Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors.

Small-cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine carcinoma of the lung associated with early metastasis and an exceptionally poor prognosis. Little progress has been made in developing efficacious targeted therapy for this recalcitrant disease. Herein, we showed that H3.3, encoded by two genes (H3F3A and H3F3B), was prominently overexpressed in SCLC. Darinaparsin (ZIO-101), a derivative of arsenic trioxide, dose- and time-dependently inhibited the viability of SCLC cells in an H3.3-dependent manner. More importantly, ZIO-101 treatment resulted in substantial accumulation of H3.3 and PARP1 besides induction of G2/M cell cycle arrest and apoptosis in SCLC cells. Through integrative analysis of the RNA-seq data from Cancer Cell Line Encyclopedia dataset, JNCI and Genomics of Drug Sensitivity in Cancer 2 datasets, we found that H3F3A expression was negatively correlated with the IC50 values of PARP inhibitors (PARPi). Furthermore, co-targeting H3.3 and PARP1 by ZIO-101 and BMN673/olaparib achieved synergistic growth inhibition against SCLC in vitro and in vivo. In conclusion, it is feasible to target H3.3 by ZIO-101 to potentiate the response rate of PARPi in SCLC patients.

FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11.

The response rate of topotecan, as a second-line chemotherapeutic drug for small cell lung cancer, is ~20%. DNA/RNA helicase SLFN11 (schlafen family member 11), a member of the Schlafen (SLFN) family, is a crucial determinant of response to many DNA damaging agents, expression of SLFN11 tends to augment the antitumor effects of the commonly used DNA-targeting agents. In the present study we investigated how SLFN11 expression regulated the sensitivity of small cell lung cancer to topotecan. We showed that SLFN11 expression levels were positively associated with the sensitivity to topotecan in a panel of seven SCLC cell lines. Topotecan treatment induced different patterns of the DNA response network in SCLC cells: DNA damage response (DDR) was more prominently activated in SLFN11-deficient SCLC cell line H82 than in SLFN11-plentiful SCLC cell line DMS273, whereas topotecan induced significant accumulation of p-Chk1, p-RPA2 and Rad51 in H82 cells, but not in DMS273 cells. We unraveled that SLFN11 expression was highly negatively correlated to the methylation of the SLFN11 promoter. HDAC inhibitors FK228 and SAHA dose-dependently increased SLFN11 expression through suppressing DNA methylation at the SLFN11 promoter, thereby sensitizing SCLC cells to topotecan. Finally, we assessed the methylation status of the SLFN11 promoter in 27 SCLC clinical specimens, and found that most of the clinical samples (24/27) showed DNA methylation at the SLFN11 promoter. In conclusion, it is feasible to combine topotecan with FK228 to improve the response rate of topotecan in SCLC patients.

Combinations of proteasome inhibitors with obatoclax are effective for small cell lung cancer.

Proteasome inhibitors, bortezomib (BTZ), and carfilzomib (CFZ) are approved drugs for hematological malignancies, but lack anticancer activities against most solid tumors. Small cell lung cancer (SCLC) is a very aggressive neuroendocrine carcinoma of the lungs demanding effective therapy. In this study we investigated whether BTZ or CFZ combined with obatoclax (OBX), an antagonist for MCL-1 and a pan-BCL family inhibitor, could cause synergistic growth inhibition of SCLC cells. We showed that combined application of BTZ or CFZ with OBX caused synergistic growth inhibition of human SCLC cell lines (H82, H526, DMS79, H196, H1963, and H69) than single agent alone. Both BTZ-OBX and CFZ-OBX combinations displayed marked synergism on inducing apoptosis (~50% increase vs BTZ or CFZ alone). A comprehensive proteomics analysis revealed that BTZ preferentially induced the expression of MCL-1, an antiapoptotic protein, in SCLC cells. Thus, proteasome inhibitor-OBX combinations could specifically induce massive growth inhibition and apoptosis in SCLC cells. Subsequent proteome-wide profiling analysis of activated transcription factors suggested that BTZ- or CFZ-induced MCL-1 upregulation was transcriptionally driven by FOXM1. In nude mice bearing in SCLC H82 xenografts, both BTZ-OBX, and CFZ-OBX combinations exhibited remarkable antitumor activities against SCLC tumors evidenced by significant reduction of tumor size and the proliferation marker Ki-67 signals in tumor tissues as compared with single agent alone. Thus, proteasome inhibitor-OBX combinations are worth immediate assessments for SCLC in clinical settings.

Metachronous colorectal cancer in Taiwan: analyzing 20 years of data from Taiwan Cancer Registry.

BACKGROUND: The risk of metachronous colorectal cancer in patients with colorectal cancer is higher than the rate of sporadic colorectal cancer in the average population. We conducted a large-scale, population-based study, with many more clinical cases than in previously published studies, to calculate the incidence of metachronous colorectal cancer. METHODS: This is a retrospective study based on data obtained from the Taiwan Cancer Registry from 1988 to 2007. Between 1988 and 2002, we analyzed 70,906 patients who were diagnosed with colon or rectal cancer and traced the occurrence of metachronous lesions with at least 5 years of follow-up. RESULTS: Of these patients, 1,192 (730 males, 462 females; mean age 62.73 ± 12.92 years) developed metachronous cancers. The 15-year cumulative incidence of metachronous cancer was 1.68%. Within 2 years of the index cancer, 51.69% of the metachronous cancers appeared, and 61.27% of the metachronous cancers appeared within 3 years. CONCLUSIONS: Most metachronous lesions were noted within 3 years of initial diagnosis of the index cancer. Surveillance colonoscopy to ensure the absence of metachronous disease is essential for patients after curative surgery within 1 year, especially for those patients who did not receive complete colonoscopy before their first operation for colorectal cancer.

Evaluation of the appropriate age range of colorectal cancer screening based on the changing epidemiology in the past 20 years in taiwan.

Introduction. According to the recommendation of the United States Preventative Services Task Force, most countries provide average-risk screening for colorectal cancers (CRCs) between the ages of 50 and 75 years. However, the age range of screening should be modified because of an increasing life span. Methods. Totally 124,314 CRC cases were registered in Taiwan Cancer Registry from 1988 to 2007. The 20-year study period was divided into four 5-year increments. We divided the patients into four age groups (under age 50, age 50-74, age 74-84, and over age 85) in each increment to determine whether there were changes in the age distribution. Results. In the subgroup of patients under age 50, the number of CRC cases increased, but they accounted for a decreasing proportion of the total CRCs. In the 50-74 age group, the proportion of CRC cases also dropped. In contrast, the proportion increased in the 75-84 age group. Therefore, 43.63% of CRC patients would not be delegated to screen in the period of 2003-2007 if the CRC screening were restricted in the 50-74 age group. Conclusions. CRC screening for healthy individuals aged over 75 years is necessary.

Gender differences in colorectal cancer during the past 20 years in Taiwan.

PURPOSE: Gender differences in colorectal cancer (CRC) incidence have been previously reported. We designed this population-based study to determine if this gender difference was restricted to specific patient subgroups. METHODS: Using the Taiwan Cancer Registry database, we identified a total of 124,314 CRCs registered from 1988 to 2007. We compared the incidence of CRCs by gender in all CRCs, in colon and rectal cancers considered separately, and in right-sided versus left-sided colon cancers. RESULTS: In individuals aged 50 years and older, the incidence of CRCs was lower in females compared with males. For right-sided colon cancers, the incidence in both genders was similar. Because the proportion of right-sided colon cancer accounted for only one fourth of the total CRCs, its influence on the incidence of total CRCs is reduced. CONCLUSIONS: Although the incidence of total CRCs is male dominant, the actual gender difference in CRC incidence in Taiwan is limited to the left side of the colon.