tbuckley/cabot-search huggingface dataset:
Second-generation inhibitors of fatty acid synthase for lung cancer treatment
Authors: H. Orita, J. Coulter, E. Tully, M. Pinn, J. Thupari, M. Pomper, C. Townsend, D. Ettinger, F. Kuhajda, E. Gabrielson
Journal: Journal of Clinical Oncology (2007)

18185 Fatty acid synthase (FAS) is highly expressed in many human cancers, including lung cancers. Previous work has shown that blocking FAS activity by cerulenin, a natural antibiotic, or C75, a first-generation synthetic small molecule, leads to apoptosis in cells that overexpress this enzyme. However, the use of C75 is limited by the dose-dependent anorexia that appears to be associated with stimulation of fatty acid oxidation. Pharmacokinetics studies show that the activity of C75 peaks within hours of administration and by 24 hours, approximately 80% of activity is lost. Thus, the effectiveness of C75 is limited by this short duration of anti-neoplastic activity and the prolonged anorexic effects.Several second-generation novel FAS-inhibitory compounds have been synthesized that show significant inhibition of FAS, without parallel stimulation of fatty acid oxidation. Among the most promising of the compounds is C93, which inhibits FAS at nearly equal potency as C75, but has significantly less stimulation of fatty acid oxidation. We treated mice with xenografts (orthotopic and subcutaneous) developed from 3 different human lung cancer cell lines (H460, A549, and LX-7) with daily intraperitoneal injections of C93 (5 days/week) at 50 mg/kg for 4 weeks and observed significant (up to 70%) inhibition of tumor growth in all xenograft models tested. Furthermore, no significant weight loss and no organ-specific toxicity were recognized in treated animals. These results suggest that it is possible to pharmacologically uncouple inhibition of FAS from stimulation of fatty acid oxidation, and thus achieve anti-neoplastic activity by inhibition of FAS without significant drug-induced anorexia. Finally, we tested an oral formulation of C93 with the intent of developing a dosing protocol suitable for clinical applications. Similar levels of drug in tumor tissue, and similar inhibition of fatty acid synthase enzyme activity, were seen after oral and intraperitoneal administrations of drug. Furthermore, repeated oral administration of C93 to animals with subcutaneous H460 lung cancer xenografts inhibited tumor growth to a similar level observed after intraperitoneal administration. Thus, fatty acid synthase appears to be a promising target for lung cancer treatment. No significant financial relationships to disclose.
Industry–Academic Relationship in a New Era of Drug Discovery
Authors: Patrick Vallance
Journal: Journal of Clinical Oncology (2016)

The pharmaceutical industry is entering a renewed period of productivity as a result of advances in the understanding of human biology, particularly in the areas of genetics and immunology. The relationship between industry and academia needs to evolve to maximize the opportunity. In four areas—target identification, the molecule itself, experimental medicine, and larger-scale clinical testing—there are specific needs for academic partnerships that should be open and transparent and include talent, skills, and career development.
Abstract 2460: Characterizing PAX3-FOXO1 dependent cell death in alveolar rhabdomyosarcoma reveals novel strategies for combination therapy
Authors: Marco Wachtel, Johannes Ommer, Beat Schäfer
Journal: Cancer Research (2016)

Abstract Rhabdomyosarcoma is the most common soft tissue sarcoma in children. The aggressive alveolar subtype (aRMS) is characterized by chromosomal translocations, most often by t(2;13) resulting in the expression of the oncogenic fusion protein PAX3-FOXO1. Expression of this chimaeric transcription factor is critical for tumorigenesis and cell survival. However, the exact mechanism of cell death after loss of PAX3-FOXO1 activity has not been determined so far. Our aim was thus to characterize the cell death pathways activated upon silencing of PAX3-FOXO1. In addition, we aimed at finding drugs further sensitizing aRMS cells to this mode of cell death. We used combined shRNA and CRISPR approaches, as well as a small molecule screen to demonstrate that after shRNA-mediated silencing of PAX3-FOXO1 expression, aRMS cells undergo intrinsic apoptosis in a NOXA-dependent manner. In accordance, we can show that the BH3-mimetic ABT-263 sensitizes aRMS cells to PAX3-FOXO1 silencing via this cell death pathway. Interestingly, ABT-199 was less effective, suggesting that Bcl-xl plays a major anti-apoptotic role in aRMS. Furthermore, induction of cell death is dependent on PI3K activity and antagonized by GSK3, suggesting that inhibition of PI3K in this sarcoma might have an anti-apoptotic impact. In contrast, combination of ABT-263 or GSK-3 inhibitors with small molecule drugs affecting PAX3-FOXO1 activity such as PLK1 and aurora kinase inhibitors can cooperate to enhance cell death in aRMS cells. These studies demonstrate the importance of elucidating biological mechanisms to guide development of rational drug combinations. Citation Format: Marco Wachtel, Johannes Ommer, Beat Schäfer. Characterizing PAX3-FOXO1 dependent cell death in alveolar rhabdomyosarcoma reveals novel strategies for combination therapy. [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 2460.
Abstract 3200: New epigenetic mechanism of disulfiram targeting chromatin remodeling in neuroblastoma
Authors: Simon Jacques-Ricard, Noel Raynal, Gregory Armaos, Elodie Da Costa, Annie Beaudry
Journal: Cancer Research (2016)

Abstract Pediatric neuroblastoma is one of the most common extra cranial cancers in children. Despite an improvement in survival with the currently available therapies, neuroblastoma with an amplification of the transcription factor MYCN have a very poor prognosis. New therapeutic approaches must be developed to increase the survival of patients. One such approach is epigenetic drug therapy. Neuroblastoma, like many other pediatric cancers, contains several epigenetic alterations at the level of DNA methylation and histone modifications. In a screening of FDA approved drugs, we discovered some molecules having characteristics of epigenetic drugs that were unknown until now. Our study seeks to demonstrate the efficacy of these molecules in the treatment of neuroblastoma cell lines. Following preliminary tests, one of the molecules approved by the FDA stood out: disulfiram, a medication approved for the treatment of chronic alcoholism. We treated neuroblastoma cell lines (MYCN amplified: IMR-32, N91 and SK-N-DZ; MYCN non-amplified: SK-N-AS and SK-N-SH) for 48 hours with disulfiram at clinically relevant concentrations (from 10 nM to 50 μM). Our results demonstrate a 50% growth inhibition (IC50) of 50nM for the cell lines tested. In addition, after analysis by flow cytometry, we found a cell cycle block in G2/M. We also observed a decrease in the transcription factor MYCN and a reduction in acetylation of several histone marks by Western blots analysis. Further studies are underway to determine the mechanism of action of disulfiram and we also plan on doing RNA sequencing and ChIP sequencing. This study will evaluate the efficacy of disulfiram alone as well as in combination with other epigenetic drugs, such as DNA methyltransferase inhibitor decitabine, for the treatment of neuroblastoma. Citation Format: Simon Jacques-Ricard, Noel Raynal, Gregory Armaos, Elodie Da Costa, Annie Beaudry. New epigenetic mechanism of disulfiram targeting chromatin remodeling in neuroblastoma. [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 3200.
Abstract 132: Comprehensive genomic analysis of human papillomavirus-associated oral cancers
Authors: David E. Symer, Keiko Akagi, Kevin R. Coombes, Weihong Xiao, Robert K. L. Pickard, Amit Agrawal, Maura L. Gillison
Journal: Cancer Research (2016)

Abstract Human papillomavirus-associated oral cancers comprise a distinct disease that is increasing in frequency in Western countries. Recent genomic landscape studies of oral cancers and of HPV-associated cervical cancers identified the most commonly mutated genes in each. Here we report a comprehensive analysis of 83 HPV-positive oropharyngeal cancers studied by whole genome sequencing (WGS), and an additional 46 tumors evaluated by the Cancer Genome Atlas project (TCGA) by exome sequencing. We confirmed recurrent mutations in previously reported, frequently mutated candidate driver genes including PIK3CA, as well as several novel gene targets, each occurring recurrently at frequencies of more than approximately 3%. Our WGS data demonstrated recurrent focal genomic instability associated with HPV insertional mutagenesis. We observed dramatic changes in genomic copy number variants (CNVs) at chromosome 3q as well as numerous other chromosomal regions that are recurrently gained or lost in HPV-positive tumors. RNA-Seq data from this collection of oral cancers defined differentially expressed transcript levels and other molecular alterations associated with single nucleotide variants (SNVs), CNVs and other genomic structural variants in the tumors. Together, our results reveal a unique pattern of somatic variants that distinguishes HPV+ oral cancers both from HPV- oral cancers as well as other HPV+ tumors arising in distinct tissues including the uterine cervix. These data shed new light on the molecular pathogenesis of oral cancers, and provide new opportunities for development of diagnostic and therapeutic strategies for affected patients. Citation Format: David E. Symer, Keiko Akagi, Kevin R. Coombes, Weihong Xiao, Robert K. L. Pickard, Amit Agrawal, Maura L. Gillison. Comprehensive genomic analysis of human papillomavirus-associated oral cancers. [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 132.
Abstract 4408: Mutant ABL1 is a genetic dependency in non-small cell lung cancer amenable to pharmacological intervention
Authors: PEDRO Torres-Ayuso, Ewelina Testoni, Natalie L. Stephenson, Anna A. Marusiak, Eleanor W. Trotter, Andrew Hudson, Cassandra L. Hodgkinson, Christopher J. Morrow, Caroline Dive, John Brognard
Journal: Cancer Research (2016)

Abstract Non-small cell lung cancer (NSCLC) is the most frequent lung cancer subtype and it affects near 1.5 million patients worldwide annually. The lack of actionable mutations in NSCLC patients presents a significant hurdle in the administration of targeted therapies for this disease, and their identification is an urgent unmet need. Here we identify somatically mutated ABL1 as a genetic dependency that is required to maintain NSCLC cell survival. We demonstrate that NSCLC cancer cells with ABL1 mutations are sensitive to ABL inhibitors and we verify that the drug-induced effects on cell viability are specific to pharmacological inhibition of the ABL1 kinase. Consistent with structural modeling, we demonstrate that mutations in ABL1 identified in primary NSCLC tumors and a lung cancer cell line increase downstream pathway activation compared to wild-type ABL1. Finally, we show that imatinib suppresses lung tumor growth in vivo, specifically in lung cancer cells harboring a gain-of-function (GOF) mutation in ABL1. In summary, our results suggest that NSCLC patients with ABL1 mutations could be stratified for treatment with imatinib in combination with other therapies. Citation Format: PEDRO Torres-Ayuso, Ewelina Testoni, Natalie L. Stephenson, Anna A. Marusiak, Eleanor W. Trotter, Andrew Hudson, Cassandra L. Hodgkinson, Christopher J. Morrow, Caroline Dive, John Brognard. Mutant ABL1 is a genetic dependency in non-small cell lung cancer amenable to pharmacological intervention. [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 4408.
Abstract 1091: miR-125 family of miRNAs mediates prostate cancer cell proliferation and migration
Authors: Sinead T. Aherne, Fiona O’Neill, Stephen F. Madden, Martin Clynes, Conor C. Lynch
Journal: Cancer Research (2016)

Abstract Background: Prostate cancer is the second most common malignancy in American men and causes ∼27540 deaths per annum. microRNAs (miRNAs) are a class of short non-coding RNAs that regulate the expression of protein-coding genes via either mRNA degradation or translational repression. These small molecules are known to be aberrantly expressed in prostate cancer (PCa) and possess both tumor suppressive and oncogenic properties. miR-125 is a highly conserved miRNA family comprised of three homolog members hsa-miR-125a, hsa-miR-125b-1, and hsa-miR-125b-2. Members of this family have been attributed both disease suppressing and promoting functions in certain contexts however their role in PCa has yet to be fully elucidated. Methods: miRNA expression was evaluated in a publicly available dataset (GSE21032) comprised of 28 normal, 98 primary PCa and 13 metastasis samples. miR-125 expression was assessed in a panel of 8 prostate cell lines comprising PrEC prostate epithelial cells, RWPE-1, BPH1, DU145, LNCaP, C4-2B, PC3, and PC3-2M cell lines using the Qiagen miScript system. MirWalk was used to identify predicted targets of the miRNAs. miR-125 expression was transiently inhibited in LNCaP, C4-2B, PC3, and PC3-2M cell lines using miScript miRNA inhibitors and miRNA and target mRNA expression, cell proliferation and migration were measured post-transfection. Results: Analysis of human data revealed miR-125a-3p was significantly up-regulated in metastasis samples compared to both primary PCa and normal tissues (log fold change (FC) 1.743, p-value 9.01E-08 logFC = 1.536 p-value = 8.80E-08 respectively). Next, we validated miR-125 family member expression in prostate cancer cell lines compared to PrEC and RWPE-1 prostate epithelial cells. Most notably, we observed that miR-125b-2 expression was significantly higher in all prostate cancer cell lines. Inhibition of miR-125b-2, significantly reduced the proliferation of the LNCaP, C4-2B, and PC3-2M cell lines. Moreover, inhibition of this miRNA significantly impaired prostate cancer cell migration by 43.8% (p-value = 0.003). Using MirWalk, we examined potential targets for regulation by miR-125b-2 and identified the potent tumor suppressor Quaking family as top hit. Our results show that inhibition of miR-125b-2 significantly enhanced the expression of Quaking family members (1.79 fold). Conclusions: Our results demonstrate that the miR-125 family of miRNAs plays a role in regulating prostate cancer cell proliferation and migration, potentially by mitigating Quaking activity. Citation Format: Sinead T. Aherne, Fiona O’Neill, Stephen F. Madden, Martin Clynes, Conor C. Lynch. miR-125 family of miRNAs mediates prostate cancer cell proliferation and migration. [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 1091.
Authors’ reply: National pneumococcal vaccination programmes for children in Europe, 2001-2007 – updated table
Authors: H De Carvalho Gomes, M Muscat, D L Monnet, J Giesecke, P L Lopalco
Journal: Eurosurveillance (2009)

Preview this article: Authors' reply: National pneumococcal vaccination programmes for children in Europe, 2001-2007 – updated table, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/14/18/art19200-en-1.gif
Pharmacokinetic (PK) analysis of two dosing schedules of the angiokinase inhibitor BIBF 1120 in patients with hormone- refractory prostate cancer (HRPC) who progressed after docetaxel treatment
Authors: J. Droz, A. Fléchon, F. Joly, H. de Mont-Serrat, R. Kaiser, P. Stopfer, S. Oudard
Journal: Journal of Clinical Oncology (2008)

14578 Background: BIBF 1120 is a novel, oral, potent angiokinase inhibitor blocking the VEGFR 1/2/3, FGFR 1/3, and PDGFR α/β tyrosine kinases at nanomolar concentrations. This randomized, open-label, multicenter Phase II study evaluated the efficacy, safety and PK of two doses of BIBF 1120 in patients with metastatic HRPC that had progressed after docetaxel therapy. Methods: Patients were randomly assigned and treated with BIBF 1120 until disease progression or dose-limiting toxicity. The primary endpoint was response rate defined as a confirmed decline of PSA by ≥20%. PK analysis using high-performance liquid chromatography-mass spectroscopy was performed for PK samples of 36 patients. PK sampling occurred on Days 1 and 29, and every 2 weeks thereafter. Trough plasma concentrations were taken 8–14 hrs after dosing. The distribution of BIBF 1120 plasma concentrations was described using graphs and descriptive statistics. Results: 81 patients were randomly assigned to receive either 250 mg bid (n=41) or 150 mg bid (n= 40) of BIBF 1120 as monotherapy. On Day 1, BIBF 1120 plasma concentrations increased within the first 3 hours after dosing in the 150 mg bid and 250 mg bid groups; maximum values were 66.3 ng/mL and 124 ng/mL, respectively. On Day 29, maximum plasma concentrations were 54.9 ng/mL and 112 ng/mL in the 150 mg bid and 250 mg bid groups, respectively. BIBF 1120 plasma levels had reached steady state by Day 29 in both groups; this may have occurred earlier but there was no PK sampling between Days 1 and 29. Overall, pre-dose plasma concentrations remained stable over the 155-day observation period in both groups; interpatient variability was moderate to high. No systematic change in trough plasma concentrations or deviation from dose proportionality of BIBF 1120 was observed in either group. The gMean pre-dose plasma concentrations of BIBF 1120 were higher in the 250 mg bid group compared with the 150 mg bid group. Conclusions: For both dose groups, BIBF 1120 pre-dose concentrations did not deviate from dose-linearity in this study. For both dose groups, pre-dose concentrations remained stable over the treatment period. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim, Boehringer Ingelheim France Boehringer Ingelheim, Pharmion, sanofi-aventis AstraZeneca, sanofi-aventis Boehringer Ingelheim
Abstract 65: <i>In vivo</i> pooled shRNA library screens identify cancer genes driving epithelial ovarian cancer
Authors: Michiko Kodama, Takahiro Kodama, Justin Newberg, Neal G. Copeland, Nancy A. Jenkins
Journal: Cancer Research (2016)

Abstract Background &amp; Aims: Epithelial ovarian cancer (EOC) is the 5th leading cause of cancer-related deaths in the USA. Most cases of EOC are diagnosed at an advanced stage with peritoneal carcinomatosis (PC), which seriously affects mortality. To identify therapeutic targets for EOC, we performed in vivo loss of function screens using pooled shRNA libraries. Methods: To discover tumor suppressor genes (TSGs) involved in PC formation, the human EOC cell line, SKOV3, was transduced with a pooled shRNA library containing 42,450 shRNAs targeting 7490 druggable genes. Transduced cells that were highly evasive as measured in Boyden chamber assays were then injected intraperitonealy into female nude mice. Eighteen PC tumors that developed were then sequenced and enriched shRNAs identified. SKOV3 cells transduced with the druggable shRNA library were also injected into nude mice without further in vitro manipulation and 12 PC tumors sequenced in order to identify potential oncogenes as measured by shRNA depletion. Results: Enrichment screening of invasive cells identified 34 potential TSGs targeted by two or more shRNAs. Knockdown of the two most highly ranked genes, RAD51C and TXN, by individual shRNAs, was subsequently shown to accelerate PC formation following intraperitoneal injection of transduced SKOV3 cells. Individual knockdown of these two genes was subsequently shown to increase cell invasion in Boyden chamber assays and adhesion to the extracellular matrix in vitro. These results suggest that RAD51C and TXN are suppressors of human EOC metastasis through their negative regulation of cell adhesion and cell invasion. Finally, shRNA depletion screening identified 17 potential oncogenes. These genes included three known oncogenes, ERBB2, RAF1 and FOS, in addition to eight genes that showed a significant positive correlation between their mRNA levels and poor patient survival in human EOCs. Knockdown of the second ranked oncogene, KPNB1, significantly decreased in vitro cell proliferation in multiple human EOC cell lines, suggesting that KPNB1 may be a new potential therapeutic target of human EOC. KPNB1 knockdown in SKOV3 cells downregulated AURKA, MYBL2, CCNE1 and CDK2 mRNA levels, suggesting that KPNB1 may function by positively regulating the cell cycle. Conclusion: In vivo pooled shRNA library screens are a powerful tool for identifying novel cancer genes and new potential drug targets in human epithelial ovarian cancer. Citation Format: Michiko Kodama, Takahiro Kodama, Justin Newberg, Neal G. Copeland, Nancy A. Jenkins. In vivo pooled shRNA library screens identify cancer genes driving epithelial ovarian cancer. [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 65.
Abstract 808: Microsatellite instability in metastatic colorectal cancer (mCRC)
Authors: Jee Hung KIM, Chang-gon Kim, Joong Bae Ahn, MinKyu Jung, Seung Hoon Beom, Joo Hoon Kim, Soo Jin Heo, Sang Joon Shin
Journal: Cancer Research (2016)

Abstract Background: Although early stage colorectal cancer (CRC) with microsatellite instability (MSI) phenotype has a more favorable prognosis, impact on outcome of MSI status in metastatic CRC (mCRC) is rarely known. We aim to explore patterns of metastatic spread and prognosis of CRC with MSI-H (high-level MSI) in comparison to MSI-L (low-level of MSI)/MSS. Methods: Patients with mCRC who underwent testing for MSI were identified using retrospective cohort of Yonsei Cancer Center. Patients were categorized to MSI status (MSI-H vs. MSS-L/MSS). Patterns of metastatic spread, surgical resection after recurrence and outcome between two groups were compared. Results: A total of 944 patients were evaluated. Of all, 34 patients (3.6%) had MSI-H tumors. A distinct pattenrs of metastatic spread was observed in MSI-H tumors, namely higher rates of peritoneal metastasis (41% vs 10%, P &amp;lt; 0.001), intraabdominal lymph node metastasis (14.7% vs 4.8%, P = 0.011), and lower rates of lung metastasis (8.8% vs 24.6%, P = 0.034), liver metastasis (20.6% vs 53.6%, P &amp;lt; 0.001). Patients with MSI-H tumors were less likely to receive metastectomy (24.8% vs 55.9%, P &amp;lt; 0.001). Median overall survival was inferior in MSI-H tumor compared with MSI-L/MSS tumor (16.3 months vs 38.1 months, P = 0.005). Conclusions: Different patterns of metastatic spread and receipt of surgical resection in MSI-H mCRC is demonstrated in this study. In addition, MSI-H phenotype is associated with poorer survival in mCRC on the contrary to early stage disease. Future studies focusing on deeper understanding of tumor biology and therapeutic response in this rare disease entity are warranted. Citation Format: Jee Hung KIM, Chang-gon Kim, Joong Bae Ahn, MinKyu Jung, Seung Hoon Beom, Joo Hoon Kim, Soo Jin Heo, Sang Joon Shin. Microsatellite instability in metastatic colorectal cancer (mCRC). [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 808.