Inhibition of Translesion DNA Synthesis as a Novel Therapeutic Strategy to Treat Brain Cancer

Abstract

Temozolomide is a DNA-alkylating agent used to treat brain tumors, but resistance to this drug is common. In this study, we provide evidence that efficacious responses to this drug can be heightened significantly by coadministration of an artificial nucleoside (5-nitroindolyl-2 0 -deoxyriboside, 5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. Conversion of this compound to the corresponding nucleoside triphosphate, 5-nitroindolyl-2 0 -deoxyriboside triphosphate, in vivo creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA. Accordingly, 5-NIdR synergized with temozolomide to increase apoptosis of tumor cells. In a murine xenograft model of glioblastoma, whereas temozolomide only delayed tumor growth, its coadministration with 5-NIdR caused complete tumor regression. Exploratory toxicology investigations showed that high doses of 5-NIdR did not produce the side effects commonly seen with conventional nucleoside analogs. Collectively, our results offer a preclinical pharmacologic proof of concept for the coordinate inhibition of translesion DNA synthesis as a strategy to improve chemotherapeutic responses in aggressive brain tumors.Significance: Combinatorial treatment of glioblastoma with temozolomide and a novel artificial nucleoside that inhibits replication of damaged DNA can safely enhance therapeutic responses. Cancer Res; 78(4); 1-14. Ó2018 AACR.

Combination therapy to checkmate Glioblastoma: clinical challenges and advances

“…It has the ability to cross the blood–brain barrier (BBB) making it particularly effective in the treatment of brain tumors [ 98 – 100 ]. However, in addition to severe side effects of TMZ such as myelotoxicity, ulcers, nausea, vomiting, fatigue and toxic DNA damage, the resistance to this drug is common in GBM patients [ 101 , 102 ]. A potential approach in the first-line treatment of GBM may be to explore a more effective combination regimen.…”

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…In mice, activation of Yap/Taz in the intestine with Lgr5‐Cre mediated double knockout of Lats1/2 produced gastric cancers (GC) due to strong Myc expression. [ 107 ] In human GC cells (HFE‐145), overexpression of YAP 5SA or TAZ 4SA increased growth in soft agar and increased invasion in transwell migration assays. [ 107 ] In other GC cell lines, knockdown of YAP reduced tumor growth after xenografting into mice and promoted resistance to chemotherapy, [ 108 ] as well as reducing EMT induced by Helicobacter pylori infection of GC cells.…”

“…[ 107 ] In human GC cells (HFE‐145), overexpression of YAP 5SA or TAZ 4SA increased growth in soft agar and increased invasion in transwell migration assays. [ 107 ] In other GC cell lines, knockdown of YAP reduced tumor growth after xenografting into mice and promoted resistance to chemotherapy, [ 108 ] as well as reducing EMT induced by Helicobacter pylori infection of GC cells. [ 109 ] This preliminary evidence supports a key role for YAP/TAZ in gastric cancer growth and invasion.…”

Identification of cephalomannine as a drug candidate for glioblastoma via high-throughput drug screening

“…Glioblastoma (GBM) is the most common and invasive malignant primary brain tumor in adults 1,2) . Its prognosis remains poor, even with the current standard of care, i.e., a combination of surgery, radiotherapy, and chemotherapy 3,4) . The disease course of GBM is typically rapid, and it has a 5-year survival rate of only 10% and a median survival time of 15 months following intensive treatment [5][6][7][8] .…”