Search

Objective: To review and evaluate vismodegib, the first US Food and Drug Administration (FDA) approved treatment for locally advanced (laBCC) or metastatic basal cell carcinoma (mBCC) that has recurred after surgery or for patients in which surgery or radiation is not an option. Data Sources: A literature search using PubMed was conducted through January 2013, using the terms vismodegib, GDC-0449, and Erivedge. Additional literature was found through the reference citations of identified articles. Study Selection and Data Extraction: Potential sources were limited to human studies published in English with a priority placed on those focused on laBCC or mBCC. Data Synthesis: Vismodegib is a selective inhibitor of the hedgehog (Hh) pathway approved for the treatment of laBCC or mBCC that has recurred after surgery, or for patients for whom surgery or radiation is contraindicated. Vismodegib inhibits cancer cell growth and survival by binding Smoothened, a transmembrane protein involved in the Hedgehog signal transduction. Vismodegib is administered orally at a dose of 150 mg daily. It is primarily eliminated through the feces unchanged but does have some oxidative metabolites produced from the recombinant cytochrome P450 (CYP) 2C9 and CYP3A4/5. Despite CYP450 involvement, it appears to have very few drug interactions. The most common adverse events reported with vismodegib include muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, anorexia, and diarrhea. FDA approval was based on a single arm phase II study that demonstrated an objective response rate of 30% in mBCC patients and 45% in laBCC patients. Vismodegib was approved by the FDA on January 30, 2012 for use in patients with advanced basal cell carcinoma, and continues to be studied in other patient populations for additional potential uses. Conclusions: Based on a review of current evidence, vismodegib provides an effective and well-tolerated treatment for otherwise untreatable basal cell carcinoma.

MicroRNAs (miRNAs) are endogenous, non-coding RNA transcripts that regulate gene expression. Here, we report 175 putative novel miRNAs identified in uterine cancers profiled by Next Generation Sequencing. Our data indicate that one of these putative miRNAs (BCM-173) is conserved across multiple species and is expressed at levels similar to known human miRNAs. Functionally, this miRNA promotes the growth and migration of uterine cancer cell lines by targeting vinculin and altering the distribution of focal adhesions. These results expand our insight into the repertoire of human miRNAs and identify novel pathways by which dysregulated miRNA expression promotes uterine cancer growth.

Uterine leiomyosarcoma (uLMS) is an aggressive malignancy characterized by its early metastasis, high rates of recurrence, and poor prognosis. Multiple obstacles complicate the clinical management of uLMS. These include the fact that most uLMS are typically identified only after a woman has undergone hysterectomy or myomectomy, the limited efficacy of adjuvant therapy for early stage disease, and the poor response of metastatic disease to current treatments. Here, we discuss recent insights into the molecular basis of uLMS and discuss emerging options for its clinical management. Particular attention is given to the biologic basis of these strategies with the goal of understanding the rationale motivating their use.

Dysregulated microRNA (miRNA) expression is a well-established feature of human cancer. However, the role of specific miRNAs in determining cancer outcomes remains unclear. Using Level 3 expression data from the Cancer Genome Atlas (TCGA), we identified 61 miRNAs that are associated with overall survival in 469 ovarian cancers profiled by microarray (p

Introduction: UPSC is a rare but aggressive malignancy that accounts for no more than 5 to 10% of uterine cancers, but more than 40% of associated uterine cancer deaths. The molecular events responsible for the poor clinical outcomes observed with UPSC are largely unknown. Epithelial cell transforming sequence 2 oncogene (ECT2) is a guanine nucleotide exchange factor (Rho-GEF) that catalyzes the exchange of GDP for GTP by Rho family GTPases. High levels of ECT2 expression have been reported in brain, lung and breast cancers, where they were shown promote metastasis. However, the role of ECT2 in UPSC has not been previously explored. Methods: After obtaining IRB permission, ECT2 mRNA and protein expression were measured in flash frozen specimens of normal proliferative endometrium (n=8) and UPSC (n =8) by quantitative real-time PCR (qPCR) and Western blot. Established cultures of UPSC cell lines (UPSC-ARK1, UPSC-ARK2) were transfected with either an siRNA targeting ECT2 or a non-targeting control (Dharmacon) using Lipofectamine 2000 (Invitrogen). Reduced expression of ECT2 following transfections with ECT2 siRNAs was confirmed by qPCR and Western blot. Standard MTS and Caspase 3/7 assays (Promega) were utilized to measure proliferation and apoptosis. Colony formation and Boyden chamber assays were used to measure metastatic capacity, migration and invasion in vitro. Results: Our data indicate that ECT2 is overexpressed >4-fold in nearly all UPSC specimens tested (n=8, p Conclusions: Overexpression of ECT2 plays a critical role in promoting the growth and metastasis of UPSC. Targeting ECT2 expression may provide an effective strategy for improving outcomes for UPSC and other human cancers where hyperactivation of metastasis-promoting Rho GTPases are observed. Citation Format: Claire M. Mach, Thomas J. Magliaro, Matthew L. Anderson. Overexpression of ECT2 promotes proliferation and metastasis of UPSC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4448. doi:10.1158/1538-7445.AM2014-4448

MicroRNAs (miRNAs) are endogenous RNA transcripts that play a critical role in regulating pleuripotency and differentiation. Altered miRNA expression is a well-established feature of nearly all human cancers. However, the mechanisms by which dysregulated miRNA expression promote tumorigenesis remain poorly understood.To evaluate the role of miRNAs in uterine leiomyosarcoma (uLMS), we profiled patterns of small RNA expression in matched specimens of healthy myometrium (n=34), uterine leiomyomas (n=34) and uterine leiomyosarcoma (n=12) using Next Generation Sequencing (NGS). After quantile normalization, patterns of mature miRNA transcripts were compared. We found that 37 individual miRNAs were differentially expressed >2-fold (p8-fold, p2-fold when uLMS were compared to myometrium (p Note: This abstract was not presented at the meeting. Citation Format: Matthew L. Anderson, Gyoung Eun Kim, Claire M. Mach, Chad J. Creighton, Dina Lev. miR-10b functions as a novel tumor suppressor in uterine leiomyosarcoma by promoting overexpression of SDC1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5242. doi:10.1158/1538-7445.AM2014-5242

Curcumin (diferuloylmethane) is a commonly used spice and nutritional supplement that has demonstrated potential anti-tumor and anti-inflammatory activity. There is limited information regarding curcumin metabolism and the potential for drug-drug interactions. The objective of this study was to characterize the hepatic metabolism of synthetic curcumin used in the liposomal curcumin formulation.High-throughput cytochrome P450 (CYP450) metabolism inhibition assays were conducted in vitro evaluating CYP450 3A4, 2C8, 2C9, and 2D6. An ex vivo model of cryopreserved human hepatocytes was used to evaluate the CYP450 metabolism induction potential of curcumin for CYP P450 3A4, 2C8/2C9, and 2D6.In the in vitro CYP450 inhibition studies, curcumin at any concentration did not inhibit CYP450 3A4 or CYP450 2D6 activity. At a curcumin concentration of 58.3 microM, 10.5% and 22.5% inhibition of CYP450 2C9 and CYP450 2C8 activity, respectively, was observed. In the ex vivo hepatocyte inductions studies, minimal to no induction of CYP450 3A4, CYP450 2C8/2C9 or CYP450 2D6 was observed. Rifampicin did not induce the metabolism of curcumin and curcumin did not induce its own metabolism.There is low potential for CYP450 mediated drug interactions at physiologic serum concentrations of liposomal curcumin. Based on preliminary data, liposomal curcumin will not interact with other chemotherapy agents that are metabolized and/or eliminated via the primary drug metabolizing CYP450 pathways.

Curcumin is a food chemical present in tumeric (Curcuma longa) that has pharmacological activity to suppress carcinogenesis and inhibits multiple signaling pathways such as nuclear factor kappaB (NF-kappaB), cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8). Oral curcumin has poor oral bioavailability limiting its clinical activity; however, a patent pending liposomal formulation of curcumin was developed to improve drug delivery and has demonstrated activity in multiple cancers. This study was designed to determine the minimum effective dose (MED) as well as the optimal dosing schedule of liposomal curcumin in a xenograft mouse model of human pancreatic cancer.The MED determination and optimal schedule was evaluated in female athymic nude mice injected subcutaneously with MiaPaCa-2 cells. Dosing was initiated at an average tumor size of 5mm. For the MED, mice were treated with the following dose levels of liposomal curcumin: no treatment, liposome only, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg given by tail vein injection three times weekly for 28 days. For the optimum dosing schedule, three additional schedules were evaluated and compared to the control of three times weekly; daily (five days per week), every four days, and weekly for 28 days. All mice were weighed and tumor measurements taken three times weekly to evaluate toxicity and efficacy.The 20 mg/kg dose had the greatest decrease in tumor growth at 52% decrease in tumor growth when compared to no treatment control mice. MED was determined to be 20 mg/kg and was used for the optimal dosing schedule determination. Daily dosing and three times per week dosing had greater inhibition of tumor growth with no discernable difference than once weekly or every 4 day dosing. No toxicity was observed at any dose or schedule.The MED for liposomal curcumin is 20 mg/kg given once daily three times per week to achieve optimal tumor growth inhibition. This was dose recommended for additional preclinical studies to define safety and tolerability of liposomal curcumin in rat and dog models.

Many small nuclear RNA gene promoters are activated by SphI postoctamer homology (SPH)-binding factor/selenocysteine tRNA gene transcription activating factor (SBF/Staf). Whereas this transcription factor was initially identified by its ability to bind to SPH elements in such promoters, it was more recently shown to have the capacity to activate transcription of a synthetic mRNA gene promoter through a distinct activation domain. Here, we show that the human interferon regulatory factor-3 (IRF-3) gene promoter contains a functional SPH element that is bound by SBF/Staf in vitro and in transfected cells.

The RNA binding protein LIN28 and its paralog LIN28B function at a critical junction of pleuripotency, metabolism and metastasis. Reactivation of LIN28 has been recently reported in epithelial ovarian cancer (EOC), where it is hypothesized to play a key role in maintaining tumor stem cells. Associations between single nucleotide polymorphisms in the LIN28B promoter and ovarian cancer susceptibility have also been identified. However, the clinical significance of these observations and the mechanisms by which either LIN28 gene contributes to ovarian cancer have not been explored. Using Western blot, qPCR and immunohistochemistry, we found that a) LIN28 but not LIN28B is highly expressed in epithelia lining the distal fallopian tube and b) reactivation of LIN28 (1/8 specimens) and dysregulated expression of LIN28B (4/8 specimens) occur in EOC. To assess clinical significance of these events, we interrogated the TCGA ovarian cancer database, examining correlations between LIN28, LIN28B expression and outcomes by Kaplan-Meier analysis (n=581). Our results indicate that LIN28 expression is associated with shorter disease free interval in women with optimally debulked high grade serous ovarian cancers (p Collectively, these observations indicate that LIN28 likely plays an important role in regenerating epithelia that normally line the distal fallopian tube. Although our data also suggest that reactivation of LIN28 plays a key role in promoting ovarian cancer recurrences, LIN28 does not contribute to this process by targeting the differentiation of pluripotent cells via a let-7-mediated mechanism. Rather, this role appears to be most robust for its paralog LIN28B. Future work will focus on further dissecting the unique roles of these two gene products in ovarian cancer initiation and metastasis as well as their response to treatment. Citation Format: Claire Mach, Ying-Wooi Wan, Zhandong Liu, Matthew L. Anderson. LIN28 paralogs impact ovarian cancer predisposition and tumorigenicity via distinct molecular pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1955. doi:10.1158/1538-7445.AM2013-1955

Background: Epithelial ovarian cancer is the 5th leading cause of cancer death in women. Our objective was to identify key genetic events important for the pathogenesis of this lethal disease. Methods: Levels of microRNA (miRNA) expression were examined in specimens of primary papillary serous carcinomas, normal ovary and distal fallopian tube using Next Generation Sequencing and a custom expression array. Chromosomal gains and losses were also examined by CGH. SYBR Green reagents were used to measure relative expression of target gene expression by quantitative real-time PCR. Functional impact of altered miRNA expression was tested using standard MTT and Caspase 3/7 assays to measure proliferation and apoptosis (Promega). Key outcome demographics were coded and correlated with miRNA and gene expression by Kaplan-Meier analysis. Results: A total of 140 miRNAs were differentially expressed when papillary serous ovarian cancers were compared to either fimbrae of normal fallopian or normal ovary. Of these, 36 miRNAs were found to correlate with either overall survival, disease free interval (DFI) or platinum sensitivity. Nineteen (19) of these clinically significant miRNAs mapped to single primate-specific genomic locus located at 19q13.41. This locus spanned 125 Kb of non-coding DNA and encoded a total of 44 miRNAs, most all of which showed significant copy number variation in papillary serous ovarian cancers (n = 178) and showed copy losses in the majority of tumors. Using established algorithms for target prediction, we found that this miRNA cluster collectively targeted more than 2800 distinct genes. Key loci included gene products implicated in the epithelial-to-mesenchymal transition (Snail, Slug) as well as both the G1-S and G2-M cell cycle checkpoints (MYCN and Wee1). Transfection of established ovarian cancer cell lines with individual 19q13.41 miRNAs significantly reduced expression of Snail, Slug, Wee1, resulting in altered proliferation and apoptosis. Conclusions: Altered expression of 19q13.41 cluster miRNAs correlate with significant clinical outcomes for women with papillary serous ovarian cancers. These miRNAs appear to play a key role in regulating the expression of gene products critical for the ongoing proliferation and metastasis of ovarian cancer. Future work will focus on dissecting the role of individual 19q13.41 miRNAs in ovarian and other cancers as well as validating the novel nanoparticle-based strategies we have developed for therapeutic miRNA delivery. Supported by NIH TCGA and the Ovarian Cancer Research Foundation (OCRF) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2029.

Previously, pre-clinical dose finding tolerance study in a human xenograft pancreatic cancer model of intravenous liposomal curcumin determined 20 mg/kg TIW was to be the optimum dose and schedule for anticancer activity. Follow up pharmacokinetic and dose finding studies in a health rat model evaluated doses up to 40 mg/kg was not associated with weight loss, hematological, serologic, or dose-limiting toxicity. In canine model, a single-dose finding tolerance study ranging from 2 mg/kg up to 40 mg/kg revealed the maximum tolerated dose (MTD) of liposomal curcumin to be 20 mg/kg or 540 uMol/L of curcumin maximal blood concentration. Toxicity observed at this dose level was characterized by a brief single episode of reversible hematuria. The dose limiting toxicity was observed at a single dose of 40 mg/kg of liposomal curcumin. Following dose on day 1, life threatening toxicity followed within 48 hours with the dogs exhibiting irreversible acute hemolysis with hematuria, over 60% blood loss, and associated serologic abnormalities. A control cohort of dogs infused with the same quantity of liposome contained in the 40/mg/kg dose was without ensuing toxicity. These changes suggest the mechanism of hemolysis following 40mg/kg curcumin is due to an oxidant effect. Following acute hemolysis, the iron chelation activity of curcumin could contribute to unremitting anemia by blocking iron reutilization. In conclusion, at concentrations below the canine MTD of 20 mg/kg, curcumin acts as an anti-oxidant, and acts as a pro-oxidant at higher concentrations. The disparity between rodent and canine sensitivity to liposomal curcumin may be due to species differences in pharmacokinetics and/or curcumin metabolism. Ongoing study will define liposomal curcumin pharmacokinetic parameters at the MTD in canine mode as well define tolerability of multiple dosing in dogs. In addition hematological studies are being conducted to determine the mechanism of hemolysis that was observed at higher dose levels and identify potential biomarkers for predicting toxicity. Preliminary data suggests liposomal curcumin will have promising anticancer activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A29.