Mutational inactivation of the tumor suppressor gene ARID1A is a key driver of tumorigenesis in various types of cancer, making it a promising therapeutic target for anticancer drug development. Here, we performed a synthetic lethal drug screening in an approved drug library with ARID1A isogenic CRC cell lines and identified estramustine phosphate sodium (EMP), an FDA approved antimicrotubule chemotherapy drug, as a synthetic lethal partner of ARID1A. ARID1A loss increases the vulnerability to EMP. Mechanistically, ARID1A loss increases the phosphorylation level of MAP4 (microtubule-associated protein 4), which is a key microtubule dynamics regulator in cancer cells. Therefore, ARID1A loss attenuates microtubule stabilizing activity of MAP4 and creates a dependence on its residual activity. By targeting MAP4, EMP severely disrupts microtubule dynamics, affecting bipolar spindle formation and positioning, and inducing mitotic cell death in ARID1A-deficient cells. Furthermore, we identified that MAP4 is phosphorylated by PI3K, which is activated by ARID1A loss. These findings highlight MAP4 as a key regulator of microtubule dynamics in ARID1A-deficient cells and unveil a novel synthetic lethality relationship between ARID1A and EMP.

Prostate cancer antigen-1/ALKBH3, a DNA/RNA demethylase of 3-methylcytosine, 1-methyladenine (1-meA), and 6-meA, was found in prostate cancer as an important prognostic factor. Additionally, 1-meA has been associated with other cancers. The ALKBH3 inhibitor HUHS015 was found to be effective against prostate cancer both in vitro and in vivo . Herein, we investigated the effect of HUHS015 in combination with drugs for prostate cancer approved in Japan (including bicalutamide, cisplatin, mitoxantrone, prednisolone, ifosfamide, tegafur/uracil, docetaxel, dacarbazine, and estramustine) by treating DU145 cells with around IC 50 value concentrations of these drugs for 3 days. Additionally, the cells were observed for additional 9 days after drug removal. Combination treatment with dacarbazine, estramustine, tegafur/uracil, and HUHS015 showed a slight additive effect after 3 days. After drug washout of them and mitoxantrone, the combined effects and levels were enhanced and sustained, although the effects of each treatment alone declined. HUHS015 combined with cisplatin or docetaxel elicited synergistic and sustained effects. In vivo , combining HUHS015 and docetaxel, the first chemotherapeutic agent for castration-resistant prostate cancer, showed notable effects in the DU145 xenograft model. In conclusion, HUHS015 exhibited a synergistic effect with docetaxel and drugs acting on DNA in vitro , even after drug removal. Since cancer chemotherapy is typically administered during rest periods due to its high toxicity, combining it with an ALKBH3 inhibitor could be a promising strategy for enhancing cancer treatment, as it can elicit an additive effect during treatment, allowing dosage reduction, and synergistically sustain the effect after drug washout during rest periods.

Treatment of castration-resistant prostate cancer is and has been a challenge. In 1957, the chemist Imre Könyves came to Sweden as a refugee from Hungary and started to work at AB Leo, a pharmaceutical company in Helsingborg. In 1961, he started to synthesize compounds where the oestrogens were linked to a mustard group by a carbamate. This resulted in estramustine phosphate, which was initially tested against mammary cancer with disappointing results. He then started a cooperation with urology professor Gösta Jönsson, Head of the Department of Urology at the Lund University Hospital, to test estramustine phosphate against prostate cancer. Jönsson started clinical estramustine phosphate tests in 1966. His studies were one-armed and consecutive, with a "favourable response" in 83% of previously untreated patients. These favourable results could not be reproduced in later randomized controlled studies suggesting that estramustine phosphate as primary treatment was not better than conventional estrogenic treatment. Conclusions: Even if the results of Gösta Jönsson's studies could not be confirmed, the subsequent randomized studies of estramustine phosphate may hide the desired action of estramustine phosphate in a subgroup of patients. It has still not been elucidated whether estramustine phosphate has effects in this subgroup of patients with ostrogen-resistant prostate cancer.

Estramustine (EM), a clinically successful hormone-refractory anti-prostate cancer drug, exhibited potent anti-proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH-SY5Y and IMR-32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre-treatment of neuroblastoma cells with ROS scavengers (N-acetyl cysteine and dithiothreitol) reduced the anti-proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin-1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule-depolymerizing agents may be considered for developing pro-ferroptosis chemotherapeutics.

The S100 family proteins (S100s) participate in multiple stages of tumorigenesis and are considered to have potential value as biomarkers for detecting and predicting various cancers. But the role of S100s in lung adenocarcinoma (LUAD) prognosis is elusive. Transcriptional data of LUAD patients were retrieved from TCGA, and relevant literature was extensively reviewed to collect S100 genes. Differential gene expression analysis was performed on the LUAD data, followed by intersection analysis between the differentially expressed genes (DEGs) and S100 genes. Unsupervised consensus clustering analysis identified two clusters. Significant variations in overall survival between the two clusters were shown by Kaplan-Meier analysis. DEGs between the two clusters were analyzed using Lasso regression and univariate/multivariate Cox regression analysis, leading to construction of an 11-gene prognostic signature. The signature exhibited stable and accurate predictive capability in TCGA and GEO datasets. Subsequently, we observed distinct immune cell infiltration, immunotherapy response, and tumor mutation characteristics in high and low-risk groups. Finally, small molecular compounds targeting prognostic genes were screened using CellMiner database, and molecular docking confirmed the binding of AMG-176, Estramustine, and TAK-632 with prognostic genes. In conclusion, we generated a prognostic signature with robust and reliable predictive ability, which may provide guidance for prognosis and treatment of LUAD.

Radiotherapy (RT) for high-risk localized prostate cancer (HRLPC) can be controversial in the context of increasing detection of suspicious lymph nodes via advanced imaging techniques. The EORTC 22683 trial initially established RT with androgen deprivation therapy (ADT) as the standard of care for HRLPC, but many patients remain uncured. GETUG-AFU-12 showed that addition of docetaxel and estramustine to ADT improved relapse-free survival but not overall survival. STAMPEDE later demonstrated that abiraterone acetate with ADT and RT significantly improved failure-free survival and overall survival. Ongoing trials such as ENZARAD, ATLAS, DASL-HiCap, and GETUG-P17 ALADDIN are investigating the efficacy of new androgen receptor pathway inhibitors combined with RT and ADT. These studies aim to refine treatment strategies for HRLPC, particularly in the context of advanced imaging and patient upstaging. PATIENT SUMMARY: Addition of newer medications to standard radiation therapy has shown promise in improving survival for men with high-risk prostate cancer. Ongoing studies are testing these options to find the best combination. The aim is to increase the chances of curing prostate cancer, especially as advanced scan techniques are detecting more cases.