Clinical and preclinical advances in PSMA-Directed Antibody-Drug conjugates (ADCs): Current status and hope for the future.

Prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein overexpressed in a variety of tumors, especially in nearly all prostate cancers, which makes it a potentially attractive antigen for targeted cancer therapies. More importantly, PSMA, due to no shedding into circulation and efficient internalization after antibody binding, becomes a potential target for antibody-drug conjugates (ADCs), a valid and emerging paradigm of cancer treatment. Four and eight PSMA-directed ADCs have been or are currently being investigated in clinical trials (three of which failed to confirm the promising results while one is currently being evaluated in an ongoing clinical study) and preclinical studies, respectively, for the treatment of PSMA-positive solid tumors, especially prostate cancer. The present study aims to completely review clinical- and preclinical-stage PSMA-directed ADCs.

Nectin-4-directed antibody-drug conjugates (ADCs): Spotlight on preclinical and clinical evidence.

Nectin-4 (Nectin cell adhesion molecule 4), a type I transmembrane cell adhesion protein, was demonstrated to be overexpressed in a variety of tumors, making it an attractive antigen for targeted therapies such as antibody-drug conjugates (ADCs). Of great note, the US Food and Drug Administration (FDA)-approval of the first Nectin-4-directed ADC, enfortumab vedotin (EV), in urothelial cancer (UC) not only introduced Nectin-4 as a clinically validated and reliable target antigen but also confirmed the evolving role of Nectin-4-directed ADCs as novel and promising cancer therapeutics. In addition to EV, there have been or are currently being seven and eleven Nectin-4-directed ADCs, respectively, in various stages of clinical trials and preclinical development, offering a promising future for the treatment of Nectin-4-positive cancer patients. This study reviewed clinical- and preclinical-stage Nectin-4-directed ADCs.

Progress of antibody-drug conjugates (ADCs) targeting c-Met in cancer therapy; insights from clinical and preclinical studies.

The cell-surface receptor tyrosine kinase c-mesenchymal-epithelial transition factor (c-Met) is overexpressed in a wide range of solid tumors, making it an appropriate target antigen for the development of anticancer therapeutics. Various antitumor c-Met-targeting therapies (including monoclonal antibodies [mAbs] and tyrosine kinases) have been developed for the treatment of c-Met-overexpressing tumors, most of which have so far failed to enter the clinic because of their efficacy and complications. Antibody-drug conjugates (ADCs), a new emerging class of cancer therapeutic agents that harness the target specificity of mAbs to deliver highly potent small molecules to the tumor with the minimal damage to normal cells, could be an attractive therapeutic approach to circumvent these limitations in patients with c-Met-overexpressing tumors. Of great note, there are currently nine c-Met-targeting ADCs being examined in different phases of clinical studies as well as eight preclinical studies for treating various solid tumors. The purpose of this study is to present a broad overview of clinical- and preclinical-stage c-Met-targeting ADCs.

Combination of SIX4-siRNA and temozolomide inhibits the growth and migration of A-172 glioblastoma cancer cells.

Glioblastoma is one of the most common and invasive types of primary brain malignancies in adults, accounting for 45.5% of malignancies. Its annual prevalence is low compared to other cancers. The survival rate of this disease is about 14 months after diagnosis. Temozolomide (TMZ) is a common chemotherapy drug used to treatment of glioblastoma, but drug resistance against this drug is an important barrier to successful treatment of this cancer. Today, siRNAs play a significant role in cancer treatment. SIX4 is a transcriptional regulatory molecule that can act as a transcriptional suppressor and an activator in target genes involved in differentiation, migration, and cell survival processes. The aim of this study was to evaluate the effect of SIX4-siRNA on A-172 glioblastoma cells, its role as a tumor suppressor, and its combination with TMZ. We studied the cytotoxic effect of the SIX4-siRNA and TMZ on A-172 cells using the MTT assay investigated their effect on apoptosis and cell cycle of A-172 cells used wound healing assays to assess their effect on cell migration. Finally, we used qRT-PCR to study the mRNA expression levels of genes involved in apoptosis and migration of tumoral cells after treatments. Based on our results, silencing SIX4-siRNA expression reduced the cell viability of A-172 cells and sensitize these cells to TMZ. Furthermore, we observed an increase in apoptosis and cell cycle arrest, and a decrease in migration. Bax and caspase-9 overexpression and BCL2 and MMP9 downregulation were detected in the combination of SIX4-siRNA and TMZ. According to our results, the combination of SIX4-siRNA and TMZ can be a very useful strategy for successful glioblastoma treatment.