (autophagosomes), followed by "digestion” in the lysosome. Importantly, autophagy deficiency causes breast cancer in animal models and humans. In established breast tumors, however, there is controversy about whether autophagy helps kill the tumor or supports its survival. This confusion may be due to methods of studying autophagy, which have focused on the autophagosome rather than its contents, which were thought to be randomly collected. Recent studies show that autophagy is often "selective” using cargo-specific receptors. Significantly, the consequences of cargo selection can be either pro- or anti-tumorigenic. Everolimus, an FDA-approved drug for estrogen receptor-positive breast cancer, increases bulk autophagy by inhibiting a protein called mTOR. The Mercer lab has discovered that drugs targeting mTOR may also increase "selective” autophagy. They have identified CALCOCO1, a coactivator for estrogen receptor signaling and a risk factor for breast cancer, as a novel autophagy receptor. They propose to study CALCOCO1 in this role and determine its significance in the growth and survival of breast cancer cells. Their long-term goal is to identify CALCOCO1-specific cargo and pursue CALCOCO1 as a new therapeutic target and biomarker in breast cancer.
Exploiting Metabolic Addictions to Reduce Breast Cancer Mortality: Susan Waltz, PhD, professor in the Department of Cancer Biology; Susanne Wells, PhD, professor in the Department of Pediatrics, researcher at Cincinnati Children’s; Elyse Lower, MD, professor in the Department of Internal Medicine, Division of Hematology Oncology
About the study: Two researchers and a clinician with a history of collaboration in the field of breast cancer joined forces to investigate a new signaling axis that is tightly linked to breast cancer mortality. Published studies have shown that the RON receptor tyrosine kinase—a protein on the cell surface used to activate specific body functions—and the DEK oncogene are both highly expressed in human breast cancers and are independent predictors of early recurrence and overall survival for breast cancer patients. Recent studies have established mechanistic and functional connections between RON and DEK. These researchers discovered that these two proteins work together as a signaling axis that cooperatively amplifies activation of the protein Catenin beta-1, or β-catenin. β-catenin is an essential transcription factor that is frequently upregulated in breast cancer and controls the self-renewal of stem-like cells which are a prime driver of recurrent disease. Additionally, in all subtypes of breast cancer, researchers have shown that high levels of RON and DEK combined are highly predictive of early relapse, risk of spread, poor survival and β-catenin expression in human breast cancer patient samples. New preliminary data show a relationship between the RON-DEK axis in reprogramming cellular metabolism. RON and DEK overexpression increase the accumulation of glycolytic end products (lactate, NAD+ and alanine)—glycolysis involves the breaking down of a sugar—and act independently to promote copying of key enzymes that regulate glycolysis, lactic acid fermentation (metabolic process by which sugars are converted into cellular energy) and cholesterol synthesis. Emerging published studies also highlight links between β-catenin and metabolism, in line with this protein being critical for normal cell reproduction and stabilization. Therefore, researchers predict that targeting the RON/DEK/β-catenin signaling axis by targeting specific metabolic activities will be an efficient strategy to affecting mortality in recurrent and metastatic breast cancer, which could change and revolutionize current treatment regimens for the disease.
Novel Polymeric Nanoparticle System Targeting RON and EGFR Signaling for Enhanced Combination Therapy: Joo-Youp Lee, PhD, associate professor in the Department of Chemical and Environmental Engineering
About the study: Currently, there is no treatment to stop or prevent the spread of cancer (metastasis), and there is no effective cure once metastatic breast cancer occurs. Development of new therapeutic approaches to target progressive and metastatic breast cancer are desperately needed. Many aggressive breast cancers overexpress (overproduce) either RON or the protein EGFR receptor tyrosine kinase, or both. Recent studies have shown that receptor tyrosine kinases (RTKs) may activate redundant signaling pathways to promote tumor cell growth and limit therapeutic efficacy. This means combined treatment of EGFR and the RON signaling axes presents a promising strategy to target a wide array of breast cancer types. The combinations of RON and EGFR inhibitors along with chemotherapeutic drugs can lead to a better therapeutic strategy for aggressive breast cancer types. This strategy can simultaneously target multiple RTKs and lead to the minimal use of DNA-damaging chemo drugs. In this study, researchers aim to establish the best therapeutic strategy made up of RON and/or EGFR inhibitors with a chemo drug across several breast cancer cell lines overexpressing RON and/or EGFR RTKs, incorporating them into a nanoparticle delivery system for combination therapy. Combined treatment with EGFR inhibitor and doxorubicin (the chemotherapy drug) require a consecutive co-delivery system with a desired time delay for maximum therapeutic efficacy, and the team has already developed a nanoparticle system for this. Researchers expect a new nanoparticle system with RON and EGFR inhibitors along with a chemo drug will broaden the applicability of combination therapy against differing and aggressive breast cancers.
Therapeutic Targeting of Breast Cancer Stem Cells: Combined Modulation of BRCA2 and STAT3: Paul Andreassen, PhD, associate professor in the Department of Pediatrics; researcher at Cincinnati Children’s
About the study: Recurrence and metastasis associated with breast cancer is a devastating clinical problem often attributed to therapy-resistant cancer stem cells. Therefore, a strategy to kill cancer stem cells may be key to establishing more effective treatments and improved survival for breast cancer patients. To effectively kill cancer stem cells, researchers in this study have identified a potential rationale-based strategy for combining existing inhibitors, many of which are already in clinical use. The strategy begins with the STAT3 transcription factor, a protein that controls the rate of transcription of part of the genetic information from DNA to messenger RNA. Inhibitors of STAT3 have demonstrated activity fighting breast cancer stem cells but have not been successful enough to advance to clinical trials. Surprisingly, these researchers show that lack of BRCA2, which is frequently mutated in breast cancer, reduces the levels of activated STAT3 and sensitizes triple negative breast cancer cells to STAT3 inhibitors. Additionally, they have found that STAT3 inhibitors work together with PARP inhibitors in BRCA2-deficient cells. In this study, researchers want to determine whether the combination of STAT3 inhibitors and PARP inhibitors can specifically suppress BRCA2-deficient cancer stem cells. Also, researchers accidentally discovered that inhibitors of the kinase (protein) mTOR can cause slowed function of BRCA2 and activated STAT3. Since most breast cancers are capable of producing functional BRCA2, researchers will also test whether the inclusion of mTOR inhibitors along with STAT3 and PARP inhibitors can target BRCA2 breast cancer stem cells. This team hopes to generate initial mechanistic understanding of how new inhibitor combinations act and test the effectiveness of these combinations as a general therapeutic strategy based on targeting breast cancer stem cells.
Doxycycline-Coated Silicone Implants Decrease Incidence of Bacterial Infection: Ryan Gobble, MD, assistant professor in the Division of Plastic Surgery, Department of Surgery
About this study: Doxycycline is a tetracycline antibiotic with activity against a broad range of bacteria and is a commonly used antibiotic in soft tissue infections. This research team has developed a new and effective technique for coating doxycycline onto silicone. Breast implants with a silicone shell are used in breast reconstructions but are plagued by bacterial infection, which often requires the removal of the implant. Researchers want to see if coating the silicone shell of breast implants with doxycycline will decrease bacterial infection, eliminating the need for repeat surgeries and improving outcomes for reconstructive patients.