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Esophageal cancer is one of the most aggressive tumors, and the outcome remains poor. One contributing factor is the presence of tumors that are less responsive or have increased malignancy when treated with conventional chemotherapy, radiotherapy, or a combination of these. Cancer-associated fibroblasts (CAFs) play an important role in the tumor microenvironment. Focusing on conventional cancer therapies, we investigated how CAFs acquire therapeutic resistance and how they affect tumor malignancy. In this study, low-dose chemotherapy or radiotherapy-induced normal fibroblasts showed enhanced activation of CAFs markers, fibroblast activation protein, and α-smooth muscle actin, indicating the acquisition of malignancy in fibroblasts. Furthermore, CAFs activated by radiotherapy induce phenotypic changes in cancer cells, increasing their proliferation, migration, and invasion abilities. In in vivo peritoneal dissemination models, the total number of tumor nodules in the abdominal cavity was significantly increased in the co-inoculation group of cancer cells and resistant fibroblasts compared to that in the co-inoculation group of cancer cells and normal fibroblasts. In conclusion, we demonstrated that conventional cancer therapy causes anti-therapeutic effects via the activation of fibroblasts, resulting in CAFs. It is important to select or combine modalities of esophageal cancer treatment, recognizing that inappropriate radiotherapy and chemotherapy can lead to resistance in CAF-rich tumors.

Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression.Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8+ or forkhead box protein 3 (FoxP3+) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody.Results: CD8+ TILs and CAFs were negatively correlated in intratumoral tissues (P < 0.001), whereas FoxP3+ TILs were positively correlated (P < 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8+ and increased FoxP3+ TILs, compared with cancer cells alone. In vitro, IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P < 0.001) with fewer CD8+ TILs than untreated tumors (P < 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3+ TILs increased in IL6-treated tumors (P < 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8+ TILs in intratumoral tissues.Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. Clin Cancer Res; 24(19); 4820–33. ©2018 AACR.

Supplementary Figure 1. Subgroup analysis of TILs in intra-tumoral tissues according to UICC Stage. Supplementary Figure 2. Correlation between CAFs and ratios of peri- to intra-tumoral of CD8+ or FoxP3+ TILs. Supplementary Figure 3. Quantification of cytokines secreted into cell culture supernatants. Supplementary Figure 4. Fibroblasts and cancer cells cooperate to promote the release of IL-6 in human-derived esophageal cancer cell line. Supplementary Figure 5. IL-6 suppresses tumor immunity of SCCVII subcutaneous tumors in C3H/HeJ mice. Supplementary Figure 6. Correlation between IL-6 staining and αSMA+ CAFs in human esophageal cancer specimens. Supplementary Figure 7. Correlation among αSMA+ CAFs, IL-6 and hypoxia conditions in human esophageal cancer specimens Supplementary Table 1. Correlation between CD8+ or FoxP3+ TILs and clinicopathological characteristics of esophageal cancer. Supplementary Table 2. Univariate analysis of pathologic features and tumorinfiltrating lymphocytes for OS and DFS in esophageal cancer. Supplementary Table 3. Univariate analysis of OS and DFS in the subgroups in intratumoral tissues. Supplementary Table 4. Multivariate analysis of CD8+ and FoxP3+ TILs for OS and DFS in esophageal cancer.

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation.

The usefulness of laparoscopic and endoscopic cooperative surgery (LECS) for gastric submucosal tumors in the cardiac region has been reported in recent years. However, LECS for submucosal tumors at the esophagogastric junction with hiatal sliding esophageal hernia has not been reported, and its validity as a treatment method is unknown. The patient was a 51-year-old man with a growing submucosal tumor in the cardiac region. Surgical resection was indicated because a definitive diagnosis of the tumor was not determined. The lesion was a luminal protrusion tumor, located on the posterior wall of the stomach 20 mm from the esophagogastric junction, and had a maximum diameter of 16.3 mm on endoscopic ultrasound examination. Because of the hiatal hernia, the lesion could not be detected from the gastric side by endoscopy. Local resection was considered to be feasible because the resection line did not extend into the esophageal mucosa and the resection site could be less than half the circumference of the lumen. The submucosal tumor was resected completely and safely by LECS. The tumor was diagnosed as a gastric smooth muscle tumor finally. Nine months after surgery, a follow-up endoscopy showed reflux esophagitis. LECS was a useful technique for submucosal tumors of the cardiac region with hiatal hernia, but fundoplication might be considered for preventing backflow of gastric acid.

Lymph node metastasis is a pathognomonic feature of spreading tumors, and overcoming metastasis is a challenge in attaining more favorable clinical outcomes. Esophageal cancer is an aggressive tumor for which lymph node metastasis is a strong poor prognostic factor, and the tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in particular, has been implicated in esophageal cancer progression. CAFs play a central role in the TME and have been reported to provide suitable conditions for the progression of esophageal cancer, similar to their role in other malignancies. However, little is known concerning the relevance of CAFs to the lymph node metastasis of esophageal cancer. Here, we used clinical samples of esophageal cancer to reveal that CAFs promote lymph node metastasis and subsequently verified the intercellular relationships in vitro and in vivo using an orthotopic metastatic mouse model. In the analysis of clinical samples, FAP+ CAFs were strongly associated with lymph node metastasis rather than with other prognostic factors. Furthermore, CAFs affected the ability of esophageal cancer cells to acquire metastatic phenotypes in vitro; this finding was confirmed by data from an in vivo orthotopic metastatic mouse model showing that the number of lymph node metastases increased upon injection of cocultured cancer cells and CAFs. In summary, we verified in vitro and in vivo that the accumulation of CAFs enhances the lymph node metastasis of ESCC. Our data suggest that CAF targeted therapy can reduce lymph node metastasis and improve the prognosis of patients with esophageal cancer in the future.

Purpose: OBP-301 (Telomelysin) is an attenuated type-5 adenovirus that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 sensitises human cancer cells to ionising radiation by inhibiting DNA repair, and radiation enhances coxsackievirus and adenovirus receptor-mediated OBP-301 infection on the contrary. We assessed OBP-301 with radiotherapy in oesophageal cancer patients unfit for standard chemoradiation treatments. Methods: A phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed oesophageal cancer patients deemed unfit to undergo surgery or chemotherapy. Study treatment consisted of OBP-301 administration by intratumoural needle injection using a flexible endoscope on days 1, 18 and 32. Radiotherapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. Results: Of the 13 patients, 7, 3 and 3 patients were treated with 10(10), 10(11) and 10(12) virus particles, respectively. Study group comprised 10 males and 3 females, with a median age of 82 years (range, 53-91 years). All patients developed a transient, self-limited lymphopenia. Distribution studies revealed transient virus shedding in the plasma. Eight patients had local complete response (CR); all of them exhibited no pathologically viable malignant cells in biopsy specimens, and 3 patients had a partial response. The objective response rate was 91.7%. The clinical CR rate was 83.3% in stage I and 60.0% in stage II/III. Histopathological examination revealed massive infiltration of CD8 thorn cells and increased PD-L1 expression. Conclusion: Multiple courses of endoscopic intratumoural OBP-301 injection with radiotherapy are feasible and provide clinical benefits in patients with oesophageal cancer unfit for standard treatments. (C) 2021 Elsevier Ltd. All rights reserved.

Colorectal cancer (CRC) tumorigenesis and progression are linked to common oncogenic mutations, especially in the tumor suppressor APC, whose loss triggers the deregulation of TCF4/β-Catenin activity. CRC tumorigenesis is also driven by multiple epi-mutational modifiers, such as transcriptional regulators. We describe the common (and near-universal) activation of the zinc finger transcription factor and Let-7 target PLAGL2 in CRC and find that it is a key driver of intestinal epithelial transformation. PLAGL2 drives proliferation, cell cycle progression, and anchorage-independent growth in CRC cell lines and non-transformed intestinal cells. Investigating effects of PLAGL2 on downstream pathways revealed very modest effects on canonical Wnt signaling. Alternatively, we find pronounced effects on the direct PLAGL2 target genes IGF2, a fetal growth factor, and ASCL2, an intestinal stem cell-specific bHLH transcription factor. Inactivation of PLAGL2 in CRC cell lines has pronounced effects on ASCL2 reporter activity. Furthermore, ASCL2 expression can partially rescue deficits of proliferation and cell cycle progression caused by depletion of PLAGL2 in CRC cell lines. Thus, the oncogenic effects of PLAGL2 appear to be mediated via core stem cell and onco-fetal pathways, with minimal effects on downstream Wnt signaling.

Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression. Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8+ or forkhead box protein 3 (FoxP3+) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody. Results: CD8+ TILs and CAFs were negatively correlated in intratumoral tissues (P < 0.001), whereas FoxP3+ TILs were positively correlated (P < 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8+ and increased FoxP3+ TILs, compared with cancer cells alone. In vitro, IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P < 0.001) with fewer CD8+ TILs than untreated tumors (P < 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3+ TILs increased in IL6-treated tumors (P < 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8+ TILs in intratumoral tissues. Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. Clin Cancer Res; 24(19); 4820–33. ©2018 AACR.

// Takayuki Ninomiya 1 , Toshiaki Ohara 1, 2 , Kazuhiro Noma 1 , Yuki Katsura 1 , Ryoichi Katsube 1 , Hajime Kashima 1 , Takuya Kato 1 , Yasuko Tomono 3 , Hiroshi Tazawa 1, 4 , Shunsuke Kagawa 1 , Yasuhiro Shirakawa 1 , Fumiaki Kimura 5 , Ling Chen 6, 7 , Tomonari Kasai 6 , Masaharu Seno 6 , Akihiro Matsukawa 2 and Toshiyoshi Fujiwara 1 1 Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan 2 Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan 3 Shigei Medical Research Institute, Okayama, Japan 4 Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan 5 Department of Internal Medicine, Tamano General Hospital, Okayama, Japan 6 Department of Medical and Bioengineering Science, Okayama University Graduate School of Natural Science and Technology, Okayama, Japan 7 Department of Pathology, Tiajin Central Hospital of Gynecology Obstetrics, Tianjin, People’s Republic of China Correspondence to: Toshiaki Ohara, email: t_ohara@cc.okayama-u.ac.jp Keywords: cancer stem cells, induced pluripotent stem cells, iron chelators, stemness Received: May 16, 2017 Accepted: September 23, 2017 Published: October 12, 2017 ABSTRACT Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.

Cancer-associated fibroblasts (CAFs) are strongly implicated in tumor progression, including in the processes of tumorigenesis, invasion, and metastasis. The targeting of CAFs using various therapeutic approaches is a novel treatment strategy; however, the efficacy of such therapies remains limited. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a novel targeted therapy employing a cell-specific mAb conjugated to a photosensitizer, has been introduced as a new type of phototherapy. In this study, we have developed a novel NIR-PIT technique to target CAFs, by focusing on fibroblast activation protein (FAP), and we evaluate the treatment efficacy in vitro and in vivo. Esophageal carcinoma cells exhibited enhanced activation of fibroblasts, with FAP over-expressed in the cytoplasm and on the cell surface. FAP-IR700-mediated PIT showed induced rapid cell death specifically for those cells in vitro and in vivo, without adverse effects. This novel therapy for CAFs, designed as local control phototherapy, was safe and showed a promising inhibitory effect on FAP(+) CAFs. PIT targeting CAFs via the specific marker FAP may be a therapeutic option for CAFs in the tumor microenvironment in the future.

e16064 Background: Mouse models of intestinal tumorigenesis have been developed and many of them involve mutations in the Apc gene. However, human intestinal tumors contain multiple additional sporadic mutations in tumor suppressor genes (TSGs). Our goal is to develop a novel mouse model of intestinal tumorigenesis that can recapitulate the natural history of mutations in diverse stages of tumor development. Methods: We used multiple guide RNAs to achieve random mutations in the canonical TSGs, Apc, Pten, Smad4, and Tp53. We generated transgenic (PPAS) mice that constitutively express the appropriate guide RNAs. Moreover, we achieved inducible Cas9 expression in icCas9N mice intestine using the Villin promoter to drive both a doxycycline-dependent activator and a doxycycline-inactivated repressor. We fed the doxycycline chow to PPAS:icCas9 double transgenic mice from the age of 6 to 8 weeks, and harvested intestine at 12 weeks. Results: We examined seven PPAS;icCas9 mice, and detected intestinal tumors in all the mice. Two mice had small intestinal tumor, three mice had colonic tumor, and two mice had tumors in both small and large intestine. The average number of tumors were 0.86, 1.57, 2.43 in small intestine, colon, and both respectively. We analyzed mutations in 11 tumors in 6 mice. The mutation patterns of Apc, Pten, Smad4 and Tp53 in tumors shared three distinct patterns. One was characterized by mutations in all four TSGs (n = 9). The second showed mutation in APC and Smad4 and Pten (n = 1). The third showed mutation only in Tp53 (n = 1). Normal intestine and colon in PPAS:icCas9 mice had no mutations. Conclusions: This model provides a powerful platform for modeling intestinal tumorigenesis driven by the canonical signaling pathway which are commonly dysregulated in colon cancer. This model provides a means for rapid development of intestinal tumors in mice, enabling an investigation of the relationship between novel candidate regulators of tumorigenesis and the canonical signaling pathways regulated by these four common TSGs. [Table: see text]

Lymph node metastasis is a pathognomonic feature of spreading tumors, and overcoming metastasis is a challenge in attaining more favorable clinical outcomes. Esophageal cancer is an aggressive tumor for which lymph node metastasis is a strong poor prognostic factor, and the tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in particular, has been implicated in esophageal cancer progression. CAFs play a central role in the TME and have been reported to provide suitable conditions for the progression of esophageal cancer, similar to their role in other malignancies. However, little is known concerning the relevance of CAFs to the lymph node metastasis of esophageal cancer. Here, we used clinical samples of esophageal cancer to reveal that CAFs promote lymph node metastasis and subsequently verified the intercellular relationships in vitro and in vivo using an orthotopic metastatic mouse model. In the analysis of clinical samples, FAP

Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

Forkhead box protein p3 (Foxp3) is crucial to the development and suppressor function of regulatory T cells (Tregs) that have a significant role in tumor-associated immune suppression. Development of small molecule inhibitors of Foxp3 function is therefore considered a promising strategy to enhance anti-tumor immunity. In this study, we developed a novel cell-based assay system in which the NF-κB luciferase reporter signal is suppressed by the co-expressed Foxp3 protein. Using this system, we screened our chemical library consisting of approximately 2,100 compounds and discovered that a cancer chemotherapeutic drug epirubicin restored the Foxp3-inhibited NF-κB activity in a concentration-dependent manner without influencing cell viability. Using immunoprecipitation assay in a Treg-like cell line Karpas-299, we found that epirubicin inhibited the interaction between Foxp3 and p65. In addition, epirubicin inhibited the suppressor function of murine Tregs and thereby improved effector T cell stimulation in vitro. Administration of low dose epirubicin into tumor-bearing mice modulated the function of immune cells at the tumor site and promoted their IFN-γ production without direct cytotoxicity. In summary, we identified the novel action of epirubicin as a Foxp3 inhibitor using a newly established luciferase-based cellular screen. Our work also demonstrated our screen system is useful in accelerating discovery of Foxp3 inhibitors.

Advances in molecular and cellular biochemistry, such as the development of targeted cancer therapy, have dramatically improved the prognosis of cancer patients. Emerging data have suggested that bevacizumab treatment may act by controlling the cancer microenvironment. Many reports have examined the interaction of cancer cells with the tumor microenvironment, and cancer-associated fibroblasts (CAFs) are thought to play a central role in this process. We speculated that the cancer microenvironment and in particular, CAFs, strongly influence the development of esophageal cancer. We have analyzed the signaling pathways of molecular targets. However, inhibition of a single signaling pathway is insufficient to treat cancer effectively. Photoimmunotherapy is a molecular-targeted specific cancer therapy using near-infrared radiation, which was introduced by Mitsunaga et al. in 2011. We are using its specific method of killing cells to target CAFs. We will report the results of its effect on cancer cells in the future.

The first case of dural metastasis occurred in a 60s years old woman, who presented with bone metastasis to the right breast. Nine months later, disorientation and left hemiplegia developed, the right coronal bone metastasis enlarged, and dural metastases were detected close to the tumor, as observed by using cranial magnetic resonance imaging (MRI). Whole brain radiation and chemotherapy(weekly paclitaxel)were administered. The right coronal bone metastasis reduced remarkably, and the dural metastases almost disappeared, as observed on a cranial MRI scan. The second case of dural metastasis occurred in a 50s years old woman who presented with multiple bone metastases. Extensive bone metastases to the skull and dural metastases to the side of the head were observed on cranial MRI scans. Subsequently, the patient experienced a severe headache, and whole brain radiation and pharmacotherapy with anastrozole and trastuzumab were administered. Cranial MRI revealed that the skull bone metastasis reduced and the dural metastases almost disappeared. We report that radiotherapy and pharmacotherapy were effective in these 2 cases of dural metastases of breast cancer.

Background: As like rising of PD-1 antibody, targeting therapy to tumor immunosuppression have been shown dramatic cure responses in melanoma and other malignancies. However there are still problems that the responders of those checkpoint inhibitors are limited. Recently, it is considered that tumor immunosuppression may be caused by not only cancer cells but also tumor microenvironments (TME). Cancer-associated fibroblasts (CAFs) are one of the major components and have a central role for tumor progression in TME. It has been hypothesized that they can also play an essential role in tumor immunosuppression. In this study, we evaluated the correlation between CAFs and tumor immunity system, especially tumor-infiltrating lymphocytes (TILs) in clinical samples and further in vivo study. Materials and methods: Total 140 cases of esophageal cancer were evaluated for the presence of CAFs and TILs by immunohistochemistry (IHC). CAFs were defined as fibroblasts expressing alpha smooth muscle actin. CD8+ cytotoxic T lymphocytes and FoxP3+ regulatory T cells were investigated as TILs in each specimen’s intratumoral and peritumoral tissues. The outcome was set as the correlation between CAFs and TILs, and Overall survival. In vivo experiments, we used a mouse-derived cancer cell (colon26-Luc) and mouse embryonic fibroblasts (NIH/3T3). BALB/c or BALB/c-nu/nu mice were inoculated with only cancer cells (control) or cancer cells with CAFs (co-CAFs) into right flank to examine the immunosuppression affected by CAFs. The proliferation was examined by in vivo imaging system. Result: In clinical analysis, CD8+ TILs and CAFs demonstrated strong relations, which were significantly “negative” correlation and showed moderate correlation coefficient in intratumoral tissues (P Conclusion: Our results suggest that Both CD8+ and FoxP3+ TILs in intratumoral tissues are independent prognostic factors, and CAFs have a significant correlation to those TILs. We consider that CAFs may affect tumor immunosuppression by regulating the migration of TILs. Citation Format: Takuya Kato, Kazuhiro Noma, Hajime Kashima, Yuki Katsura, Hiroaki Sato, Takayuki Ninomiya, Toshiaki Ohara, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Cancer-associated fibroblasts contribute to tumor immunosuppression by regulating tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5934. doi:10.1158/1538-7445.AM2017-5934

Background: Cancer associated fibroblasts (CAFs) are activated fibroblasts and an important player in the tumor microenvironment. Their activity promotes cancer cell proliferation, migration, and invasion, and metastasis. The most prognostic factor in tumor progression is metastasis. Cancer metastasis is a multi-step process that tumor cells detach from primary site, survive in the bloodstream, and seed in target organ. Although previous studies have focused on the interaction between CAFs and cancer cells in primary tumor site, the roles of CAFs in blood circulation remain largely unknown. We investigated the effect of CAFs coexisting with cancer cells in bloodstream on tumor metastasis in vivo mouse model, and also examined the effect of CAFs in subcutaneous tumor. Methods: We used female BALB/c-nu/nu mice and BALB/c mice in the experiments. Cancer cells were mouse mammary carcinoma cell lines 4T1 transfected with luciferase, colon cancer cell lines Colon 26 transfected with luciferase. Fibroblast cell lines were mouse embryonic fibroblast MEF and NIH-3T3. In venous injection mouse model, we injected 1 × 106 cancer cells alone or the same number of cancer and fibroblast co-cultured together. When we injected cancer cells transfected with luciferase, the mice were subjected to in vivo imaging system (IVIS) and measured luminescence intensity of metastatic sites. We have also harvested lung and compared its weight and metastatic nodule under microscopy. Furthermore, in subcutaneous tumor metastatic mouse model, cancer cells alone or mixed with cancer cells and CAFs were subcutaneously inoculated into the mice. Results: In the group of mice injected with cancer cells and fibroblasts, luminescent intensity of each lungs were higher than cancer cell alone. Harvested lung weight and the number of metastatic nodules were also higher in the group with cancer cells and fibroblasts.In subcutaneous model, mice inoculated with cancer cells and fibroblast had much more metastatic sites than cancer cells alone. Conclusions: Our data indicate that CAFs promote tumor metastasis by stimulating cancer cells in blood circulation, as well as in primary tumor site.These findings suggest that CAFs in both bloodstream and primary site could be a promising therapeutic target. CAF-targeted therapy could reduce tumor metastasis and improve the prognosis of cancer patients. Citation Format: Hajime Kashima, Kazuhiro Noma, Hiroaki Sato, Yuki Katsura, Takuya Kato, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Cancer associated fibroblasts promote tumor metastasis coexisting with cancer cells in blood circulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5905. doi:10.1158/1538-7445.AM2017-5905

Background: Iron plays a crucial role in the various metabolic pathways and it is essential for life. However excess of iron is known to cause cancer. There are many reports that iron depletion treatment indicates antitumor effect. Previously, we have confirmed that iron depletion treatment indicates antitumor effect against Cancer stem cell (CSC) model, miPS-LLCcm, which was converted from murine induced pluripotent stem cell (miPS cell) in Okayama university (Chen at el. PLOS ONE 2012), and also suppresses CSC markers. Many tumors contain phenotypically and functionally heterogenous cancer cells due to pluripotency of CSC. Although there are various theories about the origin of CSC, miPS has a pluripotency and regarded as the top of the hierarchy, it can be the candidate of the origin of CSC. miPS cell is known to form teratoma when inoculated into nude mouse because of its undifferentiated status. We hypothesized if we could suppress the stemness and tumorigenicity of miPS cell by iron depletion treatment, it can be applied to the therapy for CSC and undifferentiated status cancer cell. In this study, we investigated the stemness and tumorigenecity of miPS cell with iron depletion treatment. Methods: We used miPS cell(cell name : iPS-MEF-Ng-20D-17) purchased from Riken Cell Bank(Japan). Deferasirox (DFX), an popular commercial available oral iron chelator was used for iron depletion treatment. Western blot analysis was done to examine the expression of the stemness markers including Nanog, Oct3/4, Sox2, Klf4, c-Myc. Subcutaneous model of miPS cell and miPS cell treated with DFX (50μM) were used in vivo study. Tumors were harvested for immunohistochemistry. Results: Stemness markers of miPS cell were suppressed strongly by DFX in western blot analysis. DFX also suppressed the subcutaneous tumor growth. The average tumor volume of the control group was 665.3±430.8mm3 while that of the DFX treated group was 204.3±76.2 mm3(p Citation Format: Yuki Katsura, Toshiaki Ohara, Hajime Kashima, Hiroaki Sato, Takuya Kato, Takayuki Ninomiya, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Tumorigenesis of murine iPS cell is prevented by iron depletion with downregulation of stemness markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 925. doi:10.1158/1538-7445.AM2017-925

We reviewed 66 cases of traumatic rib fracture by traffic accident between January 2009 and December 2011. The age of patients ranged from 18 to 88 years, with an average age of 55.6, and they were predominantly male. They met with traffic accident when driving automobiles in 30 cases, driving motorcycles in 15 cases, and walking in 9 cases. The average number of fractured ribs was 4.1±3.2.Multiple rib fractures were observed in 75.8% of patients. Injuries other than rib fractures were involved in all patients who suffered over 7 rib fractures. Except one who died of pneumonia 62 days after traffic accident, 7 of 8 patients died within 48 hours:6 in a shock state and 1 in cardiac pulmonary arrest on arrival. About 80 % of the patients with rib fractures were hospitalized. As traffic accidents could cause any type of injuries including rib fractures, it is important to examine the whole body when patients were transported to a hospital.

For the total synthesis of (+)-taxusin, the AC-ring fragment 8 was prepared from an optically active 2-bromo-3-siloxycyclohexenecarbacetal 5 via 4 steps and was converted to the dienol silyl ether 13. The thus-obtained 13 underwent B-ring cyclization in the presence of Me2AlOTf to produce the ABC endo-tricarbocycle 14 having C9α, C10β-substituents, which was converted to the cyclopropyl ketone 21a. Introduction of C19 methyl via reductive cleavage of the cyclopropane ring under Birch conditions and successive in situ treatment of the resulting enol with methanol gave the C3α-protonated ketone 24. Next, 24 was converted to the allylsilane 29, which was then oxidized with m-CPBA to produce the fully functionalized taxusin carbon skeleton. Finally, removal of the silyl protecting groups followed by acetylation completed the total synthesis of (+)-taxusin.

Enantioselective synthesis of a taxol C-ring fragment containing an allylsilane moiety is described. Diastereoselective [4 + 2] cycloaddition of the pyrone with ( R )- t -butylbenzyl vinyl ether followed by appropriate transformations gave a mixture of two regioisomeric cyclohexenyl sulfides, which was converted to the title compound with almost complete diastereo- and enantioselectivities by treating with Li and 4,4′-di- t -butylbiphenyl followed by quenching with chlorotrimethylsilane.

Background: Iron overload is known to cause cancer. Iron depletion treatment has been reported to have an anti-cancer effect. However, it is unclear whether iron depletion treatment is also effective in cancer stem cells (CSCs) or not. Recently, new CSCs model, miPS-LLCcm, was epigenetically established from murine induced pluripotent stem cells (miPS cells) in Okayama university (Chen at el. PLOS ONE 2012). In this model, Green Fluorescent Protein (GFP) was designed under Nanog promoter lesion. Therefore, GFP positive cells indicated the undifferentiated cancer progenitor cells. The tumor tissue derived from miPS-LLCcm cells involved glandular structure, angiogenesis, and cytokeratin positive lesion in immunostaining. We hypothesized that CSCs depended on iron in proliferation and differentiation. Thus, we also hypothesized iron depletion treatment might have a novel therapeutic effect. Methods: We used miPS-LLCcm cells as CSCs, colon26 and 4T1 cells as differentiated cancer cells. Iron depleted condition was simulated by iron free medium with 1% fetal bovine serum. Transferrin (Holo) and iron chelators (Deferoxamine and Deferasirox) additional examinations were done to reveal the dependency of iron. Cell viability was examined by XTT assay 48 hours after administration of transferrin and iron chelators. Western blot analysis was done to examine the effect of iron depletion on iron related markers and stemness markers including TfR-1, DMT-1, Nanog, SOX2, c-Myc, Oct3/4, Klf-4, E-cadherin. Subcutaneous tumor model of miPS-LLCcm cells was used in vivo. Deferoxamine (30mg/kg/day) and deferasirox (30mg/kg/day) were administrated directly into the tumor. Tumors were collected for immunostaining. Results: Transferrin strongly promoted cell proliferation of miPS-LLCcm in iron depleted condition. However, Transferrin did not promote proliferation of colon26 and 4T1 in the condition. Iron depletion by iron chelators suppressed miPS-LLCcm proliferation and the expression of stemness markers including Nanog, SOX2, c-Myc, Oct3/4, Klf-4, and E-cadherin in vitro study. Deferasirox more strongly suppressed the expression of stemness markers than deferoxamine. Iron depletion by iron chelators suppressed subcutaneous tumor growth. The average tumor volume of the control group was 1270.8 ± 411.2 mm3 while that of deferoxamine treatment group was 502.5 ± 207.5 mm3 (p Conclusions: Iron is a key element of the proliferation and stemness in CSCs model. Iron control therapy including iron chelators is a novel therapeutic target of CSCs. Citation Format: Toshiaki Ohara, Takayuki Ninomiya, Kazuhiro Noma, Hajime Kashima, Yuki Katsura, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Iron control is a novel therapeutic target of cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2510.

Backgrounds: Cancer associated fibroblasts (CAFs) are thought to play an essential role in cancer invasion, migration, metastasis, and tumor immunosuppression. However, there has been still a little evidence of the correlation of tumor immunosuppression and CAFs in human esophageal carcinoma. The other hand, as like rising of PD-1 antibody targeting therapy to tumor immunosuppression have been shown dramatic cure responses in melanoma and now ongoing to other malignancies. Tumor-infiltrating lymphocytes (TILs) are considered typically to represent a host immune response against carcinoma. In many types of tumors TILs have been shown their strong correlation to patient's clinicopathological features. In this study, we evaluated the prognostic correlation of CAFs and TILs, which are classified respectively in tumor-associated CD8+ cytotoxic T lymphocytes (CTL) and FoxP3+ regulatory T cells (Treg) in surgically resected esophageal carcinoma. Materials and methods: Total 58 cases with esophageal carcinoma in our institution were evaluated for the presence of CAFs and TILs by immunohistochemistry. TILs of CTL and Treg were calculated each in the intratumoral and the peripheral tissues, and the cutoff for subgroups was defined at the median value. CAFs were defined as fibroblasts expressing alpha smooth muscle actin (α-SMA), and evaluated with the α-SMA scoring by using “Area Index”, which is calculated by imageJ. TILs and CAFs were assessed for the associations with pathological invasion depth (pT), lymph node metastases (pN), histological types, and disease-free survival (DFS) or overall survival (OS). Result: In intratumoral tissues, Treg was significantly associated with advanced T stages, and Treg and a CTL/Treg ratio were associated with lymph node metastasis. Higher CTL, higher CTL/Treg ratio and lower Treg were significantly associated with improved DFS and OS in univariate analysis. Furthermore, multivariate analysis demonstrated selected higher CTL as an independent prognostic factor (P = 0.010). On the other hand, in peripheral tissues, CTL, Treg, and CTL/Treg ratio were not correlated with clinicopathological factors or the any prognosis. Additionally the overexpression of CAFs was strongly associated with poor prognosis (P = 0.002) and the “Area Index” of α-SMA was inversely correlated with the CTL and CTL/Treg ratio in intratumoral tissues (P = 0.029, 0.017). It suggests that CAFs accumulation in tumor tissue is correlated to status of intratumoral immunesuppression. Conclusion: The CTL in intratumoral tissues are independent prognostic factors, and are considered to play an essential role in tumor immunity. Our results demonstrate that CAFs are significant correlation of immunosuppression in esophageal carcinoma. In the future, targeting CAFs therapy itself might improve tumor immunosuppression, and there is possibility to prolong a prognosis. Citation Format: Takuya Kato, Kazuhiro Noma, Yuki Katsura, Hajime Kashima, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Prognostic correlation of tumor-infiltrating lymphocytes (TILs) and cancer associated fibroblasts (CAFs) in patients with human esophageal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4160.

Background: The tumor and its microenvironment have dynamic interactions and signaling that strongly affect tumor progression. Cancer associated fibroblasts (CAFs) are activated fibroblasts and thought to be an important player in the tumor microenvironment. Although there are several indicators of CAF, fibroblast activation protein (FAP) is unique in its selectivity for CAFs in comparison with other markers. The aim of this study is to investigate CAFs expressing FAP and its relationship to cancer metastasis in esophageal cancer. Methods: Sections of paraffin-embedded resected primary human esophageal cancer specimens from 2008 through 2010 in Okayama University hospital were stained with antibody directed against FAP. Overall percentage of stromal FAP staining of the primary tumor was assessed semi-quantitatively (0, 1, 2, 3, 4, 5) and staining intensity was also graded (none, weak, intermediate, strong). Survival time and time to recurrence data were analyzed using Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models. Results: 49 patients with resected specimens were available for study with 26 (53.1%) stage I, 8 (16.3%) stage II, 14 (28.6%) stage III, and 1 (2.0%) stage IV patients. All patients were divided to 2 groups, FAP high group and FAP low group, which are 25 patients (51%) and 24 (49%) respectively. The cutoff for subgroups was defined at the median value. FAP (immune) expression at tumoral stroma was a significant predictive factor for lymph node metastasis (p Conclusions: Our clinicopathological analysis indicates that patients whose esophageal carcinoma have high levels of stromal FAP expression are more likely to have an aggressive disease progression and a potential development of metastases and recurrence. Although therapeutic strategies targeting the tumor cells have been generally inadequate in esophageal carcinomas yet, here we announce that a stroma-targeted therapy should be considered. Now we are ongoing to evaluate metastatic potential of CAFs in vitro and vivo, in order to elucidate the function of FAP expressing CAFs and, in future to establish a novel therapeutic strategy. Citation Format: Hajime Kashima, Kazuhiro Noma, Yuki Katsura, Takuya Kato, Ryoichi Katsube, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Correlation of FAP(fibroblast activation protein)-expressing cancer associated fibroblasts (CAFs) and tumor metastasis in esophageal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1560.

Enantioselective synthesis of a taxol C-ring fragment containing an allylsilane moiety is described. Diastereoselective [4 + 2] cycloaddition of the pyrone with ( R )- t -butylbenzyl vinyl ether followed by appropriate transformations gave a mixture of two regioisomeric cyclohexenyl sulfides, which was converted to the title compound with almost complete diastereo- and enantioselectivities by treating with Li and 4,4′-di- t -butylbiphenyl followed by quenching with chlorotrimethylsilane.

Background: Iron overload is known to cause cancer in animal models. Several studies have shown that iron deprivation treatment has a strong anti-cancer effect. However, it is unclear whether iron deprivation treatment suppresses cancer stem cells or not. A cancer stem cell model, miPS-LLCcm, was recently epigenetically established from murine induced pluripotent stem cells (miPS cells) in Okayama University. In this model, the green fluorescent protein (GFP) and the puromycin resistant gene were inserted into the 59-bp untranslated region of the Nanog gene of miPS cells. By this procedure, undifferentiated cancer progenitor cells are recognized as GFP positive cells. We then examined the iron dependency of these cancer stem cells both in in vitro and in vivo studies and we used this model to examine the possibility of cancer stem cells by iron deprivation. Materials and Methods: In in vitro studies, the miPS-LLCcm cells were used as cancer stem cells and colon26 and 4T1 cells were used as differentiated murine cancer cells. Puromycin was used to purify the cancer stem cells before seeding of the miPS-LLCcm cells. The dependency on iron for cell proliferation was examined following transferrin addition. Transferrin (Holo) was used to simulate an iron rich condition. Iron free medium and the iron chelators, Deferasirox and Deferoxamine, plus 1% fetal bovine serum (FBS) were used to simulate iron depletion conditions. Cell proliferation assays and flow cytometric analyses were performed 48 hours after adjustment of the iron concentration level. In in vivo studies, an iron depleted diet was used to simulate iron depleted conditions. Nude mice were divided into normal diet and iron depleted diet groups. The mice were fed with these diets for three weeks and then a suspension of miPS-LLCcm cells was injected into the backs of the nude mice. Tumor size was measured and the tumors were immunohistologically examined. Results: In the in vitro studies, transferrin strongly promoted the proliferation of cancer stem cells under iron depletion conditions compared to no transferrin(p Conclusions: Iron is a key element for the proliferation and differentiation of cancer stem cells. Iron controlling therapy including iron chelators is a novel therapeutic target of cancer stem cells. Citation Format: Takayuki Ninomiya, Toshiaki Ohara, Hajime Kashima, Ryoichi Katsube, Kazuhiro Noma, Yasuko Tomono, Akifumi Mizutani, Tomonari Kasai, Masaharu Seno, Shinji Kuroda, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuhiro Shirakawa, Shunsuke Kagawa, Toshiyoshi Fujiwara. Iron control is a novel therapeutic target of cancer stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4243. doi:10.1158/1538-7445.AM2015-4243

Background: Telomerase activation is considered to be a critical step in carcinogenesis and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We constructed an adenovirus 5 vector OBP-301 (Telomelysin), in which the hTERT promoter drives expression of E1A and E1B genes. OBP-301 causes selective replication and lysis of a variety of human cancer cells, and also inhibits the repair of radiation-induced DNA double-strand breaks, leading to radiosensitization. A phase I study has confirmed the safety and biological activity of intratumoral administration of OBP-301 alone in patients with advanced solid tumors in the United States. To further determine the feasibility, efficacy, and pharmacokinetics of OBP-301 in combination with radiotherapy, a phase I/II study was designed in elderly patients with esophageal cancer. Methods: Patients with histologically confirmed esophageal cancer who were not eligible for standard treatments such as surgery and chemotherapy were enrolled into this study (UMIN000010158). Study treatment consisted of intratumoral needle injections of OBP-301 on days 1, 18, and 32 of treatment. Radiation therapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. Virus administration was performed by intratumoral injection of the primary or metastatic tumor through a flexible endoscope. OBP-301 doses will be escalated initially in cohorts of two for the first 9 patients (1 × 10e10 and 1 × 10e11 virus particles [vp]). Six subsequent patients will receive the highest dose (1 × 10e12 vp). Virus shedding will be monitored in the saliva, sputum, urine, and plasma by a quantitative DNA-PCR assay. Results: Six patients were enrolled and treated in the cohort with 1 × 10e10 vp of OBP-301. The patients comprised 4 males and 2 females, with median age of 83.5 years (range, 68 to 92 years). Only two patients had prior platinum-based chemotherapy. By November 2014, 3 patients completed treatment. All patients developed a transient, self-limited lymphopenia. A 92-year-old female showed a grade 4 lymphopenia classified as being possibly related to the treatment, although it recovered by the interruption of radiation. No other virus-related toxicities were noted. Objective responses were complete response (CR) in 2 patients and partial response (PR) with tumor regression, resulting in reopening of the esophagus, in 1 patient. Pathological analysis in biopsy specimens obtained from completely responded patients demonstrated no viable malignant cells for 3 to 5 months after the treatment completion. Conclusions: Multiple courses of endoscopic OBP-301 injection in combination with locoregional radiotherapy were feasible and well tolerated in elderly patients with esophageal cancer, and appeared to provide clinical benefit. Citation Format: Shunsuke Tanabe, Hiroshi Tazawa, Shunsuke Kagawa, Kazuhiro Noma, Kiyoto Takehara, Takeshi Koujima, Hajime Kashima, Takuya Kato, Shinji Kuroda, Satoru Kikuchi, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Phase I/II trial of endoscopic intratumoral administration of OBP-301, a novel telomerase-specific oncolytic virus, with radiation in elderly esophageal cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT123. doi:10.1158/1538-7445.AM2015-CT123

The synthesis of a series of 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-2-arylbenzofuran and 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methylbenzofuran-2-carboxamide derivatives as novel alpha(2C)-adrenergic receptor antagonists are described. Their affinity at three different human alpha(2)-adrenergic receptors is reported, and some of these compounds exhibited high affinity for the alpha(2C)-adrenergic receptor with high subtype selectivity. Among them, compound 10e has been found to show the anti-L-dopa-induced dyskinetic activity in marmosets. The structure-activity relationship of these compounds is also discussed.

Enantioselective total synthesis of taxol has been accomplished. Coupling reaction of the optically pure A-ring hydroxy aldehyde with the aromatic C-ring fragment followed by Lewis acid mediated eight-membered B-ring cyclization gave the desired ABC endo-tricarbocycle. The C-ring moiety of this product was reduced under Birch conditions to the cyclohexadiene derivative, which was oxygenated by singlet oxygen from the convex β-face to give the C4β,C7β-diol stereoselectively. For introduction of the C19-methyl, the cyclopropyl ketone was prepared via cyclopropanation of the C-ring allylic alcohol or conjugate addition of a cyano group to the C-ring enone. Reductive cleavage of the cyclopropane ring followed by isomerization of the resulting enol to the corresponding ketone gave the crucial synthetic intermediate containing the C19-methyl group. Regioselective transformation of three hydroxyl groups of this intermediate, conversion of the C4-carbonyl group to the allyl chloride, and introduction of the C10-o...