Identification Of Novel Targets For The Treatment Of Pancreatic Cancer Patients.

Abstract Pancreatic cancer (PC) is the 12th most common cancer worldwide. Despite a large panel of chemo- and targeted therapeutics options, patient prognosis remains poor with a 5-years overall survival below 10%. Thus, there is still a critical need to develop more efficient therapeutic alternatives. Antibody drug conjugates (ADC) and small molecule drug conjugates (SMDC) combine the oncolytic activity of highly potent chemotherapies with the target specificity of an antibody or a small molecule. Both ADC and SMDC are of increasing interest for cancer treatment, as they allow more specific delivery of chemotherapies to the tumor site. Facing the clinical needs for PC treatment, here we present an in-silico analysis to reveal specific targets for further ADC/SMDC development. 4HF Biotec has developed a proprietary platform connecting large clinical, OMICS and drug sensitivity data from various sources. It includes annotation for more than 1,800 preclinical models (cell lines, cell line-derived xenografts, and patient-derived xenografts), up to 11,000 patient tumors and 22,000 normal tissues (TCGA, GTEx and various GEO datasets). For tumor target discovery purposes, we designed and implemented the platform with specific analytics tools. To identify specific targets for PC, we first decided to analyze preclinical models, to focus on genes expressed by tumor cells and not by stroma cells. This aspect is particularly important in the context of PC which often have a high stroma content. Differential gene expression analysis of 113 PC preclinical models versus 1,737 tumor models from up to 30 tumor entities revealed 327 PC specific genes potentially targetable. Then, a similar analysis was performed by testing TCGA patient tumors (179 pancreatic tumors vs 9,521 patient tumors from other entities) and revealed 1,292 pancreatic specific genes. Finally, PC patient tumors were compared to 709 samples from various normal organs allowing to identify 1,156 tumor specific genes. At the intersection of these three analyses, we identified 56 PC-specific target candidates for ADC/SMDC development. Among the top candidates, MUCL3 (mucin like 3) was one of the most promising genes. Its mRNA expression is almost exclusively restricted to pancreatic and stomach samples in both preclinical models and TCGA patient tumors. It is overall not frequently expressed by normal tissues, and restricted to subsets of stomach, esophagus, and lung samples. The gene encodes for a transmembrane protein with a long weakly glycosylated extracellular part. A detailed analysis of the protein characteristics and expression modalities will be shown. The present work demonstrates that our in silico platform helps to identify promising targets for PC treatment using ADC/SMDC approaches. Our analyses revealed MUCL3 as one of the top candidates, further analyses will be needed to determine its druggability using small molecules or antibodies. Citation Format: Anne-Lise Peille, Alexandra Musch, Hoor Al-Hasani, Heinz-Herbert Fiebig, Vincent Vuaroqueaux. Identification of novel targets for the treatment of pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1173.