Defining the Efficacy of Blocking Serine Phosphorylated STAT3 in the Treatment of Gastric Cancer
Abstract
Scientific Objectives: The goal of my Career Development Award is to deliver a new strategy to prevent the development of stomach cancer in Service members and the wider community. Stomach (also known as gastric) cancer is the second most lethal cancer in the world, accounting for ~10% of cancer deaths worldwide. Its incidence is associated with chronic inflammation, commonly caused by the most widespread infection in the world, Helicobacter pylori (H. pylori). My previous work has shown that a specific protein called Signal Transducer and Activator of Transcription (STAT)3 plays a key role in whether chronic H. pylori results in stomach cancer by modulating our expression of proteins that drive cellular processes including proliferation and survival. We know that too much STAT3 production or activity leads to inappropriate proliferation and survival of cells, which is observed in nearly 50% of gastric cancer patient tissue. We also know when we remove, or delete, STAT3 from mice, we achieve a significant reduction in disease burden for mice with stomach cancer and an increased latency to develop disease in those who do not. Unfortunately, research also shows that there is likely to be severe side effects for humans if STAT3 deletion is used to prevent stomach cancer. Human patients with mutant non-functional STAT3 develop severe immunological conditions. In mice, deletion of STAT3 leads to death of embryos before birth. Recently, my team and I found an activity of STAT3 that is critical for its role in promoting tumor development but dispensable for its activity in normal tissue. Targeting this activity of STAT3 is likely to be a tumor-specific vulnerability capable of being exploited therapeutically. My team has already generated compelling initial data showing that mice lacking this activity are protected from developing stomach cancer. In this project, we will use mouse models that closely resemble human stomach cancer to define the effectiveness of targeting this activity of STAT3 for the treatment of stomach cancer. Career Goals: I have made significant advances towards my career goal of running a successful, internationally recognized cancer research laboratory. I was recruited to the Hudson Institute to establish an independent laboratory in 2012, and I have been successful in attracting competitive funding to support my research program, which employs two postdoctoral scientists, a research assistant, and two students. In addition, I have formed national and international collaborations with other cancer researchers and with clinicians, including my Designated Mentor for this fellowship, Prof. Jenkins. Our collaboration has generated the data underpinning my application. The success of this application would enable me to employ experienced staff 100% dedicated to this project, which is critical to the completion of this ambitious and exciting project. The data generated from this project will be published in high profile journals and presented at key cancer conferences, increasing the profile of this project and my laboratory. I will use this increased profile to attract talented staff, competitive funding, and expand this research program in which we define fundamental biological mechanisms that underpin cancer, test the effectiveness of targeting these processes in preclinical animal models of cancer, and liaise with our clinical partners to target the most clinically relevant treatment problems. The ultimate goal of this research pipeline is to translate our findings into clinical practice improving outcomes for cancer patients. Ultimate Applicability: A major reason for the lethality of gastric cancer is late detection and lack of effectiveness of current front-line therapies. This project will define the prevalence and the role for a unique activity of STAT3. This activity of STAT3 may prove a useful biomarker to predict patient outcome, but more importantly it is likely to be an eff
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610628
Entities
People
- Daniel J Gough
Organizations
- Monash University
- United States Army