https://openworks.mdanderson.org/sumexp21/1175/thumbnail.jp

Chou, Cody

Clowers, Michael J.

Eckols, Kris T.

Moghaddam, Seyed Javad

Peng, Stephen

Ramos-Castaneda, Marco A.

Tweardy, David J.

English

OpenWorks @ MD Anderson

Results Background• Lung adenocarcinoma (LUAD) is an aggressive form of non-small cell lung cancer1• 30% of LUAD patients have mutations in the Kirsten rat sarcoma viral oncogene (K-ras)1• K-ras mutations are challenging to directly treat due to drug resistance2• Transcription factor STAT3 is a major component of tumor associated inflammation in K-ras mutant tumors3• STAT3 upregulates immune checkpoint molecules PD-1/PD-L14• Targeting downstream or co-occurring pathways of K-ras may provide new targeted therapyAimWe treated a K-ras mutant lung cancer mouse model, CC-LR, with TTI-101 (a STAT3 inhibitor) and/or anti-PD-1 to investigate the significance of targeting downstream/co-occurring pathways of K-rasMethodology• CC-LR lung cancer mice were treated with TT1-101 (provided by Tweardy and Eckols) and/or anti-PD-1 from 10 to 14 weeks of age• Lung samples were extracted and stained with Hematoxylin and Eosin (H&E) staining to determine tumor area percentageEffect of Combined PD-1 and STAT3 Pathway Blockade Treatment on K-ras Mutant Lung CancerCody Chou1,2 , Michael J. Clowers1, Marco A. Ramos-Castaneda1, and Seyed Javad Moghaddam1Department of Pulmonary Medicine1, The University of Texas MD Anderson Cancer Center, Houston, TX, USAKing Foundation High School Summer Program2, Houston, TX, USANeturophil Lymphocyte Macrophage0255075100BALF Immune Cell Lineages (%) CC-LRaPD1aPD1 + TTI-101TTI-101Figure 4. immune cell composition of different treatments in CC-LR mice. Figures produced by Michael J. ClowersEffect of Combined PD-1 and STAT3 Pathway Blockade Treatment on K-ras Mutant Lung CancerCody Chou1,2 , Michael J. Clowers1,3, Marco A. Ramos-Castaneda1, Stephen Peng1, T. Kris Eckols4, David J. Tweardy4, Seyed Javad Moghaddam1,31Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA2King Foundation High School Summer Program, Houston, TX, USA3The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA4Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USAFigure 1. K-ras induced lung cancer mouse model, CC-LR, breeding scheme.Figure 2. Injection of TTI-101 reduces tumor number and area in CC-LR mice. Figures produced by Marco A. Ramos-Castaneda and Stephen Peng.Figure 3. TTI-101 +/- anti-PD1 treatment trends toward reduced surface tumor number, but not tumor area, in CC-LR mice. Figures produced by Michael J. Clowers and Cody ChouCC-LRaPD1TTI-101aPD1 + TTI-1010204060Surface Tumor NumberVehicleTTI-101020406080Surface Tumor Number✱✱✱VehicleTTI-1010510152025Tumor Area %✱TTI-101: 100mg/kg/dayReferences1) Goldstraw, P. et al. Non-small-cell lung cancer. The Lancet 378, 1727-1740 (2011).2) Mayekar, M. K. & Bivona, T. G. Current landscape of targeted therapy in lung cancer. Clinical Pharmacology & Therapeutics 102, 757-764 (2017).3) Ji, H. et al. K-ras activation generates an inflammatory response in lung tumors. Oncogene 25, 2105-2112 (2006). 4) Bu, L L et al. “STAT3 Induces Immunosuppression by Upregulating PD-1/PD-L1 in HNSCC.” Journal of dental research vol. 96,9 (2017): 1027-1034. doi:10.1177/0022034517712435Conclusion• Based on preliminary data, single treatment of TTI-101 trends toward reduced tumor number• Combination treatment of TTI-101 and anti-PD-1 trends toward reduced tumor number and area.• Combination treatment, when compared to single treatment, is not significant • Personalized treatment with TT1-101 and anti-PD-1 may serve as an alternative approach in the future0 7 14 21 280.951.001.051.10 Normalized Daily Weight by Treatment GroupDaysFold Change from Starting WeightaPD1TTI-101TTI-101 + aPD1CC-LRns✱✱✱✱✱✱Figure 5. TTI-101 oral gavage causes modest weight loss in CC-LR mice. Figures produced by Michael J. Clowers and Cody ChouFuture Work• We plan to perform immunohistochemistry staining todetect pSTAT3• We also plan to perform qPCR to detect inflammatory markers in the tumor environment

Effect of Combined PD-1 and STAT3 Pathway Blockade Treatment on K-ras Mutant Lung Cancer

https://openworks.mdanderson.org/cgi/viewcontent.cgi?article=1175&context=sumexp21

Effect of Combined PD-1 and STAT3 Pathway Blockade Treatment on K-ras Mutant Lung Cancer

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