tbuckley/cabot-search huggingface dataset:
Abstract 1750: Preclinical efficacy of Hsp90 inhibition by using PF-04942847 in osteosarcoma
Authors: Marc Baud'Huin, Benjamin Ory, Franck Verrecchia, Dominique Heymann, Francoise Redini, Francois Lamoureux
Journal: Cancer Research (2015)

Abstract This work was supported by foundation ARC and INSERM, France. Introduction and Objective: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among new therapeutic approaches, Heat shock protein (HSP) 90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival. In this study, we assessed the in vitro and in vivo antitumor properties of a novel synthetic HSP90 inhibitor, PF-04942847 both in vitro and in vivo in osteosarcoma. Methods: The effects of the HSP90 inhibitor were evaluated in vitro on U2OS, SaOS2, MNNG/HOS, KHOS, MG63, G292, CAL72, SJSA1 and 143B cell growth and apoptosis. The signaling pathways were analyzed by western blotting. The consequence of HSP90 therapy in vivo was evaluated in athymic mice bearing MNNG/HOS xenografts. The effect of PF-04942847 on osteoclastogenesis was assessed in vitro on purified human CD14+ monocytes. Results: In our panel of osteosarcoma cell lines, PF-04942847 inhibited cell growth in a dose-dependent manner (IC50 ± 50nM) and induced apoptosis with an increase of sub-G1 fraction and PARP cleavage. These biologic events were accompanied by decreased expression of Akt, Erk, MYC, c-MET, STAT-3, and modulation of HSP expression. When administered orally 3 times/week (25mg/kg) to mice bearing osteosarcoma tumors, PF-04942847 significantly inhibited tumor growth by 40% and prolonged survival compared to controls. Moreover, in contrast to 17-AAG, the novel PF-04942847 compound inhibits osteoclast differentiation in vitro. Conclusions: Targeting HSP90 using PF-04942847 inhibited osteosarcoma tumor growth in vitro and in vivo and appears to inhibit osteoclastogenesis. All these data provides a strong rationale for clinical evaluation of PF-04942847 in osteosarcoma. Citation Format: Marc Baud'Huin, Benjamin Ory, Franck Verrecchia, Dominique Heymann, Francoise Redini, Francois Lamoureux. Preclinical efficacy of Hsp90 inhibition by using PF-04942847 in osteosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1750. doi:10.1158/1538-7445.AM2015-1750
Abstract LB-247: Querying the RAS genomic network with siRNAs and and flow cytometry: Automatic, multidimensional phenotyping of 135 cancer cell lines by Gaussian mixture fitting and expectation maximization
Authors: Arnaud Amzallag, Tina L. Yuan, Rachel Bagni, Ming Yi, Robert Stephens, Sridhar Ramawamy, Frank McCormick, Cyril H. Benes
Journal: Cancer Research (2015)

Abstract To discover novel therapeutic modalities and genomic predictors of response, large screen utilizing small molecules or sh/siRNA are performed on increasingly large collections of cancer cell lines. However these screens suffer from two main limitations: 1) the off-target effects of the probes 2) the coarse measurement of the cellular response that cannot distinguish between different outcomes such as proliferation block and apoptosis. Here we profile 50 lung cancer cell lines using highly specific combinations of siRNAs against effector nodes of KRAS, and measured several characteristics of phenotypic response by flow cytometry including viability, level of reactive oxygen species and cell membrane integrity. For each assay [node-cell line], typically 25,000 events were measured. We often observed multi modal distributions following node silencing. We used the expectation maximization algorithm to fit the different cell populations induced by the gene silencing. This allows us to automatically extract the proportion of dying cells, and also provides estimates of the cell growth impairment. Assessment of replicates shows that our results are highly reproducible, provide an accurate estimate of the proportion of dying cells, and reveal the complexity of multi-modal response of KRAS cancer cell lines to perturbation of key signaling nodes. Using the genomic profiling and pharmaceutical screen of the same cell lines, we reveal the association of specific node silencing with 1) the basal genomic state of the cell lines 2) the activity of a panel of drugs with the goal of identifying new targeting modalities and patient selection strategies for KRAS mutant cancers. Citation Format: Arnaud Amzallag, Tina L. Yuan, Rachel Bagni, Ming Yi, Robert Stephens, Sridhar Ramawamy, Frank McCormick, Cyril H. Benes. Querying the RAS genomic network with siRNAs and and flow cytometry: Automatic, multidimensional phenotyping of 135 cancer cell lines by Gaussian mixture fitting and expectation maximization. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-247. doi:10.1158/1538-7445.AM2015-LB-247
Abstract 308: The role of PTEN PDZ-binding domain in mammary gland tumorigenesis
Authors: Mingfei Yan, Penelope Or, Andrew Chan
Journal: Cancer Research (2015)

Abstract PTEN functions as a key negative regulator of PI3K-Akt pathway through its lipid phosphatase activity. Mutations or loss of PTEN is frequently observed in brain, breast, prostate and endometrial cancer. PTEN also possesses a PDZ-binding domain (PDZ-BD) at its carboxyl terminus, which can be recruited by PDZ-containing proteins like ZO-1 to cell tight junction. Therefore, PTEN may have a potential role in regulating epithelial tight junction integrity. To study the role of PTEN PDZ-BD in breast epithelial tumorigenesis, a PTEN-ΔPDZ mice lacking this domain was generated and further crossed with MMTV-PyMT breast cancer model. As a result, PTENΔPDZ/MMTV-PyMT mice show enhanced tumor growth and metastasis. To elucidate tumor suppressive mechanisms of PTEN PDZ-BD, three-dimensional cultures of PTENΔPDZ mouse mammary epithelial cells (MMEs) was carried out. Though PTEN-ΔPDZ MMEs spheres have normal morphogenesis in 3D culture, they possess larger diameters than wild-type (WT). Besides, both tight junction (ZO-1) and adherent junction (E-Cadherin) of MMEs were examined in 3D culture, though no major differences in cell junction and polarity was observed between PTEN-ΔPDZ and PTEN-WT. Future work will study signaling activities of PTEN-ΔPDZ/MMTV-PyMT breast cancer cells, morphogenesis, polarity and cell junction of PTEN-ΔPDZ/MMTV-PyMT MMEs in 3D cultures. This work was supported by NIH RO1 (CA133669), Hong Kong Research Grant Council (460713) and Hong Kong PhD Fellowship Scheme (PF12-13584) Citation Format: Mingfei Yan, Penelope Or, Andrew Chan. The role of PTEN PDZ-binding domain in mammary gland tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 308. doi:10.1158/1538-7445.AM2015-308
Abstract 4710: Evaluation of the glutaminase inhibitor CB-839 in non-small cell lung cancer
Authors: Lindsey K. Boroughs, Pei-Hsuan Chen, Ling Cai, Mirna Rodriguez, Winter Zhang, Kenneth E. Huffman, Lauren A. Byers, Luc Girard, Adi F. Gazdar, John V. Heymach, Michael A. White, John D. Minna, Ethan Emberley, Alison Pan, Frank Parlati, Ralph J. DeBerardinis
Journal: Cancer Research (2015)

Abstract Glutamine is an abundant nutrient used by cancer cells to support energetic and biosynthetic pathways. Given that many cancer cells exhibit glutamine dependence, there has been interest in developing inhibitors targeting glutaminase, which catalyzes conversion of glutamine to glutamate. CB-839 is a glutaminase inhibitor with preclinical efficacy in suppressing cancer cell growth in culture and in vivo. It is now in Phase I clinical trials for solid and hematological malignancies, including non-small cell lung cancer (NSCLC). Here we set out to identify biomarkers predicting sensitivity of NSCLC cells to CB-839, using a highly annotated panel of 81 cell lines. These lines had heterogeneous oncogenotypes and displayed about a 5-fold range in their ability to tolerate glutamine deprivation. Assessing CB-839 sensitivity in ∼40 lines revealed a 5-fold difference in growth suppression among cell lines. There was a strong correlation between CB-839 sensitivity and both glutamine dependence and glutamate secretion. In a subset of 4 representative cell lines, CB-839 suppressed [U-13C]glutamine metabolism in both sensitive and insensitive cells suggesting other mechanisms contribute to CB-839 sensitivity. To identify potential biomarkers predicting CB-839 sensitivity, the glutamine dependence and drug sensitivity phenotypes were correlated with several orthogonal high-content data sets including mutational analysis of commonly-mutated oncogenes and tumor suppressors; sensitivity to chemotherapeutic agents; gene expression arrays; and reverse phase protein arrays (RPPA). Although we did not identify a strong correlation between mutational status and CB-839 sensitivity, expression of phospho-Rb (S807/811) and Smad3 did correlate with drug sensitivity. In addition, sensitivity to glutamine withdrawal correlated with expression of c-Myc and MEK2 protein. While further work is necessary to examine the importance of these proteins in glutamine metabolism, we hypothesize that one or more of these may represent novel biomarkers predicting sensitivity to glutaminase inhibition. Citation Format: Lindsey K. Boroughs, Pei-Hsuan Chen, Ling Cai, Mirna Rodriguez, Winter Zhang, Kenneth E. Huffman, Lauren A. Byers, Luc Girard, Adi F. Gazdar, John V. Heymach, Michael A. White, John D. Minna, Ethan Emberley, Alison Pan, Frank Parlati, Ralph J. DeBerardinis. Evaluation of the glutaminase inhibitor CB-839 in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4710. doi:10.1158/1538-7445.AM2015-4710
Abstract 1475: Therapeutic responses in a novel patient-derived xenograft mouse model for rare acinar cell pancreatic carcinoma
Authors: Laura A. Marlow, Adam C. Mathias, Louis K. Dawson, William F. Durham, Kenneth A. Meshaw, Robert J. Mullin, Aidan J. Synnott, Ricardo Paz-Fumagalli, Murli Krishna, Daniel Von Hoff, Daniel L. Small, Gerardo Colon-Otero, John A. Copland
Journal: Cancer Research (2015)

Abstract Acinar cell carcinoma of the pancreas (ACC) is an uncommon malignancy, accounting for less than 1% of all pancreatic neoplasms. Because of its rarity, only a few retrospective studies are available to help guide management. We previously reported the case of a patient with metastatic ACC who achieved prolonged survival with doxorubicin as a result of personalized treatment designed in part on the basis of molecular and in-vitro data collected on analysis of the tumor and primary cells in culture developed from the liver metastasis. We now report the characterization of a patient derived xenograft (PDX) mouse model originating from this patient's ACC liver metastasis tissue. Antitumor activity of multiple drugs (5-FU, irinotecan, oxaliplatin, gemcitabine, bevacizumab, erlotinib, doxorubicin and imatinib) used as single agent therapy is demonstrated. Of the targeted and cytotoxic therapies used, oxaliplatin produced a dramatic and prolonged response to therapy even after withdrawal of treatment. Bevacizumab produced a significant response, as well. Serum lipase and tissue amylase levels correlated with the antitumor response to therapy. Thus, we have developed and characterized an ACC PDX model that may be used in drug discovery for the treatment of this rare cancer for which no standard of care exists. Note: This abstract was not presented at the meeting. Citation Format: Laura A. Marlow, Adam C. Mathias, Louis K. Dawson, William F. Durham, Kenneth A. Meshaw, Robert J. Mullin, Aidan J. Synnott, Ricardo Paz-Fumagalli, Murli Krishna, Daniel Von Hoff, Daniel L. Small, Gerardo Colon-Otero, John A. Copland. Therapeutic responses in a novel patient-derived xenograft mouse model for rare acinar cell pancreatic carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1475. doi:10.1158/1538-7445.AM2015-1475
Randomized, controlled phase II trial of exemestane compared with medroxyprogesterone after nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer.
Authors: T. Wang, H. Huang, S. Zhang, L. Bian, Z. Jiang
Journal: Journal of Clinical Oncology (2011)

e11088 Background: The third-generation nonsteroidal aromatase inhibitors(AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor-positive breast cancer. Because many patients subsequently experience progress or relapse, it is important to identify agents with efficacy after AI failure. This study is in order to understand efficacy and safety of exemestane and medroxyprogesterone for the advanced breast cancer after AI failure. Methods: Evaluation of exemestane versus medroxyprogesterone study is a randomized, controlled phase II clinical trial in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteriodal AI. The primary end point was progress free survial (PFS). Exemestane 25mg orally was administered once daily and medroxyprogesterone 1000mg orally once daily. Results: A total of 40 women were randomly assigned to exemestane (n=20) or medroxyprogesterone (n=20). Approximately 60% of patients had received at least two prior endocrine therapies. Median PFS was 6 months in exemestane group and 3 months in medroxyprogesterone group (P= 0.790). Overall response rate (0 vs 15%) and clinical benefit rate (30% vs 35%, P= 0.736) was similar between exemestane and medroxyprogesterone respectively. Both treatments were well tolerated. There are 6 patients who have grade 1 and grade 2 weight gain in medroxyprogesterone group. There are 2 patients who experienced grade 2 blood sugar increasement. Conclusions: Exemestane and medroxyprogesterone can be used as the treatment choices in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteriodal AI. We need to carry on the phase III clinical trial to prove the efficacy and safety of the two drugs.
MM-011: A Phase 2 Study of Pomalidomide Plus Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma in Japan
Authors: Shotaro Hagiwara, Shinichiro Okamoto, Kosei Matsue, Shinsuke Iida, Kazutaka Sunami, Takuya Komeno, Kenshi Suzuki, Kiyoshi Ando, Masafumi Taniwaki, Kensei Tobinai, Takaaki Chou, Hitomi Kaneko, Hiromi Iwasaki, Chie Uemura, Hiromi Tamakoshi, Mohamed H Zaki, Thomas Doerr, Yoshiaki Kuroda, Tatsuo Ichinohe
Journal: Blood (2015)
Results of a Belgian multicenter retrospective study to determine the incidence of HER2 gene amplification in patients scored as immunohistochemistry 0 or 1+.
Authors: D. Larsimont, C. Colpaert, R. Salgado, N. Vermeesen, V. D'hondt, T. De Celle
Journal: Journal of Clinical Oncology (2011)

549 Background: Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 10% to 25% of breast cancers and is linked with aggressive tumor growth and poor prognosis. Accurate identification of HER2-positive disease is critically important to ensure these patients benefit from effective HER2-targeted therapy. In Belgium, tumors identified as immunohistochemistry (IHC) 2+ or 3+ are retested using in situ hybridization (ISH). Reimbursement of HER2-directed therapy is provided for patients with a positive ISH result (defined in Belgium as HER2/chromosome 17 ratio of > 2.0). The objective of this study was to determine the proportion of patients who are not currently retested (i.e. IHC 0/1+) but who are HER2-positive by silver in situ hybridization (SISH). Methods: Participating laboratories (33 peripheral and one central) each completed a HER2 testing questionnaire. Retrospectively collected tumor samples with a score of IHC 0/1+ from patients with primary or metastatic breast cancer were reanalyzed using Ventana INFORM HER2 DNA and chromosome 17 probes (Roche Tissue Diagnostics). Samples with a HER2/chromosome 17 ratio of > 2.0 were considered HER2-positive. Results: Results of the questionnaire showed that methods of IHC testing varied between participating laboratories: 85% used a “home-brew” assay, 12% used a CE-IVD IHC testing kit, and for 3% this information was not available. Of those samples collected for SISH, 472 (90.8%) were evaluable and 16 samples were in situ cancers that were excluded from analysis. HER2-positive status was detected in 3.1% (n=14 of 456) of samples in total, including 2.5% (n=4 of 163) of samples classified as IHC 0, and 3.4% (n=10 of 293) of samples classified as IHC 1+. Conclusions: The findings of this study suggest that IHC testing may result in false negatives. Last year in Belgium approximately 6,800 patients were categorized as IHC 0/1+. If the results of our study are representative of centers across the country, approximately 200 of these patients may be HER2-positive by SISH and may benefit from HER2-targeted therapy. A prospective trial is currently in progress to validate these results.
Biomarker analysis of pivotal phase II study of oral panobinostat (PAN) in relapsed/refractory Hodgkin lymphoma (HL) patients following autologous stem cell transplant (ASCT).
Authors: S. J. Harrison, A. K. Hsu, P. J. Neeson, A. Younes, A. Sureda, A. Engert, M. Li, P. Savage, R. Bugarini, C. Le Corre, D. E. Williams, J. D. Gallagher, A. Shen, D. Ritchie
Journal: Journal of Clinical Oncology (2011)

8046 Background: Panobinostat (PAN) is an oral pan-histone deacetylase inhibitor (pan-HDACi). Thymus and Activation-Regulated Chemokine (TARC) is a major mechanism by which Reed-Sternberg cells drive intra-tumoral accumulation of reactive cells. TARC levels decrease with HDACi in HL cell lines and reflect disease activity in patients (pts). In a pivotal HL study, PAN achieved durable responses in heavily pretreated relapsed/refractory pts after ASCT. Prospective analysis of cytokine/chemokine levels was done to identify biomarkers for disease activity and to assess correlation with treatment response to PAN. This presentation focuses on TARC analysis. Methods: PAN was administered 40 mg TIW, every week in 21-day cycles. Response was assessed every 2 cycles by CT/MRI scan. Blood was collected at screening, days 5, 8, and 15 of cycle 1, day 1 of cycles 2-4, and end of treatment. Milliplex Map Human Cytokine/Chemokine panel II (Millipore) was used to analyze TARC. Results: Of 129 treated pts, 74% had tumor reduction and 35 achieved response: 5 complete (CR), 30 partial (PR). Samples were collected from 117 pts for analysis. Baseline TARC levels were similar across pts with CR, PR, SD, and PD. Reduction of TARC on treatment was observed as early as cycle 1 day 8. Percent change, calculated as a geometric mean of ratios of TARC level at cycle 1 day 15 to baseline, showed a reduction of TARC level to 72% in CR, 78% in PR, 90% in SD, and no change in PD pts. Pts with higher reduction were at less risk compared to pts with lower reduction of TARC, hazard ratio 2.22 [CI 95%; 1.27, 3.90] and median PFS in the high reduction group was 9.9 months vs. 4.9 months for the low reduction group. Similar trends were observed at other time points. Conclusions: Early TARC reduction was observed post treatment with PAN in HL pts with disease control and the level of TARC reduction at C1D15 was highest in patients achieving CR and PR, providing further evidence to support the MoA of HDACi in HL. Further analysis is ongoing to correlate changes in TARC vs. time to response and target lesion reduction and these updated results may support TARC as a potential biomarker for monitoring HL response to PAN.
Abstract 2453: The role of p21 in the toxicity of mitomycin C and decarbamoylmitomycin C
Authors: Elise Champeil, Shu-Yuan Cheng, Bik Tzu Huang, Jiwon Seo
Journal: Cancer Research (2015)

Abstract The mitomycins are a family of antitumor antibiotics made by Streptomyces. One member of this family, mitomycin C (MC), is currently used to treat certain cancers. Its mode of action has been extensively examined. In comparison, 10-decarbamoyl mitomycin C (DMC) has not been the object of such intense investigation. It has recently been found to form similar or identical adducts with DNA as mitomycin C (MC). In particular, DMC generates a unique stereoisomeric interstrand crosslink (beta isomer, β-ICL). Although the DNA-adducts of both drugs share common structural features, the biochemical responses to the two drugs are different. In particular, contrary to MC, the DNA-adducts generated by DMC treatment (β-ICL) rapidly activate a p53-independent signal transduction pathway. Thus, the study MC-DMC provides an ideal model for identifying structural features determining the cell signaling outcome in the presence or the absence of a functioning p53 pathway. In particular, we are interested in correlating MC and DMC-adducts structures with the role of p21 in the toxicity of the α-ICL and β-ICL. In this report, we present the following preliminary results 1) Synthesis of the beta DNA monoadduct of DMC via post-oligomerization methods 2) Role of p21 in the upstream p53-independent signaling pathway in response to MC/DMC and the α-ICL. Citation Format: Elise Champeil, Shu-Yuan Cheng, Bik Tzu Huang, Jiwon Seo. The role of p21 in the toxicity of mitomycin C and decarbamoylmitomycin C. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2453. doi:10.1158/1538-7445.AM2015-2453
BIRB796 Inhibits p38 MAPK/Hsp27 Pathway and Enhances Cytotoxicity Triggered by Bortezomib, Hsp90 Inhibitor, and Dexamethasone in Multiple Myeloma.
Authors: Hiroshi Yasui, Teru Hideshima, Hiroshi Ikeda, Janice Jin, Enrique M. Ocio, Tanyel Kiziltepe, Yutaka Okawa, Sonia Vallet, Shweta Chhetri, Kenji Ishitsuka, Yu-Tzu Tai, Klaus Podar, Dharminder Chauhan, Chris Pargellis, Neil Moss, Noopur Raje, Kenneth C. Anderson
Journal: Blood (2006)