Seyed Javad M. Moghaddam, MD
University of Texas M.D. Anderson Cancer Center
Research Project:
Developing Immuno-Prevention and Treatment Modalities for KRAS Mutant Lung Cancer
Grant Awarded:
- Lung Cancer Discovery Award
Research Topics:
- basic biologic mechanisms
- combination therapies experimental therapeutics
- immunology immunotherapy
Research Disease:
- lung cancer
Note that back in 2020 due to the COVID-19 pandemic, my laboratory was completely shut down for 3 months, and partially shut down working with a shift schedule and limited staff for 6 more months during which we had to stop expanding our mouse colonies. This led to an extended delay of several projects due to the time we had to spend reviving our mouse colonies which lasted until mid-2021. We also had issues hiring personnel to perform these studies due to COVID-influenced restrictions and hesitancy. However, we still managed to expand the colony of the genetic mouse model required for a portion of this project and performed most of the related studies planned for Aim 1, and a small part of Aim 3. We collected and analyzed samples, and produced very promising data (see below). I have presented these data on 2-3 occasions, and a manuscript describing the results was prepared and submitted to a peer-reviewed journal (JCI Insight) for publication which was very recently accepted for publication and went online ahead of print this month. We are currently working to produce more mice to perform the studies proposed in Aim 2, and the remainder of Aim 1, and 3.
Update: In summary, we demonstrated that IL-1ß blockade effectively suppresses K-ras mutant lung tumorigenesis by shifting the immunosuppressive tumor microenvironment to an anti-tumor phenotype, possibly via modulating the NF-?B and STAT3 pathways and subsequently leading to reduced tumor cell proliferation, and angiogenesis while increasing tumor cell death. These findings support the importance of IL-1ß as a potential target with preventive and therapeutic benefits for patients with K-ras mutant lung adenocarcinoma with highly translational potential in the clinical setting.
Focusing on Gender Specific Cell-Signaling Pathways Involved in Lung Cancer Growth (2017-2018)
Mutations of KRAS gene are the most common genetic alterations found in lung cancer. These mutations are heavily associated with tobacco exposure, and poor prognosis. Unfortunately, our knowledge of the molecular mechanisms affecting KRAS-induced lung cancer growth is deficient. Moreover, attempts at targeting KRAS mutant lung tumors with drugs have thus far failed, clearly indicating that alternative strategies are needed. Our goals are to understand gender- and cell-specific signaling pathways that are involved in KRAS mutant lung cancer growth, and to target these pathways and ultimately develop personalized therapies for this fatal subtype of lung cancer.
Update: We found that the deletion of a gene and its respective protein called STAT3 in cells lining the airways resulted in a significant reduction of KRAS mutant tumors in female mice, whereas it caused a dramatic increase in tumor growth in male mice. We also found depletion of a particular type of white blood cells called neutrophils in male mice resulted in reduced lung tumor growth, while inhibiting estrogen (sex hormone) receptor signaling in female mice led to the development of lung tumors. These findings suggest a dynamic interplay between estrogen signaling and KRAS/STAT3 pathways in lung cancer development.
Page last updated: September 6, 2023
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