SLITRK6

Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody-drug conjugates (ADCs) providing targeted drug delivery have shown antitumor activity in this setting. AGS15E is an investigational ADC that delivers the cytotoxic drug monomethyl auristatin E to cells expressing SLITRK6, a UC-associated antigen.

This was a multicenter, single-arm, phase 1 dose-escalation and expansion trial of AGS15E in patients with mUC (NCT01963052). During dose escalation, AGS15E was administered intravenously at 6 levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLTs) and the recommended phase 2 dose (RP2D) for the dose-expansion cohort. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in patients with and without prior chemotherapy, and with prior checkpoint inhibitor (CPI) therapy. Best overall response was also examined.

Ninety-three patients were recruited, including 33 patients previously treated with CPIs. The most common treatment-emergent adverse events were fatigue (54.8%), nausea (37.6%), and decreased appetite (35.5%). Peripheral neuropathy and ocular toxicities occurred at doses of ≥0.75 mg/kg. AGS15E increased in a dose-proportional manner after single- and multiple-dose administration; accumulation was low. Five DLTs occurred from 0.50‒1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORRs in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively.

DLTs with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined.

Urinary bladder urothelial carcinoma (UBUC) and upper tract urothelial carcinoma (UTUC) harbor analogous morphology with comparable cytogenetic changes as well as prognostic factors but their similar biological activities still remain controversial. SLITRK6 gene has been demonstrated to have distinct role in urothelial cancers with a distinction between UTUC and UBUC.

The study included a total of 80 patients of urothelial carcinoma including 60 UBUC and 20 UTUC cases. The tumor tissues from both the groups were evaluated for gene expression at mRNA level by qRT-PCR and protein expression by immunohistochemistry (IHC) and western blot.

Significantly more than 4-fold high mRNA expression of SLITRK6 was observed in UTUC against 1.2-fold in UBUC (p<0.0001). The overall SLITRK6 expression by IHC was observed in 80% of the UBUC cases in comparison to 100% strong expression in UTUC patients and among two groups expression exhibited a significant difference for moderate to strong expression (p=0.0005). The protein expression by western blot analysis in UTUC samples was considerably higher as compared to UBUC samples (1.64 vs. 0.76 respectively: p=0.01). A strong concordance exhibited for the higher mRNA and protein expression in both UTUC and UBUC cases (∼75%) wherein 80%, 75% and 70% higher expression of SLITRK6 was detected by qRT-PCR, Western blot and IHC respectively.

To conclude, although SLITRK6 exhibits a strong expression in both UTUC and UBUC but was considerably observed higher in majority of UTUC cases. Therefore, SLITRK6 appears as a promising novel possible gene target for urothelial carcinoma in particular UTUC.

To investigate the role of SLITRK6 in lung adenocarcinoma (LUAD) and the underlying mechanism in it, clinical tissues and tissue microarray of LUAD were used to detect the expression of SLITRK6. In vitro cell viability assay and colony formation assay in LUAD cells were conducted to investigate SLITRK6 related biological functions. In vivo subcutaneous model was used to determine the role of SLITRK6 in LUAD growth. It was found that the expression of SLITRK6 was significantly upregulated in LUAD tissues compared with that in para-cancerous tissues. Knockdown of SLITRK6 suppressed the proliferation and colony formation of LUAD cells in vitro. Meanwhile, the growth of LUAD cells was also inhibited by SLITRK6 knockdown in vivo. Furthermore, we found that SLITRK6 knockdown could suppress the glycolysis of LUAD cells by regulating the phosphorylation of AKT and mTOR. All results suggest that SLITRK6 promotes LUAD cell proliferation and colony formation by regulating PI3K/AKT/mTOR signaling and Warburg effect. SLITRK6 may serve as a potential therapeutic target for LUAD in future.