Abstract 3942: Differential expression of a novel transport receptor, SORT1 (sortilin), in cancer versus healthy tissues that can be utilized for targeted delivery of anti-cancer drugs

Abstract

Sortilin (SORT1), or neurotensin receptor-3, is a scavenging receptor in the Vacuolar Protein Sorting 10 protein (Vps10p) family. SORT1 is involved in the internalization and trafficking of its ligands through an endocytic process and is associated with cancer cell survival and progression, making SORT1 a candidate for novel drug delivery. We recently reported on the pattern and prevalence of SORT1 expression in endometrial, breast, ovarian, colorectal, pancreas cancers, and skin melanoma. To better understand SORT1 expression, we screened tissues from different cancer types using the same immunohistochemistry (IHC) method. A total of 19 cancer tissue microarrays (TMAs) with 1394 evaluable cancer cores were screened. Each cancer core was scored using an H-score ranging from 0 to 300, where 0 corresponds to no cell stained for SORT1, while 300 corresponds to strong SORT1 staining in all cells. The table below summarizes the % of cores with moderate to high SORT1 expression (defined as H-score ≥100) as well as the average H-Score for each cancer type evaluated. Sub-analyses of SORT1 expression by tumor histological sub-type, stage and grade are also being performed. A total of 234 healthy or normal adjacent tissues cores were also assessed. Weak or null staining was observed in these tissues. Moderate staining was observed in specific cell types in kidney tubules and glomeruli, colonic mucosa, splenic sinusoidal spaces in red pulp, blood vessels in smooth muscle of spleen and colon, dendritic and axonal extensions of pyramidal-type neurons in brain, and testicular seminiferous tubules. SORT1 is currently being studied as a cancer target in a first-in-human (FIH) study of a peptide-drug conjugate (clinicaltrial.gov: NCT04706962). These results suggest that SORT1 is highly expressed in multiple tumors and is a promising target for the delivery and internalization of cancer therapeutic agents. Table 1. Cancer Type No. evaluable cores % of indication with H-score ≥ 100 Average H-Score Endometrial 94 90 197 Thyroid 108 92 188 Melanoma 155 83 184 Lung 152 58 112 SCLC 44 95 183 NSCLC 108 43 82 Bladder 118 81 156 Testis 40 100 116 Small intestine 54 63 102 Eye 26 46 83 Cervix 376 38 75 Prostate 150 39 71 Liver 121 23 52 Citation Format: Guylaine Roy, Pratik Kadekar, Lynn Marie Douglas, Maude Frappier, Jean-Christophe Currie, Jess Dhillon, Gregory Cesarone, Richard Siderits, Karen Kirchner, Michel Demeule, Christian Marsolais. Differential expression of a novel transport receptor, SORT1 (sortilin), in cancer versus healthy tissues that can be utilized for targeted delivery of anti-cancer drugs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3942.

Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing

“…SORT1 expression is elevated in several human malignancies including breast, ovarian, prostate, colon, pancreatic, skin, and pituitary cancers ( 51 – 55 ). Recently, screening of 19 cancer TMAs with 2800 evaluable cancer cores confirmed that SORT1 is highly expressed in multiple tumors and may therefore be a promising target for the delivery and internalization of anticancer therapeutic agents ( 56 , 57 ). The current study employed the syngeneic SORT1-positive B16-F10 melanoma tumor model to assess the biological activity of TH1902 within the iTME and to confirm its preclinical potential for use in combination immunotherapy.…”