A Case of High-Grade Neuroendocrine Carcinoma That Improved with Bevacizumab plus Modified FOLFOX6 as the Fourth-Line Chemotherapy

High-grade neuroendocrine carcinoma differs from usual neuroendocrine carcinoma, and its prognosis is dismal. In this case report, a case of high-grade neuroendocrine carcinoma that improved with bevacizumab plus modified FOLFOX6 as the fourth-line chemotherapy is presented. A 29-year-old male with a huge liver tumor was diagnosed with high-grade neuroendocrine carcinoma originating from the liver. Multiple liver and bone metastases were found one month after surgery. He was treated with three chemotherapy regimens used for the management of small-cell lung cancer with extensive disease. However, none of them could be maintained because of tumor progression. He was then treated with bevacizumab plus modified FOLFOX6 as the fourth-line regimen. Dramatic tumor shrinkage was obtained, and a partial response was achieved. This case suggests that high-grade neuroendocrine carcinoma can be treated with bevacizumab in combination with cytotoxic chemotherapy

A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring human epidermal growth factor receptor 2 amplification (JUPITER trial)

Introduction: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol. Methods/Design: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response. Discussion: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab. Trial registration: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150

Id4, a New Candidate Gene for Senile Osteoporosis, Acts as a Molecular Switch Promoting Osteoblast Differentiation

Excessive accumulation of bone marrow adipocytes observed in senile osteoporosis or age-related osteopenia is caused by the unbalanced differentiation of MSCs into bone marrow adipocytes or osteoblasts. Several transcription factors are known to regulate the balance between adipocyte and osteoblast differentiation. However, the molecular mechanisms that regulate the balance between adipocyte and osteoblast differentiation in the bone marrow have yet to be elucidated. To identify candidate genes associated with senile osteoporosis, we performed genome-wide expression analyses of differentiating osteoblasts and adipocytes. Among transcription factors that were enriched in the early phase of differentiation, Id4 was identified as a key molecule affecting the differentiation of both cell types. Experiments using bone marrow-derived stromal cell line ST2 and Id4-deficient mice showed that lack of Id4 drastically reduces osteoblast differentiation and drives differentiation toward adipocytes. On the other hand knockdown of Id4 in adipogenic-induced ST2 cells increased the expression of Pparγ2, a master regulator of adipocyte differentiation. Similar results were observed in bone marrow cells of femur and tibia of Id4-deficient mice. However the effect of Id4 on Pparγ2 and adipocyte differentiation is unlikely to be of direct nature. The mechanism of Id4 promoting osteoblast differentiation is associated with the Id4-mediated release of Hes1 from Hes1-Hey2 complexes. Hes1 increases the stability and transcriptional activity of Runx2, a key molecule of osteoblast differentiation, which results in an enhanced osteoblast-specific gene expression. The new role of Id4 in promoting osteoblast differentiation renders it a target for preventing the onset of senile osteoporosis

Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells

Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), is frequently overexpressed in non-small-cell lung cancer (NSCLC) and that an EZH2 inhibitor, 3-deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH2 was recently shown to be required for the activity of histone deacetylases (HDACs) that interact with another PRC2 protein, EED. To develop a more effective epigenetic therapy for NSCLC, we determined the effects of co-treatment with 3-deazaneplanocin A and the HDAC inhibitor vorinostat (SAHA) in NSCLC cells. The co-treatment synergistically suppressed the proliferation of all tested NSCLC cell lines, regardless of their epidermal growth factor receptor (EGFR) status. The synergistic effect was associated with slightly decreased histone H3 lysine 27 trimethylation, modestly increased histone acetylation, and the depletion of EZH2 and other PRC2 proteins. The co-treatment resulted in an accumulation of p27Kip1, decrease in cyclin A, and increased apoptotic fraction in an additive/synergistic manner. Interestingly, the co-treatment strongly suppressed EGFR signaling, not only in EGFR-wild-type NSCLC cells, but also in EGFR-mutant cells, mainly through dephosphorylation of EGFR. Furthermore, the co-treatment suppressed the in vivo tumor growth of EGFR-mutant, EGFR-tyrosine kinase-resistant H1975 cells more effectively than did each agent alone, without visible toxicity. These results suggest that the combined pharmacological targeting of EZH2 and HDACs may provide more effective epigenetic therapeutics for NSCLC

Crystalline silica-exposed human lung epithelial cells presented enhanced anchorage-independent growth with upregulated expression of BRD4 and EZH2 in autocrine and paracrine manners.

Crystalline silica-induced inflammation possibly facilitates carcinogenesis. Here, we investigated its effect on lung epithelium damage. We prepared conditioned media of immortalized human bronchial epithelial cell lines (hereinafter bronchial cell lines) NL20, BEAS-2B, and 16HBE14o- pre-exposed to crystalline silica (autocrine crystalline silica conditioned medium), a phorbol myristate acetate-differentiated THP-1 macrophage line, and VA13 fibroblast line pre-exposed to crystalline silica (paracrine crystalline silica conditioned medium). As cigarette smoking imposes a combined effect on crystalline silica-induced carcinogenesis, a conditioned medium was also prepared using the tobacco carcinogen benzo[a]pyrene diol epoxide. Crystalline silica-exposed and growth-suppressed bronchial cell lines exhibited enhanced anchorage-independent growth in autocrine crystalline silica and benzo[a]pyrene diol epoxide conditioned medium compared with that in unexposed control conditioned medium. Crystalline silica-exposed nonadherent bronchial cell lines in autocrine crystalline silica and benzo[a]pyrene diol epoxide conditioned medium showed increased expression of cyclin A2, cdc2, and c-Myc, and of epigenetic regulators and enhancers, BRD4 and EZH2. Paracrine crystalline silica and benzo[a]pyrene diol epoxide conditioned medium also accelerated the growth of crystalline silica-exposed nonadherent bronchial cell lines. Culture supernatants of nonadherent NL20 and BEAS-2B in crystalline silica and benzo[a]pyrene diol epoxide conditioned medium had higher EGF concentrations, whereas those of nonadherent 16HBE14o- had higher TNF-α levels. Recombinant human EGF and TNF-α promoted anchorage-independent growth in all lines. Treatment with EGF and TNF-α neutralizing antibodies inhibited cell growth in crystalline silica conditioned medium. Recombinant human TNF-α induced BRD4 and EZH2 expression in nonadherent 16HBE14o-. The expression of γH2AX occasionally increased despite PARP1 upregulation in crystalline silica-exposed nonadherent lines with crystalline silica and benzo[a]pyrene diol epoxide conditioned medium. Collectively, crystalline silica- and benzo[a]pyrene diol epoxide-induced inflammatory microenvironments comprising upregulated EGF or TNF-α expression may promote crystalline silica-damaged nonadherent bronchial cell proliferation and oncogenic protein expression despite occasional γH2AX upregulation. Thus, carcinogenesis may be cooperatively aggravated by crystalline silica-induced inflammation and genotoxicity

Impact of histamine type-2 receptor antagonists on the anticancer efficacy of gefitinib in patients with non-small cell lung cancer

Purpose Gefitinib is one of the standard treatments for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutations. It has been reported that acid suppressants (AS) decrease the anti-tumor effect of gefitinib by reducing its solubility. AS is sometimes necessary in cancer patients; however, previous reports have not shown the most compatible AS with gefitinib administration in cancer patients. This study was conducted to determine if histamine type 2 receptor antagonists (H2RAs) can affect the anti-tumor efficacy of gefitinib. Methods Eighty-seven patients with NSCLC who were administered gefitinib were retrospectively investigated. Patients who were co-administered H2RA were compared with non-AS control patients. H2RA was administered once a day at about 3-5 or 8-12 h after gefitinib intake. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR), and adverse effects. Results Median PFS in H2RA group and control group was 8.0 months and 9.0 months, respectively, with no significant difference (p = 0.82). The incidence of liver dysfunction was significantly less in patients administered H2RA, whereas there were no differences between the two groups with regard to skin toxicity and diarrhea. Multivariate analysis suggested that H2RA co-administration is not a risk factor for worse PFS and OS (hazard ratio of 0.95, 0.86; 95% confidence interval of 0.60-1.48, 0.52-1.43;p = 0.82 and 0.60, respectively). Conclusion This study demonstrated that concomitant administration of H2RA with gefitinib does not affect the efficacy of gefitinib