tbuckley/cabot-search huggingface dataset:
Abstract 4650: Novel resveratrol-analog HPIMBD inhibits breast cancer cell metastasis by reversal of epithelial-mesenchymal transition
Authors: Anwesha Chatterjee, Amruta Ronghe, Subhash Padhye, Hari K. Bhat
Journal: Cancer Research (2015)

Abstract Epithelial-mesenchymal transition (EMT) is a biological process that mediates a phenotypical change in the polarized epithelial cells to mesenchymal cells. The process of EMT increases a cell's migratory and invasive properties. It is well documented that the process of EMT plays a very critical role in cancer metastasis. The objective of this study was to characterize the role of a novel Resveratrol analog 4-(E)-{4-hydroxyphenylimino)-methylbenzene, 1,2-diol} (HPIMBD) on EMT in human breast cancer cells. Human breast cancer cells MDA-MB-231 were treated with Resveratrol (Res) and HPIMBD for up to 48 hours. Protein expression levels of E-cadherin, matrix metalloproteases (MMPs), snail, slug, zeb1/2 and nuclear migration of β-catenin were quantified after treatment with Res or HPIMBD and compared with that of the vehicle-treated control cells. mRNA expression levels of β-catenin and wnt-7b were also quantified. Migration MDA-MB-231 cells was determined after treatment with Res or HPIMBD by wound healing assay. Treatment with HPIMBD significantly up-regulated E-cadherin protein expression levels. The up-regulation of E-cadherin by HPIMBD was associated with suppression of snail, slug and Zeb1 protein levels. HPIMBD significantly down-regulated mRNA expression levels of β-catenin and wnt-7b. Furthermore, HPIMBD restricted nuclear migration of β-catenin. Treatment of breast cancer cells with HPIMBD resulted in down-regulation of MMP3 and MMP9 but not MMP2 protein expression levels. Treatment with HPIMBD also prevented breast cancer cell migration. Our studies demonstrtae that HPIMBD decreases the metastatic properties of breast cancer cells by inhibition of EMT and down-regulation of wnt/β catenin pathway. These findings suggest that HPIMBD may have a potential in inhibtion of EMT and may be explored as as a potential therapy to prevent breast cancer metastasis. Note: This abstract was not presented at the meeting. Citation Format: Anwesha Chatterjee, Amruta Ronghe, Subhash Padhye, Hari K. Bhat. Novel resveratrol-analog HPIMBD inhibits breast cancer cell metastasis by reversal of epithelial-mesenchymal transition. [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 4650. doi:10.1158/1538-7445.AM2015-4650
Abstract LB-203: Obesity promotes resistance to anti-VEGF therapy in breast cancer via pro-inflammatory and angiogenic pathways
Authors: Joao Incio, Daniel McManus, Priya Suboj, Nuh Rahbari, Shan M. Chin, Suboj Babycutty, Trupti Vardan-Kaur, Yuhui Huang, Keehoon Jung, Dan Duda, Raquel Soares, Dai Fukumura, Rakesh K. Jain
Journal: Cancer Research (2015)

Abstract Background: Most breast cancer (BC) patients are overweight or obese at the time of diagnosis. Obesity is associated with increased risk, recurrence, and worse prognosis of BC. It has been shown that obesity associates with worse outcome in metastatic kidney or colon cancer treated with bevacizumab. If and how excess body weight contributes to the failure of anti-VEGF therapy in BC is unknown. Results: Here we found that diet-induced obesity promoted resistance to anti-VEGF therapy in two syngeneic mouse breast cancer models. The effects of anti-VEGF therapy on tumor growth and metastasis, VEGF downstream signaling pathways and vessel density were significantly attenuated in obese mice. Under obesity condition, intra-tumor adipocytes increased. These adipocyte-rich regions in breast cancers were hypoxic and overexpress IL-6 or FGF-2 by adipocytes, fibroblasts, and myeloid cells. In IL-6 overexpressing obese breast cancer model (E0771), neutralization of IL-6, either genetically or pharmacologically, abrogated the obesity-induced resistance to anti-VEGF therapy seen in both primary and metastasis sites. This occurred due to a reversion of the obesity-augmented STAT3 signaling and cell proliferation, of hypoxia via vessel normalization, and of immunosuppression. In another breast cancer model (MCaIV), which overexpress FGF-2 under obesity, anti-FGF receptor antibody restored tumor sensitivity to anti-VEGF treatment in obesity. Conclusion: Our findings indicate that obesity promotes resistance to anti-VEGF therapy in breast cancer via the production of pro-inflammatory and angiogenic factors that circumvent the loss of VEGF signaling. Citation Format: Joao Incio, Daniel McManus, Priya Suboj, Nuh Rahbari, Shan M. Chin, Suboj Babycutty, Trupti Vardan-Kaur, Yuhui Huang, Keehoon Jung, Dan Duda, Raquel Soares, Dai Fukumura, Rakesh K. Jain. Obesity promotes resistance to anti-VEGF therapy in breast cancer via pro-inflammatory and angiogenic pathways. [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-203. doi:10.1158/1538-7445.AM2015-LB-203
Abstract SY35-01: The next generation of ADCs
Authors: Jonathan G. Drachman
Journal: Cancer Research (2015)

Abstract The concept of an antibody-drug conjugate (ADC) is deceptively simple: a monoclonal antibody against a tumor-specific antigen delivers a potent cytotoxic payload directly to the malignant cells, resulting in targeted killing. However, this apparent simplicity belies a complex product with multiple interacting components. Working to optimize these components, we have identified three important concepts that impact the therapeutic potential of ADCs. First, we have learned that stability of an ADC can vary according to the specific conjugation site on the antibody. During the development of engineered cysteine antibodies (EC-mAbs), we evaluated various cysteine substitutions and found that S239C on the IgG heavy chain is particularly stable when conjugated using standard maleimide chemistry. Alternatively, we have devised a method for producing stable conjugation to native cysteine residues by designing maleimides that catalyze their own ring-opening after coupling to the antibody. These modifications in ADC stability appear to result in both improved activity and decreased toxicity in preclinical models. Second, we have observed that modulation of ADC hydrophobicity results in profound changes in both biodistribution and antitumor activity. When utilizing typical drug-linkers, ADCs with a high drug-to-antibody ratio (DAR &amp;gt;4) appear to be cleared from circulation more rapidly by reticuloendothelial cells. By reducing drug-linker hydrophobicity, we can circumvent this clearance pathway and it becomes possible to increase the DAR, resulting in more potent ADCs that retain desirable pharmacokinetic properties. We have achieved a similar result with the use of short, discrete PEG oligomers to mask the drug linker, thereby reducing the apparent hydrophobicity of the ADC. Finally, the chemical properties of the released payload have a major impact on both efficacy and toxicity. The difference between polar and nonpolar payloads will be discussed, including bystander activity, potential mechanisms of resistance, and adverse events observed in clinical trials. A new class of DNA crosslinking payloads is represented by the pyrrolobenzodiazepines (PBD) dimer, which is several logs more potent than auristatins and has the ability to overcome multi-drug resistance phenotypes. These examples demonstrate how rapidly the ADC field is evolving and provide hope that the next generation of ADCs will be even more effective and well-tolerated in the fight against cancer. Citation Format: Jonathan G. Drachman. The next generation of ADCs. [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 SY35-01. doi:10.1158/1538-7445.AM2015-SY35-01
Phase II study of oral ridaforolimus in patients with metastatic and/or locally advanced recurrent endometrial cancer: NCIC CTG IND 192.
Authors: H. Mackay, S. Welch, M. S. Tsao, J. J. Biagi, L. Elit, P. Ghatage, L. A. Martin, K. S. Tonkin, S. Ellard, S. K. Lau, L. McIntosh, E. A. Eisenhauer, A. M. Oza
Journal: Journal of Clinical Oncology (2011)

5013 Background: Loss of PTEN function occurs in 26-83% of endometrial carcinomas (EC) leading to deregulation of PI3K/AKT/mTOR signaling. Intravenous (IV) inhibitors of mTOR have demonstrated activity in advanced EC. Ridaforolimus is an orally administered analog of rapamycin that inhibits mTOR. Methods: NCIC CTG conducted a 2-stage phase II study to assess the activity (objective response) of ridaforolimus in women with measurable EC. Prior hormonal therapy, radiotherapy and adjuvant chemotherapy were allowed. Patients (pts) received ridaforolimus 40 mg PO daily x 5 days per week in 4 week cycles. Tumor response was assessed every 2 cycles. Results: 35 pts were enrolled; 1 pt cancelled without receiving treatment. Of the remaining 34, 33 are now evaluable for safety and 26 for response. Follow-up is ongoing. 11 pts had received prior chemo-, 7 hormonal and 22 radio-therapy. Median age was 63 (range 43-89) yrs; 7 pts had adenocarcinoma, 21 endometrioid, 4 serous and 2 mixed histology. 113 (range 1-13) cycles of treatment were administered. Median delivered dose intensity was 59% of planned therapy due to dose reductions or omissions. The most common drug related adverse events (AEs) of any grade (%pts) were mucositis (64%), fatigue (64%), anorexia (48%), diarrhea (45%), nausea (42%), taste alteration (42%) and rash (36%). Grade 3 lymphopenia occurred in 7 pts and grade 3 anemia in 2. Four serious, unexpected, possibly drug related AEs were observed: 1 pt fatigue, dyspnea and hypoxia, 1 fatal pulmonary/GI hemorrhage, 1 colitis, and 1 renal dysfunction possibly secondary to inadvertent ingestion of a CYP3A4 inhibitor. 13 pts discontinued treatment due to toxicity. To date, 2 pts (both chemo-naive) had a confirmed partial response (PR) (7.7%; 95% CI: 0.9, 25.1%) duration 7.9 and 8.3 months, with stable disease seen in 15 pts (58%), median duration 6.6 months (range 1.9-7.3). 9 pts had progressive disease (35%). Correlative studies including PTEN and PI3K mutation status are underway. Conclusions: Oral ridaforolimus shows evidence of activity in recurrent EC. AEs were frequent in this predominantly elderly population.
Abstract 241: A novel tumor suppressor miRNA co-regulating EMT and p53-independent cell survival in breast cancer
Authors: Umar Raza, Stefan Uhlmann, Emre Yurdusev, Stefan Wiemann, Ozgur Sahin
Journal: Cancer Research (2015)

Abstract Breast cancer is the most common cancer and the second leading cause of cancer-related deaths among women. MicroRNAs (miRNAs) have been shown to be key regulators of cancer-related processes including cell proliferation, survival, migration and invasion. Here, we performed a small scale miRNA mimic screen to identify miRNAs leading to inhibition of cell survival and epithelial-mesenchymal transition (EMT), both of which are key parameters for tumor growth and metastasis. We identified a miRNA (miR-644) which leads to apoptosis in p53-mutated breast cancer cell lines, but not in p53-wild type ones. Furthermore, in vitro migration and invasion assays revealed that miR-644 inhibits both migration and invasion by interfering with the EMT process. Then, we combined whole genome mRNA profiling with target prediction algorithms to determine the potential targets of this miRNA, and identified transcriptional co-repressor CTBP1 as a novel direct target which is already known for limiting apoptosis by repressing Bax transcription. CTBP1 has also been reported to bind ZEB transcription factors and assists EMT by enhancing ZEB-mediated downregulation of E-Cadherin. We showed that silencing of CTBP1 phenocopies the effects of miR-644 in induction of p53-independent apoptosis and blocking EMT and cell invasion. Currently, we are testing the role of miR-644 and its target CTBP1 in tumor growth and metastasis in in vivo assays. Overall, our results suggest that miR-644 is a novel tumor suppressor miRNA co-regulating EMT and cell survival and it could be a potential target for breast cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Umar Raza, Stefan Uhlmann, Emre Yurdusev, Stefan Wiemann, Ozgur Sahin. A novel tumor suppressor miRNA co-regulating EMT and p53-independent cell survival in breast 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 241. doi:10.1158/1538-7445.AM2015-241
Heater-Cooler Cautions Updated
Authors: Rebecca Voelker
Journal: JAMA (2016)

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Combined Analysis of Valproic Acid Induced MicroRNA and Gene Expression Changes in Acute Myeloid Leukemia.
Authors: Annika C. Russ, Martin Dugas, Sonja C. Schmid-Fetzer, Richard F. Schlenk, Jonathan R. Pollack, Konstanze Dohner, Mathias Schmid, Hartmut Dohner, Lars Bullinger
Journal: Blood (2007)
Docetaxel clearance is non linear and not predicted by CYP3A phenotyping when administered with ketoconazole
Authors: W. P. Yong, B. C. Goh, L. Z. Wang, N. Norita, F. Lu, R. Lim, L. K. Soo, S. C. Lee, H. S. Lee
Journal: Journal of Clinical Oncology (2004)

2058 Background: Previously we reported that CYP3A phenotyping with midazolam could predict interindividual docetaxel pharmacokinetic variability (J Clin Oncol 2002;20:3683). We hypothesized that strong inhibition of CYP3A activity could reduce interindividual variability of docetaxel leading to more uniform pharmacokinetics (PK), and that CYP3A phenotyping could predict this inhibition. Methods: A dose escalation study was conducted using intravenous docetaxel over 1 hour q3w in combination with ketoconazole 2 days before and after docetaxel. Intravenous midazolam PK using a dose of 1 mg was also studied in these patients. Results: Twenty patients with tumors refractory to standard chemotherapy were enrolled at docetaxel doses of 10 (1 pt), 20 (6 pts), 25 (6 pts), 30 (5 pts) mg/m2; 2 were non evaluable. Median age, Karnofsky performance status and no. of previous chemotherapy regimens were 62 years (34–77), 90% and 2 respectively. Dose-limiting toxicities were observed at 20 (fatigue), 25 (neutropenic fever), and 30 mg/m2 (fatigue). Docetaxel clearance showed surprisingly increased variability with ketoconazole across and within dose levels, and increased significantly with dose (r= 0.54, p =0.02). Clearance was 4.4 ± 3.2, 9.6 ± 4.2 and 22.7 ± 7 L/h/m2.at doses of 20, 25, 30 mg/m2, respectively. Midazolam clearance was 62.3 ± 30.4 mL/min, which is 7-fold slower with ketoconazole compared to our previous data, and did not correlate with docetaxel clearance. Body-surface area did not correlate with the clearance of docetaxel (r = 0.06, p = 0.82). Conclusions: In vivo inhibition of CYP3A does not affect midazolam and docetaxel equally, and does not reduce variability of docetaxel PK. Docetaxel clearance in the presence of CYP3A inhibition is nonlinear, suggesting activation of alternate metabolic pathways or routes of clearance. Treatment at fixed docetaxel doses of 50 and 60 mg is planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration National Health Group, Singapore
333. Simultaneous Disruption of Five SerpinA1 Genes in Mice Using CRISPR/Cas9 to Generate the First Animal Model of Alpha-1 Antitrypsin Deficiency
Authors: Andrew Cox, Florie Borel, Weiying Li, Michael Brodsky, Christian Mueller
Journal: Molecular Therapy (2015)

Alpha-1 antitrypsin (AAT) deficiency is a common autosomal co-dominant genetic disorder. This condition affects up to 1:2500 individuals of European ancestry, leading to the development of lung and in certain cases liver disease. AAT, as a member of the serpin family, is a protease inhibitor predominantly synthesized in the liver. Upon secretion into the blood stream, AAT's principle physiological role occurs in the lungs where it inactivates excess neutrophil elastase, thereby preventing potential damage to the alveoli. In humans, a glutamate to lysine change at position 342 of the protein, known as a PiZ mutation, accounts for over 90% of cases. This and other mutations lead to reduced serum levels of AAT in addition to reduced protein function. With time, the decreased levels of AAT allows for unopposed neutrophil elastase activity, causing the eventual breakdown of alveolar elastin thus resulting in emphysema. Currently, a serum deficient genetic animal model simulating the lung condition does not exist, which severely limits the development of innovative therapeutics. Our goal is to use CRISPR/Cas9 technology to generate an AAT knock-out mouse to study the pulmonary disease. Unlike humans, mice have five highly conserved tandem copies of the serpinA1 gene. This phenomenon has made it difficult to create knockout mice using traditional approaches. With the advent of novel genome editing techniques, this problem has reached a feasible threshold. To this end, we designed four guide RNA (gRNA) constructs to target conserved regions within all 5 copies of the serpinA genes. The gRNA constructs were initially evaluated using a single strand annealing assay. By co-transfecting a gRNA/Cas9 complex with appropriate reporters, the intensity of resulting GFP measured target efficiency. Afterwards, embryonic stem cell transfection and zygote microinjection were used to deliver the genome editing complex for in vitro and in vivo studies. During the screening process, 200 embryonic stem cell samples and 40 transgenic mice were evaluated by quantifying AAT serum levels and sequencing specific target regions within the genome. Upon completion, several knock-outs were identified and founder lines were established. Ongoing studies aim to determine the susceptibility of developing emphysema after challenging the knockout mice with porcine pancreatic elastase. We expect the mice will display a distinguishable pulmonary phenotype, aside from decreased levels of AAT as determined by ELISA, which will allow for the characterization of airway pathophysiology. This mouse model is of particular clinical significance as it presents the first opportunity to test current and novel therapeutics aimed at augmenting serum levels of AAT.
Safety of MGMT Gene Transfer into Hematopoietic Progenitors: A Phase I Clinical Trial Using Retroviral Gene Transfer of G156A MGMT To Protect Hematopoiesis during BG Plus Alkylating Agent Treatment of Advanced Malignancies.
Authors: Jane S. Reese, Karen T. Lingas, Colin L. Sweeney, Joanna M. Brell, Stanton L. Gerson
Journal: Blood (2007)
천자검사를 받은 복수 환자의 원인 분석
Authors: 황보영 ( Young Hwangbo ), 정지헌 ( Ji Heon Jung ), 심재준 ( Jae Joon Shim ), 김병호 ( Byung Ho Kim ), 정성훈 ( Sung Hoon Jung ), 이창균 ( Chang Kyun Lee ), 장재영 ( Jae Young Jang ), 동석호 ( Seok Ho Dong ), 김효종 ( Hyo Jong Kim ), 장영운 ( Young Woon Chang ), 장린 ( Rin Chan)
Journal: Clinical and Molecular Hepatology (2007)
Surface Plasmon Resonance Study of Apoptotic Regulators Bcl-2, Bcl-w, Bcl-XL, and Mcl-1 Indicate That the Preclinical Small Molecule Inhibitor (SMI) TW-37 Binds to the Hydrophobic Groove Competitively with tBid To Form a Heterodimer Which Cannot Be Disrupted by 200-Fold Molar Excess of TW-37.
Authors: Anton-Scott Goustin, Anshu Giri, Shaomeng Wang, Ayad Al-Katib, Mohammad M. Ramzi
Journal: Blood (2007)
Abstract 2582: Gefitinib [epidermal growth factor receptor (EGFR) inhibitor] plus etoricoxib (COX-2 inhibitor) versus oral methotrexate in advanced, recurrent head and neck squamous cell carcinoma (HNSCC): results of a randomized pilot study
Authors: Hemant Malhotra, Archit Joshi, Sandeep Jasuja, Ajay Yadav
Journal: Cancer Research (2015)

Abstract Background: There are very few options for the treatment of patients of SCCHN who relapse after surgery and/or radiotherapy and/or chemotherapy other than best supportive care (BSC). Over expression of the EGFR has been demonstrated in more than 80% of patients with SCCHN. In the present study, we compared the response rates, overall survival, toxicity profile and quality of life in patients of recurrent SCCHN receiving oral methotrexate versus a combination of EGFR inhibitor (Gefitinib) + COX II inhibitor (Etoricoxib). Patients and Methods: Twenty five patients of Advanced and Recurrent HNSCC were included in each group. Patients were randomly assigned to receive Gefitinib (250 mg twice a day before meals) plus Etoricoxib (120 mg/day) [Group A] or Oral Methotrexate (15 mg/week) [Group B]. All patients received BSC. Patients were follow-up 4 weekly with routine blood investigations and quality of life questionnaires - QLQ C-30 and QLQ H &amp; N-35. CT scan of Head and Neck was done every 8 weeks. EGFR mutation studies were not performed. Results : Partial Response (PR) was seen in 6.25% of patients in group-A; and 0% from group-B. Stable Disease (SD) observed in 25% of patients from group-A and 10% patients from group-B. At the end of study, mean overall survival (OS) in group-A was 107.15 days; whereas mean overall survival in group-B was 73.95 days. The difference in survival was statistically significant (P&amp;lt;0.05). Comparing the QOL between two groups by EORTC QLQ C-30 and EORTC H &amp; N-35 at 4 and 8 weeks, patients of group-A had better quality of life. No dose-limiting toxicities were seen in group-A or B. Most common toxicity observed in group A were skin rash and diarrhoea while on group B it was mucositits. Conclusions: In this small pilot study, in patients with advanced and recurrent SCCHN, dual targeted treatment (EGFR and COX II) with combination of Gefitinib plus Etoricoxib improved response rates, quality of life and overall survival as compared to oral methotrexate. The combination was well tolerated with minor side-effects and should be considered in this poor prognostic subset of patients. Larger, multi-centric studies are needed to confirm these results. Citation Format: Hemant Malhotra, Archit Joshi, Sandeep Jasuja, Ajay Yadav. Gefitinib [epidermal growth factor receptor (EGFR) inhibitor] plus etoricoxib (COX-2 inhibitor) versus oral methotrexate in advanced, recurrent head and neck squamous cell carcinoma (HNSCC): results of a randomized pilot study. [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 2582. doi:10.1158/1538-7445.AM2015-2582