Published in UAB Insight, Winter 2008
Comprehensive Cancer Center Awarded
$11.5 Million
The National Institutes of Health’s National Cancer Institute (NCI) has renewed UAB’s Specialized Program of Research Excellence (SPORE) in breast cancer. SPORE grants promote interdisciplinary research and speed translation of basic science findings to the clinical trials arena to decrease incidence, morbidity, and mortality of breast cancer. The $11.5 million, 5-year award recognizes contributions UAB investigators have made to cancer research. UAB has held a breast cancer SPORE grant since 2000.
“The biggest hurdle for obtaining a SPORE grant is translating basic science into successful clinical trials within 5 years, which is a very short time frame,” says SPORE coprincipal investigator (co-PI) Albert F. LoBuglio, MD. “Our researchers demonstrated their projects’ translational potential with significant advancements in understanding prognostic indicators in breast cancer, development of novel therapeutic and chemotherapeutic strategies, and a critical mass of clinical studies developed within the SPORE,” says Fay Fletcher Kerner Professor and Chair of Surgery Kirby I. Bland, MD, breast cancer SPORE PI. “Investigators have developed 12 clinical protocols, generated a robust publication track record, invested in highly successful research and career development programs, and leveraged funds that resulted in other peer-reviewed grants,” he says.
Breast cancer remains the most frequently diagnosed cancer in women, with an estimated 41,000 deaths in 2007. The national breast cancer SPORE strategy has generated remarkable discoveries in the molecular mechanisms of breast cancer. “This grant, which is the foundation of our breast cancer program, has far-reaching implications. Its renewal provides continued support for basic and clinical research that will directly impact cancer treatment,” says Comprehensive Cancer Center Director and Evalina B. Spencer Chair in Oncology Edward E. Partridge, MD.
The SPORE funds four projects, three cores, a career development program to recruit and train breast cancer researchers, and a pilot project component for innovative early phase cancer research.
Antibody Targets DR5
Cancer center researchers are testing a UAB-developed monoclonal antibody called TRA-8 in patients whose breast cancer does not respond to available therapies. TRA-8 targets tumor cell death receptor 5 (DR5) and induces cancer cell death while sparing healthy cells.
Breast and other cancer cells may differentially express increased levels of DR5 during malignant transformation. The addition of chemotherapy enhances the antitumor efficacy of TRA-8 in multiple tumor models. The agents use complementary pathways that synergistically enhance efficacy, says Tong Zhou, MD, who led the team that developed TRA-8.
“Preclinical work on cancer tissues relating to TRA-8 sensitivity aims to identify a molecular signature in malignant tumors that will predict which patients will benefit from therapy,” LoBuglio says. Coinvestigators LoBuglio, Zhou, and radiation biologist Donald J. Buchsbaum, PhD, also hope to discover how breast cancer cells develop resistance to TRA-8.
Retinoids for Chemoprevention
UAB has designed and synthesized two new classes of nuclear retinoid X receptor (RXR)-selective retinoids called rexinoids. The compound UAB30, patented by UAB scientists in 2001, “is the most active and the least toxic of the hundreds of types of retinoids we have developed during the last 15 years,” says co-PI and Professor of Biophysics and Chemistry Donald D. Muccio, PhD. “Animal models and preliminary data in humans show UAB30 inhibits breast cancer development without the side effects of other compounds in this class,” he says. “Current chemoprevention options exist to prevent estrogen receptor-positive breast cancer. Rexinoids may inhibit both estrogen receptor-negative and estrogen receptor-positive breast cancer with a low toxicity profile,” says Clinton J. Grubbs, PhD, an expert in animal models of chemoprevention.
The NCI’s Rapid Access to Preventive Intervention Development Program facilitated UAB30’s preclinical development as a new chemopreventive agent. A phase 1 trial is scheduled, and further research will evaluate whether the agent alters proliferation, apoptosis, or RXR downstream target genes in breast cancer cells. “Early studies also will help determine novel retinoids’ efficacy as general cancer preventives,” says breast surgical oncologist and co-PI Helen Krontiras, MD.
Klf4 Cancer Gene Biomarkers
This SPORE project builds on previous UAB research that identified Kruppel-like factor 4 (Klf4) as a new oncogene that is upregulated in breast cancer and squamous cell carcinoma. UAB investigators have shown its level of expression correlates with patient survival. “Klf4 also has some tumor initiation properties and may represent one of the earliest steps in cancer development,” says molecular geneticist and co-PI J. Michael Ruppert, MD, PhD.
“More recently we have identified pathways regulated by KLF4 and used this information to identify drugs that may be especially effective as therapies for Klf4-postive cancers,” he says. “Klf4 antibodies can potentially indicate which patients are at risk for recurrence or relapse and which are likely to respond to Klf4 pathway inhibitors.” Ruppert and colleagues have identified two inhibitors that may benefit individuals with Klf4-positive breast cancers and will test them as single agents and in combination.
“We also want to determine if Klf4 levels can be used to tailor therapy so that patients with aggressive cancers get more intensive treatment while those with less aggressive, less invasive tumors can avoid unnecessary toxicity,” Ruppert says.
Klf4 was central to a recent breakthrough in embryonic stem cell research. Together, Klf4 and three other genes are able to convert adult fibroblasts into induced pluripotent stem cells, which have many properties of embryonic stem cells.
Gamma/Delta T cells
“Imagine an anticancer agent that can induce immune resistance to cancer via rare human γd-T cells, one of the body’s most basic defences against cancer. This is the basis for the fourth SPORE project — a truly novel approach to immunotherapy,” LoBuglio says.
Coinvestigators Richard D. Lopez, MD, and Kurt R. Zinn, DVM, PhD, pioneered large-scale ex vivo expansion of human γd-T cells. Importantly, these cells retain their innate antitumor activity in vitro against a variety of human tumor cell lines, including breast cancers. Lopez and Zinn hope to use γd-T cells to develop specific immunotherapies for cancer resistant to other therapies.
“It is notable that these four projects result from research by UAB investigators,” Bland says. “The UAB30 rexinoids and DR5 antibody [TRA-8] are patented UAB products; the Klf4 pathway work was advanced in Ruppert’s laboratory, and Lopez and colleagues’ ability to generate large numbers of cells in vitro made the γd-T cell project possible.”
Career Development
The SPORE grant includes discretionary funds for career development and pilot projects. Each year two researchers will receive a career development award that enables collection of preliminary data for breast cancer studies and facilitates recruitment of promising basic and clinical investigators early in their careers.
The SPORE funds three or four pilot projects. These projects must be innovative, demonstrate significant potential, and encourage collaborations among investigators. The grant can fund projects for a second year, target them for R01 research support, or elevate them to a full SPORE project.
“One of the important NCI measurements for SPORE renewal is successful investment in career development and pilot programs,” LoBuglio says. “A career development grant resulted in the monoclonal antibody project, and the γd-T cell studies began as a pilot project.”
The SPORE funds three cores. The Administrative and Clinical Trials Core oversees human clinical trials. The Biostatistics and Database Core provides centralized statistical services, collaborative research, and data management. The Tissue Resources, Immunopathology, and Molecular Assays Core provides fresh, frozen, and paraffin breast tissue preparations, as well as histology services, and maintains a breast tumor bank of well characterized breast tumor specimens. The assay component enables morphological and pathological analysis methods that are too intensive for many individual projects to support, such as tissue microdissection, tissue arrays, antibody arrays, immunoelectron microscopy, and computerized cytomorphometric analysis.
“The breast cancer SPORE is the foundation of our women’s research effort in the Comprehensive Cancer Center, and its award is a positive statement about our researchers’ quality of work,” Bland says. “Our scientists are making steady progress in breast cancer treatment.”
“The UAB breast SPORE has grown into one of the most productive and highest-ranked efforts combating breast cancer in the United States,” LoBuglio says, “and our discoveries will continue to advance research and treatment for years to come.”
For more information:
Dr. Kirby Bland
Dr. Albert LoBuglio
1.800.UAB.MIST
mist@uabmc.edu