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• ACC presents high risk for recurrence and refractoriness to anti-cancer treatments. • LGALS3BP is largely expressed in ACC patients. • LGALS3BP is a potential target for ADC therapy in ACC. Adenoid cystic carcinoma (ACC) is a rare type of cancer that typically arises from glandular tissues, most commonly in the salivary glands. Although relatively rare, it represents a serious clinical issue as the management of the disease is highly complex being the only therapeutic options represented by invasive surgery and/or radiotherapy. In the present study, we have explored the potential of galectin-3 binding protein (LGALS3BP) as a novel target for antibody-drug conjugate (ADC) therapy in ACC. RNAseq was conducted on a panel of 10 ACC patient-derived xenografts (PDX)s tissues and 6 normal salivary glands to analyze LGALS3BP gene expression. Protein expression was assessed in ACC PDX and primary tumor tissues using immunohistochemistry. Anti-LGALS3BP ADC named 1959-sss/DM4, was tested in high LGALS3BP expressing ACC PDX model ST1502B. RNAseq analysis revealed that LGALS3BP expression was highly expressed in ACC PDX tissues compared to normal salivary gland tissues. As evaluated by immunohistochemical analysis, LGALS3BP protein was found to be heterogeneously expressed in 10 ACC PDX and in tumor tissues derived from a cohort of 37 ACC patients. Further, treatment with 1959-sss/DM4 ADC led to durable tumor growth inhibition (TGI) in 100% of animals without observed toxicity. Our study provides strong evidence that LGALS3BP is a promising therapeutic target for ACC, warranting further expedited preclinical and clinical investigation. [ABSTRACT FROM AUTHOR]

The present study focuses on the development and validation of an HPLC-DAD methodology for the detection of a potent chemotherapeutic agent, Maytansinoid Ravtansine (DM4), and its metabolite, S-methyl-DM4 (S-Me-DM4), in plasma samples. Methodologically, after a simple protein precipitation with acetonitrile and after drying 1 mL of supernatant, the sample (suspended with N,N-Dimethylacetamide, DMA) was directly analyzed by HPLC under isocratic elution using a mobile phase comprising milliQ water and methanol (25:75, v:v), both acidified with 0.1 % v:v formic acid. Employing a flow rate of 1.0 mL/min and a reversed-phase GraceSmart RP18 column thermostated at 40 °C, we achieved complete resolution and separation of DM4 and S-Me-DM4 within 13 min. The optimized injection volume of 20 μL and the wavelength set at 254 nm were utilized for quantitative analyses. Rigorous validation has not only ensured its reliability and reproducibility but has also addressed potential limitations associated with methodological inconsistency. The limit of detection and quantification of the method were 0.025 and 0.06 μg/mL for both the analytes, respectively. The calibration curve showed a good linearity in the range 0.06–20 μg/mL. For both analytes, the intraday precision and trueness were 2.3–8.2 % and −1.1 to 3.1 %, respectively, while the interday values were 0.7–10.1 % and −10.4 to 7.5 %, respectively. The developed methodology enables the concurrent determination and quantification of free DM4 and its metabolite, free S-Me-DM4, making it a valuable tool for assessing the pharmacokinetics and pharmacodynamics of DM4-based therapies. In addition, the procedure was successfully applied to analyse the presence of free DM4 or its metabolite, free S-Me-DM4, in human plasma samples spiked with the 1959-sss/DM4 antibody-drug conjugate (ADC). The utilization of the herein validated methodology allowed to confirm the presence of these analytes, thereby providing insights into their potential release from the ADC structure. [Display omitted] • Fast method for Maytansinoid Ravtansine (DM4) and its metabolite quantification. • Drug and metabolite stability study in plasma matrix. • Valuable tool for assessing the clinical evidences of DM4-based therapies. • Antibody-drug conjugates (ADCs) for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Pancreatic Ductal Adenocarcinoma (PDAC) is a very aggressive disease, lacking effective therapeutic approaches and leaving PDAC patients with a poor prognosis. The life expectancy of PDAC patients has not experienced a significant change in the last few decades with a five-year survival rate of only 8%. To address this unmet need, novel pharmacological targets must be identified for clinical intervention. ATP Binding Cassette (ABC) transporters are frequently overexpressed in different cancer types and represent one of the major mechanisms responsible for chemoresistance. However, a more direct role for ABC transporters in tumorigenesis has not been widely investigated. Here, we show that ABCC3 (ABC Subfamily C Member 3; previously known as MRP3) is overexpressed in PDAC cell lines and also in clinical samples. We demonstrate that ABCC3 expression is regulated by mutant p53 via miR-34 and that the transporter drives PDAC progression via transport of the bioactive lipid lysophosphatidylinositol (LPI). Disruption of ABCC3 function either by genetic knockdown reduces pancreatic cancer cell growth in vitro and in vivo. Mechanistically, we demonstrate that knockdown of ABCC3 reduce cell proliferation by inhibition of STAT3 and HIF1α signalling pathways, previously been shown to be key regulators of PDAC progression. Collectively, our results identify ABCC3 as a novel and promising target in PDAC therapy. [ABSTRACT FROM AUTHOR]