Search

Background: Little is known about prognostic factors of brain metastases (BM) from colorectal cancer (CRC). HER2 amplification/overexpression (HER2+) was previously described; its impact on prognosis remains uncertain., Methods: In the translational study HEROES, extensive molecular analysis was performed on primary CRC (prCRC) and their matched resected BM by means of NGS comprehensive genomic profiling and HER2 status as assessed by immunohistochemical/ in situ hybridization. Count of tumour-infiltrating lymphocytes (TILs) was also performed., Primary Objective: to describe the molecular landscape of paired BM/prCRC., Secondary Objectives: to search for new prognostic biomarkers of outcome after BM resection: intracranial-only Progression-Free Survival (BM-iPFS), Progression-Free Survival (BM-PFS), and Overall Survival (BM-OS)., Results: Out of 22 patients having paired samples of prCRC and BM, HER2+ was found on 4 (18%) BM, 3 (75%) of which also HER2+ in matched prCRC. Lower tumour mutation burden (HR 3.08; 95%CI 1.06-8.93; p = 0.0386) and HER2-negative BM (HER2neg) (HR 7.75;95%CI 1.97-30.40; p = 0.0033) were associated with longer BM-iPFS; HER2neg BM (HR 3.44; 95%CI 1.03-11.53; p = 0.0449) and KRAS mut BM (HR 0.31; 95%CI 0.12-0.80; p = 0.0153) conferred longer BM-PFS. Longer BM-OS was found in pts with TILs-enriched (≥1.6/HPF) BM (HR 0.11; 95%CI0.01-0.91; p = 0.0403)., Conclusions: This study shows HER2+ enrichment in both BM and their prCRC. TILs-enriched BM conferred better BM-OS., (© 2024. The Author(s).)

(1) Background: In the development of new and more effective anticancer approaches, combined treatments appear of great interest. Combination therapy could be of importance in the management of glioblastoma (GBM), a lethal malignancy that accounts for 42% of cancer of the central nervous system, with a median survival of 15 months. This study aimed to verify the activity on a glioblastoma cancer cell line of one of the most active compounds of a novel series of tubulin polymerization inhibitors based on the 1-(3',4',5'-trimethoxyphenyl)-2-aryl-1 H -imidazole scaffold, used in combination with a miRNA inhibitor molecule targeting the oncomiRNA miR-10b-5p. This microRNA was selected in consideration of the role of miR-10b-5p on the onset and progression of glioblastoma. (2) Methods: Apoptosis was analyzed by Annexin-V and Caspase 3/7 assays, efficacy of the anti-miR-10b-5p was assessed by determining the miR-10b-5p content by RT-qPCR. (3) Results: The results obtained show that a "combination therapy" performed by combining the use of an anti-miR-10b-5p and a 1-(3',4',5'-trimethoxyphenyl)-2-aryl-1 H -imidazole derivative is an encouraging strategy to boost the efficacy of anticancer therapies and at the same time to reduce side effects.

In the development of novel and more effective anticancer approaches, combined treatments appear to be of great interest, based on the possibility of obtaining relevant biological or therapeutic effects using lower concentrations of single drugs. Combination therapy may prove to be of utmost significance in the management of glioblastoma (GBM), a lethal malignancy that accounts for 42% of cancer cases of the central nervous system, with a median survival rate of 15 months. As regards novel therapeutic approaches, the authors have recently demonstrated that peptide nucleic acids (PNAs) that target microRNA (miRNA/miR)‑221 are very active in inducing the apoptosis of glioma cells. Furthermore, in a recent study, the authors described two novel series of tubulin polymerization inhibitors based on the 4,5,6,7‑tetrahydrothieno[2,3‑c]pyridine and 4,5,6,7‑tetrahydrobenzo[b]thiophene scaffold, which exerted a potent anti‑proliferative effect on a variety of tumor cell lines. The present study aimed to verify the activity on glioblastoma cancer cell lines of one of the most active compounds tested, corresponding to 2‑(3', 4', 5'‑trimethoxyanilino)‑3‑cyano/alkoxycarbonyl‑6‑substituted‑4 5,6,7‑tetrahydrothiene[2,3‑c] pyridine (compound 3b), used in combination with an anti‑miR‑221‑3p PNA, already demonstrated to be able to induce high levels of apoptosis. To the best of our knowledge, the results obtained herein demonstrate for the first time a 'combination therapy' performed by the combined use of a PNA targeting miR‑221 and the tetrahydrothiene[2,3‑c]pyridine derivative 3b, supporting the concept that the combined treatment of GBM cells with a PNA against a specific upregulated oncomiRNA (in the present study a PNA targeting miR‑221‑3p was used) and anti‑tubulin agents (in the present study derivative 3b was used) is an encouraging strategy which may be used to enhance the efficacy of anticancer therapies and at the same time, to reduce side‑effects.

The biological activity of a combined treatment of U251, U373 and T98G glioma cell lines with two anti-miR PNAs, directed against miR‑221 and miR‑222 and conjugated with an ocataarginine tail (R8-PNA-a221 and R8-PNA-a222) for efficient cellular delivery, was determined. Apoptosis was analyzed, and the effect of the combined treatment of glioma cells with either or both PNAs on the reversion of drug-resistance phenotype was assessed in the temozolomide-resistant T98G glioma cell line. Selectivity of PNA/miRNA interactions was studied by surface plasmon resonance (SPR)-based Biacore analysis. Specificity of the PNA effects at the cellular level was analyzed by RT-qPCR. These experiments support the concept that the effects of R8-PNA-a221 and R8-PNA-a222 are specific. The studies on apoptosis confirmed that the R8-PNA-a221 induces apoptosis and demonstrated the pro-apoptotic effects of R8-PNA-a222. Remarkably, increased pro-apoptotic effects were obtained with the co-administration of both anti-miR‑221 and anti-miR‑222 PNAs. In addition, co-administration of R8-PNA-a221 and R8-PNA-a222 induced apoptosis of TMZ-treated T98G cells at a level higher than that obtained following singular administration of R8-PNA-a221 or R8-PNA-a222.