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Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours.

Ovarian cancer (OC) is one of the leading causes of female cancer death. Recent studies have documented its extensive variations as a disease entity, in terms of cell or tissue of origin, pre-cancerous lesions, common mutations, and therapeutic responses, leading to the notion that OC is a generic term referring to a whole range of different cancer subtypes. Despite such heterogeneity, OC treatment is stereotypic; aggressive surgery followed by conventional chemotherapy could result in chemo-resistant diseases. Whereas molecular-targeted therapies will become shortly available for a subset of OC, there still remain many patients without effective drugs, requiring development of groundbreaking therapeutic agents. In preclinical studies for drug discovery, cancer cell lines used to be the gold standard, but now this has declined due to frequent failure in predicting therapeutic responses in patients. In this regard, patient-derived cells and tumors are gaining more attention in precise and physiological modeling of in situ tumors, which could also pave the way to implementation of precision medicine. In this article, we comprehensively overviewed the current status of various platforms for patient-derived OC models. We highly appreciate the potentials of organoid culture in achieving high success rate and retaining tumor heterogeneity.

Transcatheter arterial chemoembolization (TACE) is used in the treatment of hepatocellular carcinoma; however, it has limited effect on portal vein tumor thrombus (PVTT). The purpose of this study was to assess the feasibility and efficacy of radiotherapy targeting the PVTT after TACE for the tumor in the hepatic parenchyma. TACE was performed using epirubicin hydrochloride, iodized poppy seed oil, and gelatin sponge particles. Radiotherapy was performed targeting the PVTT to a total dose of 50 Gy in 25 fractions during 5 weeks. Twenty consecutive patients were treated with this combined treatment. Sixteen of 20 patients could complete the planned radiotherapy. Partial response was observed in 10, no change in 4, and progression in 6. The response rate was 50% (95% CI 28-72%). The 1-year overall survival rate was 25% (95% CI 6-44%), and the median survival time was 5.3 months. It was difficult to determine the late toxicities because of disease progression and additional TACE, and only one patient died without disease progression. Radiotherapy after TACE is feasible for patients with hepatocellular carcinoma and PVTT. The survival figure, however, is still dismal, and further investigation is needed to establish the best combination of treatment modalities.

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