tbuckley/cabot-search huggingface dataset:
Abstract 668: Induction of mammary carcinoma in tetracycline-inducible cMET(T1010I) transgenic mice
Authors: Chuanwei Yang, Ana M. Gonzalez, Naoto T. Ueno, Shuying Liu, Jinsong Zhang, Gordon B. Mills, John Mendelsohn, Prahlad Ram
Journal: Cancer Research (2016)

Abstract Gene amplification and mutations of cMET have been reported in a wide variety of tumors, including colorectal, lung, renal, liver, thyroid, and breast cancer. cMET(T1010I) mutation occurred in 5.2% out of 148 sibling pairs diagnosed with colorectal cancer in one study. This germline mutation occurs in about 1% of breast cancer patients, but its frequency increases to 2% in metastatic breast cancer. Furthermore, 16% of breast cancer cases with PI3KCA mutations have co-mutations of the cMET oncogene. To determine the functional consequences of this germline mutation and elucidate the molecular mechanisms of tumorigenesis induced by its oncogenic mutant protein, we developed a transgenic mouse model expressing human cMET(T1010I) under the control of a Tet-responsive promoter. MMTV promoter - directed expression of reverse tetracycline-controlled transactivator (rtTA) turns on the expression of the cMET(T1010I) transgene in murine mammary glands upon tetracycline administration. Thirty percent of these mice developed early onset mammary carcinoma within 5 months of transgene induction. This contrasts with previous reports of mammary tumor development in MMTV-cMET transgenic mice after more than a year. This strong phenotype is not the result of a random insertional effect of the transgene as no mammary tumors developed in the 29 transgene positive mice without mammary-specific expression of rtTA over a year in our study. Molecular characterization of these tumors is currently underway and the results may reveal mechanisms of tumorigenesis and novel therapeutic targets for patients harboring this mutation. In conclusion, we showed for the first time that the cMET(T1010I) mutation can trigger rapid breast tumorigenicity. By using organ-specific expression of rtTA to direct the expression of cMET(T1010I) in the organ of interest, our transgenic model may be used to understand the impact of cMET(T1010I) on many other cancer types such as colorectal, lung, renal, thyroid, and liver cancer. Citation Format: Chuanwei Yang, Ana M. Gonzalez, Naoto T. Ueno, Shuying Liu, Jinsong Zhang, Gordon B. Mills, John Mendelsohn, Prahlad Ram. Induction of mammary carcinoma in tetracycline-inducible cMET(T1010I) transgenic mice. [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 668.
Abstract 5138: The PD-1/PD-L1 axis and clinical outcomes in head and neck squamous cell carcinomas
Authors: Sumita Trivedi, Raja R. Seethala, Robert L. Ferris
Journal: Cancer Research (2016)

Abstract Although novel therapeutic agents targeting PD-L1 and PD-1 have emerged, our understanding of the complex interaction between the tumor microenvironment and this checkpoint receptor-ligand axis remains incomplete. PD-L1 protein expression has been demonstrated by immunohistochemistry in several solid tumors including head and neck squamous cell carcinomas (HNSCC). However, the prognostic significance of PD-L1 overexpression in HNSCC remains inconclusive. Furthermore, the interaction between human papillomavirus (HPV) positive tumors, PD-L1 on tumor cells and PD-1 on immune cells has yet to be demonstrated in an architecturally intact tumor environment. Here we demonstrate PD-L1 expression in a large cohort of mixed HPV+ and HPV-, surgically treated HNSCC using immunohistochemistry. Our findings confirm that more HPV+ tumors express PD-L1 compared with HPV- tumors (72% compared with 44%). Clinically, this correlates with improved overall and disease-free survival in in patients with HPV+ PD-L1+ tumors compared with HPV- PD-L1- tumors. By examining the intact tumor, we visualized distinct patterns of PD-L1 staining, either peripherally, at the tumor front or non-peripherally. Tumors with a peripheral staining pattern showed a trend towards decreased overall and disease-free survival, compared to those with a non-peripheral pattern of staining. By double staining PD-L1 and PD-1, we analyzed the co-expression of the ligand on tumor cells and its receptor on neighboring immune cells. Interestingly, patients whose tumors displayed co-localization of PD-1 and PD-L1 showed a trend towards improved disease-free survival compared to tumors where there was no co-localization of PD-1 and PD-L1. In conclusion, out data suggest that the presence of PD-L1 and PD-1 alone may not be sufficient to guide clinical treatment rather; careful examination of the intact tumor microenvironment may inform more targeted therapy. Citation Format: Sumita Trivedi, Raja R. Seethala, Robert L. Ferris. The PD-1/PD-L1 axis and clinical outcomes in head and neck squamous cell carcinomas. [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 5138.
Activity of gemcitabine and vinorelbine in patients with metastatic urothelial carcinoma.
Authors: Erika D. Barrett, Kara M. Olivier, Philip James Saylor, M Dror Michaelson, Richard J. Lee
Journal: Journal of Clinical Oncology (2015)

e15507 Background: After first-line, cisplatin-containing chemotherapy for metastatic urothelial carcinoma, there are no universally accepted second-line regimens. Two prior studies reported 33-48% overall response rate (ORR) to gemcitabine/vinorelbine (gem/vin). We retrospectively evaluated doublet therapy using gem/vin in patients treated at our institution for metastatic urothelial carcinoma, with or without prior chemotherapy. Methods: Thirty patients were treated between 2002-2015 with gem 1000mg/m2 and vin 25mg/m2, on days 1 and 8 every three weeks. We evaluated response rate, toxicity, and median overall survival. Results: The median age of all 30 patients was 72.5 years (range, 40-85). Nine were female. Patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. Twenty-four had received prior chemotherapy, with median of 2 prior lines of therapy (range, 1-5). Among these 24 patients, there were no complete responses, 7 partial responses (PR), 9 stable disease (SD). Median survival among pre-treated patients was 17 months, 8 months, and 6 months among patients achieving PR, SD, or progressive disease, respectively. Among the 6 patients without prior chemotherapy, there were 6 PRs, with median survival of 8.5 months. In total, there were 13 PRs, for a 43% ORR. The most common grade 3 or 4 hematologic toxicity was neutropenia (4 patients, 13%). One patient had grade 3 treatment-related acute kidney injury. Conclusions: Gem/vin is an active and well tolerated chemotherapy regimen for metastatic urothelial carcinoma. Although median overall survival for the entire cohort was 8 months, some pre-treated patients who responded to gem/vin had notably longer survival. Further prospective evaluation of this regimen, along with identification of prognostic factors, may be warranted.
Concordance of PD-L1 expression by different immunohistochemistry (IHC) definitions and in situ hybridization (ISH) in squamous cell carcinoma (SCC) of the lung.
Authors: Alex Martinez Marti, Pablo Martinez, Alejandro Navarro, Susana Cedres, Nuria Murtra-Garrell, Francesc Salva, Irene Sansano, Laura Romero, Enriqueta Felip, Paolo Nuciforo
Journal: Journal of Clinical Oncology (2014)

7569 Background: Recent clinical trials have shown that immune-checkpoint blockade can result in striking and durable responses in advanced non-small cell lung cancer. Preliminary data suggest a relationship between PD-L1 expression by IHC and objective response. No consensus about PD-L1 positivity expression exists. The aim of this study is to compare different IHC definitions and to explore the value of ISH for PD-L1 expression. Methods: Formalin-fixed paraffin-embedded tumor tissue samples from SCC were included. Clinical characteristics were analyzed. PD-L1 protein expression was evaluated by IHC using a mouse monoclonal antibody (clone h5H1). Three definitions for IHC positivity were applied: IHC 1 ≥5% of tumor cells exhibiting cell-surface staining; IHC 2 ≥1% of tumor cells exhibiting cell-surface staining; IHC 3 H-score, cut off: negative (0), positive (1-300). PD-L1 gene expression was evaluated by ISH with RNA Scope probe (Advanced Cell Diagnostics). For ISH, cut off: negative (<1), positive ( ≥1). Comparisons were made using kappa(k) correlation index. Results: 114 SCC tumors were included, median age 68.5 years, males 90.4%, current/former smokers 99.1%. By stage: IA 9.6%, IB 20.2%, IIA 16.7%, IIB 18.4%, IIIA 28.1%, IIIB 2.6%, and IV 4.3%. IHC and ISH results (see Table). According to IHC 3 20 (20.6%) SCC were positive for PD-L1. No differences by age, sex, smoking or stage were found. Median OS was 67.3 months (m), being of 58.7m for PD-L1 negative patients and of 81.5m for PD-L1 positive patients (p=0.598). A higher percentage of tumors resulted positive by ISH (29.4%), mainly due to a 13% of tumors that persistently remain negative by any IHC. K correlation index between IHC 1 versus (vs) IHC 2, IHC 1 vs IHC 3 and IHC 2 vs IHC 3 were of 0.94, 0.96 and 0.98, respectively. K correlation index for IHC3 vs ISH was 0.44. Conclusions: Our data suggests that the accuracy of different IHC definitions for PD-L1 expression have a high concordance. Results of ISH gene expression for PD-L1 warrant further investigation and can detect a subset of patients with PD-L1 pathway activation that remains negative by IHC. PD-L1 + PD-L1 - Nonevaluable IHC 1 18 79 17 IHC 2 20 78 16 IHC 3 20 77 17 ISH 30 72 12
Abstract 1050: Inhibition of the polyamine synthesis pathway is synthetically lethal with loss of argininosuccinate synthase 1 in cancer
Authors: Peter W. Szlosarek, Matthew Locke, Essam Ghazaly, Laura Lattanzio, Cristiana Lo Nigro, Sarah A. Martin
Journal: Cancer Research (2016)

Abstract Argininosuccinate synthetase 1 (ASS1) is the rate-limiting enzyme for arginine biosynthesis. ASS1 expression is lost in a range of different tumour types, including 50% of malignant pleural mesotheliomas. Starving ASS1-deficient cells of arginine with arginine blockers such as ADI-PEG20 can induce selective lethality and has shown great promise in the clinic. However, recent data has shown that ASS1-deficient tumours can become resistant to this therapy although the mechanisms behind this resistance remain unclear. We have generated the first model of ADI-PEG20 resistance in mesothelioma cells whereby we observe re-expression of ASS1, via demethylation of the ASS1 promoter. Through coordinated transcriptomic and metabolomic profiling, we have shown that ASS1-deficient cells have decreased levels of acetylated polyamines, resulting in an increased activation of the polyamine synthesis pathway. Upon arginine deprivation, we observe a decrease in polyamine metabolites in the ASS1-deficient cells only, suggesting that exogenous arginine is required to maintain polyamine biosynthesis in the absence of ASS1. We identify for the first time a compensatory increase in polyamine synthesis gene expression upon ASS1 loss and highlight a synthetic lethal dependence between ASS1-deficiency and polyamine metabolism, which could potentially be exploited for the treatment of ASS1-negative cancers. Citation Format: Peter W. Szlosarek, Matthew Locke, Essam Ghazaly, Laura Lattanzio, Cristiana Lo Nigro, Sarah A. Martin. Inhibition of the polyamine synthesis pathway is synthetically lethal with loss of argininosuccinate synthase 1 in 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 1050.
Abstract 3410: Downregulation of <i>let 7a 5p</i> predicts lymph node metastasis and prognosis in colorectal cancer: implications for chemotherapy
Authors: Ya-Wen Cheng, Tsang-Pai Liu, Po-Li Wei, Huei Lee
Journal: Cancer Research (2016)

Abstract Background. Colorectal cancer guidelines recommend adjuvant chemotherapy is based on the number of lymph nodes metastasis. Let-7a-5p is a microRNA which could inhibits migration, invasion and epithelial-mesenchymal transition by targeting HMGA2. The aim of this study was to investigate the role of let-7a-5p in clinical impact of colorectal cancer (CRC). Methods. One hundred ninety-two CRC patients were enrolled. The expression of let-7a-5p and HMGA2 in serums and tumor tissues were analyzed by real-time PCR and immunohistochemistry. Univariate (Kaplan-Meier) analysis was used to analyze primary outcomes included 5-year overall survival and tumor recurrence. Results. The expression of let-7a-5p in tumor tissues was significantly negative correlated with tumor size, stage, and lymph node metastasis in CRC patients (p = 0.024 for tumor size, p = &amp;lt;0.0001 for stage, and p&amp;lt;0.0001 for lymph node metastasis). There was a negative correlation between levels of let-7a-5p and the HMGA2 gene (p &amp;lt;0.0001), especially in CRC patients with wildtype APC gene. Patients with let-7a-5p low / HMGA2 high had poorer overall survival (OS) and disease-free survival (DFS) rates than those with let-7a-5p high / HMGA2 high, let-7a-5p high / HMGA2 low, and let-7a-5p low /HMGA2 low groups. In addition, the expression levels of let-7a-5p in PBMCs were positive correlated with in tumor tissues of CRC patients. Conclusion. We suggest that down-regulation of let-7a-5p in PBMCs and tumor tissues patients could be used to predicts lymph node metastasis and prognosis impact on chemotherapy of colorectal cancer Citation Format: Ya-Wen Cheng, Tsang-Pai Liu, Po-Li Wei, Huei Lee. Downregulation of let 7a 5p predicts lymph node metastasis and prognosis in colorectal cancer: implications for chemotherapy. [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 3410.
Abstract 5047: The MUC1 membrane-bound mucin increases tumor cell properties and chemoresistance in renal clear cell carcinoma
Authors: Kelly Gaudelot, Viviane Gnemmi, Audrey Bouillez, Jean-Baptiste Gibier, Mélanie Fanchon, Justine Woszczyk, Brigitte Hémon, Isabelle Van Seuningen, Sébastien Aubert, Michael Perrais
Journal: Cancer Research (2016)

Abstract Introduction: MUC1, an O-glycoprotein membrane-bound mucin, is overexpressed in renal clear-cell carcinomas (CRCC) with correlation to two major prognostic factors, Tumor-Node-Metastasis stage and nuclear Fürhman grade. Previously, we have shown that (i) MUC1 was significantly overexpressed in metastatic CRCC vs non-metastatic CRCC and (ii) MUC1 is a target gene of HIF-1 transcription factor which is a part of the hypoxia pathway, the main renal carcinogenetic pathway. Furthermore, CRCC is highly resistant to common systemic chemotherapies. Material and method: To better understand the roles of MUC1 in CRCC, we used two renal cell lines expressing MUC1 (786-O cells) or not (ACHN cells). 786-O cells were stably transfected with shRNA targeting MUC1 while ACHN cells with full-length MUC1. Proliferation, drug resistance, migration and invasion properties were studied in vitro in the different cellular clones using MTS cell proliferation assay, wound healing assay and Boyden chambers coated with Matrigel, respectively. Signaling pathways were screened by proteome profiler and western blot. Results and discussion: We showed that MUC1 expression was associated with increased invasion and migration properties of renal carcinomatous cells and a decrease of cell-cell interactions. MUC1 overexpressing cells (i) expressed higher levels of anti-apoptotic factors and MDR genes involved in chemoresistance processes and (ii) were more resistant to chemotherapeutic drugs. Conclusion: Our results show that MUC1 plays a role in biological properties of renal cancer cells suggesting important function for this mucin in tumour progression and chemo-resistance. Our data confirm its potential as a therapeutic target in this type of cancer. Citation Format: Kelly Gaudelot, Viviane Gnemmi, Audrey Bouillez, Jean-Baptiste Gibier, Mélanie Fanchon, Justine Woszczyk, Brigitte Hémon, Isabelle Van Seuningen, Sébastien Aubert, Michael Perrais. The MUC1 membrane-bound mucin increases tumor cell properties and chemoresistance in renal clear cell carcinoma. [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 5047.
Combined Treatment With Chondroitin Sulfate and Glucosamine Sulfate Shows No Superiority Over Placebo for Reduction of Joint Pain and Functional Impairment in Patients With Knee Osteoarthritis: A Six‐Month Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial
Authors: Jorge A. Roman‐Blas, Santos Castañeda, Olga Sánchez‐Pernaute, Raquel Largo, Gabriel Herrero‐Beaumont
Journal: Arthritis & Rheumatology (2016)

Objective To assess the efficacy and safety of combination therapy with chondroitin sulfate (CS) and glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis (OA). Methods A multicenter, randomized, double‐blind, placebo‐controlled study was performed in 164 patients with Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA and moderate‐to‐severe knee pain (mean ± SD global pain score 62.1 ± 11.3 mm on a 100‐mm visual analog scale [VAS]). Patients were randomized to receive either combined treatment with CS (1,200 mg) plus GS (1,500 mg) or placebo in a single oral daily dose for 6 months. The mean change from baseline in the VAS global pain score was set as the primary end point. Secondary outcomes included the mean change in the investigator's global assessment of disease activity, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain and function subscale scores on the WOMAC, responder rates based on the Outcome Measures in Rheumatology (OMERACT)–Osteoarthritis Research Society International (OARSI) 2004 response criteria, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was instituted to ensure patient safety and data accuracy. Results Intriguingly, in the modified intent‐to‐treat (mITT) population, CS/GS combination therapy was inferior to placebo in the reduction of joint pain (mean ± SD change in VAS global pain score over 6 months −11.8 ± 2.4 mm [19% reduction] in patients receiving CS plus GS versus −20.5 ± 2.4 mm [33% reduction] in patients receiving placebo; peak between‐group difference in global pain score at 6 months 8.7 mm [14.2%], P &lt; 0.03), but no between‐group differences were seen in the per‐protocol completers. Both placebo treatment and CS/GS combination treatment improved to a similar extent the total WOMAC score as well as the pain and function WOMAC subscale scores, both in the mITT population and in the per‐protocol completers. Neither the OMERACT–OARSI responder rate nor the frequency of rescue medication use differed between the treatment groups. Severe adverse events were uncommon and equally distributed. Conclusion The results of this trial demonstrate a lack of superiority of CS/GS combination therapy over placebo in terms of reducing joint pain and functional impairment in patients with symptomatic knee OA over 6 months. Further research might fully elucidate the suitability of CS/GS combination therapy in patients with OA.
Quantitative assessment of diagnostic markers and correlations with efficacy in two phase II studies of trastuzumab-DM1 (T-DM1) for patients (pts) with metastatic breast cancer (MBC) who had progressed on prior HER2-directed therapy.
Authors: P. LoRusso, I. E. Krop, H. A. Burris, S. J. Vukelja, K. Miller, M. Zheng, Y. Chu, M. Lu, L. C. Amler, H. S. Rugo
Journal: Journal of Clinical Oncology (2010)

1016 Background: The antibody-drug conjugate T-DM1 has shown encouraging efficacy in two phase II studies (4258g and 4374g) for pts with HER2-positive (HER2+) MBC who had progressed on prior HER2-directed therapies. Assays to quantify HER2 and PTEN expression and to assess PI3K mutation status were conducted; results were correlated with responses to T-DM1 therapy. Methods: Both trials were single-arm, with 3.6 mg/kg T-DM1 IV q3w. HER2 status was centrally retested using archival tissue. HER2 expression by qRT-PCR, PI3K mutation status by PCR-based assay, and PTEN expression by immunohistochemistry (IHC) were also assessed. Exploratory analyses of objective response rates (ORR) and progression-free survival (PFS) by independent review were conducted for biomarker-defined pt subgroups. Results: The Table summarizes ORR and median PFS based on biomarker data for pts in 4258g and 4374g (∼12 and 6 mos minimum follow-up, respectively). Conclusions: In this retrospective analysis, HER2+ status by central retesting correlated with better responses to T-DM1. HER2 expression by qRT-PCR may identify pts more likely to benefit from T-DM1 therapy. No consistent trend in T-DM1 activity was observed in pts with activating PI3K mutations and/or decreased PTEN. Future trials are needed to validate these findings. 4374g 4258g n ORR% (95% CI) n ORR% (95% CI) mPFS, mos (95% CI) Efficacy evaluable pts 107 33.6 (24.8, 43.4) 108 26.9 (19.2, 35.8) 4.6 (3.9, 8.6) Centrally retested HER2 status +a 74 40.5 (29.3, 52.3) 74 33.8 (23.2, 44.9) 8.2 (4.4, NR) Normal 14 21.4 (6.1, 50.0) 21 4.8 (<1.0, 21.8) 2.6 (1.4, 3.9) HER2 RT-PCRb ≥ Medianc 26 50.0 (29.9, 70.1) 25 36.0 (18.5, 56.9) NR (4.6, NR) Median 38 31.6 (17.5, 48.6) 25 28.0 (12.1, 47.5) 4.2 (2.7, 6.8) PI3K Mutationb Wild type 34 29.4 (15.1, 46.5) 42 35.7 (21.6, 51.9) 9.8 (4.9, NR) Mutant 8 25.0 (4.6, 65.1) 9 22.2 (4.1, 55.8) 3.9 (2.0, NR) PTEN by IHCb Normal 38 36.8 (22.6, 53.5) 30 36.7 (20.5, 56.0) 4.6 (3.1, 8.9) Decreased 3 33.3 6 16.7 (0.9, 59.8) NR (NR, NR) Abbreviation: NR, not reached as of data cut. a FISH+ and/or IHC3+. b Among pts with centrally retested HER2+ status. c Median was based on 4258g data. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Roche Genentech Genentech