Preclinical Validation of a Single-Treatment Infusion Modality That Can Eradicate Extremity Melanomas

Abstract Isolated limb perfusion (ILP) with the chemotherapeutic agent melphalan is an effective treatment option for extremity in-transit melanoma but is toxic and technically challenging to deliver locoregionally. CBL0137 is an experimental clinical drug with broad anticancer activity in animal models, owing to its ability to bind DNA in a nongenotoxic manner and inactivate the FACT chromatin modulator essential for tumor cell viability. Here, we report that CBL0137 delivered by ILP in a murine melanoma model is as efficacious as melphalan, displaying antitumor activity at doses corresponding to only a fraction of the systemic MTD of CBL0137. The ability to bind DNA quickly combined with a favorable safety profile made it possible to substitute CBL0137 in the ILP protocol, using an intra-arterial infusion method, to safely achieve effective tumor suppression. Our findings of a preclinical proof of concept for CBL0137 and its administration via intra-arterial infusion as a superior treatment compared with melphalan ILP allows for locoregional treatment anywhere a catheter can be placed. Cancer Res; 76(22); 6620–30. ©2016 AACR.</jats:p

Prevention of colorectal carcinogenesis by DNA-binding small-molecule curaxin CBL0137 involves suppression of Wnt signaling

Chemoprevention is considered a valid approach to reduce the incidence of colorectal cancer, one of the most common malignancies worldwide. Here, we investigated the tumor-preventive activity of curaxin CBL0137. This compound represents a new class of nonmutagenic DNA-binding small molecules that alter chromatin stability and inhibit the function of the histone chaperone FACT. Among downstream effects of CBL0137 treatment are activation of p53 and type I interferons and inhibition of NFkB, HSF1, and MYC. In addition, our data show that in both human and mouse colorectal cancer cells in vitro, CBL0137 inhibits the APC/WNT/b-catenin signaling pathway, which plays a key role in colon carcinogenesis. Using quantitative RT-PCR and microarray hybridization, we have demonstrated decreased expression of multiple components and downstream targets of the WNT pathway in colon cancer cells treated with CBL0137. At the same time, CBL0137 induced expression of WNT antagonists. Inhibition of WNT signaling activity by CBL0137 was also confirmed by luciferase reporter assay. Tumor-preventive activity of CBL0137 in vivo was tested in a murine model of colorectal carcinogenesis induced by 1,2-dimethylhydrazine (DMH), which is known to involve WNT pathway dysregulation. After DMH subcutaneous treatment, mice were administered CBL0137 in drinking water. Efficacy of CBL0137 in suppressing development of colorectal cancer in this model was evidenced by reduced incidence of adenocarcinomas and adenomas in both males and females and decrease in tumor multiplicity. These data support the prospective use of CBL0137 in chemoprevention of colorectal cancer as well as of other malignances associated with activated WNT signaling. © 2019 American Association for Cancer Research

Clinical and genetic characteristics of acute myeloid leukemia with t(8;21) in children and results of therapy according to protocol AML-MM-2000

A t(8;21) is the most frequent abnormality in AML in children. Patients with this genetic abnormality are traditionally expected favorable prognosis with a probability of cure up to 80 %. Known additional cytogenetic abnormalities in AML with t(8;21) not affecting prognosis. These include loss of one sex chromosome and del(9q-). Prognosis impact of additional abnormalities involving chromosomes 7 and 11 in patients with t(8;21) is unknown. The purpose of this study was to analyse of additional anomalies, that occur in patients with t(8;21), and their influence on prognosis. During the study period 173 children with AML have received AML-MM-2000 treatment protocol in Russia and Belarus. Of these, in 33 patients (11 girls and 22 boys, median age — 10.5 years) t(8;21) was detected by chromosome banding or molecular-genetic analysis. In group with t(8;21) CNS leukemia in 8 patients was detected, extramedullary lesion — in 8 patients. In 4 patients CNS leukemia combined with presence of extramedullary lesions. These factors did not influence on therapy outcome. Overall survival of AML patients with t(8;21) was 0,67 ± 0,08 compared to 0,44 ± 0,04 in patients with AML without this translocation (p = 0,04). Special subgroup consist of 5 patients with t(8;21) and identified chromosomal abnormalities affecting chromosome 7 and 11, which were a poor prognostic factor: event-free survival in this subgroup of patients (n = 5) was 0,0 ± 0,0, compared to 0,34 ± 0,16 in patients with t(8;21) without additional anomalies (n = 28) (p = 0,027).</p