Brian Lally, M.D.
Assistant Professor of Radiation Oncology
Description of Research
Dr. Lally’s major interests include lung cancer, thoracic oncology, and radiation oncology. His clinical interests are focused on lung cancer, gastrointestinal cancer, and radiosurgery. Dr. Lally’s research interest is in translational radiation oncology.
After completing his residency at Yale University, Dr. Lally participated in the NCI-funded Translational Radiation Oncology (TRADONC) post-doctoral training program at Wake Forest University. The goal of this program is to provide a common base of scientific and technical knowledge that makes one proficient in hypothesis-driven research, as well as in the design and implementation of clinical trials. He has developed a laboratory-based program from which therapeutic strategies can be tested. A heavy emphasis will be placed upon understanding the mechanism of action. Dr. Lally is continuing his population science research to gain a better understanding of how co-morbidities and technology impact outcomes, and he is developing paradigms incorporating both molecular and clinical information to individualize therapy. These paradigms will be validated via prospective clinical trials. Observations from these clinical trials can then initiate new hypotheses from which to test and refine. This is a multi-directional approach for translational research, as defined by the NCI: http://www.cancer.gov/trwg/TRWG-definition-and-TR-continuum . Thus, Dr. Lally’s research has two broad areas of interest.
When radiation therapy is applied alone or in combination with other agents, the therapeutic result is a function of both tumor response and normal tissue damage. As a radiation oncologist, Dr. Lally is interested in identifying paradigms which translate into an improved therapeutic result for radiation therapy.
1) Investigation of novel compounds as potential radiosensitizing and chemosensitizing agents. Radiosensitization is an important approach to increasing the therapeutic result. NS-123 has demonstrated both in vitro and in vivo radiosensitization without an increase in normal tissue damage; still more work is needed to understand both its mechanism of action and potential for clinical use.
Determine the ability of NS-123 to be a broad spectrum radiosensitizer. Results have shown that NS-123 has the promise to radiosensitize a wide range of tumor types. This potential needs to be investigated by performing in vivo and in vitro experiments in other tumor cell lines. Dr. Lally expects that there will be some variability in the results. Experiments will be designed to see if the molecular characteristics of the various cell lines (i.e. p53 or EGFR status) impact the ability to exhibit radiosensitization. Dr. Lally is also interested in determining if the surviving cell population has changed significantly (i.e. increased stem cell population). This information will provide some insight into which pathway(s) NS-123 is targeting and ways to optimize therapy.
Determine the ability of NS-123 to function as a sensitizer for chemotherapeutic agents which impact the DNA repair pathway. Results thus far suggest that the mechanism responsible for NS-123’s radiosensitization involves the DNA repair pathway. When cells experience DNA damage, they have several different mechanisms for repair (i.e. base excision repair, nucleotide excision repair, non-homologous end joining, etc.). Some chemotherapeutic agents, such as cisplatin, can similarly induce DNA damage; the DNA repair response may differ when compared with IR. Investigations will be performed to determine if NS-123 is a chemosensitizer. Since cisplatin is commonly used in conjunction with radiotherapy for clinical use, the translational significance of the results is straightforward.
- Identification and biological evaluation of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library. Using a high-throughput, unbiased screening approach, Dr. Lally identified 4-bromo-3-nitropropiophenone (NS-123) as a radiosensitizer of human glioma cells in vitro and in vivo (Cancer Res, 2007). NS-123 radiosensitized U251 glioma, HT-29 colorectal carcinoma and A549 lung adenocarcinoma cells in vitro, whereas NS-123 did not increase the radiation sensitivity of normal human astrocyte cells or developmental abnormalities or lethality of irradiated Zebrafish embryos. In a novel xenograft model of U251 cells implanted into Zebrafish embryos, NS-123 enhanced the tumor growth-inhibitory effects of ionizing radiation (IR) with no apparent effect on embryo development. Similar results were obtained using a mouse tumor xenograft model in which NS-123 sensitized U251 tumors to IR while exhibiting no overt toxicity. In vitro pretreatment with NS-123 resulted in accumulation of unrepaired IR-induced DNA strand breaks and prolonged phosphorylation of several surrogate markers of DNA damage after IR, suggesting that NS-123 inhibits a critical step in the DNA repair pathway.
- The impact of postoperative radiotherapy (PORT) for stage II or III non-small-cell lung cancer (NSCLC) using the Surveillance, Epidemiology, and End Result (SEER) database. PORT has been shown in multiple randomized trials to improve local control for patients with resected NSCLC. The enthusiasm for PORT, however, declined after a meta-analysis published in 1998 demonstrated a 7% absolute increase in mortality associated with PORT, despite a 24% reduction in local recurrences. The authors suggested that the addition of PORT may have had an adverse effect due to acute or delayed radiation effects, such as radiation pneumonitis or cardiotoxicity that may have been associated with older technology. In an analysis (J Clin Oncol, 2006) of more than 7000 post-operative NSCLC patients from the SEER Database treated in relatively modern times, Dr. Lally showed that patients with N2 nodal involvement had both an overall survival and disease specific survival benefit using PORT.
- In a subsequent analysis, he hypothesized that recent improvements in both the planning and delivery of thoracic radiation therapy have resulted in a reduction in death from radiation-related cardiac disease for patients receiving PORT. Using a multivariate analysis, heart disease mortality associated with PORT decreased with time (Cancer, 2007).