SORT1 expression

Here, we demonstrate that the expression of sortilin, a widely expressed transmembrane receptor involved in intracellular protein sorting, is significantly increased in functional compared to non-functional NETs and thus can be used as a biomarker for functional NETs. Furthermore, using a cell line model of functional NETs, as well as organoids, we demonstrate that inhibition of sortilin reduces cellular serotonin concentrations and may therefore serve as a novel therapeutic target to treat patients with carcinoid syndrome.

P1, N=70, Recruiting, Theratechnologies | Active, not recruiting --> Recruiting

P1, N=70, Active, not recruiting, Theratechnologies | Trial completion date: Mar 2023 --> Dec 2024 | Trial primary completion date: Mar 2023 --> Dec 2024

These results therefore suggest a regulatory role for Sortilin in the degradation or renewal of EGFR on the membrane. It would be interesting in future work to show the intracellular fate of EGFR and the role of (pro)neurotrophins in these mechanisms.

Interestingly, targeting sortilin with the orally bioavailable small molecule inhibitor AF38469 resulted in decreased GBM invasiveness, but cancer cell proliferation was not affected, showing that sortilin is targetable in GBM. Together, these data suggest the clinical relevance for sortilin in GBM and support further investigation of GBM as a clinical biomarker and therapeutic target.

TH1902 is a first-in-class PDC targeting SORT1, that consists of 2 molecules of docetaxel attached to the TH19P01 peptide via a cleavable succinyl linker. Although biological activity has been observed, the optimal dosing regimen of TH1902 is currently under evaluation. Clinical trial information: NCT04706962.

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.

P1, N=70, Active, not recruiting, Theratechnologies | Recruiting --> Active, not recruiting

Synopsis Understanding why the normal function of a scavenger receptor, SORT1, can be exploited to rapidly transport novel peptide drug conjugates (PDCs) into cancer cells Discussing the over expression of SORT1 in many solid tumours Learn about Thera’s lead PDC candidate, TH1902, across multiple solid tumours Review the potential of this novel SORT1+ platform for future developments

These events were unaffected by the presence of the P-gp inhibitors cyclosporine A or PSC-833. Therapeutic efficacy was further observed when carboplatin was combined to TH1902. Overall, TH1902 exerts a superior anticancer activity than the unconjugated docetaxel, in part, by circumventing the CSC drug resistance phenotype that could potentially reduce cancer recurrence attributable to CSC.

SORT1 is currently been studied as a cancer target in a first-in-human (FIH) study of a peptide-drug conjugate (clinicaltrial.gov: NCT04706962). Overall, 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.

Furthermore, due to its link with immune cell infiltration, the Sort1 gene represents a potentially novel predictive biomarker of HCC. The growth of HCC can be significantly inhibited by interfering with Sort1; therefore, these results provide a potential target for developing anticancer strategies for HCC.

In 5637 cells, 6 h incubation resulted in 10.2±0.3% (P>0.05) and 6.6±1.4% (P>0.05) apoptosis induction, while these values were 12.1±0.8% (P>0.05) and 27.4±4.5% (P≤0.01) after 12 h. The HFFF cells did not show significant apoptosis. The overexpression of sortilin in bladder tumor cells and its potential in inducing apoptosis via directed targeting with the specific monoclonal antibody may represent this protein as a potential candidate of targeted therapy in bladder carcinoma.

Furthermore, TH1902 combination with carboplatin also demonstrated better efficacy when compared to both taxanes-carboplatin combinations. Overall, TH1902 shows better in vivo efficacy, compared to that of docetaxel and even paclitaxel, against SORT1-positive ovarian and endometrial cancers and could be safely combined with carboplatin.

P1, N=70, Recruiting, Theratechnologies | Trial completion date: Mar 2022 --> Mar 2023 | Trial primary completion date: Mar 2022 --> Mar 2023

Moreover, considerable weight loss was associated with docetaxel treatment over 24 days while TH1902 treatments resulted in no net change in mouse body weights. In this syngeneic model, TH1902 is more tolerated and effective than docetaxel at inhibiting both melanoma xenograft growth and metastatic formation.

Our study reveals that Sortilin mediates the regulation of β-catenin by Presenilin1 and transduces the anti-invasive function of Presenilin1, which may provide novel therapeutic targets for glioblastoma treatment. Video Abstract.

Full experimental details are given for the synthesis and characterization of the four new compounds (TL020, TL023, VGD071, and DJ010). Comparison of solubilities, potencies, and cytotoxicities identified VGD071 as a promising candidate for future studies using mouse breast cancer models.

Selective ovarian tumor targeting was accomplished, demonstrating practical efficiency of the designed nanocomposite therapeutic, DTX@HNT/Au-SORT. The antitumor activity of DTX@HNT/Au-SORT (apoptosis of 90 ± 0.3%) was confirmed by in vitro experiments using a caov-4 (ATCC HTB76) cell line (sortilin expression > 70%) that was successfully targeted by the sortilin 2D8-E3 mAb, tagged on the DTX@HNT/Au.

Finally, hsa_circ_0110389 knockdown suppressed GC growth in vivo. Taken together, our findings firstly identify the role of hsa_circ_0110389 in GC progression, which is through miR-127-5p/miR-136-5p-SORT1 pathway, and our study provides novel insight for the identification of diagnostic/prognostic biomarkers and therapeutic targets for GC.

In all cases, TH1902 showed more potent inhibition than Docetaxel. These results strongly support future clinical development of TH1902 as novel therapeutics in SORT1+ cancers.