tbuckley/cabot-search huggingface dataset:
Abstract 3690: Metabolic regulation of mutant p53 stability by the mevalonate pathway
Authors: Tomoo Iwakuma, Atul Ranjan, Swathi V. Iyer, Subhash Padhye, Scott Weir, Anuradha Roy
Journal: Cancer Research (2016)

Abstract Introduction: Mutations in the p53 gene are mostly missense mutations and result in accumulation of dysfunctional p53 protein in tumors with oncogenic gain-of-function activities. Increasing evidence indicates that stabilization of mutant p53 (mutp53) in tumors is crucial for its oncogenic activities including tumor progression and drug resistance, while downregulation of mutp53 reduces oncogenicity of cancer cells. These observations suggest that malignant properties of cancer cells are dependent on the presence of mutp53, thus providing a rationale to identify compounds that deplete mutant p53 with little impact on wild-type p53. Experimental procedures: Toward this goal, we performed high throughput screens of chemical libraries (∼9,000 compounds) with Saos2 (p53 null) cells expressing a fusion protein of p53R175H and luciferase, using luciferase as a reporter. Summary of data: This screening led us to identify “statins”, a class of cholesterol-lowering medications, as compounds that induced degradation of p53R175H. We found that other inhibitors of the mevalonate pathway, such as 6-fluoromevalonate and zoledronic acid, failed to induce p53R175H degradation, while statin-mediated inhibition of HMG-CoA reductase and subsequent reduction in mevalonte-5-phosphate triggered p53R175H degradation. These results suggest that statin's effect on p53R175H is specific and independent of protein prenylation/lipidation or cholesterol synthesis. Moreover, nuclear export of p53R175H was required for the statin-mediated degradation, which was mediated through an E3 ubiquitin ligase CHIP, but not MDM2. Interestingly, statins induced degradation of mainly conformational p53 mutants with minimal effects on the levels of wild-type p53 and DNA contact mutants. Conclusions: This is the first study demonstrating that mutp53 stability is regulated through a specific process of the mevalonate pathway, thereby providing a novel regulatory mechanism of mutp53 degradation. Our findings suggest that p53 mutation status in tumors may have an impact on efficacy of statins in cancer therapy. Citation Format: Tomoo Iwakuma, Atul Ranjan, Swathi V. Iyer, Subhash Padhye, Scott Weir, Anuradha Roy. Metabolic regulation of mutant p53 stability by the mevalonate pathway. [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 3690.
Abstract 2538: The emerging role of SOX2 in cancer cell plasticity and EGFR-TKI resistance
Authors: Yu-Fan Chiu, Ming-Han Kuo, An-Chun Lee, Yu-Ting Chou
Journal: Cancer Research (2016)

Abstract Activating mutations in the epidermal growth factor receptor (EGFR) lead to the aberrant growth of lung adenocarcinoma while endowing cancer cells with sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Nonetheless, EGFR-TKI resistance often occurs in less than one year. The intriguing phenomenon that cancer cells have biological features similar to stem cells suggests that cancer and stem cells may share the same regulatory signaling pathway, but the involvement of stem cell signaling in EGFR-TKI resistance is not clear. Herein, we observed that SOX2, a master transcriptional factor controlling self-renewal of lung stem cells, was highly expressed in lung adenocarcinoma and inversely correlated with epithelial-to-mesenchymal transition (EMT). Clonogenic analysis showed that SOX2-silenecing attenuated cell growth in EGFR-mutated lung cancer cells. The selection of EGFR-TKI resistant HCC827 (delE746_A750) cells induced EMT while attenuating the expression of SOX2 and spheroid forming ability. Preselection of HCC827 (delE746_A750) cells with EMT features endowed cells with TKI resistance but suppressed SOX2 expression. Pharmacological inhibition of HDACs in EGFR-mutated lung cancer cells attenuated SOX2 expression but induced EMT, thus enhancing the development of EGFR-TKI resistance. Our findings support the notion that the switching expression between SOX2 and EMT plays a critical role in EGFR-TKI resistance, with the potential as biomarkers for lung cancer prediction. Citation Format: Yu-Fan Chiu, Ming-Han Kuo, An-Chun Lee, Yu-Ting Chou. The emerging role of SOX2 in cancer cell plasticity and EGFR-TKI resistance. [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 2538.
Abstract 2904: The alternative NF-kB2/RELB pathway is activated by LTB/LTB receptor and NIK to promote cell migration and metastasis-related gene expression in HNSCC
Authors: Rita Das, Tsu-Fan Cheng, Jamie Coupar, Anthony Saleh, Paul E. Clavijo, Xinping Yang, Zhong Chen, Carter VanWaes.
Journal: Cancer Research (2016)

Abstract Head and neck squamous cell carcinomas (HNSCC) are highly inflammatory and preferentially migrate and metastasize to lymph nodes. In this study, we find that LTβ/LTβR/NIK signaling mediates alternative RELB/NF-kB2 activation, which promotes activation of important cancer related genes and migration. We find that LTβ and LTβR are over expressed in subsets of HNSCC tissues and cell lines, and LTβ activates the alternative NF-κB pathway, enhancing nuclear translocation of RELB and NF-kB2/p52. Knockdown of LTβR decreased its target kinase NIK, and downstream NF-kB subunits RELB and NF-kB2/p52 protein expression. Knockdown of NIK protein decreased RELB and p52 protein expression, while LTβ treatment stabilized NIK, RELB and NF-kB2/p52 expression. Consistent with this, knockdown of LTBR and NIK functionally decreased NF-kB reporter gene activity, while treatment of LTB partially restored the NF-kB reporter activity. Notably, knockdown of NIK and RELB by siRNA inhibited cell migration in HNSCC. Since NIK is known as central regulator of the activation of the non-canonical pathway, we tested the effects of a NIK inhibitor 1,3[2H,4H]-Isoquinolinedione on NF-kB function and cell migration. NIK inhibitor decreased NIK protein in the cytoplasm, downstream nuclear expression of RELB and NF-kB2/p52 proteins by Western blot and RELB localization by immunofluorescence staining. We have found evidence for LTβ induction of migration/metastasis and cell death genes MET, BIRC3,and SERPINE1, and NIK knockdown inhibited cell migration and the inducible expression of MET, BIRC3, SERPINE 1 by LTB. Our data reveal the mechanisms how LTβ and NIK activation mediated alternative NF-kB pathway and contribute to migration and metastasis of HNSCC. Supported by NIDCD intramural Project ZIA-DC-000016, 73 and 74. Citation Format: Rita Das, Tsu-Fan Cheng, Jamie Coupar, Anthony Saleh, Paul E. Clavijo, Xinping Yang, Zhong Chen, Carter VanWaes. The alternative NF-kB2/RELB pathway is activated by LTB/LTB receptor and NIK to promote cell migration and metastasis-related gene expression in HNSCC. [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 2904.
Accelerating global innovation to address antibacterial resistance: introducing CARB-X
Authors: Kevin Outterson, John H. Rex, Tim Jinks, Peter Jackson, John Hallinan, Steve Karp, Deborah T. Hung, Francois Franceschi, Tyler Merkeley, Christopher Houchens, Dennis M. Dixon, Michael G. Kurilla, Rosemarie Aurigemma, Joseph Larsen
Journal: Nature Reviews Drug Discovery (2016)
Abstract 4894: Relationship of characterization of the immunological microenvironment and pathological response in advanced rectal cancer after oxaliplatin-based neoadjuvant chemotherapy
Authors: Kentaro Sekizawa, Yasushi Ichikawa, Atsushi Ishibe, Hirokazu Suwa, Masashi Momiyama, Ikuma Kato, Mitsuyoshi Ota, Itaru Endo
Journal: Cancer Research (2016)

Abstract Background: Characterization of the immunological microenvironment has been demonstrated to be associated with prognosis and the effect of chemotherapy of various cancers. Then it has been shown by their role several studies in 5-FU-based neoadjuvant chemoradiotherapy for rectal cancer. However, their role in neoadjuvant chemotherapy (NAC) for rectal cancer remains unknown. The objective of this study was to examine the relationship between immune reactions and the pathological response to induction oxaliplatin-based NAC in patients with advanced rectal cancer. Methods: A total of 65 patients with advanced rectal cancer who underwent induction oxaliplatin-based NAC followed by surgical resection were enrolled. The resected tumor specimens were counted positive cell of tumor infiltrating lymphocytes (TILs) and macrophages by using immunohistochemical staining for CD3, CD8, Foxp3, CD86, CD206. We analyzed for the relationship between the numbers of TILs or macrophages at the stroma in resected specimens and the pathological response to induction oxaliplatin-based NAC. Results: The numbers of Foxp3+ TILs in resected specimens were strongly correlated with pathological response. Patients with higher number of Foxp3+ TILs showed poor pathological response (p&amp;lt;0.001). There were no statistically significant differences between the number of CD3+, CD8+ TILs and pathological response, but patients with higher ratio of CD8+/FOXP3+ TILs was associated with good pathological response (p = 0.023). No associations were observed between the numbers of CD86+, CD206+ macrophages and pathological response. Conclusions: In rectal cancer patients, T lymphocyte-mediated immune reactions significantly correlated with pathological response of oxaliplatin-based NAC for advanced rectal cancer. These were similar to the T lymphocyte-mediated immune responses in the neoadjuvant radiation therapy for rectal cancer. Citation Format: Kentaro Sekizawa, Yasushi Ichikawa, Atsushi Ishibe, Hirokazu Suwa, Masashi Momiyama, Ikuma Kato, Mitsuyoshi Ota, Itaru Endo. Relationship of characterization of the immunological microenvironment and pathological response in advanced rectal cancer after oxaliplatin-based neoadjuvant 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 4894.
Genomic Instability in Multiple Myeloma: Inducible Transfectants Provide a Model To Define the Role of RHAMM and Centrosome/Mitotic Spindle Stability in Myelomagenesis.
Authors: Brian J. Taylor, Eva Baigorri, Mary Hay, Tony Reiman, Andrew R. Belch, Linda M. Pilarski
Journal: Blood (2006)
Abstract 2072: Inhibition of breast cancer stem cells by Hedgehog-inhibitory peptide conjugated with Elastin-like biopolymers
Authors: Jung Su Ryu, Drazen Raucher
Journal: Cancer Research (2016)

Abstract The Hedgehog(Hh) signaling pathway has been reported to play a pivotal role in cancer. Studies have shown that suppression of this aberrantly activated Hh pathway may be effective in controlling the development and proliferation of many cancers. However, to date, there is no drug in clinical application that can be used to inhibit the Hh signaling pathway and suppress cancer growth. In attempt to address this problem, we developed a thermally responsive polypeptide inhibitor of the Hh pathway. This polypeptide is derived from a mammalian tropo-elastin protein which will aggregate and accumulate at the tumor site where local hyperthermia is applied. For this study, ELP was fused to a peptide that inhibits Hh signaling by blocking interaction of Sonic Hh ligand (Shh) with the Patch-1 docking site. To improve bioavailability, ELP was further modified by adding the cell penetrating peptide, Tat. The anti-proliferative activity of Tat-Hhi-ELP was examined in three breast cancer cell lines: MCF7, MDA-MB-231, and SKBR-3. Treatment of the cells with 20 uM of peptide for 2 days resulted in maximally 40% inhibition of cell proliferation. Observed cytotoxicity was further increased two fold by application of hyperthermia. To validate that Tat-Hhi-ELP is targeting the Hh pathway, we determined the levels of GLI-1, which is a downstream target in the Hh pathway. Treatment of the breast cancer cells with Tat-Hhi-ELP resulted in reduction of GLI-1 levels, indicating that the cytotoxicity is based on hedgehog pathway inhibition. Furthermore, the formation of mammospheres was significantly reduced by treatment with Tat-Hhi-ELP in SKBR-3 cells. These results suggest that thermal targeting of ELP-based Hedgehog inhibitory peptides to breast cancer cells may be an effective and promising treatment strategy against breast cancer stem cells. Citation Format: Jung Su Ryu, Drazen Raucher. Inhibition of breast cancer stem cells by Hedgehog-inhibitory peptide conjugated with Elastin-like biopolymers. [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 2072.
Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk
Authors: Yesha M. Patel, Sunghim L. Park, Younghun Han, Lynne R. Wilkens, Heike Bickeböller, Albert Rosenberger, Neil Caporaso, Maria Teresa Landi, Irene Brüske, Angela Risch, Yongyue Wei, David C. Christiani, Paul Brennan, Richard Houlston, James McKay, John McLaughlin, Rayjean Hung, Sharon Murphy, Daniel O. Stram, Christopher Amos, Loïc Le Marchand
Journal: Cancer Research (2016)

Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3'-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10
A biopsy-guided analysis of diarrhea in patients treated with tyrosine kinase inhibitors of the vascular endothelial growth factor receptor.
Authors: Marye Boers-Sonderen, Sasja Mulder, Iris D. Nagtegaal, Lauranne Derikx, Geert Wanten, Peter Mulders, Winette T.A. Van Der Graaf, Frank Hoentjen, Carla M.L.- Van Herpen
Journal: Journal of Clinical Oncology (2015)

e15596 Background: Diarrhea is a frequently occurring adverse event of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs). It impairs quality of life and leads to dose reductions and treatment interruptions. The aim of this pilot study is to gain insight in the underlying pathophysiologal mechanism of diarrhea in patients treated with VEGFR TKIs. Methods: We included ten patients with metastatic renal cell carcinoma who were treated with a VEGFR TKI and developed diarrhea. Blood, feces and urine samples were extensively analyzed and all patients underwent endoscopy with biopsies of the upper and lower gastro-intestinal (GI) tract. Results: Besides the diarrhea, patients complained of pyrosis (n = 6) and abdominal cramps (n = 5). While decreased plasma concentrations of vitamins D and B12 were found in 6 and 7 patients, respectively, all other mineral and electrolyte levels were normal. Sigmoidoscopy was macroscopically normal in the majority of patients and particularly did not show any signs of ischemic or microscopic colitis. However, gastroduodenoscopy revealed gastro-esophageal reflux disease, bulbitis and/or duodenitis with ulcers in 8 patients. In 3 selected patients with bulbitis/duodenitis additional video capsule endoscopy revealed no additional intestinal abnormalities. Conclusions: This pilot study did not provide evidence for the existence of an ischemic colitis, microscopic colitis or malabsorption syndrome as the cause of diarrhea in VEGFR TKI-treated patients. However, mucosal abnormalities such as erosions and ulcers were found in the esophagus, stomach and duodenum in the majority of patients. Since these mucosal abnormalities predominantly occur in the upper GI tract, it is not a plausible explanation for the diarrhea. However, it provides a possible clue for other GI complaints seen in VEGFR TKI-treated patients. Based on these results we suggest to perform an upper GI endoscopy in VEGFR-TKI treated patients with GI complaints.
Activity of the mitochondrial metabolism inhibitor cpi-613 in combination with high dose Ara-C (HDAC) and mitoxantrone in high risk relapsed or refractory acute myeloid leukemia (AML).
Authors: Timothy S. Pardee, Kristin Stadelman, Scott Isom, Leslie R. Ellis, Dmitriy Berenzon, David Duane Hurd, Dianna S. Howard, Robin Harrelson, Megan Manuel, Sarah Dralle, Susan Lyerly, Bayard L. Powell
Journal: Journal of Clinical Oncology (2015)

7015 Background: CPI-613 is a novel agent that targets mitochondrial metabolism. It inhibits mitochondrial respiration in AML cells and in a single agent phase I study was active for several patients with myeloid malignancies.This trial was designed to determine the maximum tolerated dose (MTD) and efficacy of CPI-613 in combination with HDAC and mitoxantrone in relapsed or refractory AML. Methods: CPI-613 was given daily on days 1 through 5 starting at a dose of 500 mg/m2. Beginning on day 3, HDAC (3,000 mg/m2 or 1,500 mg/m2 for age ≥ 60) was given every 12 hours for 5 doses and mitoxantrone at 6 mg/m2 was given daily for 3 doses. If residual disease was present on day 14, a second cycle could be given. Patients who achieved a complete remission with or without complete count recovery (CR or CRi) could receive additional cycles with the goal of stem cell transplantation when possible. Results: A total of 48 patients are evaluable. The median age is 60 (range 21-79). Fourteen patients had refractory disease and 11 received one or more previous lines of salvage therapy. Cytogenetics were poor risk in 23, intermediate in 20, good in 4 and one patient had CML blast crisis. The overall response rate was 48% (19CR+4CRi). Three of five patients with FLT3 mutations achieved a CR/CRi (60%). Patients age ≥ 60 had a CR/CRi rate of 46% (12/26). Surprisingly, patients with poor-risk cytogenetics had a CR/CRi rate of 48% (11/23). In a historical cohort of poor-risk patients treated with HDAC, mitoxantrone and asparaginase, only 25% responded. Median survival for the entire cohort is 6.4 months. Six patients (12.5%) died on or before day 30. The CPI-613 dose has been escalated to 2750 mg/m2 with the MTD not yet determined. Stem cell transplantation was performed on 23% (11/48) of patients. Samples from patients before and after CPI-613 showed induction of phosphorylation of the E1α subunit of pyruvate dehydrogenase and AMPK consistent with the proposed mechanism of action. Conclusions: CPI-613 in combination with HiDAC and mitoxantrone is a promising salvage regimen and these data support additional studies especially in older patients and those with high-risk disease. Clinical trial information: NCT01768897.
Abstract 2956: Optimal PEGylation of an auristatin linker provides ADCs with improved pharmacological properties
Authors: Patrick J. Burke, Joseph Z. Hamilton, Scott C. Jeffrey, Joshua H. Hunter, Julia H. Cochran, Nagendra Chemuturi, Martha E. Anderson, Peter D. Senter, Robert P. Lyon
Journal: Cancer Research (2016)

Abstract As antibody-drug conjugates (ADCs) continue to emerge as an important therapeutic modality for the treatment of cancer, there is an increased effort to elucidate critical design parameters and devise improved linker technologies. The impact of drug-to-antibody ratio (DAR) on conjugate plasma pharmacokinetics (PK) is known to be an important attribute, and accelerated clearance induced by high levels of drug loading has served as a barrier to translating increased in vitro potency to in vivo xenografts. We have recently demonstrated that the incorporation of a discrete PEG24 unit into an auristatin drug-linker can greatly diminish the impact of drug loading on ADC PK. In an effort to optimize the antibody-mediated delivery of monomethylauristatin E (MMAE) as a homogeneous DAR 8 conjugate, we prepared a series of MMAE linkers using PEG units of varying lengths to identify constructs that preserve antibody PK properties and provide enhanced in vivo activity. The extent of PEGylation and linker chemistry was found to impact conjugate PK properties, biodistribution, antitumor activity, and tolerability. From that effort, a cleavable MMAE linker incorporating the glucuronide-based trigger, a self-stabilizing maleimide, and 12 PEG units emerged as the optimal design. ADCs prepared with this linker have now undergone further preclinical characterization in activity and toxicology models in which they have demonstrated an increase in therapeutic index relative to other MMAE-based ADCs. Citation Format: Patrick J. Burke, Joseph Z. Hamilton, Scott C. Jeffrey, Joshua H. Hunter, Julia H. Cochran, Nagendra Chemuturi, Martha E. Anderson, Peter D. Senter, Robert P. Lyon. Optimal PEGylation of an auristatin linker provides ADCs with improved pharmacological properties. [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 2956.
Primary melanoma with regression: Implications for management
Authors: K. Morris, K. Busam, M. S. Brady
Journal: Journal of Clinical Oncology (2005)

7530 Background: Regression is observed in approximately 5% of patients with primary cutaneous melanomas. The implications of regression for treatment are controversial. Some advocate a wider margin of resection and a lower threshold for sentinel lymph node (SLN) biopsy in this setting. We review our recent experience in order to determine whether this approach is warranted. Methods: We identified 71 patients treated at Memorial Sloan- Kettering between 1995 and 2000 with regression noted on review of the primary melanoma. Information about patient, tumor, treatment, and outcomes were obtained from review of the medical records. Results: There were 23 females and 48 males with a median age of 58. The most common primary site was the trunk (n=52, 73%), followed by extremity (n=17, 24%). Median Breslow depth of the primary melanoma for patients with invasive disease (n=63) was 0.7 mm (range 0.21 to 21 mm). There were 14 recurrences among the 71 patients (20%) at a mean follow-up of 29 months. Of those with recurrence, the initial site was distant metastasis in 10 patients followed by local recurrence in 4. SLN biopsy was performed in 29 patients and was positive in 6 (21%). All patients with positive SLNs had primary melanomas over 3 mm in Breslow depth. Of the 29 patients with “extensive” or “prominent” regression, 5 (17%) had recurrences, 4 of which were distant metastases. Conclusions: The presence of regression in a primary melanoma does not warrant adjustment of current treatment recommendations. We found no evidence that these patients are at higher risk for local or regional nodal recurrence. No significant financial relationships to disclose.