tbuckley/cabot-search huggingface dataset:
A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC).
Authors: Andrea Borghese Apolo, Howard L. Parnes, Ravi Amrit Madan, James L. Gulley, John Joseph Wright, Jean H. Hoffman-Censits, Nancy Ann Dawson, Jane B. Trepel, Kattie Khadar, Jeffrey Schlom, Maria Merino, Mark Raffeld, Seth M. Steinberg, Peter L. Choyke, Maria Liza Lindenberg, Les Folio, Piyush K. Agarwal, William Douglas Figg, Donald P. Bottaro, William L. Dahut
Journal: Journal of Clinical Oncology (2014)

307 Background: Translational studies have shown that shed MET levels in serum and urine of pts with UC correlate with stage and visceral metastases and that cabozantinib reverses HGF-driven UC cell growth and invasion. These data support the evaluation of cabozantinib in pts with mUC. Methods: In this phase II study, pts receive cabozantinib 60 mg daily in 28-day cycles. There are 3 study cohorts (1) mUC, (2) bone only mUC (3) metastatic rare bladder histology. The primary objective is to determine the response rate (RR) by RECIST. Response is assessed every 2 cycles. Tissue, blood, and urine were collected on all pts to test for MET/HGF and immune subsets. Results: 26 out of 55 pts have enrolled (19 M, 7 F): median age 62 (42-82) and median KPS of 80%. Primary sites include bladder (77%) and upper tract UC (23%). Prior therapy includes 30% pts with 1 regimen, 39% with 2, 15% with 3, 8% with 4 and 8% with 6. 81% of pts had visceral metastases (lung, liver and bone) and 19% lymph node only metastases. 23 pts (19 in cohort 1, 3 in cohort 2 and 1 in cohort 3) were evaluable for response after completing at least 4 weeks of therapy. In cohort 1, 2 pts achieved PR (1 remained on study for 10 months and 1 remains on study after &gt;12 months of therapy); 7 pts had SD for at least 16 weeks (1 remained on study for 11 months); 10 had PD; 1 is too early to assess for response; 1 was removed before restaging for toxicity and 1 was removed for not meeting eligibility. The objective RR is 11% and SD 37% for a clinical benefit of 48%. In cohort 2, 1 of 3 pts had a near resolution of bone lesions on NaF PET/CT for 11 months. In cohort 3, only pt enrolled (squamous cell carcinoma of the bladder) achieved SD for 16 weeks. Mixed responses with regression of lung, bone or lymph nodes were observed in 30% of pts with PD. Grade 3/4 toxicities included: fatigue (8%), hyponatremia (8%), hypophosphatemia (8%) diarrhea (4%), thromboembolism (4%), transaminitis (4%), hypothyroidism (4%), thrombocytopenia (4%), dysphonia (4%), hypomagnesemia (4%), creatinine increase (4%) and proteinuria (4%). Conclusions: Cabozantinib has clinical activity in pts with relapsed or refractory mUC with manageable toxicities. Further studies are underway to correlate response to therapy with MET expression. Clinical trial information: NCT01688999.
NEJ009 trial: A randomized phase III study of gefitinib (G) in combination with carboplatin (C) plus pemetrexed (P) versus G alone in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) with EGFR mutation.
Authors: Akira Inoue, Yukio Hosomi, Makoto Maemondo, Shunichi Sugawara, Terufumi Kato, Kazuhisa Takahashi, Yuka Fujita, Akihiko Gemma, Toshiyuki Harada, Satoshi Oizumi, Koichi Minato, Satoshi Morita, Toshihiro Nukiwa
Journal: Journal of Clinical Oncology (2014)

TPS8131 Background: Based on the previous phase III studies including our NEJ002 study comparing G with platinum doublet, G alone has been accepted as the standard first-line treatment for patients with EGFR-mutated NSCLC. To improve the survival in this population, we had investigated subsequent randomized phase II study (NEJ005) that evaluate the efficacy and safety of two patterns of combined regimen with G, C, and P, and selected one regimen with concurrent use of G, C, and P according to the results of interim monitoring. Methods: This randomized phase III trial was designed to compare the efficacy and safety of G alone with combined regimen with G, C, and P in patients with advanced EGFR-mutated NSCLC. Eligible patients (N=340) have pathologically confirmed stage IIIB/IV NSCLC with activating EGFR mutation including exon 18 G719A, C, or S mutation, exon 19 deletion, exon 21 L858R, or L861Q mutation. Concurrent mutation in exon 20 T790M is ineligible. Patients must have radiologically measurable disease, ECOG PS 0–1 and no prior systemic therapy. Patients will be randomized (1:1) to receive G 250 mg alone once daily or same schedule of G with C (AUC 5.0) plus P (500 mg/m2) on day1, every 3 weeks, up to 4-6 cycles, followed by maintenance P with concurrent G. The primary endpoint is overall survival (OS) and secondary endpoints include progression-free survival, best overall response, toxicity profile, and quality of life. A minimum of 168 OS events is required for 80% power to detect a OS improvement of GCP regimen versus G alone using the intent-to-treat (ITT) analysis population (HR ≤0.7). A significant (0.025 significance level) 2-sided stratified log-rank test for OS at the final analysis will be indicative of a positive study outcome. An interim analysis is planned to assess safety and whether early discontinuation of the trial is required for futility. Clinical trial information: UMIN000006340.
Distinct subclonal tumour responses to therapy revealed by circulating cell-free DNA
Authors: G. Gremel, R.J. Lee, M.R. Girotti, A.K. Mandal, S. Valpione, G. Garner, M. Ayub, S. Wood, D.G. Rothwell, A. Fusi, A. Wallace, G. Brady, C. Dive, N. Dhomen, P. Lorigan, R. Marais
Journal: Annals of Oncology (2016)

BackgroundThe application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment.Patients and methodsWe used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy.ResultsDespite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel.ConclusionWe show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.
Quality control of house dust mite extracts by broad-spectrum profiling of allergen-related enzymatic activities
Authors: J. C. Vidal-Quist, F. Ortego, P. Castañera, P. Hernández-Crespo
Journal: Allergy (2016)

Diagnosis and immunotherapy of allergy against mites is based on complex extracts from large-scale cultures. However, the analysis of their composition using specific antibodies is limited. By taking advantage of the prevailing enzymatic nature of mite allergens, we have developed a broad-spectrum biochemical method for the standardization of native mite products.Microplate-based assays have been implemented for thirteen Dermatophagoides pteronyssinus enzymatic activities, associated with Der p 1, 3, 4, 6, 8, 9, 15 and 20 allergens. The dynamics of these activities along culture growth, and their profile in purified fractions (bodies and faeces) and international reference standards (WHO/IUIS, two CBER/FDA), have been characterized. The stability of enzymatic activities and major allergens under stress conditions (40°C) has been assessed in the presence/absence of specific protease inhibitors.The analysis of enzymatic activities revealed distinct profiles along culture growth and between fractions (bodies and faeces). Remarkable differences were found when comparing international reference standards, being consistent with their source material (purified bodies or whole cultures). After 72 h at 40°C, only trypsin and alpha-amylase maintained high activity. Notably, the prominent role of trypsins in the hydrolytic degradation of major allergens is demonstrated by the use of inhibitors.Our method offers a robust approach to assess the complexity of mite extracts and highlights the critical importance of source materials for the composition and stability of finished products. The implementation of this approach in industry-based quality control procedures would contribute to the standardization of allergenic extracts used for diagnosis and immunotherapy.
Abstract 314: Cell cycle phase-specific drug resistance as an escape mechanism of melanoma cells
Authors: Kimberley A. Beaumont, David S. Hill, Sheena M. Daignault, Danae M. Sharp, Brian Gabrielli, Wolfgang Weninger, Nikolas K. Haass
Journal: Cancer Research (2016)

Abstract The tumor microenvironment is characterized by cancer cell subpopulations with heterogeneous cell cycle profiles. For example, hypoxic areas within tumors contain clusters of cancer cells that arrest in the G1 cell cycle phase. It is conceivable that cancer cells exhibit differential drug sensitivity based on their residence in specific cell cycle phases. Here, we have used two-dimensional and organotypic melanoma culture models in combination with fluorescent cell cycle indicators to investigate the effects of G1-arrest on clinically used melanoma drugs. We demonstrate that G1-arrested melanoma cells, irrespective of the underlying cause mediating G1-arrest, are resistant to induced cell death by the proteasome inhibitor bortezomib and the alkylating agent temozolomide. In contrast, G1-arrested cells were more sensitive to MAPK pathway inhibition. Of clinical relevance, pre-treatment of melanoma cells with a MAPK pathway inhibitor resulted in resistance to temozolomide or bortezomib, while in contrast pre-treatment with temozolomide did not result in resistance to the MAPK pathway inhibitor. In summary, we have established a model to study the effects of the cell cycle on drug sensitivity. Cell cycle phase-specific drug resistance is an escape mechanism of melanoma cells that has implications on the choice and timing of drug combination therapies. Citation Format: Kimberley A. Beaumont, David S. Hill, Sheena M. Daignault, Danae M. Sharp, Brian Gabrielli, Wolfgang Weninger, Nikolas K. Haass. Cell cycle phase-specific drug resistance as an escape mechanism of melanoma cells. [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 314.
Abstract 2695: Targeted therapy of leukemia and Ewing's sarcoma by human antibody-targeted nanoparticles
Authors: Hyunggyoo Kang, Jon Nagy, Timothy Trivhe
Journal: Cancer Research (2016)

Abstract Current cancer therapies have shown limited success due to the poor selectivity. The recent chemotherapy could be far more effective if higher doses could be specifically delivered to the tumor and not to normal tissues. Therefore a reliable tumor specific therapy is urgently needed to treat cancer patients. Targeted nanoparticle can attenuate the off-target toxicity and enhance the efficacy of existing therapies, which would be highly beneficial to the cancer patients. In spite of a lot of effort still the optimal formulation of nanoparticle for the actual translational applications was not established yet. Liposomes, unilamellar vesicles composed of natural and/or synthetic lipids have been an intensively studied system. By refining the early formulations and after extensive testing, recently we could invent a new type of lipid bilayer nanoparticle delivery system, HPLN (Hybrid Polymerized Liposomal Nanoparticles) and demonstrate that this new type of polymeric nanoparticle overcomes many, if not most, of the deficiencies noted and has tremendous potential as an effective delivery vehicle for treating many types of cancer. In our study it was shown that the targeted HPLN with human antibodies (antiCD99 or antiCD19) can inhibit the growth of Ewing's sarcoma and leukemia (ALL) in a murine model. The antitumor effects of of HPLN were diminished pretty much by the removal of antibody or drug (Doxorubicin), which proves efficacy of the targeted HPLNs is specifically dependent upon the targeting antibody and drug. In addition, no abnormalities in liver and kidney function tests, complete blood counts or pathology of major organs are observed from tail-vein administrations. These data provide strong evidence for the safety and efficacy of this targeted HPLN delivery system of anticancer drugs to Ewing's sarcoma and leukemia (ALL). In conclusion, our result showed a potential of targeted HPLN as a selective delivery vehicle of cytotoxic drugs to cancers. Hopefully this technology will be applied to treat many other different types of tumor cells in the future. Citation Format: Hyunggyoo Kang, Jon Nagy, Timothy Trivhe. Targeted therapy of leukemia and Ewing's sarcoma by human antibody-targeted nanoparticles. [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 2695.
Feasibility of EBUS-TBNA specimens for PD-L1 expression test in lung cancer.
Authors: Yuichi Tambo, Rie Sakakibara, Noriko Motoi, Fumiyoshi Ohyanagi, Satoru Kitazono, Atsushi Horiike, Noriko Yanagitani, Tomoyo Oguri, Yosuke Kawashima, Natsuki Takano, Yuichi Ishikawa, Makoto Nishio
Journal: Journal of Clinical Oncology (2016)

e23112 Background: Analysis of programed cell death ligand 1 (PD-L1) expression in tumor samples is necessary for anti-PD-1/PDL1 therapy. However, it is difficult to get sufficient samples in some lung cancer patients. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is commonly used to obtain samples from mediastinal lymph nodes. EBUS-TBNA is also superior to core needle biopsy or surgical resection in safety. In this study, we examined feasibility fo PD-L1 expression test in tissue samples which obtained from EBUS-TBNA. Methods: One hundred specimens were obtained from mediastinal lymph nodes of lung cancer patients by EBUS-TBNA in our institution from 2013 to 2014. FFPE tissue sections were scanned automatically by Aperio ScanScope AT Turbo (Leica). Cancer cells which positively stained with TTF-1, P40 or CK AE1/AE3 in the virtual slides were counted by Aperio Image Scope (Leica). If we could not assess cancer cell counts by virtual slides, we counted cell counts by visual contact using H-E staining slides. PDL1 expression status were evaluated by pathologist with IHC staining of anti-PDL1 antibody (anti-CD274 [EPR1161 (2)] antibody) (Abcam, Cambridge, UK). PDL1 staining were scored 0, 1+, 2+, 3+ and no evaluable. Results: Among 100 samples, 54, 17, 24 samples were contained adenocarcinoma, squamous cell carcinoma and small cell carcinoma, respectively. Two samples contained less than 100 cancer cells, 14 samples contained 100-999 cancer cells, 61 samples contained 1000-9999 cancer cells and 23 samples contained > 10000 cancer cells,. Among 100 samples, 96 samples were evaluable for PD-L1 expression but 4 samples were not evaluable due to inappropriate (Two samples did not contain more than 100 cancer cells. Two specimens were insufficient amount of sample for making PD-L1 IHC staining slides). Among 96 samples, 3+, 2+, 1+, 0 of PD-L1 expression were 8%, 34%, 47% and 9%, respectively. Conclusions: Most of EBSU-TBNA samples were contained more than 100 cancer cells and were feasible for PD-L1 expression test.
P131 Efficacy of tiotropium and olodaterol combination in patients with COPD on β-blockers: Abstract P131 Table 1
Authors: E Derom, S Korn, A Hamilton, VC Amatto, Y Zhao, F Maltais
Journal: Thorax (2015)

<h3>Rationale</h3> The efficacy and safety of a new once-daily combination with tiotropium (T), a long-acting muscarinic antagonist, and olodaterol (O), a long-acting β<sub>2</sub>-agonist, was established for the treatment of chronic obstructive pulmonary disease (COPD) in the TONADO studies (NCT01431274; NCT01431287). This analysis evaluates the efficacy of the combination in a subpopulation of patients receiving β-blockers in these studies. <h3>Methods</h3> Two replicate, randomised, double-blind, parallel-group, 52-week, Phase III trials assessed the efficacy and safety of T+O (2.5/5 μg; 5/5 μg; via Respimat® inhaler) once daily compared to the monocomponents. Key primary end-point data for the combined analysis of the replicate trials in patients with COPD receiving β-blockers during treatment are presented. <h3>Results</h3> 5136 patients were evaluable; 556 (10.8%) received β-blockers. At 24 weeks, similar improvements in mean forced expiratory volume in 1 s (FEV<sub>1</sub>) area under the curve from 0–3 h (AUC<sub>0–3</sub>) responses for T+O compared to monocomponents were seen across β-blocker subgroups (Table 1), with no significant treatment interaction effect observed. A similar trend was observed with trough FEV<sub>1</sub> and quality of life scores. <h3>Conclusions</h3> While the β-blocker patient group analysed was small, these data demonstrated similar sustained improvements in lung function, irrespective of β-blocker use. These data support the efficacy of T+O in this patient group. <h3>Funding</h3> Boehringer Ingelheim.
Abstract 4151: APC control of retinoic acid suppresses immune cell mediated intestinal proliferative response
Authors: Amanda K. Templeton, Saher Hammoud, Brad Cairns, David Jones
Journal: Cancer Research (2016)

Abstract Adenomatous polyposis coli (APC) tumor suppressor function is centered on its role in antagonizing Wnt/B-catenin mediated colonic proliferation. Our previous studies, however, established a second role wherein APC's control of retinoic acid (RA) results in intestinal epithelial cell differentiation. Surprisingly, the loss of APC or RA alone in zebrafish embryos was not sufficient to drive nuclear accumulation of B-catenin or intestinal cell proliferation. However, combining APC or RA deficiency with a KRAS mutation was sufficient to induce nuclear localization of B-catenin and the proliferative response. In contrast, the loss of RA alone in adult zebrafish results in both intestinal differentiation defects and proliferation. We were therefore interested in investigating these seemingly contradictory results. Using adult zebrafish, we show for the first time that following loss of retinoic acid adaptive immune cells (but not innate immune cells) are indirectly required to elicit the proliferative response independent of Kras activation. We demonstrate that IL-17 secretion from adaptive immune cells in response to loss of RA predisposes colonic epithelium to inflammation resulting in compromised barrier function, loss of cell polarity, reactivation of a progenitor intestinal program, and proliferation. Importantly, we find in both mouse and human intestinal organoid cultures an evolutionarily shared response with zebrafish of T cell dependent intestinal inflammation and proliferation following loss of RA. Our model demonstrates that loss of RA causes an increase in inflammatory mediators (Cox2 and Prostaglandins) that induces infiltration of IL-17 secreting T cells. In a feed-forward loop, the IL-17 acts on the primed epithelium to up-regulate proliferative signaling mediators (Raf and Rac1). Together, these studies provide an important new perspective on the ordering of molecular events that may underlie colon tumor progression. Citation Format: Amanda K. Templeton, Saher Hammoud, Brad Cairns, David Jones. APC control of retinoic acid suppresses immune cell mediated intestinal proliferative response. [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 4151.
Abstract 2609: Epigenetic reactivation of TIMP-3 in human prostate cancer cells by green tea polyphenols
Authors: Gauri Deb, Vijay S. Thakur, Eswar Shankar, Sanjay Gupta
Journal: Cancer Research (2016)

Abstract Metastasis is responsible for more than 90% of prostate cancer-associated mortality in the United States. Metastasis is facilitated by remodeling of the extracellular matrix by a family of proteolytic enzymes known as matrix metalloproteinases (MMPs). These zinc-dependent proteases elicit pivotal role in the proteolytic degradation of structural components of extracellular matrix contributing to the metastatic process. High levels of MMP-2/9 in the plasma and urine has been correlated with metastasis. MMPs are produced in a latent form (pro-MMP) that require activation and are inhibited by tissue inhibitors of matrix metalloproteinases (TIMPs). TIMPs inhibit MMPs by binding in a 1:1 stoichiometry through strong noncovalent interactions. In prostate cancer, low levels of TIMP3 has been associated with aggressive tumor phenotype and poor disease-free survival. Loss of TIMP3 in prostate cancer is attributed to epigenetic silencing tipping the balance towards active MMPs driving metastasis. Green tea polyphenols (GTP) and its major constituent, epigallocatechin-3-gallate (EGCG) has been shown to suppress prostate cancer metastasis, however the mechanism has not been fully elucidated. We determined whether treatment with GTP/EGCG has ability to restore induction of TIMP3 and play a key role in suppressing invasiveness in prostate cancer. Treatment of prostate cancer LNCaP and DUPRO cells with 10μg/mL GTP and 20μM EGCG for 72 h significantly induced TIMP3 mRNA and protein levels. Silencing of enhancer of zeste homolog 2 (EZH2) and class I histone deacetylases (HDACs) significantly increased the expression of TIMP3 which was independent of DNA hypermethylation. Treatment of prostate cancer cells with GTP/EGCG significantly reduced EZH2 and class I HDAC protein levels; H3K27 trimethylation activity; and transcriptional activation of TIMP-3 was found to be associated with decreased EZH2 localization and H3K27 trimethylation enrichment at the TIMP3 promoter with a concomitant increase in histone H3K9/18 acetylation. EGCG/GTP treatment also caused a global reduction in histone methylation thereby increasing histone acetylation to revive and activate TIMP3 levels. Furthermore, EGCG/GTP exposure significantly reduced MMP2/9 gelatinolytic activity and abrogated invasive and migration capabilities in prostate cancer cells. Taken together, our findings suggests that TIMP-3 induction could be a key epigenetic event modulated by GTPs in restoring MMP: TIMP balance to delay prostate cancer invasion and metastasis. Citation Format: Gauri Deb, Vijay S. Thakur, Eswar Shankar, Sanjay Gupta. Epigenetic reactivation of TIMP-3 in human prostate cancer cells by green tea polyphenols. [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 2609.