Glutamine-Mediated Tumor-Stromal Interaction: A Novel Target for Pancreatic Cancer Treatment
Abstract
The Principal Investigators (PIs) career goals in cancer research: My career goal is to establish my own research team with the focus on fighting against pancreatic cancer with our bodys own immune system. This proposed study will lay the foundation for achieving my career goal of becoming a pancreatic cancer researcher, which aligns with one of the fiscal year 2018 (FY18) Peer Reviewed Cancer Research Programs (PRCRP) topic areas. To attain these goals, I have developed a Researcher Development Plan in consultant with my mentor and dissertation committee members. This proposed plan will help strengthen my technical, analytical, critical thinking, scientific writing, presenting, mentoring, and networking skills through hands-on experiments, discussions with my mentor and dissertation committee members, as well as participating in seminars, workshops, and conferences. I strongly believe that successful completion of this proposed study will facilitate my growth toward becoming a well-rounded pancreatic cancer researcher. Scientific Objective and Rationale: The ultimate applicability of this proposed study is to develop a therapeutic regimen with improved efficacy and reduced toxicity for pancreatic cancer patients. Pancreatic cancer is a devastating disease with appallingly poor outcomes. For all stages of pancreatic cancer combined, only about 8% of patients are still alive 5 years after being diagnosed. Surgical removal is the only way to achieve long-term survival. However, among the 10% to 15% of patients who are eligible for surgery, 80% develop relapse. Unfortunately, for the majority of patients with inoperable tumor, most of them will have passed by the end of the first year. The poor outcome is in part due to resistance to conventional chemotherapy. Previous studies in our laboratory turned the spotlight on pancreatic stellate cells, the most abundant and active cell type surrounding pancreatic cancer cells. Through secretion of an amino acid called glutamine, pancreatic stellate cells support the growth of pancreatic cancer cells and assist in the development of therapeutic resistance. Gemcitabine Monotherapy has been the standard of care for advanced pancreatic cancer for over two decades despite the fact that half of the patients pass within 6 months. The addition of Abraxane to gemcitabine since 2013 has made incremental improvement on survival, but at the cost of increased toxicity. Recent findings in our laboratory identified a compound, palmatine, which, when administrated together with gemcitabine, kills pancreatic stellate and cancer cells at lower doses. Given our data that palmatine targets the potential mechanism of Abraxane resistance, we propose a clinical application of palmatine in combination with gemcitabine and Abraxane for pancreatic cancer treatment. The clinical benefits of this combination comes in threefold: (i) by disrupting the interaction between pancreatic stellate and cancer cells, palmatine can reduce therapeutic resistance, improve the effectiveness of chemotherapy, and prolong the life of pancreatic cancer patients; (ii) palmatine shows less toxicity in normal cells versus cancer cells in our preliminary study, thus have the potential to reduce toxicity and improve quality of life; and (iii) palmatine met the many criteria of oral drug delivery, which is the most preferred route of drug administration with high flexibility and patient compliance. This proposed application will be able to benefit all pancreatic cancer patients since active and fast-growing pancreatic stellate cells are a prominent characteristic for nearly all pancreatic cancer patients. Particularly, this combination is best for patients who appears to be less fit. These patients are weaker and are more likely to experience serious adverse effects. I am aware that thorough toxicological and formulation studies need to be conducted prior to translating laboratory-based discoveries to clinic. Accordingly, I
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910596
Entities
People
- Xiaoyu Yang
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio