Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases.

Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery in resectable patients shows limited benefit, and novel treatments are urgently needed. The majority of CRC-PMs represent the CMS4 molecular subtype of CRC, and here we queried the vulnerabilities of this subtype in pharmacogenomic databases to identify novel therapies. This reveals the copper ionophore elesclomol (ES) as highly effective against CRC-PMs. ES exhibits rapid cytotoxicity against CMS4 cells by targeting mitochondria. We find that a markedly reduced mitochondrial content in CMS4 cells explains their vulnerability to ES. ES demonstrates efficacy in preclinical models of PMs, including CRC-PMs and ovarian cancer organoids, mouse models, and a HIPEC rat model of PMs. The above proposes ES as a promising candidate for the local treatment of CRC-PMs, with broader implications for other PM-prone cancers.

Peritoneal Metastases from Extraperitoneal Primary Tumors: Incidence, Treatment, and Survival from a Nationwide Database.

The objective of this study was to assess the incidence, treatment, and survival of patients with synchronous peritoneal metastases (PM) from extraperitoneal primary tumors. A cohort was selected from the Netherlands Cancer Registry (NCR), in which all patients diagnosed with PM in 2017 and 2018 were screened for eligibility. The five most common primary extraperitoneal origins of PM were included for further analyses: lung, breast, urinary tract, and kidney cancer and malignant melanoma. Survival was investigated using log-rank test between different primary tumor locations. In total, 480 patients were diagnosed with synchronous PM from extraperitoneal origins. The proportion of patients with PM per extraperitoneal origin ranged between 0.1 and 1.1%, with the highest proportion in lung cancer patients. Of all patients, 234 (49%) received tumor-directed treatment and 246 (51%) received no tumor-directed treatment. Survival in patients with PM from lung, breast, urinary tract, and kidney cancer and malignant melanoma was 1.6 months, 15.7 months, 5.4 months, 3.4 months, and 2.1 months, respectively (p < 0.001). In this study, a small, although significant number of patients with extraperitoneal cancer developed PM. The reported survival in patients with PM ranged between 1.6 and 15.7 months. Only half of the patients with PM received tumor-directed treatment and survival in patients without tumor-directed treatment was only 1.2 months. These findings are stressing the need to explore new diagnostic tools that may enable earlier diagnosis of PM and may potentially lead to a more effective treatment.