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Barrigenol-like triterpenoids (BATs), which contain an unusual oleanane substituted by many hydroxyl groups as the skeleton, are subdivided into five subtypes: barrigenol A1, barrigenol A2, barrigenol R1, barringtogenol C, and 16-deoxybarringtogenol C. The variations in acyl derivatives, hydroxyl groups, and carbohydrate chains in their structures have enhanced the diversity of BATs. Moreover, the stable polyhydroxy-replaced pentacyclic skeleton provides an ideal platform for structural modifications. To date, more than 500 BAT derivatives have been isolated from plants. Synchronously, BATs possess anti-tumour, anti-Alzheimer's disease, anti-inflammatory, anti-microbial, anti-obesity and anti-allergic activities by regulating numerous cellular molecules. Some BAT derivatives, such as escin obtained from Aesculus hippocastanum L. and xanthoceraside isolated from Xanthoceras sorbifolia Bunge, have been used to treat encephaloedema or inflammatory diseases. This review aims to provide comprehensive information about the chemistry, sources, bioavailability, and anti-tumour effects of BATs, with a particular emphasis on the molecular mechanisms of action. The pharmacokinetics and clinical progress are also concerned. More than 300 structures identified over past 25 years are summarized here (249 compounds) and in the supplementary information (114 compounds). Accordingly, the pharmaceutical activity of barrigenol triterpenoids suggests that some compounds should be developed as promising anti-tumour or anti- Alzheimer's disease agents in future.

Cancer is a disorder which has noted a significant rise in incidence worldwide and continues to be the largest cause of mortality. It has a dramatic impact on human life expectancy and quality of life in spite of the increase in technology and the treatments available for cancer patients. These new therapeutic options being chemotherapy, radiotherapy, photolytic therapy and catalytic therapy are known to have many adverse reactions and also no better positive outcomes than before. Hence, research is now focused more on utilizing the vast repertoire of traditional medicinal knowledge i.e. the use of flora for treatment of cancer rather than the use of chemicals. One such herb is the Crocus sativus L., commonly known as Saffron, rich in carotenoids - crocin, crocetin and safranal. Various studies have been carried out over the past few years to confirm the anti-cancer properties of saffron, both in vivo using animal models and in vitro using human malignant cell lines on various types of cancers with positive results. The proposed mechanism of actions has also been worked upon. This review is aimed to provide a brief overview on the anti-tumor potential of saffron focusing on the molecular mechanism involved.

Radiation damage can occur in nuclear power plant workers when physical protections fail, which results in nuclear leakage through the protective layers. Alternatively, workers may be unable to use physical protection in time (in the case of a sudden nuclear weapons attack). In addition, patients who receive local radiotherapy and are not allowed to adopt local physical protection may experience radiation damage. Thus, protection against chemical radiation has become indispensable. In view of the side effects caused by synthetic radioprotective agents (such as amisfostine), searching for radioprotective agents from plant sources is an alternative strategy. Radiation damage can cause multiple signalling pathway disturbances, leading to multiple organ injuries. Changes in these signalling pathways can lead to apoptosis, necrosis, and autophagy, as well as organ fibrosis, atrophy, and inflammation. Through literature searches, we determined that most targets for treating radiation injury are mechanistically opposite those of anti-tumour agents. This is likely attributable to the idea that anti-tumour agents promote cell necrosis or apoptosis, whereas the goal of anti-radiation agents is to promote cell survival or autophagy. This observation has important theoretical and practical significance when searching and developing new radioprotective agents derived from plant extracts. Further, it has important guiding value for meeting military needs and serving the public.

Background: Thymic carcinoma is a rare malignant disease, and standard treatment for advanced/metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Several multi-targeted inhibitors have demonstrated efficacy as second-line treatment. Lenvatinib is a novel multi-targeted inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor, RET, c-Kit, and other kinases. It has shown anti-tumour activity and manageable toxicity profiles and has been approved for thyroid cancer and hepatocellular cancer in several countries. Methods: The open-label, single-arm, multi-centre phase II trial investigated the efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma. Patients with pathologically confirmed thymic carcinoma that progressed following at least one platinum-based chemotherapy were enrolled. Lenvatinib was administered orally once daily until disease progression or unacceptable adverse events. The primary endpoint was objective response rate (ORR) by independent central review. Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety profiles. Findings: Between April 2017 and February 2018, 42 patients were enrolled from eight institutions in Japan. The median follow-up period was 15·5 months (interquartile range: 13·1–17·5 months). The ORR was 38·1% (90% confidence interval [CI]: 25·6–52·0%); 16 of 42 patients had partial response, while 24 of 42 patients had stable disease. The DCR was 95·2% (95% CI: 83·8–99·4%). The median duration of PFS was 9·3 months (95% CI: 7·7–13·9 months), and the median OS was not reached. The most frequent treatment-related adverse events were hypertension, diarrhoea, palmar-plantar erythrodysaesthesia syndrome, proteinuria, hypothyroidism, and reduced platelet count. Interpretation: The efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma was confirmed. These encouraging results suggested that lenvatinib can become a standard treatment option for patients with previously treated advanced/metastatic thymic carcinoma. Trial Registration: This trial is registered as JMA-IIA00285 and UMIN000026777. Funding Statement: Lenvatinib was provided by Eisai Co., Ltd. (Bunkyō, Tokyo, Japan) and distributed by SAROUTE Co., Ltd (Shinjuku-ku, Tokyo, Japan). The funder of the study was the Center for Clinical Trials, Japan Medical Association, which approved the study protocol and the final version but did not contribute to the clinical data collection. Declaration of Interests: JS reports honoraria from Chugai Pharmaceutical Co.. NY reports research grant from Chugai Pharmaceutical Co., Taiho Pharmaceutical, Eisai, Eli Lilly, Quintiles, Astellas, Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical, Takeda, Janssen Pharma, MSD, Merck and GSK; and honoraria from Ono Pharmaceutical, Chugai Pharmaceutical Co., AstraZeneca, Pfizer, Eli Lilly, Bristol-Myers Squibb and Sysmex; and personal fees for consulting from Eisai, Otsuka, Takeda, Boehringer Ingelheim and Cimic. YO* reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Kissei, Ignyta, Janssen and LOXO; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Boehringer Ingelheim, Pfizer, Kyowa Hakko Kirin, Celtrion, Amgen and Nippon Kayaku. YO** reports research grant from Chugai Pharmaceutical Co. and Takeda, and received personal fees from MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical Co., Takeda, Eli Lilly, AstraZeneca, Boehringer Ingelheim and Pfizer. SN reports research grant from AstraZeneca, Pfizer, Eli Lilly, MSD and Merck, and personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Novartis, Shionogi and Yakult. HM reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Takeda, Abbvie, Daiichi-Sankyo and IQvia; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, MSD and Takeda. MS reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, EPS international, Novartis, MSD, Takeda and Ignyta; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis and MSD. TK reports reserch grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Bristol-Myers Squibb and Merck; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim and Nippon Kayaku. KN reports personal fees from Chugai Pharmaceutical Co., Taiho Pharmaceutical and Bayer. RM reports research grant from Ministry of Health, Labour and Welfare, Japan. YK reports personal fees from Chugai Pharmaceutical Co.. All other authors declare no competing interests. YO*; Yuichiro Ohe, YO**; Yusuke Okuma Ethics Approval Statement: The study was approved by the institutional review board at each participating institution and was conducted in accordance with the principles of Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all the patients before enrolment in the study.

Three new Annonaceous acetogenins, squamocin-IV ( 1 ), squamocin-V ( 2 ) and squamoxinone-E ( 3 ), together with seven other known Annonaceous acetogenins ( 4 – 10 ) were isolated from the seeds of Annona squamosa . The structures of all of the isolates were established and characterized through spectral and chemical methods. The new Annonaceous acetogenins 1–3 were evaluated for their cytotoxicity against the Hep-G2, SMMC-7721, BEL-7402, BGC-803 and H460 human cancer cell lines. Compound 3 exhibited the best cytotoxic activity, with IC 50 values of 0.103, 0.687, 4.19, 0.43 and 6.56 μg/mL, respectively for the cell lines above; meanwhile, Compound 1 showed selective cytotoxic activity against H460, with an IC 50 value of 0.049 μg/mL. The first mono-ACG ( 2 ) composed of 38 carbons was discovered.

Background Gut microbiota composition might influence the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remained unclear. Molecular mechanism whereby the gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. The main metabolites of the gut microbiota are short-chain fatty acids (SCFAs), which are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluated in mice and in patients treated with anti-CTLA-4 if SCFAs levels could be related to the clinical outcome. Methods Thirty-nine patients with metastatic melanoma were treated with ipilimumab were prospectively enrolled. Fecal microbiota composition was assessed using 16S metagenomic analysis and quantitative PCR (Q-PCR) analyses for Faecalibacterium prausnitzii (F. prausnitzii) at baseline. Stool and serum concentrations of acetate, propionate and butyrate were also evaluated in two independent cohorts in accordance with clinical outcomes. Peripheral blood lymphocytes immunophenotypes were studied in parallel. The anti-CTLA-4 anti-tumor effect was also evaluated in mice models in with or without butyrate supplementation. Results Systemic butyrate was linked to Faecalibacterium prausnitzii enrichment in the stool of patients. High blood SCFAs levels (mainly propionate or butyrate) were associated with resistance to CTLA-4 blockade and were associated with a rise of Treg cells. During the course of anti-CTLA-4 treatment, butyrate limited the up-regulation of CD80/CD86 expression on dendritic cells, the induction of tumor-specific T cells and the accumulation of memory T cells in mice with cancer. In patients, restricted accumulation of memory T cells and IL-2 impregnation after ipilimumab treatment was observed. Conclusions Altogether, these results suggested that gut microbial metabolites might favor an immune tolerance profile that limits anti-CTLA-4 activity. Legal entity responsible for the study Institut Gustave Roussy. Funding This study was funded by Gustave Roussy Cancer Campus, Fondation Gustave Roussy, the Institut national de la sante et de la recherche medicale (INSERM), the Centre national de la recherche scientifique (CNRS), SIRIC SOCRATE (INCa DGOS INSERM 6043), SIRIC SOCRATE 2.0 (INCa-DGOS-INSERM_12551), MMO program: ANR-10IBHU-0001); Direction General de l'Offre de Soins (DGOS; TRANSLA 12-174); Institut National du Cancer (INCa; 2012-062 N_ Canceropole: 2012-1-RT-14-IGR-01). Dr. Clelia Coutzac was supported by fellowships from Fondation pour la Recherche Medicale (FRM) from 2015 to 2016. Disclosure C. Coutzac: Honoraria (self): AMGEN; Honoraria (self): Servier. L. Lacroix: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy: BMS; Advisory/Consultancy: Genomic Health; Advisory/Consultancy: Illumina; Advisory/Consultancy: Qiagen; Advisory/Consultancy: Novartis Thermofisher; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Dyn; Speaker Bureau/Expert testimony: Vela diagnostics; Speaker Bureau/Expert testimony: Luye Pharma. F. Carbonnel: Advisory/Consultancy: enterome; Advisory/Consultancy: Amgen; Advisory/Consultancy: Astra; Advisory/Consultancy: MSD; Advisory/Consultancy: BMS; Advisory/Consultancy: Janssen; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Abbvie; Advisory/Consultancy: Mayoly Spindler; Advisory/Consultancy: Takeda; Advisory/Consultancy: Pileje; Advisory/Consultancy: Roche. P.A. Ascierto: Advisory/Consultancy: Bristol Myers-Squibb; Advisory/Consultancy, Research grant/Funding (self): Roche-Genentech; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (self): Array; Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Incyte; Advisory/Consultancy: NewLink Genetics; Advisory/Consultancy: Genmab; Advisory/Consultancy: Medimmune; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Syndax; Advisory/Consultancy: SunPharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Idera. C. Robert: Advisory/Consultancy: Roche; Advisory/Consultancy: GSK; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen; Advisory/Consultancy: BMS. N. Chaput: Research grant/Funding (self): Cytune Pharma; Research grant/Funding (self): GSK; Speaker Bureau/Expert testimony, Research grant/Funding (self): Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca. All other authors have declared no conflicts of interest.

Chitosan and chitosan oligosaccharides (COS) have been reported to possess various biomedical properties, including antimicrobial activities, immuno-enhancing effects, and anti-tumour activities. COS have attracted considerable interest due to their physicochemical properties, and potential applications in the food and pharmaceutical industries, especially in cancer therapies. This paper describes the preparation of COS and their physicochemical properties, and modification, which aids understanding of their biological activities. Based on the latest reports, several biological and anti-tumour activities of COS will be discussed. The proposed anti-tumour mechanisms of COS are summarised, to provide comprehensive insights into research on the molecular level. Finally, the potential applications and future development of the biopolymer will be discussed.

Background ZW25, a novel IgG1 bispecific antibody, targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated and unique mechanisms of action, including improved receptor internalization and downregulation relative to trastuzumab. Safety, anti-tumor activity, and biomarker data from an ongoing phase 1 trial of ZW25 monotherapy in solid tumors other than breast cancer, are presented here. Methods Eligible patients with HER2 IHC 3+, IHC 2+/FISH+, or IHC 2+/FISH- tumors confirmed by central review of fresh or archival biopsies, who had progressed on all standard therapies, were enrolled. Assessments included tumor evaluations (RECIST 1.1 Q8W), circulating tumor DNA (ctDNA; pre-dose C1 D1, C2 D15, treatment end), and standard safety evaluations. Results A total of 43 patients, including 17, 6, 10, and 10 with gastroesophageal adenocarcinoma (GEA), biliary tract cancers, colorectal cancer, and other cancers, respectively, received single agent ZW25 at 10 mg/kg QW or 20 mg/kg Q2W. The median number of prior therapies was 3 (range 1-6) for all patients. For GEA and non-GEA patients, 88% and 35% respectively received at least one unique prior HER2 therapy. The most common treatment-related adverse events (all Grade 1 or 2) were diarrhea (49%) and infusion related reaction (34%). The objective response rate (all partial response (PR)) for response evaluable patients was 41% (14/34), stable disease (SD) in 38% (13/34), and progressive disease in 21% (7/34). The majority of patients (74%; 25/34) experienced a decrease in the sum of diameters for their target lesions. Compared to FISH, the positive predictive value of HER2 amplification in pre-dose C1D1 ctDNA was 90% (95% CI 79-96%), negative predictive value 45% (25-67%), and diagnostic accuracy 79% (63-90%). Disease control (PR or SD) > 5 months was associated with lower level of copy number adjusted mutational variant allele frequency in pre-treatment ctDNA (Mann Whitney p = 0.0085). Conclusions ZW25 has been well tolerated with promising single agent activity in heavily pre-treated patients. These data support further clinical development of this bispecific antibody in HER2-expressing solid tumors. Clinical trial identification NCT03929666. Legal entity responsible for the study Zymeworks, Inc. Funding Zymeworks, Inc. Disclosure F. Meric-Bernstam: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): CytomX; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): eFFECTOR; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Guardant Health; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self): Sumitomo Dainippon Pharma; Dialectica; Advisory / Consultancy: Genentech; Inflection; Pieris; Darwin Health; Samsung Bioepis; Aduro; Spectrum; OrigiMed; Debio; Xencor; Jackson Laboratory; Mersana; Seattle Genetics; Zymeworks; Kolon; Parexel International. M. Beeram: Speaker Bureau / Expert testimony, Speaker’s bureau: Genentech. K. Lee: Honoraria (self): BMS; Honoraria (self): Eli Lilly; Research grant / Funding (institution): ALX Oncology; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics; Travel / Accommodation / Expenses: BMS. Y. Kang: Advisory / Consultancy: Ono; Advisory / Consultancy: BMS; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSKBiopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Merck; Advisory / Consultancy: Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Astellas; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis. J. Chaves: Shareholder / Stockholder / Stock options: Northwest Medical Specialties, PLLC. C. Vaklavas: Advisory / Consultancy, no compensaton: Genentech; Advisory / Consultancy: Daiichi-Sankyo; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Tracon; Research grant / Funding (institution): Innocrin; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): H3 Biomedicine. D. Oh: Advisory / Consultancy: Genentech; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Zymeworks; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Array; Research grant / Funding (institution): Eli Lilly. E. Elimova: Full / Part-time employment, spouse is employee in vaccine global division: Meric; Advisory / Consultancy: BMS; Honoraria (self): Zymeworks. C. Ferrario: Honoraria (self): Pfizer; Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Merck; Honoraria (self): Astellas Pharma; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Merck; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony, Speaker’s bureau: Novartis; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Cascadian Therapeutics; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck; Novartis; Roche/Genentech; Sanofi; Pfizer; Janssen; Zymeworks; Travel / Accommodation / Expenses: Novartis; Roche. A. Fortenberry: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. G. Rowse: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. T. Gray: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. R. Lai: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. E. Hamilton: Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Lilly; Advisory / Consultancy, No personal compensation: Lilly; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, No personal compensation: Pfizer; Research grant / Funding (institution): Genentech/Roche; Speaker Bureau / Expert testimony, No personal compensation: Genentech/Roche; Advisory / Consultancy: Flatiron Health; Research grant / Funding (institution): Cascadian Therapeutics; Research grant / Funding (institution): Hutchinson MediPharma; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): StemCentrx; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Verastem; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Rgenix; Novartis; Mersana; TapImmune; BerGenBio; Tesaro; Medivation; Kadmon, Boehringer Ingelheim; Eisai; H3 Biomedicine; Radius Health; Acerta; Takeda; Macrogenics; Immunomedics; FujiFilm; Effector. All other authors have declared no conflicts of interest.

Background Erdafitinib (Erda), a pan-FGFR tyrosine kinase inhibitor, recently received accelerated approval by US FDA for treatment of post-platinum advanced UC pts with certain FGFR3 or 2 alterations. Erda induces dose dependent hyperphosphatemia via inhibition of PO4 excretion. Methods Ph1 data and PK/PD modeling identified a serum PO4 level of ≥ 5.5 mg/dL as a PD target with acceptable tolerability. In a ph2 study (NCT02365597) pts started Erda at 8mg/day, serum PO4 was assessed every cycle, and Cycle 1 Day 14 (C1D14). Up-titration on C1D15 to 9mg/day occurred if serum PO4 was Results 99 patients started 8 mg Erda and 41% were up-titrated to 9 mg based on C1D14 PO4 levels. The ORR and DCR were higher (42.7% and 85.3%) when maximum PO4 levels were >5.5 mg/dL as compared to below (34.8% and 65.2%, respectively). Median OS and PFS were prolonged with levels >5.5 mg/dL as compared to below with hazard ratio of 0.35 (median not reached vs 6.7 months) and 0.68 (5.6 vs 3.8 months), respectively. Among patients that could not be up-titrated due to concurrent toxicities, ORR was 27.3% (n = 22; 95% CI- 8.7%, 45.9%) as compared to 48.8% (n = 41; 95% CI-33.5%, 64.1%) for patients who were up-titrated. Logistic regression analysis (ORR, DCR), and Cox regression (PFS, OS) showed that maximum phosphate levels positively correlated with ORR, DCR, PFS, and OS (Table). Table . 932P ORR, DCR, PFS, OS and maximum on-treatment serum PO4 * ORR DCR PFS OS ORb, (95% CI), p-valuec ORb, (95% CI), p-valuec HR, (95% CI), p-valuee HR, (95% CI), p-valuee Prognostic variablea Maximum PO4: per 1 mg/dL increase 1.25, (0.86, 1.81), 0.247 2.31, (1.31, 4.08), 0.004 0.78, (0.63, 0.96), 0.021 0.58, (0.43, 0.80), 0.001 Simulated outcomes via PK/PD modeling of up-titrating from 8 mg to 9 mg QDf 1.10 (0.93, 1.29), - 1.43 (1.12, 1.83), - 0.90 (0.82, 0.98), - 0.79 (0.70, 0.91), - * The median time to maximum = 1.3m. Note: a. variable in model. b. odds ratio c. Pearson’s chi-square p-value e. Pearson’s chi-square p-value f. derived from first row using OR0.43 and HR0.43, based on PKPD simulations predicting average 0.43 mg/dL increase in maximum PO4 from 8 to 9 mg at steady state. Conclusions Hyperphosphatemia in Erda treated pts is associated with improved outcomes, supporting optimization of Erda dosing via uptitration based on serum PO4. Clinical trial identification NCT02365597, February 19, 2015. Editorial acknowledgement Himabindu Gutha (SIRO Clinpharm Pvt. Ltd.) writing assistance, Dr. Harry Ma (Janssen Research & Development, LLC) additional editorial support. Legal entity responsible for the study Janssen Research & Development. Funding Janssen Research & Development. Disclosure S.T. Tagawa: Advisory / Consultancy: Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, AbbVie, Tolmar, QED, Amgen, Sanofi; Research grant / Funding (institution): Lily, Sanofi, Janssen, Astellas Pharma, Progenics, Millennium, Amgen, Bristol-Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, AVEO, Boehringer Ingelheim, Merc; Travel / Accommodation / Expenses: Sanofi, Immunomedics, Amgen. A.O. Siefker-Radtke: Advisory / Consultancy: Janssen, Threshold Pharmaceuticals, Merck, National Comprehensive Cancer Network, Eisai, Genentech, Vertex, AstraZeneca, EMD Serono, Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Genentech; Research grant / Funding (self): National Institutes of Health, Genentech, Janssen Pharmaceuticals, Millennium, Michael and Sherry Sutton Fund for Urothelial Cancer. A. Dosne: Full / Part-time employment: Janssen Research and Development. B. Zhong: Full / Part-time employment: Janssen Research and Development. W.S. Shalaby: Full / Part-time employment: Janssen Research and Development. A. O’Hagan: Full / Part-time employment: Janssen Research and Development. K. Qi: Stockholder / Stock options, Full / Parttime employment: Janssen Research and Development. P. De Porre: Full / Part-time employment: Janssen Research and Development. P. Mahadevia: Full / Part-time employment: Janssen Research and Development. Y. Loriot: Advisory / Consultancy: Astellas Oncology; AstraZeneca; Ipsen; Janssen; MSD; Roche; Sanofi; Research grant / Funding (self): Sanofi (Inst); Travel / Accommodation / Expenses: AstraZeneca; MSD; Roche. All other authors have declared no conflicts of interest.

Background Over 60% of patients (pts) with stage IV melanoma may develop brain metastases, resulting in a significantly increased morbidity and poor overall prognosis. Clinical data for melanoma brain metastases (MBM) treatments are limited, as controlled studies often exclude pts with untreated brain metastases. Methods We conducted a multicenter, retrospective case series investigation with consecutive pts with BRAF-mutant MBM who were treated with BRAF inhibitor encorafenib plus MEK inhibitor binimetinib to evaluate the antitumor response with this combination. Assessments included intracranial, extracranial & global objective response rates (ORRs; percentage of complete [CR] + partial [PR] responses) evaluated by modified RECIST version 1.1; clinical benefit rate (CBR; percentage of CR + PR + stable disease [SD] as best response); time to response, duration of response, and safety. Results A total of 17 pts with stage IV BRAF-mutant MBM who received encorafenib plus binimetinib in centers in the United States were included. Pts had received a median of 2 prior lines of treatment over a median of 520 days since their melanoma diagnosis (median of 55 days since diagnosis of MBM). Of the patients included, 82% had prior treatment with BRAF/MEK inhibitors. The intracranial ORR was 35% (with 3 CRs and 3 PRs) and CBR was 76%, with a median duration of response of 17 weeks. Eight pts with either stable disease or a response were still ongoing treatment at the time of this analysis. Among the 14 MBM pts with prior BRAF/MEK inhibitor treatment, the intracranial ORR was 21% and CBR was 71%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in pts with melanoma without brain metastases. Conclusions Combination therapy with encorafenib plus binimetinib elicited intracranial activity in pts with BRAF-mutant MBM, including in pts previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted. *K. Holbrook and J. Lutzky are co-first authors. Editorial acknowledgement Editorial assistance was provided by JD Cox and Mayville Medical Communications, with funding from Array Biopharma. Legal entity responsible for the study Array BioPharma Inc. Funding Array BioPharma. Disclosure J. Lutzky: Advisory / Consultancy, Speaker Bureau / Expert testimony: Array BioPharma; Advisory / Consultancy, Speaker Bureau / Expert testimony: Regeneron; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Bristol-Myers Squibb. A. Amin: Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Merck; Speaker Bureau / Expert testimony: Regeneron. J.M. Davis: Speaker Bureau / Expert testimony: Exelixis Inc; Advisory / Consultancy: Array BioPharma. M.A. Davies: Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: GSK; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Vaccinex; Advisory / Consultancy: Syndax; Non-remunerated activity/ies: Nanostring. A. Diab: Advisory / Consultancy: Array BioPharma. I.C. Glitza: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Array BioPharma. R.N. Amaria: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Iovance. S. Patel: Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Cardinal Health; Advisory / Consultancy: Castle Biosciences; Research grant / Funding (institution): Deciphera; Advisory / Consultancy, DSMB: Immunocore; Advisory / Consultancy: Incyte; Speaker Bureau / Expert testimony: Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Provectus; Advisory / Consultancy, Research grant / Funding (institution), DSMB: Reata. H.A. Tawbi: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Array BioPharma; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): GSK. All other authors have declared no conflicts of interest.

A synthetic approach to analogues of the terpenoid natural product antheminone A is described which employs (−)-quinic acid as starting material. A key conjugate addition step proved to be unpredictable regarding its stereochemical outcome however the route allowed access to two diastereoisomeric series of compounds. The results of biological assay of the toxicity of the target compounds towards non-small-cell lung cancer cell line A549 are reported.

The bark of Wikstroemia indica is rich in daphnoretin, which has strong antiviral and anti-tumour activities. In order to optimise the extraction conditions of daphnoretin from the bark of W. indica, various extraction parameters were chosen to identify their effects on daphnoretin extraction. Response surface methodology (RSM) was applied to obtain the optimal combination of these parameters. Results showed that the optimisation conditions for daphnoretin extraction were: ethanol concentration 67.44%, extraction time 49.44 min, temperature 60.19 °C and liquid–solid ratio 23.49:1. The maximum extraction of daphnoretin obtained experimentally was 2.18‰. The mathematical model developed was found to fit well with the experimental data. Further, four kinds of human cancer cell lines, HeLa, A549, CNE and HEp-2, were tested in vitro to explore the anti-tumour spectrum of daphnoretin. It was found for the first time that daphnoretin showed significant inhibition on the proliferation of CNE and HeLa cells.

The syntheses of five novel 2-oxyalkyl-cyclohex-2-enones, structurally related to the natural products COTC and antheminone A, are described. The target structures were selected in order to probe the influence of several key structural parameters on in vitro anti-cancer bioactivity. The results of a cytotoxicity bioassay of the compounds against non-small-cell lung cancer cell lines A549 and H460 are reported. The biological data provides useful information, which will help guide the future design of compounds in this class with enhanced anti-cancer activity.

Paclitaxel is a commonly used anticancer drug, but it frequently causes peripheral neuropathy. Neurotropin, a non-protein extract from inflamed rabbit skin inoculated with vaccinia virus, has been used to treat various chronic painful conditions. In the present study, we investigated the effect of neurotropin on the paclitaxel-induced neuropathy in rats. Repeated administration of paclitaxel induced mechanical allodynia, cold hyperalgesia, and motor dysfunction. These neuropathies were mostly reversed by the repeated administration of neurotropin. Furthermore, neurotropin ameliorated the paclitaxel-induced axonal degeneration in cultured PC12 and rat dorsal root ganglion cells, and in rat sciatic nerve. In addition, neurotropin did not affect the microtubule aggregation or anti-tumour effect induced by paclitaxel in the tumour cell lines or tumour cells-implanted mice. These results suggest that neurotropin reverses the paclitaxel-induced neuropathy without affecting anti-tumour activity of paclitaxel, and therefore may be useful for the paclitaxel-induced neuropathy in clinical settings.

Syntheses of three novel analogues of the Streptomyces metabolite COTC are described, using the versatile chiral pool starting material, (−)-quinic acid. The results of bioassays of the target compounds against two lung cancer cell lines, A549 and H460, are presented.

During 2003 and 2004, marine pharmacology research directed towards the discovery and development of novel anti-tumour agents was published in 163 peer-reviewed articles. The purpose of this review is to present a structured assessment of the anti-tumour and cytotoxic properties of 150 marine natural products, many of which are novel compounds that belong to diverse structural classes, including polyketides, terpenes, steroids and peptides. The organisms yielding these bioactive marine compounds include invertebrate animals, algae, fungi and bacteria. Anti-tumour pharmacological studies were conducted with 31 structurally defined marine natural products in a number of experimental and clinical models that further defined their mechanisms of action. Particularly potent in vitro cytotoxicity data generated with murine and human tumour cell lines was reported for 119 novel marine chemicals with as yet undetermined mechanisms of action. Noteworthy is the fact that marine anti-cancer research was sustained by a global collaborative effort, involving researchers from Australia, Austria, Canada, China, Egypt, France, Germany, Italy, Japan, Mexico, the Netherlands, New Zealand, Papua New Guinea, the Philippines, South Africa, South Korea, Spain, Switzerland, Taiwan, Thailand and the United States of America (USA). Finally, this 2003-2004 overview of the marine pharmacology literature highlights the fact that the discovery of novel marine anti-tumour agents continued at the same pace as during 1998-2002.

The successful treatment of cancer remains a huge challenge. Consequently, efforts are being made to develop alternative methods of tumour therapy. One of these is the use of live Clostridium species, based on the observation that obligatory anaerobic bacteria specifically colonize the hypoxic and necrotic regions that are present in solid tumours but normally absent in other parts of the body. Although past results have fuelled scepticism about its clinical use, recent promising findings emphasize the potential of Clostridium-directed tumour therapy. These recent developments are reviewed and the reintroduction of this tumour-targeting protein delivery system into clinical settings is discussed.

Selective drug delivery is an important approach with great potential for overcoming problems associated with the systemic toxicity of chemotherapy, in particular, platinum-based chemotherapy. Finding successful strategies for the targeting of platinum anticancer drugs has therefore been a subject of extensive research. This review paper gives an overview of some of the different approaches that have recently been used in the development of targeted platinum anticancer drugs.

Thermal electrocyclisation of the azahexatriene system has been used as a key step for the synthesis of anti-HIV and anti-tumour compounds, harman, derivatives of harman and 1-aryl-β-carbolines. A one-pot reaction sequence was used to furnish these compounds in good yield.

Efficient synthesis of phosphinate analogues (in six steps and 68-69% overall yields) of the anti-tumour agent miltefosine are reported, which involve a radical hydrophosphinylation addition reaction followed by conversion to the P(III) silyloxy intermediate and Michael-type addition as the key steps. © 2011 Elsevier Ltd. All rights reserved.

As part of the search for tamoxifen substitutes that could be useful in the treatment of breast cancer, the use of organometallic complexes has been investigated. For this purpose a synthesis has been developed for ferrocifen, the prototype of this new series of complexes. Low valent titanium-mediated (TiCl4/Zn) cross-coupling of 4-MeO-C6H4COPh with ferrocenyl ethyl ketone affords the corresponding but-l-ene in high yield (66%), from which ferrocifen, 3, is rapidly prepared in an overall yield of 41%.

The orally active platinum anti-tumour complex JM216 [bis-acetatoamminedichlorocyclohexylamineplatinum(IV)] is at present in stage II clinical trials. A procedure for synthesising the complex labelled with 191Pt or 188Pt at the platinum centre has been developed. The purity (shown by HPLC) is 98% and the specific activity (0.3–0.4 Ci/kg) is enough for in vivo and in vitro studies.

The crystal structure of the experimental anti-tumour compound a-ammine-bd-bis(butyrato)-cf-dichloro-e-cyclohexylamine platinum(IV) is reported. There are four independent molecules in the crystallographic asymmetric unit, which show two distinct conformations about the carboxylate linkage to the platinum atom. Implications for metabolic activation are discussed and the potential for base-catalysed solvolysis of platinum(IV) amine complexes is demonstrated.

Two new monogalactosyl diacylglycerols were isolated from the freshwater green alga, Chlorella vulgaris, as anti-tumour promoters, together with three monogalactosyl diacylglycerols and two digalactosyl diacylglycerols. The new monogalactosyl diacylglycerol containing (7Z,10Z)-hexadecadienoic acid showed a more potent inhibitory effect toward tumour promotion than the other glycerolipids isolated.

A range of 16 derivatives of flavone-8-acetic acid (FAA) with a 6-methyl substituent have been prepared and their anti-tumour activity evaluted in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. While many of the compounds show activity comparable to FAA in vitro , this essentially disappears in vivo , possibly due to degradation before the compounds can reach the tumour site.

[ d -Ala-4]RA-VII ( 9 ) and [ d -Ala-2]RA-VII ( 10 ) were prepared from RA-VII ( 1 ), an anti-tumour bicyclic hexapeptide from Rubia plants, by conversion of its thioamide 3 into oxazoles 4 and 5 and subsequent acid-catalysed hydrolysis.

Using the kinetically controlled Pictet–Spengler reaction, we have developed a three-step, diastereoselective and enantiospecific synthesis of the natural product demethoxy-fumitremorgin C in 21% overall yield.