Reference Detail

Ref Type

Journal Article

PMID

(26637369)

Authors

Herath NI, Devun F, Lienafa MC, Herbette A, Denys A, Sun JS, Dutreix M

Title

The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	1	2016 Jan	15-22	Mol Cancer Ther

URL

Abstract Text

Metastatic liver disease from colorectal cancer is a significant clinical problem. This is mainly attributed to nonresectable metastases that frequently display low sensitivities to available chemotherapies and develop drug resistance partly via hyperactivation of some DNA repair functions. Combined therapies have shown some disease control; however, there is still a need for more efficient chemotherapies to achieve eradication of colorectal cancer liver metastasis. We investigated the tolerance and efficacy of a novel class of DNA repair inhibitors, Dbait, in association with conventional chemotherapy. Dbait mimics double-strand breaks and activates damage signaling, consequently inhibiting single- and double-stranded DNA repair enzyme recruitment. In vitro, Dbait treatment increases sensitivity of HT29 and HCT116 colorectal cancer cell lines. In vivo, the pharmacokinetics, biodistribution and the efficacy of the cholesterol-conjugated clinical form of Dbait, DT01, were assessed. The chemosensitizing abilities of DT01 were evaluated in association with oxaliplatin and 5-fluorouracil in intrahepatic HT29 xenografted mice used as a model for colorectal cancer liver metastasis. The high uptake of DT01 indicates that the liver is a specific target. We demonstrate significant antitumor efficacy in a liver metastasis model with DT01 treatment in combination with oxaliplatin and 5-fluorouracil (mean: 501 vs. 872 mm(2), P = 0.02) compared to chemotherapy alone. The decrease in tumor volume is further associated with significant histologic changes in necrosis, proliferation, angiogenesis and apoptosis. Repeated cycles of DT01 do not increase chemotherapy toxicity. Combining DT01 with conventional chemotherapy may prove to be a safe and effective therapeutic strategy in the treatment of metastatic liver cancer.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Dbait	Dbait	0	0
DT01	DT01	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
DT01				DT01 consists of nanoparticles containing short interfering DNA that mimics DNA double strand breaks that are linked to cholesterol, resulting in activation of the DNA damage response in the liver, and potentially leading to increased sensitivity to chemotherapeutic agents (PMID: 26637369, PMID: 28374075, PMID: 27140316).
Dbait				Dbait is a nanoparticle drug containing short interfering DNA that mimic DNA double strand breaks, which has been demonstrated to result in activation of the DNA damage response with anti-metastatic tumor activity in liver (PMID: 26637369, PMID: 31858836, PMID: 31275862).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	colorectal cancer	sensitive	DT01 + Fluorouracil + Oxaliplatin	Preclinical - Cell line xenograft	Actionable	In a preclinical study, DT01 increased sensitivity of human colorectal cancer (CRC) cells harboring BRAF V600E to Eloxatin (oxaliplatin) and Adrucil (5-fluorouracil), and the combination resulted in decreased liver tumor growth in CRC cell line xenograft metastasis models (PMID: 26637369).	26637369