1.Activation of Nrf2 pathways correlates with resistance of NSCLC cell lines to CBP501 in vitro.
Mine N1, Yamamoto S1, Kufe DW2, Von Hoff DD3, Kawabe T4. Mol Cancer Ther. 2014 Sep;13(9):2215-25. doi: 10.1158/1535-7163.MCT-13-0808. Epub 2014 Jul 22.
CBP501 is an anticancer drug candidate that was investigated in two randomized phase II clinical trials for patients with nonsquamous non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). CBP501 has been shown to have two mechanisms of action, namely calmodulin modulation and G2 checkpoint abrogation. Here, we searched for a biomarker to predict sensitivity to CBP501. Twenty-eight NSCLC cell lines were classified into two subgroups, CBP501-sensitive and -insensitive, by quantitatively analyzing the cis-diamminedichloro-platinum (II) (CDDP)-enhancing activity of CBP501 through treatments with short-term (1 hour) coexposure to CDDP and CBP501 or to either alone. Microarray analysis was performed on these cell lines to identify gene expression patterns that correlated with CBP501 sensitivity. We found that multiple nuclear factor erythroid-2-related factor 2 (Nrf2) target genes showed high expression in CBP501-insensitive cell lines.
2.Phase I studies of CBP501, a G2 checkpoint abrogator, as monotherapy and in combination with cisplatin in patients with advanced solid tumors.
Shapiro GI1, Tibes R, Gordon MS, Wong BY, Eder JP, Borad MJ, Mendelson DS, Vogelzang NJ, Bastos BR, Weiss GJ, Fernandez C, Sutherland W, Sato H, Pierceall WE, Weaver D, Slough S, Wasserman E, Kufe DW, Von Hoff D, Kawabe T, Sharma S. Clin Cancer Res. 2011 May 15;17(10):3431-42. doi: 10.1158/1078-0432.CCR-10-2345. Epub 2011 Jan 10.
PURPOSE: Two phase I dose-escalation studies were conducted to determine the maximum tolerated dose (MTD) and safety profile of the G(2) checkpoint abrogator CBP501, as a single agent and in combination with cisplatin.
3.Cell cycle phenotype-based optimization of G2-abrogating peptides yields CBP501 with a unique mechanism of action at the G2 checkpoint.
Sha SK1, Sato T, Kobayashi H, Ishigaki M, Yamamoto S, Sato H, Takada A, Nakajyo S, Mochizuki Y, Friedman JM, Cheng FC, Okura T, Kimura R, Kufe DW, Vonhoff DD, Kawabe T. Mol Cancer Ther. 2007 Jan;6(1):147-53.
Cell cycle G(2) checkpoint abrogation is an attractive strategy for sensitizing cancer cells to DNA-damaging anticancer agent without increasing adverse effects on normal cells. However, there is no single proven molecular target for this therapeutic approach. High-throughput screening for molecules inhibiting CHK1, a kinase that is essential for the G(2) checkpoint, has not yet yielded therapeutic G(2) checkpoint inhibitors, and the tumor suppressor phenotypes of ATM and CHK2 suggest they may not be ideal targets. Here, we optimized two G(2) checkpoint-abrogating peptides, TAT-S216 and TAT-S216A, based on their ability to reduce G(2) phase accumulation of DNA-damaged cells without affecting M phase accumulation of cells treated with a microtubule-disrupting compound. This approach yielded a peptide CBP501, which has a unique, focused activity against molecules that phosphorylate Ser(216) of CDC25C, including MAPKAP-K2, C-Tak1, and CHK1.
4.Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma.
Krug LM1, Wozniak AJ2, Kindler HL3, Feld R4, Koczywas M5, Morero JL6, Rodriguez CP7, Ross HJ8, Bauman JE9, Orlov SV10, Ruckdeschel JC11, Mita AC12, Fein L13, He X14, Hall R14, Kawabe T15, Sharma S16. Lung Cancer. 2014 Sep;85(3):429-34. doi: 10.1016/j.lungcan.2014.06.008. Epub 2014 Jul 5.
BACKGROUND: CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin.