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Supplementary Figure 4 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Supplementary Figure 1 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Supplementary Figure and Table Legends from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Curcumin (diferuloylmethane) is a dietary phytochemical with low toxicity that exhibits growth-suppressive activity against a variety of cancer cells and possesses certain chemopreventive properties. Curcumin has already been the subject of several clinical trials for use as a treatment in human cancers. Synthetic chemical modifications of curcumin have been studied intensively in an attempt to find a molecule with similar but enhanced properties of curcumin. In this study, a series of novel curcumin analogues were synthesized and screened for anticancer activity. New analogues that exhibit growth-suppressive activity 30 times that of curcumin and other commonly used anticancer drugs were identified. Structurally, the new analogues are symmetrical 1,5-diarylpentadienone whose aromatic rings possess an alkoxy substitution at each of the positions 3 and 5. Analysis of the effects of the analogues on the expression of cancer-related genes usually affected by curcumin indicated that some induced the down-regulation of β-catenin, Ki-ras, cyclin D1, c-Myc, and ErbB-2 at as low as one eighth the concentration at which curcumin normally has an effect. The analogues, however, exhibited neither harmful nor growth-suppressive effects on normal hepatocytes where oncogene products are not activated. They also exhibited no toxicities in vivo that they may provide effective alternative therapies for the prevention and treatment of some human cancers. [Mol Cancer Ther 2006;5(10):2563–71]

Supplementary Figure 2 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Supplementary Table 1 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Supplementary Figure 3 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Supplementary Figure 5 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Introduction: We performed an exploratory analysis of circulating tumor DNA (ctDNA) in patients (pts) with RAS wild-type (WT) chemotherapy-naïve stage IV metastatic colorectal cancer (mCRC) from the ongoing phase III PARADIGM study (NCT02394834). The clonal and subclonal mutational landscapes of RAS WT pts were analyzed using a mCRC-focused custom ctDNA sequencing panel. Methods: Randomized pts (1:1) received mFOLFOX6 plus either panitumumab or bevacizumab. Pre-treatment plasma samples (DNA yield >10ng/mL and >10nM) were sequenced using the custom ctDNA panel (PlasmaSELECTTM-R 91, PGDx) to detect mCRC mutations, amplifications, and rearrangements in 90, 26, and 3 genes, respectively, as well as microsatellite instability (MSI), in 250kb targeted regions using stringent quality criteria. Pre-treatment archival tissue samples from 590 pts were analyzed by the Broad Institute Solid Tumor panel, which covered 1,072 genes with 7.3Mb targeted regions. Results: Between May 29, 2015 and June 8, 2017, 823 pts were enrolled across 197 sites. Plasma samples were collected from 756 pts, with 747 (98.8%) samples meeting the quality criteria. The average total and distinct sequencing coverages were 34,200 and 5,865, respectively, with 49.1% of bases mapping to regions of interest. Mutation frequencies in ctDNA were generally consistent with those observed in RAS-WT TCGA CRC and rectal cancers (n=283), except for TET2 and DNMT3A potentially due to clonal hematopoiesis. Mutations in BRAF, APC, CTNNB1, PTEN, PIK3CA, and MSI-status observed in ctDNA were significantly different between left and right-sided tumors, consistent with known differences in tumor sidedness. In the 747 plasma samples, 4,072 mutations were observed; 1,871 had a mutant allele frequency (MAF) Conclusion: The validated ultra-deep plasma sequencing panel was concordant with tissue sequencing and detected tumor heterogeneity. The PARADIGM study will report the efficacy of anti-EGFR/VEGF therapies; post-treatment collection of ctDNA is ongoing. The relationship between therapeutic effects and clonal and subclonal mutational landscapes will be examined in the future. Funded by Takeda Pharmaceutical Company Limited, Tokyo, Japan. ClinicalTrial.gov number: NCT02394834 Citation Format: Katsuya Tsuchihara, Riu Yamashita, Takayuki Yoshino, Kohei Shitara, Jun Watanabe, Hirofumi Yasui, Hisatsugu Ohori, Manabu Shiozawa, Kentaro Yamazaki, Eiji Oki, Takeo Sato, Takeshi Naitoh, Yoshito Komatsu, Takeshi Kato, Kazunori Yamanaka, Ikuo Mori, Masamitsu Hihara, Junpei Soeda, Takeharu Yamanaka, Kiwamu Akagi, Atsushi Ochiai, Kei Muro, Victor E. Velculescu, Hiroyuki Uetake. Clonal and subclonal mutational landscapes in circulating tumor DNA in metastatic colorectal cancer: An exploratory analysis from the phase III PARADIGM study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1974.

Curcumin (diferuloylmethane) is a dietary phytochemical with low toxicity that exhibits growth-suppressive activity against a variety of cancer cells and possesses certain chemopreventive properties. Curcumin has already been the subject of several clinical trials for use as a treatment in human cancers. Synthetic chemical modifications of curcumin have been studied intensively in an attempt to find a molecule with similar but enhanced properties of curcumin. In this study, a series of novel curcumin analogues were synthesized and screened for anticancer activity. New analogues that exhibit growth-suppressive activity 30 times that of curcumin and other commonly used anticancer drugs were identified. Structurally, the new analogues are symmetrical 1,5-diarylpentadienone whose aromatic rings possess an alkoxy substitution at each of the positions 3 and 5. Analysis of the effects of the analogues on the expression of cancer-related genes usually affected by curcumin indicated that some induced the down-regulation of β-catenin, Ki-ras, cyclin D1, c-Myc, and ErbB-2 at as low as one eighth the concentration at which curcumin normally has an effect. The analogues, however, exhibited neither harmful nor growth-suppressive effects on normal hepatocytes where oncogene products are not activated. They also exhibited no toxicities in vivo that they may provide effective alternative therapies for the prevention and treatment of some human cancers. [Mol Cancer Ther 2006;5(10):2563–71]