tbuckley/cabot-search huggingface dataset:
Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication
Authors: Shilpa Singh, Catherine A. Vaughan, Rebecca A. Frum, Steven R. Grossman, Sumitra Deb, Swati Palit Deb
Journal: Journal of Clinical Investigation (2017)

Gain-of-function (GOF) p53 mutations are observed frequently in most intractable human cancers and establish dependency for tumor maintenance and progression. While some of the genes induced by GOF p53 have been implicated in more rapid cell proliferation compared with p53-null cancer cells, the mechanism for dependency of tumor growth on mutant p53 is unknown. This report reveals a therapeutically targetable mechanism for GOF p53 dependency. We have shown that GOF p53 increases DNA replication origin firing, stabilizes replication forks, and promotes micronuclei formation, thus facilitating the proliferation of cells with genomic abnormalities. In contrast, absence or depletion of GOF p53 leads to decreased origin firing and a higher frequency of fork collapse in isogenic cells, explaining their poorer proliferation rate. Following genome-wide analyses utilizing ChIP-Seq and RNA-Seq, GOF p53-induced origin firing, micronuclei formation, and fork protection were traced to the ability of GOF p53 to transactivate cyclin A and CHK1. Highlighting the therapeutic potential of CHK1's role in GOF p53 dependency, experiments in cell culture and mouse xenografts demonstrated that inhibition of CHK1 selectively blocked proliferation of cells and tumors expressing GOF p53. Our data suggest the possibility that checkpoint inhibitors could efficiently and selectively target cancers expressing GOF p53 alleles.
β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance
Authors: Cristina Aguayo-Mazzucato, Mark van Haaren, Magdalena Mruk, Terence B. Lee, Caitlin Crawford, Jennifer Hollister-Lock, Brooke A. Sullivan, James W. Johnson, Aref Ebrahimi, Jonathan M. Dreyfuss, Jan Van Deursen, Gordon C. Weir, Susan Bonner-Weir
Journal: Cell Metabolism (2017)
Heterogeneity in chemoresponsiveness of ovarian cancer as demonstrated by an <i>ex vivo</i> chemo response assay
Authors: R. Ochs, H. Gallion, R. Coleman, T. Herzog, B.-U. Sevin, H. Schellhas, A. Wells
Journal: Journal of Clinical Oncology (2004)

5059 Background: Only a subset of patients responds to a given chemotherapeutic regimen. The purpose of this analysis was to determine whether tumors are generally sensitive or resistant regardless of regimen, or do they demonstrate heterogeneity in responsiveness across regimens. Methods: We examined the ex vivo chemoresponse of ovarian cancer cells from 256 women across 9 practices. An average of 8 drug regimens, including combinations, were tested per tumor. The assay results were scored for sensitivity or resistance based on live cell number after exposure to varied concentrations of each chemotherapeutic regimen. Patients were classified into three groups: predominantly sensitive (>83% of regimens tested scored sensitive for their tumor), predominantly resistant (>83% tested resistant), and heterogeneous. Results: 51 of 256 (20%) cases were predominantly sensitive, with a median progression free interval (PFI) of 17.7 months. 34 (13%) cases were predominantly resistant, with a median PFI of 9.9 months. Two thirds of cases (N=171) exhibited heterogeneity of response, with a median PFI of 11.4 months. Within the heterogeneous group, those who received a regimen scored as sensitive ex-vivo (no other regimens tested were scored more sensitive than the regimen they received) vs resistant ex-vivo had an improved median PFI: 12.4 months (N=46) vs 8.6 months (N=125). Conclusions: The majority of tumors tested demonstrated heterogeneity of response ex vivo. As heterogeneity of chemotherapy response for an individual patient cannot be assessed clinically, an ex vivo assay assessment is informative. Moreover, our data suggests that individualizing therapy by incorporating an ex vivo assay has the potential to increase the response rates to chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Precision Therapeutics, Inc. Precision Therapeutics, Inc. Precision Therapeutics, Inc.
The Single-parameter, Structure-based IsoPSA Assay Demonstrates Improved Diagnostic Accuracy for Detection of Any Prostate Cancer and High-grade Prostate Cancer Compared to a Concentration-based Assay of Total Prostate-specific Antigen: A Preliminary Report
Authors: Eric A. Klein, Arnon Chait, Jason M. Hafron, Kenneth M. Kernen, Kannan Manickam, Andrew J. Stephenson, Mathew Wagner, Hui Zhu, Aimee Kestranek, Boris Zaslavsky, Mark Stovsky
Journal: European Urology (2017)
International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017)
Authors: A. Younes, P. Hilden, B. Coiffier, A. Hagenbeek, G. Salles, W. Wilson, J.F. Seymour, K. Kelly, J. Gribben, M. Pfreunschuh, F. Morschhauser, H. Schoder, A.D. Zelenetz, J. Rademaker, R. Advani, N. Valente, C. Fortpied, T.E. Witzig, L.H. Sehn, A. Engert, R.I. Fisher, P.-L. Zinzani, M. Federico, M. Hutchings, C. Bollard, M. Trneny, Y.A. Elsayed, K. Tobinai, J.S. Abramson, N. Fowler, A. Goy, M. Smith, S. Ansell, J. Kuruvilla, M. Dreyling, C. Thieblemont, R.F. Little, I. Aurer, M.H.J. Van Oers, K. Takeshita, A. Gopal, S. Rule, S. de Vos, I. Kloos, M.S. Kaminski, M. Meignan, L.H. Schwartz, J.P. Leonard, S.J. Schuster, V.E. Seshan
Journal: Annals of Oncology (2017)

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.
Rapid recognition of glioma response to radiation therapy using recombinant peptides
Authors: Ralph Passarella, Roberto Diaz, Dennis Hallahan
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

1458 

Purpose: This study assessed the effectiveness of a recombinant peptide at rapidly and non-invasively determining glioma response to radiation therapy within the endothelium of treated tumors.    Methods: Phage-displayed peptide libraries were subjected to biopanning in vivo on GL261 brain tumor xenografts that were treated with 40 mg/kg Sunitinib and 3 Gy of ionizing radiation (IR). After 4 rounds of biopanning in heterotopic tumors and 2 rounds of biopanning in orthotopic tumors, phage peptide recovered from the 6th selection was sequenced to determine identity of phage peptide bound to tumor endothelium specific for Sunitinib+IR. Sensitivity and specificity of peptide detection of tumor susceptibility to IR were studied with immunohistochemical (IHC) staining and near infrared resonance (NIR) imaging. Biological effects of peptide binding in the tumor were assessed by tumor size measurement and histological examination of apoptosis.    Results: Via sequencing analysis of phage recovered from the in vivo biopanning of the T7 library GIRLRG was isolated most frequently (43.75%) along with AARLY (37.5%) and HMWRDSQ (18.75%). NIR imaging was used to monitor the biodistribution of the GIRLRG free peptide in glioma-bearing mice treated with or without IR for 5 consecutive days. At the end of treatment, we found that IR elicited a 24% decrease in tumor volume over the untreated control (p  2.5 fold increase in radiance compared to the untreated controls (p<0.05). IHC staining of the gliomas showed that the GIRLRG peptide binds within treated tumor endothelium but not within untreated tumors.    Conclusions: GIRLRG peptide binds specifically to the vascular endothelium of radiation-treated glioma. Conjugation of the peptide to near infrared imaging agents can be used to show that GIRLRG binds more specifically to IR treated glioma than to untreated glioma, such that delay in tumor growth due to IR treatment correlates to more intense peptide binding. Eventually this could lead to the peptide’s conjugation to a nanoparticle-drug complex and result in radiation targeted drug delivery.
Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib
Authors: Brooke Rothstein, Deep Joshipura, Ami Saraiya, Rana Abdat, Huda Ashkar, Yana Turkowski, Vaneeta Sheth, Victor Huang, Shiu Chung Au, Courtney Kachuk, Nicole Dumont, Alice B. Gottlieb, David Rosmarin
Journal: Journal of the American Academy of Dermatology (2017)
Erratum: Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis (Cancer Research (June 1, 2006) 66 (5816-5827))
Authors: N. Dornhöfer, S. Spong, K. Bennewith, A. Salim, S. Klaus, N. Kambham, C. Wong, F. Kaper, P. Sutphin, R. Nacamuli, M. Höckel, Q. Le, M. Longaker, G. Yang, A. Koong, A. Giaccia
Journal: Cancer Research (2006)
Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin in advanced non-small cell lung cancer (NSCLC) patient.
Authors: Markus Joerger, Joachim Von Pawel, Stefanie Kraff, Juergen R. Fischer, Wilfried Eberhardt, Thomas Christoph Gauler, Lothar Mueller, Niels Reinmuth, Martin Reck, Martin Kimmich, Frank Mayer, Hans-Georg Kopp, Dirk M. Behringer, Yon-Dschun Ko, Martin Frueh, Ralf A. Hilger, Max Roessler, Berta Moritz, Ulrich Jaehde
Journal: Journal of Clinical Oncology (2015)

8051 Background: Variability of chemotherapy exposure may cause severe toxicity or lack of efficacy. Paclitaxel (PTX) exposure (time above a plasma concentration of 0.05mM, Tc > 0.05) has been shown to predict toxicity. Whereas carboplatin dose is adapted to kidney function, PTX dosing only accounts for body-surface area. We developed a PTX dosing algorithm for avoidance of supra- or subtherapeutic PTX exposure based on Tc > 0.05 determined from a single blood sample drawn 18-30 hours after starting PTX infusion. This study was initiated to validate PK-guided PTX dosing in advanced NSCLC patients. Methods: 304 patients with advanced NSCLC were randomly assigned to receive up to 6 cycles of first-line 3-weekly carboplatin AUC 6 combined with PTX either at a standard dose of 200mg/m2 (Arm A) or at a PK-guided dose (Arm B). Initial PTX dose in Arm B was between 150 to 200 mg/m2 based on age and sex, and subsequent PTX doses were adjusted according to the previous cycle PTX Tc > 0.05 to target a Tc > 0.05 between 26 and 31 hours. Dose reductions were permitted in both arms for chemotherapy-associated toxicity. The study had a power of 90% to detect a 11% reduction of grade 4 neutropenia with PK-guided PTX dosing. Results: Major patient characteristics were male gender in 67%, current smokers in 38%, ≥ 65 years of age in 50%, performance status of 2 in 8%, squamous-cell histology in 21%.Compared to standard dosing, PK-guided dosing of PTX reduced the incidence of grade 4 neutropenia (measured on day 15 of each cycle) (15% v 21%, P = 0.029), grade ≥ 2 neuropathy (14% v 27%, P < 0.001), and grade ≥ 3 neuropathy (1% v 8%, P < 0.001). Median PTX dose at cycle 6 was significantly lower with PK-guided dosing (132 v 197 mg/m2, P < 0.001), and the proportion of patients with supratherapeutic PTX exposure was reduced from 41% in cycle 1 to 2% in cycle 6. Objective response rate was 32% and 29% in Arms A and B (P = 0.70). Progression-free survival was 5.2 and 4.7 months in Arms A and B (hazard ratio 1.1, 95% CI 0.8-1.4, P = 0.54). Conclusions: PK-guideddosing of PTX improves the risk-benefit profile in patients with advanced NSCLC, primarily by a substantial reduction of PTX-associated neuropathy. Clinical trial information: 2010-023688-16.
Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction
Authors: Masaru Obokata, Yogesh N.V. Reddy, Sorin V. Pislaru, Vojtech Melenovsky, Barry A. Borlaug
Journal: Circulation (2017)

Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Phenotyping patients into pathophysiologically homogeneous groups may enable better targeting of treatment. Obesity is common in HFpEF and has many cardiovascular effects, suggesting that it may be a viable candidate for phenotyping. We compared cardiovascular structure, function, and reserve capacity in subjects with obese HFpEF, those with nonobese HFpEF, and control subjects.Subjects with obese HFpEF (body mass index ≥35 kg/m2; n=99), nonobese HFpEF (body mass index <30 kg/m2; n=96), and nonobese control subjects free of HF (n=71) underwent detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing.Compared with both subjects with nonobese HFpEF and control subjects, subjects with obese HFpEF displayed increased plasma volume (3907 mL [3563-4333 mL] versus 2772 mL [2555-3133 mL], and 2680 mL [2380-3006 mL]; P<0.0001), more concentric left ventricular remodeling, greater right ventricular dilatation (base, 34±7 versus 31±6 and 30±6 mm, P=0.0005; length, 66±7 versus 61±7 and 61±7 mm, P<0.0001), more right ventricular dysfunction, increased epicardial fat thickness (10±2 versus 7±2 and 6±2 mm; P<0.0001), and greater total epicardial heart volume (945 mL [831-1105 mL] versus 797 mL [643-979 mL] and 632 mL [517-768 mL]; P<0.0001), despite lower N-terminal pro-B-type natriuretic peptide levels. Pulmonary capillary wedge pressure was correlated with body mass and plasma volume in obese HFpEF (r=0.22 and 0.27, both P<0.05) but not in nonobese HFpEF (P≥0.3). The increase in heart volumes in obese HFpEF was associated with greater pericardial restraint and heightened ventricular interdependence, reflected by increased ratio of right- to left-sided heart filling pressures (0.64±0.17 versus 0.56±0.19 and 0.53±0.20; P=0.0004), higher pulmonary venous pressure relative to left ventricular transmural pressure, and greater left ventricular eccentricity index (1.10±0.19 versus 0.99±0.06 and 0.97±0.12; P<0.0001). Interdependence was enhanced as pulmonary artery pressure load increased (P for interaction <0.05). Compared with those with nonobese HFpEF and control subjects, obese patients with HFpEF displayed worse exercise capacity (peak oxygen consumption, 7.7±2.3 versus 10.0±3.4 and12.9±4.0 mL/min·kg; P<0.0001), higher biventricular filling pressures with exercise, and depressed pulmonary artery vasodilator reserve.Obesity-related HFpEF is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments.
Disseminated histiocytoses: Biomarkers beyond BRAFV600E.
Authors: Zoran Gatalica, Nurija Bilalovic, Juan Palazzo, Ryan P. Bender, Jeffrey Swensen, Sherri Z. Millis, Semir Vranic, Daniel D. Von Hoff, Robert John Arceci
Journal: Journal of Clinical Oncology (2015)

e22207 Background: Histiocytoses are rare tumors characterized by the primary accumulation of monocytes, macrophages and dendritic cells. The most frequent subtypes are Rosai-Dorfman disease (RDD), Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD) and follicular dendritic cell sarcomas (FDCS). Clinical presentations range from localized to disseminated, life threatening disease. Identification of an activating BRAFV600E mutation in the majority of ECD and LCH cases provided the basis for the use of BRAF and MEK inhibitors in these patients. Responses have been reported with BRAF inhibitors, but no curative treatment has yet been developed. Thus, additional targeted therapies are needed. Methods: Twenty-two cases (M:F = 13:9, age range 2-65 years) of histiocytic diseases (4 RDD, 10 LCH, 4 ECD, 2 FDCS, 1 histiocytic sarcoma [HS] and 1 blastic plasmacytoid dendritic cell neoplasm [BPDCN]) were analyzed using immunohistochemical and molecular methods (cobas 4800 BRAFV600 Mutation Test and The TruSeq Amplicon-Cancer Panel) in search of biomarkers for targeted therapy. Results: An activating BRAFV600E mutation was found in LCH and ECD (4/10 and 4/4 of cases, respectively) but not in extranodal RDD, FDCS, HS and BPDCN; PTEN mutation (c.635-7_639del) was identified in the case of HS. Overexpression of immune response modulating molecule PD-L1 (CD274) on neoplastic histiocytes ( ≥ 2+/ ≥ 5%) was seen in 3/4 ECD, 8/8 LCH, 2/2 FDCS and 1/1 HS, with 76% concordance between the 2 antibodies used in the study (SP142 and MAB1561, Spring Bioscience and R&D Systems, respectively). No overexpression of PD-L1 was seen in RDD and BPDCN, regardless of the antibody used. PD-1-positive lymphocytes were variably present in all entities. Conclusions: The study confirmed the importance of BRAF V600E as a key mutation in ECD (100%) and LCH (40%), but not in RDD, FDCS, HS and BPDCS. Importantly, comprehensive profiling identified increased expression of PD-L1/CD274 in the majority of LCH, ECD, FDCS and HS cases. This result provides the basis for consideration of a clinical trial to test PD-L1 inhibitors in these diseases.
A phase I trial of the IGF-1R antibody IMC-A12 in combination with temsirolimus in patients with metastatic breast cancer.
Authors: Gini F. Fleming, VeraJean Suman, Matthew P. Goetz, Paul Haluska, Timothy Jerome Moynihan, Rita Nanda, Olufunmilayo I. Olopade, Timothy J. Pluard, Charles Erlichman, Helen X. Chen, Zhanfang Guo, Matthew James Ellis, Cynthia X. Ma
Journal: Journal of Clinical Oncology (2012)

534 Background: mTOR plays a critical role in promoting tumor cell growth. In preclinical studies, the anti-tumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated by IGF-1R. We designed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacodynamic effects of the IGF-1R antibody IMC-A12 in combination with temsirolimus (tem) in patients (pts) with metastatic breast cancer (MBC) where mTOR is frequently activated. Methods: A 3+3 phase I design was chosen. Tem and IMC-A12 were administered IV days (d) 1, 8, 15, and 22 of a 4-week cycle in pts with MBC refractory to standard therapies. Tumor response was evaluated by RECIST. Adverse events (AE) were reported using CTC v3.0. Serum IGF 1 and C-peptide levels on d2 (24h post infusion) and d8 prior to drug infusion were compared to baseline (BL) using paired t-test. Results: Of 26 pts enrolled, 4 did not complete cycle 1 due to progression (3) or co-morbid condition (1). MTD was determined from remaining 22 pts aged 34-72 (median 48) years with ECOG PS 0 (55%) or 1 (45%). 86% had ER+ cancer. Median number of regimens for MBC was 4. Two DLTs at the starting DL (DL 1) necessitated dose de-escalation of tem to 20mg (DL-1), then to 15 mg (DL-2) which was tolerable (Table). Subsequent dose escalation of IMC-A12 led to DLTs in 0 of 6 in DL-2A and 2 of 3 pts in DL-2B. The MTD was defined as DL-2A. Other AEs included gr 1/2 fatigue, neutropenia, anemia, and hyperglycemia. No CR or PR, but 4 SD lasting ≥ 4 months were observed. At DL-2, -2A and -2B, serum IGF 1 levels were significantly elevated on d2 (p &lt;0.002) and d8 compared to BL (p &lt;0.001), but C-peptide levels were not found to differ from BL. Conclusions: The MTD for the combination of IMC-A12 and tem in pts with MBC is lower than that observed for single agents alone. A phase II study is ongoing in MBC. The study is supported in part by ASCO CDA, Komen Craft to CXM, N01-CM62205 and N01-CM-2011-00071. [Table: see text]
Over expression of Capping protein Z line alpha 1(CAPZA 1) and protein phosphatase 1 (PP 1) in malignant melanoma as identified by subtractive hybridization
Authors: V. Trisal, M. Zhou, B. Shen, D. Chu
Journal: Journal of Clinical Oncology (2004)

7518 Background: Several genetic alterations have been implicated in the development of melanoma. However the expression of oncogenes, tumor supressor, mismatch repair and apoptosis related genes and their interactions in melanoma have not been completely clarified. We sought to identify the unique genes that are specifically implicated in the development of progressive forms of melanoma. Methods: Nine Malignant melanoma cell lines and one primary culture of pure normal human skin melanocytes were used in subtractive hybridization. Total RNA was isolated from cell lines and primary cell cultures. Poly-A RNA was purified and cDNA was synthesized. A two-step hybridization was performed and the differentially expressed sequences were amplified. The sequences were cloned in a vector and the fragments were sequenced. Fragments showing high homology with previously described sequences were considered to represent known genes. Results: Multiple genes were found to be underexpressed and a large number were overexpressed between the different cell lines and the normal skin melanocytes. Capping Protein z-line alpha 1 (CAPZA1), protein Phosphatase 1 (PP1), clone CTB-89H12 and FLJ 13207 were identified to be over expressed genes in melanoma cell lines. Melanocyte specific protein (Pmel17) and Mitochondrial carrier (adenine nucleotide translocator) were identified to be underexpressed in melanoma cell lines. Underexpression of Pmel17 on subtractive hybridization was not confirmed on the RT-PCR analysis of individual cell lines. CAPZA1 and PP1 were further found to be overexpressed in the melanoma cell lines with minimal expression in melanocytes on RT-PCR analysis of all the samples. Conclusions: The selective over-expression of CAPZA 1 and PP 1 is associated with malignant melanoma and may represent valuable candidate genes in the further management of this disease. No significant financial relationships to disclose.