Long non-coding RNA UCA1 enhances tamoxifen resistance in breast cancer cells through a miR-18a-HIF1α feedback regulatory loop

Abstract

Recent studies reported that long non-coding RNAs (lncRNAs) might play critical roles in regulating endocrine resistance of breast cancer. Urothelial carcinoma-associated 1 (UCA1) is an lncRNA with an oncogenic role in breast cancer. This study aimed to investigate whether UCA1 is involved in acquired tamoxifen resistance in estrogen receptor (ER)-positive cancer cells. Our findings reveal that tamoxifen induces UCA1 upregulation in ER-positive breast cancer cells in a HIF1α-dependent manner. UCA1 upregulation results in significantly enhanced tamoxifen resistance. The upregulated UCA1 sponges miR-18a, which is a negative regulator of HIF1α. Therefore, UCA1 upregulation is further enhanced through a miR-18a-HIF1α feedback loop. In addition, our data also showed that miR-18a is a modulator of tamoxifen sensitivity due to its regulative effect on cell cycle proteins. miR-18a inhibitor reduced the sensitivity of MCF-7 cells to tamoxifen, while miR-18a mimics sensitized BT474 cells to tamoxifen. Therefore, miR-18a downregulation also partly contributes to acquired tamoxifen resistance in the cancer cells. These findings provide some useful information for future clinical treatment of tamoxifen resistance.

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Serum HE4 superior to CA125 in predicting poorer surgical outcome of epithelial ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) remains the deadliest form of gynecological cancers. Optimal tumor debulking, no matter the primary or the interval, is the most important prognostic factor for EOC, so there is an urgent demand for biomarkers to predict surgical outcome. The aim of this study was to investigate whether serum human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) could predict surgical outcome of EOC. The levels of preoperative serum HE4 and CA125 were determined by electrochemiluminescence (ECLIA) in 82 EOC patients, comprising 39 subjected to primary debulking surgery (PDS) and 43 with extensive stage III or IV disease to neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS). Among 39 patients subjected to primary debulking surgery, HE4 was superior to CA125 in predicting surgical outcome (area under curve [AUC] 0.758 vs. 0.633). At a cutoff of 353.22 pmol/L, HE4 reached 77.4 % in sensitivity and 75 % in specificity. The prediction of surgical outcome of interval debulking surgery based on preoperative HE4 and CA125 values was performed in 43 patients who received NACT-IDS. The difference of AUC between HE4 and CA125 (0.793 vs. 0.663) indicating that HE4 was the better biomarker to predict surgical outcome of IDS. A pre-IDS HE4 value of 154.3 pmol/L is the optimal cutoff to identify patients who would not benefit from IDS with a sensitivity of 92.9 % and a specificity of 69 %. The change (>70 %) of HE4 before and after neoadjuvant chemotherapy could predict optimal interval debulking surgery. Serum HE4 was superior to CA125 in predicting surgical outcome of primary debulking surgery and interval debulking surgery. The change (absolute value or percentage) of HE4 in neoadjuvant chemotherapy could predict the outcome of interval debulking surgery.

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Study of apoptosis-related interactions in colorectal cancer

Abstract

Abnormalities in apoptotic functions contribute to the pathogenesis of colorectal cancer. In this study, molecular interactions behind the apoptotic regulation have been explored. For this purpose, enrichment analysis was performed considering microRNAs (miRNAs) that putatively target TP53 and altered during colon cancer. This revealed gene associated with both TP53 and miRNAs. Further analysis showed that a significant molecular interaction between the shortlisted candidates (TP53, miR-143, KRAS, BCL2, and PLK1) exists. Mutation study was conducted to confirm the clinical relevance of candidates. It showed that the mutation extent does not significantly alter survival in patients thus making these candidates suitable as drug targets. Overall, we showed the importance of interactions between TP53, miR-143, KRAS, BCL2, and PLK1 with respect to colorectal cancer using bioinformatics approach.

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Poly r(C) binding protein is post-transcriptionally repressed by MiR-490-3p to potentiate squamous cell carcinoma

Abstract

Squamous cell skin carcinoma remains a leading cause of cancer-related mortality with a huge cost of treatment, necessitating discovery and validation of potent therapeutic targets. Poly r(C) binding protein 1 (PCBP1) has been previously shown to function as a tumor suppressor. Previous work has shown that PCBP1 expression is inversely correlated to maintenance of cancer stem cells in squamous cell skin carcinoma and prostate cancer, respectively. However, the precise mechanism that regulates PCBP1 expression has not been elucidated. Here, we show that loss of PCBP1 protein expression observed in CD34+ COLO-16 cells is orchestrated by translational silencing. Translational silencing is caused by targeting of PCBP1 mRNA by miR-490-3p. Exogenous manipulation of miR-490-3p levels can accordingly modulate PCBP1 protein expression, thus suggesting that miR-490-3p as a potential biomarker in squamous cell skin cancer with therapeutic benefits.

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A critical overview of long non-coding RNA in glioma etiology 2016: an update

Abstract

With the development of whole genome and transcriptome sequencing technologies, a growing body of long non-coding RNAs (lncRNAs) has been identified and is receiving increasing attention. LncRNAs are non-protein encoding transcripts whose functions are crucial for advancing our comprehensive understanding of biological processes in human health and diseases, specifically glioma. It has been established that lncRNAs are differently expressed in the central nervous system and may play a vital role in glioma. As of June 2016, 20 lncRNAs have been identified that may play a role in glioma pathogenesis. Investigation into the role of lncRNAs in glioma may help to identify potential biomarkers which can improve the diagnosis and treatment of glioma. In this paper, we review current understanding of the function of lncRNAs in glioma initiation and progression.

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Geldanamycin, an inhibitor of Hsp90, increases paclitaxel-mediated toxicity in ovarian cancer cells through sustained activation of the p38/H2AX axis

Abstract

Paclitaxel is a mitotic inhibitor used in ovarian cancer chemotherapy. Unfortunately, due to the rapid genetic and epigenetic changes in adaptation to stress induced by anticancer drugs, cancer cells are often able to become resistant to single or multiple anticancer agents. However, it remains largely unknown how paclitaxel resistance happens. In this study, we generated a cell line of acquired resistance to paclitaxel therapy, A2780T, which is cross-resistant to other antimitotic drugs, such as PLK1 inhibitor or AURKA inhibitor. Immunoblotting revealed significant alterations in cell-cycle-related and apoptotic-related proteins involved in key signaling pathways. In particular, phosphorylation of p38, which activates H2AX, was significantly decreased in A2780T cells compared to the parental A2780 cells. Geldanamycin (GA), an inhibitor of Hsp90, sustained activation of the p38/H2AX axis, and A2780T cells were shown to be more sensitive to GA compared to A2780 cells. Furthermore, treatment of A2780 and A2780T cells with GA significantly enhanced sensitivity to paclitaxel. Meanwhile, GA cooperated with paclitaxel to suppress tumor growth in a mouse ovarian cancer xenograft model. In conclusion, GA may sensitize a subset of ovarian cancer to paclitaxel, particularly those tumors in which resistance is driven by inactivation of p38/H2AX axis.

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The biology of extracellular vesicles with focus on platelet microparticles and their role in cancer development and progression

Abstract

Extracellular vesicles (EVs) are a heterogeneous group of structures which can be classified into smaller in size and relatively homogenous exosomes (EXSMs)—spherical fragments of lipid bilayers from inner cell compartments—and bigger in size ectosomes (ECSMs)—a direct consequence of cell-membrane blebbing. EVs can be found in body fluids of healthy individuals. Their number increases in cancer and other pathological conditions. EVs can originate from various cell types, including leukocytes, erythrocytes, thrombocytes, and neoplastic cells. Platelet microparticles (PMPs) are the most abundant population of EVs in blood. It is well documented that PMPs, being a crucial element of EVs signaling, are involved in tumor growth, metastasis, and angiogenesis and may participate in the development of multidrug resistance by tumor cells. The aim of this review is to present the role of PMPs in carcinogenesis. The biology and functions of PMPs with a particular emphasis on the most recent scientific reports on EV properties are also characterized.

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IL-13 receptor α2 stimulates human glioma cell growth and metastasis through the Src/PI3K/Akt/mTOR signaling pathway

Abstract

Glioma is a malignant tumor that affects all kinds of people all over the world. It demonstrates remarkable infiltrative and invasive features. The high expression of interleukin-13 receptor subunit alpha-2 (IL-13Rα2) reportedly plays a pivotal role in some cancers. However, whether IL-13Rα2 contributes to glioma remains unknown. This study demonstrates that IL-13Rα2 is significantly up-regulated in human glioma tissue samples. It is also associated with late stages of disease progression and diminished survival in glioma patients. Gain- and loss-of-function studies demonstrate that IL-13Rα2 promotes the growth, migration, and invasion of glioma cells. In addition, mechanistic investigations show that IL-13Rα2 activates Scr, phosphatidylinositol 3 kinase (PI3K), Akt, and mTOR. Also, restraining Scr in glioma cells attenuates the activation of Scr/PI3K/Akt/mTOR pathway by IL-13Rα2, whereas the silencing of Scr markedly rescues the pro-invasive effect of IL-13Rα2. In conclusion, our results suggest that the high expression of IL-13Rα2 is significantly associated with the growth and metastasis of human glioma cells via the Scr/PI3K/Akt/mTOR pathway, while IL-13Rα2 may be a potential therapeutic target for glioma treatment.

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Emerging tale of UPR and cancer: an essentiality for malignancy

Abstract

A set of cellular response to counter any alteration in homeostasis of a cell originating at endoplasmic reticulum is collectively termed as unfolded protein response (UPR). It initially is adaptive in nature as to restore cellular normalcy failing in course often activates pro-apoptotic signaling pathway resulting in cell death. UPR has emerged as an essential adaptation mechanism that cross talk with various cellular processes for cancer pathogenesis. Interestingly, it plays diverse role in plethora of signaling pathways instrumental in transformation, cell invasion, cell migration, metastasis, neovascularization, proliferation, and maintenance of energy metabolism of cancerous cells. In cancerous cells, it is triggered by change in microenvironment of a cell usually driven by hypoxia, acidosis, and nutrient deprivation, which often leads to positive selection pressure involving the reprogramming of energy metabolism which promotes channelization of limited metabolites into the hexosamine biosynthetic pathway (HBP). Substantial evidences suggest the role of UPR in oncogene (Myc, mTOR, RAS, HER2) driven cancer transformation and progression. In this review, we have comprehensively underlined the role played by UPR in adaptation, transformation, proliferation, invasion, and metastasis of cancerous cells.

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Hint1 suppresses migration and invasion of hepatocellular carcinoma cells in vitro by modulating girdin activity

Abstract

Histidine triad nucleotide-binding protein 1 (Hint1) is a haploinsufficient tumor suppressor gene. Its role in cancer cell migration has not been previously speculated. In the current study, we examined the expression of Hint1 in metastatic and non-metastatic lymph nodes of hepatocellular carcinoma (HCC) patients and further elucidated the effect of Hint1 expression on girdin expression and phosphorylation of AKT and ERK1/2 and on the migration of HCC cells in vitro. Expression of Hint1 and girdin in primary HCC tissues and metastatic and non-metastatic lymph nodes was determined by RT-PCR assays. HepG2 cells were transfected with plasmid vectors overexpressing Hint1 or small interfering RNA (siRNA) targeting Hint1, girdin, Hint1 plus girdin, or the scrambled RNA. Migration and invasion of HCC cells were examined by wound and Transwell assays. Protein expression was detected by immunofluorescence and immunoblotting assays. RT-PCR assays revealed that the messenger RNA (mRNA) transcript levels of Hint1 were markedly lower than those of primary HCC tissues and non-metastatic lymph nodes (P < 0.01). By contrast, the mRNA transcript levels of girdin were significantly higher than non-metastatic lymph nodes (P < 0.05). Furthermore, siRNA knockdown of HINT1 resulted in a significant increase in the mRNA transcript levels of girdin in HepG2 cells (P < 0.05). Wound assays and Transwell assays showed that Hint1 knockdown by siRNA significantly enhanced the migration and invasion of HepG2 cells compared to HepG2 cells transfected with scrambled siRNA. Hint1 knockdown also led to significantly increased phosphorylation of girdin and AKT in HepG2 cells (P < 0.05), which, however, was effectively aborted by girdin knockdown by siRNA (P < 0.05). Hint1 is downregulated in metastatic lymph nodes and is implicated in migration and invasion of HCC cells in vitro by modulating girdin and AKT expression and phosphorylation. The Hint1-girdin-AKT signaling axis should be further dissected for its role in HCC migration and invasion and may be therapeutically targeted to suppress tumor growth and metastasis.

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TRPM7 channel inhibition mediates midazolam-induced proliferation loss in human malignant glioma

Abstract

The melastatin-like transient receptor potential 7 (TRPM7) has been implicated in proliferation or apoptosis of some cancers, indicating the potential of TRPM7 as an anti-anaplastic target. Here, we identified the characteristic TRPM7 channel currents in human malignant glioma MGR2 cells, which could be blocked by a pharmacologic inhibitor Gd³⁺. We mined the clinical sample data from Oncomine Database and found that human malignant glioma tissues expressed higher TRPM7 mRNA than normal brain ones. Importantly, we identified a widely used clinical anesthetic midazolam as a TRPM7 inhibitor. Midazolam treatment for seconds suppressed the TRPM7 currents and calcium influx, and treatment for 48 h inhibited the TRPM7 expression. The inhibitory effect on TRPM7 accounts for the proliferation loss and G₀/G₁ phase cell cycle arrest induced by midazolam. Our data demonstrates that midazolam represses proliferation of human malignant glioma cells through inhibiting TRPM7 currents, which may be further potentiated by suppressing the expression of TRPM7. Our result indicates midazolam as a pharmacologic lead compound with brain-blood barrier permeability for targeting TRPM7 in the glioma.

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Transcriptome sequencing of HER2-positive breast cancer stem cells identifies potential prognostic marker

Abstract

In cancer stem cell theory, breast cancer stem cells (BCSCs) are postulated to be the root cause of recurrence and metastasis in breast cancer. Discovery of new biomarkers and development of BCSC-targeted therapy are practical issues that urgently need to be addressed in the clinic. However, few breast cancer stem cell targets are known. Given that there are few BCSCs, performing transcriptome sequencing on them thus far has not been possible. With the emergence of single-cell sequencing technology, we have now undertaken such a study. We prepared single-cell suspensions, which were sorted using flow cytometry from breast tumor tissue and adjacent normal breast tissue from two HER2-positive patients. We obtained BCSCs, breast cancer cells, mammary cells, and CD44⁺ mammary cells. Transcriptome sequencing was then performed on these four cell types. Using bioinformatics, we identified 404 differentially expressed BCSC genes from the HER2-positive tumors and preliminary explored transcriptome characteristics of BCSCs. Finally, by querying a public database, we found that CA12 was a novel prognostic biomarker in HER2-positive breast cancer, which also had prognostic value in all breast cancer types. In conclusion, our results suggest that CA12 may be associated with BCSCs, especially HER2-positive BCSCs, and is a potential novel therapeutic target and biomarker.

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SRC ACTIVATES TROP2 VIA CYCLIN D1

Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of SRC tyrosine kinase activity in approximately ninety percent of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predict poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 [TACSTD2/Trop2/M1S1] is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, epitope characteristics and prostatosphere formation. Cyclin D1 was induced by v-Src, and Src kinase induction of Trop2 ICD nuclear accumulation, required cyclin D1. Cyclin D1 induced abundance of the Trop2 proteolytic cleavage activation components (PS2, TACE) and restrained expression of the inhibitory component of the Trop2 proteolytic complex (Numb). Prostate cancer patients with increased nuclear Trop2 ICD and cyclin D1, and reduced Numb, had reduced recurrence-free survival probability (hazard ratio 4.35). Cyclin D1 therefore serves as a transducer of v-Src-mediated induction of Trop2 ICD by enhancing abundance of the Trop2 proteolytic activation complex.

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Autophagy Inhibition as a Therapeutic Strategy

The finding that cancer chemotherapeutic drugs and ionizing radiation often promote autophagy has provided the foundation for clinical trials combining autophagy-blocking agents with antitumor drugs and radiation. The premise driving these trials is that therapy-induced autophagy is cytoprotective; consequently, inhibition of autophagy is anticipated to sensitize malignancies to therapy. However, it is well-established that autophagy may also mediate the toxicity of antitumor drugs while evidence also exists for a nonprotective function of autophagy. Consequently, given that it cannot be predicted what form autophagy will take upon treatment with chemotherapy or radiation, the current ongoing clinical trials are likely to generate contradictory or inconsistent results, with the potential consequence that autophagy inhibition could be dismissed as therapeutic strategy based on what are essentially false-negative outcomes. Appropriate interpretation of the outcomes of these trials would require knowledge as to whether the drugs or radiation used promote the cytoprotective form of autophagy in the tumor cells as well as whether the chloroquine or hydroxychloroquine actually inhibit the autophagy. Ultimately, it will be necessary to identify those patients for whom the strategy of autophagy inhibition would be anticipated to improve the response to therapy. However, this is currently not feasible in the absence of appropriate bioassays or predictive markers for characterization of the autophagy or the effectiveness of pharmacologic approaches for autophagy inhibition in the clinic. Cancer Res; 76(19); 1–5. ©2016 AACR.

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Vimentin-Specific Chromobodies to Visualize EMT in Real Time

The epithelial–mesenchymal transition (EMT) is a complex cellular program involved in the progression of epithelial cancers to a metastatic stage. Along this process, epithelial traits are repressed in favor of a motile mesenchymal phenotype. A detailed characterization and monitoring of EMT-related processes is required for the design of screening strategies needed to develop novel antimetastatic therapies. Overexpression of the canonical EMT biomarker vimentin correlates with increased tumor growth and invasiveness, as well as with reduced patient survival across various epithelial cancers. Moreover, recent findings have demonstrated an active role of vimentin in regulating and reorganizing the cellular architecture toward a migratory and invasive phenotype. However, current studies suffer from a lack of appropriate methods to trace the induction and dynamics of vimentin in cell-based assays. Recently, we have reported a novel intrabody (chromobody)–based approach to study the spatiotemporal organization of endogenous vimentin upon induction of EMT by high-content imaging. In this review, we discuss the relevance of the chromobody technology with regard to the visualization of EMT-related processes in living systems. Cancer Res; 76(19); 1–5. ©2016 AACR.

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B Cells, Cancer Immunity, and Autoantibodies

There is increasing evidence supporting a role for B cells in tumor immunology. Paraneoplastic syndromes occurring before a cancer diagnosis have pointed to the potential for harnessing the humoral immune response for early cancer detection. The presence of tumor-infiltrating B lymphocytes has been linked to a favorable clinical outcome in many types of cancers. However, B cells represent a heterogeneous population with functionally distinct subsets, and the balance among subtypes impacts tumor development. Here, we review recent findings related to B cells and to the humoral immune response in cancer and their translational significance. Cancer Res; 76(19); 1–5. ©2016 AACR.

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HERG inhibitors associated with better GBM survival

Purpose:Glioblastoma(GBM) is the most malignant primary brain tumor, with a median survival of less than two years. More effective therapeutic approaches are needed to improve clinical outcomes. Experimental Design:Glioblastoma patient-derived cells(GPDCs) were isolated from patient GBMs and implanted in mice to form xenografts. Immunohistochemistry was performed for hERG expression and tumor proliferation. Sphere-forming assays with hERG blocker E-4031 were performed on a highand low hERG expressing lines. A GBM TMA(115 patients) was used to correlate hERG expression with patient survival. Clinical data was analyzed to determine if patient survival was affected by incidental administration of hERG inhibitory drugs, and the correlative effect of patient GBM hERG expression levels. Results:hERG expression was upregulated in GBM xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared to low hERG-expressing GPDCs. GBM TMA analysis showed worse survival for GBM patients with high hERG expression versus low expression, 43.5 vs. 60.9 weeks respectively (p= 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared to patients who did not (p=0.0015). Subgroup analysis showed that GBM patients with high hERG expression who received hERG blockers had improved survival (p=0.0458). There was no difference in survival for low hERG-expressing GBM patients who received hERG blockers (p=0.4136). Conclusions:Our findings suggest that hERG is a potential GBM survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be re-purposed as adjuvant GBM therapy in high hERG-expressing GBM patients.

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RG7787 for Mesothelioma Therapy

Purpose: Evaluate anti-tumor efficacy of the reduced immunogenicity anti-mesothelin immunotoxin RG7787 plus nab-Paclitaxel against primary mesothelioma cell lines and tumor xenografts and utility of mesothelin as a biomarker of tumor response. Experimental Design: Early passage human malignant mesothelioma cell lines NCI-Meso16, NCI-Meso19, NCI-Meso21 and NCI-Meso29 were evaluated for sensitivity to RG7787 or nab-Paclitaxel alone or in combination. In addition, the anti-tumor activity of RG7787 plus nab-Paclitaxel was evaluated using NCI-Meso16, NCI-Meso21 and NCI-Meso29 tumor xenografts in immunodeficient mice. Serum mesothelin was measured at different time-points to determine if its levels correlated with tumor response. Results: All four primary mesothelioma cell lines highly expressed mesothelin with 41x103 to 346x103 mesothelin sites/cell and were sensitive to RG7787 with IC50 ranging from 0.3 to 10 ng/ml. Except for NCI-M-19, these cells were also sensitive to nab-Paclitaxel with IC50 of 10 to 25 ng/ml. In-vitro, RG7787 plus nab-Paclitaxel led to decreased cell viability compared to either agent alone. In NCI-Meso16 tumor xenografts, treatment with RG7787 plus nab-paclitaxel led to sustained complete tumor regressions. Similar anti-tumor efficacy was observed against NCI-Meso21 and NCI-Meso29 tumor xenografts. In all three tumor xenograft models changes in human serum mesothelin correlated with response to therapy and were undetectable in mice with complete tumor regression with RG7787 and nab-Paclitaxel. Conclusions: RG7787 plus nab-Paclitaxel is very active against primary human mesothelioma cells in vitro as well as in vivo, with serum mesothelin levels correlating with tumor response. These results indicate that this combination could be useful for treating patients with mesothelioma.

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Regulation of Head and Neck Squamous Cancer Stem Cells by PI3K and SOX2

Background: We have an incomplete understanding of the differences between cancer stem cells (CSCs) in human papillomavirus–positive (HPV-positive) and –negative (HPV-negative) head and neck squamous cell cancer (HNSCC). The PI3K pathway has the most frequent activating genetic events in HNSCC (especially HPV-positive driven), but the differential signaling between CSCs and non-CSCs is also unknown.

Methods: We addressed these unresolved questions using CSCs identified from 10 HNSCC patient-derived xenografts (PDXs). Sored populations were serially passaged in nude mice to evaluate tumorigenicity and tumor recapitulation. The transcription profile of HNSCC CSCs was characterized by mRNA sequencing, and the susceptibility of CSCs to therapy was investigated using an in vivo model. SOX2 transcriptional activity was used to follow the asymmetric division of PDX-derived CSCs. All statistical tests were two-sided.

Results: CSCs were enriched by high aldehyde dehydrogenase (ALDH) activity and CD44 expression and were similar between HPV-positive and HPV-negative cases (percent tumor formation injecting ≤ 1x10³ cells: ALDH⁺CD44^high = 65.8%, ALDH^-CD44^high = 33.1%, ALDH⁺CD44^high = 20.0%; and injecting 1x10⁵ cells: ALDH^-CD44^low = 4.4%). CSCs were resistant to conventional therapy and had PI3K/mTOR pathway overexpression (GSEA pathway enrichment, P < .001), and PI3K inhibition in vivo decreased their tumorigenicity (40.0%–100.0% across cases). PI3K/mTOR directly regulated SOX2 protein levels, and SOX2 in turn activated ALDH1A1 (P < .001 013C and 067C) expression and ALDH activity (ALDH⁺ [%] empty-control vs SOX2, 0.4% ± 0.4% vs 14.5% ± 9.8%, P = .03 for 013C and 1.7% ± 1.3% vs 3.6% ± 3.4%, P = .04 for 067C) in 013C and 067 cells. SOX2 enhanced sphere and tumor growth (spheres/well, 013C P < .001 and 067C P = .04) and therapy resistance. SOX2 expression prompted mesenchymal-to-epithelial transition (MET) by inducing CDH1 (013C P = .002, 067C P = .01), followed by asymmetric division and proliferation, which contributed to tumor formation.

Conclusions: The molecular link between PI3K activation and CSC properties found in this study provides insights into therapeutic strategies for HNSCC. Constitutive expression of SOX2 in HNSCC cells generates a CSC-like population that enables CSC studies.

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Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression

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Statistical controversies in clinical research: prognostic gene signatures are not (yet) useful in clinical practice

With the genomic revolution and the era of targeted therapy, prognostic and predictive gene signatures are becoming increasingly important in clinical research. They are expected to assist prognosis assessment and therapeutic decision making. Notwithstanding, an evidence-based approach is needed to bring gene signatures from the laboratory to clinical practice. In early breast cancer, multiple prognostic gene signatures are commercially available without having formally reached the highest levels of evidence-based criteria. We discuss specific concepts for developing and validating a prognostic signature and illustrate them with contemporary examples in breast cancer. When a prognostic signature has not been developed for predicting the magnitude of relative treatment benefit through an interaction effect, it may be wishful thinking to test its predictive value. We propose that new gene signatures be built specifically for predicting treatment effects for future patients and outline an approach for this using a cross-validation scheme in a standard phase III trial. Replication in an independent trial remains essential.

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Overuse of colorectal cancer screening services in the United States and its implications

As a standard way for prevention and early detection of colorectal cancer (CRC), colonoscopy has been used for CRC screening in the United States for more than one decade. An article entitled "Assessing Colore...

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Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis.

Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis.

Cancer Biol Ther. 2016 Sep 13;:0

Authors: Reilly JE, Neighbors JD, Hohl RJ

Abstract
The isoprenoid biosynthetic pathway (IBP) plays a critical role in providing substrates and enzymes necessary for the post-translational modification and thus activation of a number of proteins involved in prostate cancer metastasis. Previous work by our lab found novel compound disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which inhibits the IBP enzyme geranylgeranyl diphosphate synthase (GGDPS), reduced protein geranylgeranylation without altering protein farnesylation. This activity significantly reduced adrenal gland tumor burden in a murine model of human prostate cancer metastasis which relied on treatment of established disease. The present study determined the ability of GGDPS inhibition to slow the development of prostate cancer metastasis in a preventative murine model. Using tail vein injection of human derived PC-3 prostate cancer cells four days after initiating daily GGOHBP or vehicle treatments, we found GGOHBP significantly reduced whole body tumor burden, significantly slowed the development of tumors, and prolonged overall survival as compared to vehicle treated animals. The observed reduction in soft tissue tumor burden corresponded to a biochemical reduction in Rap1A geranylgeranylation, which for prostate cancer is important in its own merit and which serves as a surrogate marker for Rho family, i.e. Rac, protein modification. This effect was present in all treated mice pointing to strong target engagement, which was not observed in non-tumor burdened tissues or control mice. Our findings reiterate a role for protein geranylgeranylation in the development of prostate cancer metastasis in vivo.

PMID: 27624889 [PubMed - as supplied by publisher]

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Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis.

Related Articles

Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis.

Cancer Biol Ther. 2016 Sep 13;:0

Authors: Reilly JE, Neighbors JD, Hohl RJ

Abstract
The isoprenoid biosynthetic pathway (IBP) plays a critical role in providing substrates and enzymes necessary for the post-translational modification and thus activation of a number of proteins involved in prostate cancer metastasis. Previous work by our lab found novel compound disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which inhibits the IBP enzyme geranylgeranyl diphosphate synthase (GGDPS), reduced protein geranylgeranylation without altering protein farnesylation. This activity significantly reduced adrenal gland tumor burden in a murine model of human prostate cancer metastasis which relied on treatment of established disease. The present study determined the ability of GGDPS inhibition to slow the development of prostate cancer metastasis in a preventative murine model. Using tail vein injection of human derived PC-3 prostate cancer cells four days after initiating daily GGOHBP or vehicle treatments, we found GGOHBP significantly reduced whole body tumor burden, significantly slowed the development of tumors, and prolonged overall survival as compared to vehicle treated animals. The observed reduction in soft tissue tumor burden corresponded to a biochemical reduction in Rap1A geranylgeranylation, which for prostate cancer is important in its own merit and which serves as a surrogate marker for Rho family, i.e. Rac, protein modification. This effect was present in all treated mice pointing to strong target engagement, which was not observed in non-tumor burdened tissues or control mice. Our findings reiterate a role for protein geranylgeranylation in the development of prostate cancer metastasis in vivo.

PMID: 27624889 [PubMed - as supplied by publisher]

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Phase I study of the second-generation, recombinant, human EGFR antibody necitumumab in Japanese patients with advanced solid tumors

Abstract

Purpose

To establish the safety and pharmacokinetic profile of necitumumab in Japanese patients with advanced solid tumors not responsive to standard therapy or for which no standard therapy was available.

Methods

In this phase I study, patients aged ≥20 years with advanced solid tumors, and an Eastern Cooperative Oncology Group performance statuses of 0–1 were enrolled in a 3 + 3 design, with dose-escalation based on dose-limiting toxicity (DLT). Planned dose levels were: cohort 1: 600 mg IV, days 1 and 8, every 3 weeks; cohort 2: 800 mg IV, day 1, every 2 weeks; and cohort 3: 800 mg IV, days 1 and 8, every 3 weeks. After the first 6-week cycle, patients with an objective response or stable disease could continue to receive necitumumab (same dose and schedule) until disease progression or other withdrawal criteria were met. Safety, antitumor activity, and pharmacokinetics were assessed.

Results

Fourteen of 15 enrolled patients received all scheduled infusions in cycle 1 (median cycles: N = 2, range 1–4). No DLTs were observed. The most common treatment-emergent adverse events were headache (73 %), dry skin (67 %), pruritus (60 %), and rash (53 %), mostly grade 1/2. All patients achieved serum trough concentrations >40 µg/mL, a level associated with antitumor activity in preclinical models. No patients had an objective response; stable disease was seen in 67 % of patients.

Conclusions

Necitumumab can be safety administered to Japanese patients at dose levels established in Western patients: 800 mg every 2 weeks, or on days 1 and 8 of a 3-week cycle.

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A dose-finding study for oxaliplatin, irinotecan, and S-1 (OIS) in patients with metastatic or recurrent gastrointestinal cancer

Abstract

Purposes

To determine the maximum tolerated dose (MTD), recommended dose (RD), and activity of combined oxaliplatin, irinotecan, and S-1 chemotherapy for metastatic or recurrent gastrointestinal (GI) cancer.

Methods

Oxaliplatin and irinotecan were administered intravenously on day 1, and S-1 was administered orally on days 1–7, every 2 weeks. This phase I study used the following dose levels for oxaliplatin/irinotecan/S-1: level 1, 85/120/60 mg/m²; level 2, 85/120/80 mg/m²; level 3, 85/120/100 mg/m²; level 4, 85/150/100 mg/m²; and level 5, 85/180/100 mg/m². Treatment was repeated for a maximum of 12 cycles, until disease progression, or until unacceptable toxicity.

Results

Twenty-four patients were enrolled between October 2012 and February 2014 (median age 59 years). During the first cycle, one of the six patients in levels 1, 3, and 4 developed a dose-limiting toxicity (grade 3 febrile neutropenia), and none of the three patients in level 5 developed a dose-limiting toxicity. As the planned maximum dose did not reach the MTD, the level 5 dose was defined as the RD. Twenty-one patients were evaluated for response, which included 2 cases of complete response and 8 cases of partial response, with an overall response rate of 47.6 %.

Conclusions

The combination of oxaliplatin, irinotecan, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced GI cancer. The RD was 85 mg/m² of oxaliplatin, 180 mg/m² of irinotecan, and 100 mg/m² of S-1 every 2 weeks.

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Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis.

Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis.

Cancer Biol Ther. 2016 Sep 13;:0

Authors: Reilly JE, Neighbors JD, Hohl RJ

Abstract
The isoprenoid biosynthetic pathway (IBP) plays a critical role in providing substrates and enzymes necessary for the post-translational modification and thus activation of a number of proteins involved in prostate cancer metastasis. Previous work by our lab found novel compound disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which inhibits the IBP enzyme geranylgeranyl diphosphate synthase (GGDPS), reduced protein geranylgeranylation without altering protein farnesylation. This activity significantly reduced adrenal gland tumor burden in a murine model of human prostate cancer metastasis which relied on treatment of established disease. The present study determined the ability of GGDPS inhibition to slow the development of prostate cancer metastasis in a preventative murine model. Using tail vein injection of human derived PC-3 prostate cancer cells four days after initiating daily GGOHBP or vehicle treatments, we found GGOHBP significantly reduced whole body tumor burden, significantly slowed the development of tumors, and prolonged overall survival as compared to vehicle treated animals. The observed reduction in soft tissue tumor burden corresponded to a biochemical reduction in Rap1A geranylgeranylation, which for prostate cancer is important in its own merit and which serves as a surrogate marker for Rho family, i.e. Rac, protein modification. This effect was present in all treated mice pointing to strong target engagement, which was not observed in non-tumor burdened tissues or control mice. Our findings reiterate a role for protein geranylgeranylation in the development of prostate cancer metastasis in vivo.

PMID: 27624889 [PubMed - as supplied by publisher]

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Phase I study of the second-generation, recombinant, human EGFR antibody necitumumab in Japanese patients with advanced solid tumors

Abstract

Purpose

To establish the safety and pharmacokinetic profile of necitumumab in Japanese patients with advanced solid tumors not responsive to standard therapy or for which no standard therapy was available.

Methods

In this phase I study, patients aged ≥20 years with advanced solid tumors, and an Eastern Cooperative Oncology Group performance statuses of 0–1 were enrolled in a 3 + 3 design, with dose-escalation based on dose-limiting toxicity (DLT). Planned dose levels were: cohort 1: 600 mg IV, days 1 and 8, every 3 weeks; cohort 2: 800 mg IV, day 1, every 2 weeks; and cohort 3: 800 mg IV, days 1 and 8, every 3 weeks. After the first 6-week cycle, patients with an objective response or stable disease could continue to receive necitumumab (same dose and schedule) until disease progression or other withdrawal criteria were met. Safety, antitumor activity, and pharmacokinetics were assessed.

Results

Fourteen of 15 enrolled patients received all scheduled infusions in cycle 1 (median cycles: N = 2, range 1–4). No DLTs were observed. The most common treatment-emergent adverse events were headache (73 %), dry skin (67 %), pruritus (60 %), and rash (53 %), mostly grade 1/2. All patients achieved serum trough concentrations >40 µg/mL, a level associated with antitumor activity in preclinical models. No patients had an objective response; stable disease was seen in 67 % of patients.

Conclusions

Necitumumab can be safety administered to Japanese patients at dose levels established in Western patients: 800 mg every 2 weeks, or on days 1 and 8 of a 3-week cycle.

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A dose-finding study for oxaliplatin, irinotecan, and S-1 (OIS) in patients with metastatic or recurrent gastrointestinal cancer

Abstract

Purposes

To determine the maximum tolerated dose (MTD), recommended dose (RD), and activity of combined oxaliplatin, irinotecan, and S-1 chemotherapy for metastatic or recurrent gastrointestinal (GI) cancer.

Methods

Oxaliplatin and irinotecan were administered intravenously on day 1, and S-1 was administered orally on days 1–7, every 2 weeks. This phase I study used the following dose levels for oxaliplatin/irinotecan/S-1: level 1, 85/120/60 mg/m²; level 2, 85/120/80 mg/m²; level 3, 85/120/100 mg/m²; level 4, 85/150/100 mg/m²; and level 5, 85/180/100 mg/m². Treatment was repeated for a maximum of 12 cycles, until disease progression, or until unacceptable toxicity.

Results

Twenty-four patients were enrolled between October 2012 and February 2014 (median age 59 years). During the first cycle, one of the six patients in levels 1, 3, and 4 developed a dose-limiting toxicity (grade 3 febrile neutropenia), and none of the three patients in level 5 developed a dose-limiting toxicity. As the planned maximum dose did not reach the MTD, the level 5 dose was defined as the RD. Twenty-one patients were evaluated for response, which included 2 cases of complete response and 8 cases of partial response, with an overall response rate of 47.6 %.

Conclusions

The combination of oxaliplatin, irinotecan, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced GI cancer. The RD was 85 mg/m² of oxaliplatin, 180 mg/m² of irinotecan, and 100 mg/m² of S-1 every 2 weeks.

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Synergistic effect of fenretinide and curcumin for treatment of non-small cell lung cancer

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Biologic and Clinical Perspectives on Thyroid Cancer

Advances in the understanding of the genetic and biologic characteristics of thyroid cancer, coupled with the development of new molecular targeted therapeutics, have led to the improved diagnosis and treatment of patients with this cancer. In this review, we focus on the effect of these…

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