3 Cancer and Cell Biology Grad Students Receive Federal F31 Research Awards

Three graduate students in the University of Cincinnati College of Medicine's Cancer and Cell Biology Graduate Program have received Ruth L. Kirschstein Predoctoral Individual National Research Service Awards (F31 awards) from the National Institutes of Health to conduct cancer research in the labs of UC scientists and promote their growth as future researchers.

The purpose of the F31 program is to help promising predoctoral students obtain individualized, mentored research training from faculty sponsors while conducting dissertation research and developing their skills to become independent scientists in the field. 

"This speaks not only to the caliber of students we have within our department but also the faculty present at this university—three of these awards within a year's time is a huge deal," says Jun-Lin Guan, PhD, Francis Brunning Professor and chair of the Department of Cancer Biology, where the Cancer and Cell Biology Graduate Program is based. 

Ken Greis, PhD, professor in the department and director for the graduate program, says he's glad to see this come to fruition years after planting the seed.

"A few years ago, I proposed to then Graduate School Dean (Robert) Zierolf a transition of our PhD qualifying exam process from writing and defending an R01-style grant to the development of F31 fellowships," he says. "The goal would be that the F31 could be defended as part of the qualifying exam, then edited based on feedback from faculty during the oral exam, and then, could finally be submitted for funding. Why not capitalize on the opportunity to receive funding for all the effort put forth in preparing for the qualifying exam?"

He says that Zierolf provided some seed funding to make the transition which has led to all eligible students writing and submitting F31 applications. 

"We are reaping the rewards of those efforts to the betterment of our graduate program and the future success of our trainees," he says.  

The Awardees

Mark Althoff, a graduate research assistant in the program, received $108,108 over a three year period to study in the lab of José Cancelas, MD, PhD, director of research at Hoxworth Blood Center and a professor in UC's Department of Pediatrics. In this lab, Althoff will focus on the cellular and molecular mechanisms of hematopoietic stem cell migration and differentiation. Hematopoietic stem cells are the "mother" stem cells that create all other kinds of blood cells. 

"My project is centered on hematopoietic stem cell polarity, and its subsequent maintenance of these cells' activity," he says. "Cell polarity is one of the most basic properties of all living cells, and loss of polarity is often a trademark of cancer. Polarization plays a pivotal role in hematopoietic stem cell biology, regulating its dormancy, fate determination and function. 

"These stem cells are highly inactive cells that are maintained in a polarized fashion with the ability to rapidly enter the cell cycle and differentiate through changes in response to microenvironmental cues following cell stress or damage. We are investigating how the bone marrow microenvironment affects various cell polarity regulators that define dormant hematopoietic stem cell function and self-renewal ability."

He says the potential of these stem cells to rebuild the hematopoietic system has allowed for the development of transplantation approaches to treat cancer and blood diseases. 

"The hunt for molecular targets to expand functional hematopoietic stem cells remains a priority in the field where manipulation of cellular dormancy is required for cell culture," Althoff continues. "Our goal is to identify new targets that can be used clinically to improve stem cell transplantation efficacy and improve certain blood diseases."

Nick Brown, a graduate research assistant who received $63,612 over two years, will be working in the lab of Susan Waltz, PhD, professor in the Department of Cancer Biology and a member of both the Cincinnati Cancer Center and UC Cancer Institute, looking at new ways to target therapy-resistant prostate cancer. 

"Despite many new innovative approaches being tried to treat men with prostate cancer, many men eventually succumb to the disease after their tumors become resistant to therapy," he says, adding that prostate cancer is the second leading cause of cancer death in men. "A major hurdle is reactivation of the androgen receptor, despite androgen deprivation therapy. This receptor is a transcription factor (a protein that minds to certain DNA strands) that moves into the nucleus after being bound by androgens, which are hormones, and promotes transcription of many genes, several of which code for metabolic proteins that regulate lipid and protein biosynthesis. Reactivation of the androgen receptor leads to rapid tumor growth and in most cases death of the patient."

Brown says preliminary data suggests a receptor found on the surface of cells called Ron tyrosine kinase, which has been linked to many types of cancer, is important in activating the androgen receptor in prostate cancer, which leads to resistance.  

"Our team will look at the Ron receptor as a potential new activator of the androgen receptor and determine the potential of targeting this receptor to combat therapeutic resistance in prostate cancer. This research may have important clinical implications for the treatment of patients with resistance to certain therapies."

Sonya Ruiz-Torres, also a graduate research assistant, will be using her three-year F31 award (she says the amount is currently unknown) to study the underlying developmental mechanisms that cause extreme susceptibility of patients with the DNA repair defect Fanconi anemia to squamous cell carcinomas.

Connecting new molecular pathways raises hopes of finding new treatments for susceptibility to squamous cell carcinoma (skin or mucus membrane cancers).

Ruiz-Torres will perform her studies in the laboratory of Susanne Wells, PhD, a professor in the Department of Pediatrics and a member of both the Cincinnati Cancer Center and UC Cancer Institute.

"Human skin and mucosa, or the lining of our oral cavity and throat, are composed predominantly of keratinocytes, which play a critical role in maintaining barriers against environmental harm," she says. "Included in these harms are DNA toxins that cause genome instability and DNA damage. DNA repair mechanisms are a critical secondary defense once DNA damage has occurred. 

"While all cells in the body have evolved sophisticated mechanisms to repair DNA damage, the consequences of defective repair are distinct for different organs and are likely rooted in developmental processes that remain poorly understood. Nowhere is the importance of organ-specific DNA repair more apparent than in the inherited genome instability disorder Fanconi anemia, where every cell in the body is incapable of properly repairing certain types of DNA damage. A universal molecular feature of the disease is the absence of a functional Fanconi anemia DNA repair pathway, caused by mutations in genes associated with the pathway."

Ruiz-Torres says people with this condition are highly susceptible to skin cancer as well as cancer in the lining of the mouth, esophagus, and anogenital tract.

"Recent analysis using electron microscopy of what appear to be normal skin samples in this population shows defects in keratinocyte organization and adhesion; additionally, earlier studies in animal and human keratinocytes have indicated that Fanconi anemia pathway loss can cause a high rate of cells in normal skin," she says. "I have developed a 3-D genetically engineered skin model in hopes of determining the effect of the Fanconi anemia pathway loss on normal keratinocytes and its contribution to squamous cell carcinoma development. 

"The studies of epidermal lineages may help define new molecular functions for the Fanconi anemia pathway and help us explore origins of human cancer susceptibility with potential advances for squamous cell carcinoma prevention."