tbuckley/cabot-search huggingface dataset:
Impact of nilotinib treatment on subclinical cardiovascular biomakers.
Authors: Martine Gardembas, Samir Henni, Anne Corby, Loukmann Omarjee, Norbert Ifrah, Georges Leftheriotis
Journal: Journal of Clinical Oncology (2015)

7045 Background: Nilotinib is a tyrosine kinase inhibitor targeting the BCR-ABL1 oncoprotein. It has been approved for the treatment of chronic myeloid leukemia-CP. Recently, a higher rate of cardiovascular events (CVE) have been reported as part of the non hematological nilotinib related adverse events. Although the CVE events may be influenced by several factors including pro-atherogenic and anti-angiogenic properties of nilotinib, the contribution in the atherosclerotic process still remains unclear. The purpose of this cross-sectional study was to determine the impact of nilotinib treatment on subclinical atherosclerotic biomarkers. Methods: 15 patients (mean 44 yrs ±14 yrs, 8 men) treated with nilotinib (Nilo) were compared to 30 age- and gender-matched patients with metabolic syndrom (MS) and 30 healthy controls. Subclinical atherosclerosis was assessed by the presence of carotid, aortic and femoral plaques, intima media thickness (IMT), arterial stiffness (Beta index), ankle brachial pressure index (ABI), and brachial arterial pressure (BAP). The overall cardiovascular risk (CVR) was determined according the 10 years-Framingham CV score. Statistical differences (p < 0.05) between the groups were determined by Chi2 and Kruskal-Wallis or ANOVA statistics as appropriate (Stata 12.1). Results: Median duration exposure to nilotinib was 1299 days (range 252-2196). Plaques were significantly more frequent (p = 0.007) in the Nilo group (53%) than in healthy controls (13 %,) but no difference between Nilo and MS group (63%, p = 0.371). There were no statistically significant differences in IMT (p = 0.271), Beta stiffness index (p = 0.428), ABI and BAP. The CVR score in Nilo group was similar than in the control group ( p = 0,136). Conclusions: Patients treated with nilotinib exhibited a higher amount of plaques although at a lower CVR score. These data would suggest that patients treated with nilotinib, likely develop focal lesions rather than a systemic arteriosclerotic process. Subclinical cardiovascular biomarkers could provide more targeting options for the personalized follow-up of patients treated with nilotinib. However, these preliminary data need to be confirmed in a larger longitudinal study. Clinical trial information: NCT02161978.
The relationship between overall survival (OS) and progression-free survival (PFS) in gastrointestinal stromal tumor (GIST).
Authors: Ipek Özer Stillman, Lauren N. Strand, Jane Chang, Ateesha F. Mohamed, Kyle Fahrbach, Katherine E. Tranbarger Freier
Journal: Journal of Clinical Oncology (2014)

10557 Background: OS is the gold-standard measure of treatment efficacy in cancer. However, PFS is often used as primary endpoint when OS follow-up is long and/or post-progression therapy is common. In unresectable and/ or metastatic GIST, a previous study showed a moderately strong linear relationship between median PFS (mPFS) and median OS (mOS). This study presents an updated analysis. Methods: A systematic literature review identified fourteen clinical trials and five observational studies of sufficient quality from Jan 1995 to Dec 2013 (29 total treatment arms; 2,189 patients). These studies encompassed first and later lines of treatment with targeted therapies. Scatter plots and linear regressions (weighted by the number of patients) were used to evaluate the relation between mOS and mPFS for all arms combined. Sensitivity analyses investigated the impact of treatment line, treatments, and study quality score. Results: mOS and mPFS (in months) were positively related with an overall correlation of 0.912 in linear regression (slope = 2.083, standard error [SE] = 0.178; intercept = 5.618, SE = 2.436; adjusted R2= 0.830). Eliminating four influential datapoints using the Difference in Beta Scaled, reduced the estimates for association, though the association was still strong (overall correlation = 0.724). The correlation was greater in later lines of therapy (first line = 0.518; second line = 0.797; third- and later-line = 0.702). Conclusions: This study showed a strong relationship between mPFS and mOS in GIST, especially in later lines of therapy. The number of studies included is relatively small and some treatment arms have <50 patients, which is not unexpected in a rare disease like GIST. While these findings provide some insight into PFS as a surrogate marker for OS, analyses of patient level data are needed to fully establish its validity in GIST.
Neoadjuvant radiotherapy (RT) combined with capecitabine (Cape) and sorafenib (Sor) in patients (pts) with locally advanced, k-ras-mutated rectal cancer (LARC): A phase I/II trial SAKK 41/08.
Authors: Roger Von Moos, Dieter Koeberle, Sabina Schacher, Stefanie Hayoz, Ralph C. Winterhalder, Arnaud Roth, Gyorgy Bodoky, Panagiotis Samaras, Martin D Berger, Daniel Rauch, Piercarlo Saletti, Ludwig Plasswilm, Peter Thum, Urs R. Meier, Pu Yan, Paola Izzo, Dirk Klingbiel, Daniela Baertschi, Kathrin Zaugg
Journal: Journal of Clinical Oncology (2014)

3531 Background: K-ras mutation is found in up to 40% of LARC. Sor is a multitarget tyrosine kinase inhibitor including raf and VEGFR and has demonstrated radiosensitizing effects. Sor might improve outcome of standard preoperative radio-chemotherapy in patients with k-ras mutated LARC. Methods: Pts with k-ras mutated T3-4 and/or N+, M0 disease by MRI were included. Recommended doses from phase I part consisted of RT 1.8 Gy/day x25 with Cape 825mg/m2bid x 33 in combination with Sor 400mg/d. The primary endpoint for the phase II part was pathological complete response (pCR) prospectively defined as grade 3 (near complete regression) or 4 (complete regression) in the histological grading system according to Dworak (DC). A pCR rate of 8% or lower was considered uninteresting and of 22% or higher was promising. Secondary endpoints included sphincter preservation, R0 resection, downstaging and safety. Results: 54 pts were treated in 18 centers in Switzerland und Hungary, 40 pts were included into the single arm phase II part. Median dose intensity per day was 100.0% for RT, 98.6% for Cape and 100.0% for Sor respectively. pCR rate was 60.0% (95%CI: 43.3%, 75.1%) by central independent pathological review (15.0% DC grade 4; 45.0% DC grade 3). Sphincter preservation was achieved in 89.5%, R0 resection in 94.7% and downstaging in 81.6% of the pts. The most common grade 3 toxicities included diarrhea (15.0%), skin toxicity outside of the RT field (12.5%), pain (7.5%), skin toxicity in RT field, proctitis, fatigue and cardiac ischemia (each 5.0%). Laboratory AEs grade 3/4 were neutropenia (1 pt grade 4; 1 grade 3), creatinine elevation (1 pt grade 3). Conclusions: The combination of Sor to standard RCT with Cape in k-ras mutated LARC tumors is highly active with acceptable toxicity and deserves further investigation. Clinical trial information: NCT00869570.
High epiregulin (<i>EREG</i>) gene expression plus <i>K-ras</i> wild-type (WT) status as predictors of cetuximab benefit in the treatment of advanced colorectal cancer (ACRC): Results from NCIC CTG CO.17—A phase III trial of cetuximab versus best supportive care (BSC)
Authors: D. J. Jonker, C. Karapetis, C. Harbison, C. J. O’Callaghan, D. Tu, R. J. Simes, L. Xu, M. J. Moore, J. R. Zalcberg, S. Khambata-Ford
Journal: Journal of Clinical Oncology (2009)

4016 Background: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), improves overall survival (OS) and progression free survival (PFS) in patients with K-ras WT chemotherapy refractory ACRC. Gene expression of the EGFR ligand epiregulin (EREG) may further predict benefit from cetuximab. Methods: CRC tumour samples were analyzed from a phase III clinical trial of cetuximab plus BSC vs BSC alone (NEJM 2007; 357(20)). EREG gene expression was detected in tumour-derived genomic RNA blinded to clinical outcome by quantitative real time-PCR. Using a pre-specified threshold for “high” EREG derived from a prior study (CA225–045), the predictive effect of (1) high vs low EREG among K-ras WT and (2) high EREG/K-ras WT status (“Combimarker”) versus all other patients on OS and PFS was examined using a Cox model with tests for treatment-biomarker interaction. Results: Both EREG gene expression levels and K-ras mutation status were ascertained in 385 (67%) of the total study population (193 cetuximab, 192 BSC). In the K-ras WT subset, OS was better for cetuximab than BSC among patients with high EREG (HR 0.43; p&lt;0.0001) but not for low EREG patients (HR 0.77, p=0.28). The test for interaction showed a non-significantly larger treatment effect in the high EREG group (HR 0.62, p=0.13). High EREG AND K-ras WT status (“Combimarker”) was present in 139 (36%). Within the Combimarker positive group the median PFS was 5.4 vs 1.9 months (HR, 0.31; p&lt;0.0001), and median OS 9.8 vs 5.1 months (HR, 0.43; p&lt;0.001) in the cetuximab vs BSC arms, respectively. In the rest (n=246, 64%) cetuximab was not associated with improved PFS (HR, 0.82; p=0.12) or OS (HR, 0.90; p=0.45). The test for treatment-Combimarker interaction showed a larger cetuximab effect on OS (HR 0.52; p=0.007) and PFS (HR 0.49; p=0.001) in the Combimarker positive group. Conclusions: In the setting of pre-treated ACRC, patients with both high EREG gene expression and K-ras wild- type status may benefit from cetuximab therapy. Determination of EREG gene expression levels should be prospectively evaluated in patient selection for EGFR targeted therapy. [Table: see text]
Prolonging the platinum-free interval (PFI) with trabectedin to allow retreatment with platinum-based chemotherapy in patients with platinum-refractory and -resistant recurrent ovarian cancer (PROC).
Authors: Antonio Casado Herraez, Hector Callata, Aranzazu Manzano, Pluvio Coronado, Teresa Alonso, Barbara Sanchiz, Pablo Gajate, Santiago Cabezas, Jose Antonio Vidart, Eduardo Diaz Rubio
Journal: Journal of Clinical Oncology (2013)

e16543 Background: Dose-dense therapy and administration of sequential non-platinum agents in PROC plays a role in reverting platinum-resistance and may improve the prognosis of such patients over years (Bamias A, 2013). The PFI extension is one of the current strategies to improve survival in partially platinum-sensitive (PPS) ROC, with a PFI 6-12 months (Poveda A, 2011). Trabectedin is a minor groove DNA-binder, which may play a role in reverting platinum resistance in patients with PROC and PPS ROC. Methods: Trabectedin 1.1-1.5 mg/m 2 as single agent was given as a 3-h infusion every 3 weeks with antiemetic and steroid premedication. Tumor response was assessed every 12 weeks. Results: Overall, 27 patients (24 with PROC and 3 with PPS ROC) treated from 2003 to 2013 in a single institution were included in the analysis. The patients had a median age of 63 years (range 45-81), most had serous-papillary (67%), clear-cell (11%), endometrioid (7%) and other (15%) histological subtypes and received a median of 5 prior chemotherapy lines (range: 1-9), 89% of whom also received other non-platinum agents. A median of 4.9 trabectedin cycles (range 1-14) was given. The overall response rate (ORR) was 15%, with a median duration of response of 16.5 weeks (range 5.86-44.43), while 41% of patients achieved stable disease (SD) lasting ≥4 months as best response. Thirteen of 27 patients were retreated with platinum-based chemotherapy after progression with trabectedin treatment. The ORR to platinum retreatment was 54% (n = 7) and SD was achieved in 8% (n = 1) of these patients, for an overall clinical benefit of 61%. Conclusions: Intercalation of a non-platinum therapy with trabectedin prior to subsequent platinum rechallenge may contribute to prolong PFI and to re-sensitize the patients with PROC and PPS ROC to further platinum-based therapies leading to a significant clinical benefit. Further prospective studies are warranted to determine the contribution of sequential treatments with trabectedin in patients with PROC and PPS ROC.
Enhanced topical penetration, system exposure and anti-psoriasis activity of two particle-sized, curcumin-loaded PLGA nanoparticles in hydrogel
Authors: Lin Sun, Zeyu Liu, Lun Wang, Dongmei Cun, Henry H.Y. Tong, Ru Yan, Xin Chen, Ruibing Wang, Ying Zheng
Journal: Journal of Controlled Release (2017)
Lenvatinib combined with dacarbazine versus dacarbazine alone as first-line treatment in patients with stage IV melanoma.
Authors: Michele Maio, Jessica Cecile Hassel, Michele Del Vecchio, Alessandro Testori, Paolo Antonio Ascierto, Ernie Marshall, Hiliary Glen, Paul Lorigan, Elaine Meek, Song Liou, Jeff Paul Hodge, Fabrina Bologna, Harish P. Dave
Journal: Journal of Clinical Oncology (2013)

9027 Background: Lenvatinib (E7080; LEN) is an oral, receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ . In a phase I study qd dosing of &gt;/= 20mg LEN demonstrated PRs and prolonged SD in patients (pts) with advanced melanoma. Dacarbazine (DTIC) upregulates the proangiogenic factor VEGF and has been shown to confer resistance in melanoma cell lines (Lev, JCO 2004; 22:2092-2100). Treatment of melanoma pts with LEN + DTIC may potentiate the therapeutic effects of DTIC. Methods: This was a phase II study in pts with metastatic melanoma randomized 1:1 to receive LEN (20 mg QD) + DTIC (1000 mg/m 2 Q 21 d) or DTIC (1000 mg/m 2 Q 21 d). Pts were stratified by LDH level and stage IV subclass. Eligible pts were ECOG PS 0/1 and had no prior systemic therapies. BRAF status was determined from circulating tumor DNA. The primary endpoint was PFS by independent assessment. Results: In a modified ITT analysis,a total of 78 of 81 pts were evaluable for efficacy; 59% were male, 59% were Stage IV M1c, 22% had elevated LDH, 29% had prior adjuvant therapy and 49% BRAF wild-type (wt). Most common AEs in the LEN + DTIC arm were hypertension (48%), nausea (38%), constipation (33%), and diarrhea (31%). Most common Grade 3/4 AEs in LEN + DTIC were hypertension (26%) and neutropenia (10%). There were no deaths due to an AE. Median PFS increased in LEN + DTIC compared to DTIC alone (see Table). An improvement in median PFS was observed in BRAFwt pts on the combination. Conclusions: A 2.7-fold increase in the median PFS was observed in pts administered LEN + DTIC compared to single agent DTIC. A 2.5 fold increase in the median PFS was observed in the combination arm in pts with BRAFwt melanoma. The AE profile observed with the LEN + DTIC was consistent with observed LEN monotherapy studies. These data suggest further evaluation of LEN + DTIC in BRAFwt melanoma is warranted. Clinical trial information: NCT01133977. [Table: see text]
Landscape of genetic alterations in patients with metastatic uveal melanoma.
Authors: Sophie Piperno-Neumann, Ellen Kapiteijn, James M. G. Larkin, Richard D. Carvajal, Jason J. Luke, Heike Seifert, Inge Roozen, Mustapha Zoubir, Thiruvamoor Ramkumar, Caroline Emery, Adnan Derti, Padmaja Yerramilli-Rao, F. Stephen Hodi, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2014)

9043 Background: Uveal melanoma (UM) is a rare type of cancer with a mutational profile distinct from skin melanoma and poor prognosis in a metastatic setting. In the context of a dose-escalation clinical trial of the PKC inhibitor AEB071 (sotrastaurin) in UM we conducted genomic profiling of 52 formalin-fixed, paraffin-embedded biopsies from metastatic patients (pts), primarily from liver. Methods: Massively parallel sequencing of 288 clinically-relevant cancer genes was performed by Foundation Medicine at high depth (median 646X) to characterize mutations, amplifications (≥6 copies) and homozygous deletions. Results: Alterations of known or likely functional significance were frequent only in genes previously implicated in UM but two novel patterns were observed. All but two pts (96%) had a known activating mutation in either GNAQ (63%; Q209P/L/R or R183Q) or GNA11 (33%; Q209L). While this mutually exclusive pattern is a known feature of UM the higher prevalence reported here is likely due to the sequencing depth, as evidenced by low allele frequencies in some pts even after correcting for tumor purity. In addition truncations or splice site mutations in BAP1 were observed frequently (62%), in line with previous reports. The tumors harbored nearly complete mutual exclusivity between partial or putatively complete amplifications of chromosome 8q (52%) and recurrent mutations in SF3B1 (19%; R625C/H or V701F), a pattern previously unreported. In addition BAP1 mutations were frequent in 8q-amplification pts (23/25 [85%]) but rare in SF3B1-mutant pts (2/10 [20%]), suggesting complementary and redundant consequences of these lesions with BAP1 mutations respectively. Mutations of known or likely functional impact were otherwise rare. P53 and SMARCA4 were mutated in two pts each and 15 genes were mutated in a single pt. We then investigated the effect of genetic subtype on the baseline levels of pMARCKS as an indicator of PKC activity. No relationship with any gene or within GNAQ/GNA11 mutant subtypes was observed. However, pMARCKS levels were attenuated upon AEB071 treatment. Conclusions: High-depth sequencing of clinical pt metastases sheds new light on the interplay among the small group of genetic alterations observed in uveal melanoma.
Biomarkers of response to Akt inhibitor MK-2206 in breast cancer.
Authors: Takafumi Sangai, Argun Akcakanat, Huiqin Chen, Emily Tarco, Yun Wu, Kim-Anh Do, Todd W Miller, Carlos L. Arteaga, Gordon B. Mills, Ana M. Gonzalez-Angulo, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2012)

1054 Background: Akt significantly contributes to cancer pathogenesis. PTEN, a negative regulator of PI3K/Akt signaling, is mutated or decreased, and PIK3CA is frequently mutated in multiple cancer lineages. We hypothesized that MK-2206, an allosteric Akt inhibitor, would inhibit Akt signaling thus blocking cancer cell growth, and PTEN and/or PIK3CA mutations may confer MK-2206 sensitivity in breast cancer. Methods: After determining sensitivity to MK-2206 in16 cell lines, the effect on Akt signaling was tested by reverse-phase protein array analysis and western blotting. The effect to cell cycle progression and cell death were analyzed by flow cytometry. Using RNA knockdown technique, the effect of PTEN, PIK3CA and Akt on MK2206 sensitivity was tested. Anti-tumor effect in vivo with or without paclitaxel was tested using PTEN-mutant ZR75-1 breast cancer xenografts. Results: MK-2206 inhibited Akt signaling and cell cycle progression, and increased apoptosis in a dose-dependent manner in breast cancer cell lines. Cell lines with PTEN or PIK3CA mutations were more sensitive to MK-2206 (P=0.0337), however, a number of lines with PTEN/PIK3CA mutations were MK-2206-resistant. Small interfering RNA (siRNA) knockdown of PTEN in breast cancer cells increased Akt phosphorylation concordant with increased MK-2206 sensitivity. Stable transfection of PIK3CA E545K or H1047R mutant plasmids into normal-like MCF10A breast cells enhanced MK-2206 sensitivity. Cell lines that were less sensitive to MK-2206 had lower ratios of Akt1/Akt2 and had less growth inhibition with Akt siRNA knockdown. In ZR75-1 xenografts, MK-2206 treatment inhibited Akt signaling, cell proliferation, and tumor growth. In vitro, MK-2206 showed a synergistic interaction with paclitaxel in MK-2206-sensitive cell lines, and this combination had significantly greater antitumor efficacy than either agent alone in vivo. Conclusions: MK-2206 has antitumor activity alone and in combination with chemotherapy. This activity may be greater in tumors with PTEN loss or PIK3CA mutation, providing a strategy for patient enrichment in clinical trials. However, not all tumors with PIK3CA/PTEN aberrations are MK-2206-sensitive, emphasizing the need for additional markers of response.
Compartmentalized Spherical Collagen Microparticles for Anisotropic Cell Culture Microenvironments
Authors: Satoru Yoshida, Masahiro Takinoue, Hiroaki Onoe
Journal: Advanced Healthcare Materials (2017)

This paper describes a new fabrication method for obtaining anisotropic spherical hydrogel microparticles with different types of extracellular matrix (ECM) hemispheres for use in 3D cell culture. To fabricate the microparticles, a mixture of an ECM precursor solution and sodium alginate is ejected into a calcium chloride solution under large centrifugal acceleration by a centrifuge‐based microfluidic device; the calcium alginate hydrogel plays a significant role as a “sacrificial gelation template” to maintain the ECM molecules in each hemisphere. This fabrication method enables gaining control of the hemispherical volume, density, and type of ECM. Using the microparticles, cells could be successfully encapsulated in each hemisphere selectively with high viability, which are then suitable for culture in the microparticles to form microtissues. It is believed that the proposed anisotropic ECM microparticles will facilitate the coculture of multiple cell types in different ECMs, which is similar to in vivo microenvironments, facilitating control of cell behavior in an anisotropic microenvironment for the benefit of large‐scale and quantitative analyses in vitro.
Evaluation of MLN4924, an investigational NEDD8-activating enzyme (NAE) inhibitor, as a novel targeted agent with single-agent antitumor activity in mantle cell lymphoma (MCL) and Hodgkin lymphoma preclinical models.
Authors: Richa Dawar, Matthew John Barth, Cory Mavis, Jospeh J. Skitzki, Myron Stefan Czuczman, Pavel Klener, Francisco J. Hernandez-Ilizaliturri
Journal: Journal of Clinical Oncology (2012)

e18539 Background: MLN4924 is a novel, potent, and selective inhibitor of NAE, an essential component of the ubiquitin-proteosome system (UPS). We have previously demonstrated that the UPS plays a pivotal role in the development of rituximab and chemotherapy resistance in B-cell lymphomas. There is a scientific need to target the UPS more efficiently in an attempt to reverse acquired resistance to biological and chemotherapeutic agents in relapsed/refractory aggressive lymphoma. To this end, we studied the anti-tumor activity of MLN4924 in rituximab-chemotherapy sensitive and resistant pre-clinical models. Methods: A panel of Burkitt (BL), diffuse large B-cell (DLBCL), MCL and HL lymphoma cell lines and primary tumor cells isolated from patients with non-Hodgkin lymphoma (NHL) (N=10) were exposed to escalating doses of MLN4924 alone or in combination with a panel of chemotherapeutic agents for up to 72 hrs. Cell viability was determined by alamar Blue reduction or CellTiter-glo assay. Apoptosis was determined by Western blotting. Cell cycle analysis was performed by flow cytometry. Results: MLN4924 demonstrated activity in all cell lines in a time-and dose-dependent manner, including the rituximab/chemotherapy-resistant cell lines. The most potent activity was noted in MCL and HL cell lines (IC50 doses were tenfold lower as compared to DLBCL or BL cell lines). A variable degree of anti-tumor activity was observed in primary tumor cells isolated from NHL patients. Induction of apoptosis was observed in rituximab-resistant cell lines. MLN4924 exhibited synergistic anti-tumor activity when combined with bortezomib, bendamustine, and cytarabine in MCL cell lines. Conclusions: MLN4924 exhibits potent in vitro cytotoxic activity against a variety of human B-cell lymphoma cell lines and primary tumor cells isolated from NHL patients. Significant activity was observed in MCL cell lines. Experiments investigating the in vivo activity of MLN4924 are ongoing. MLN4924 is a highly promising agent for the treatment of relapsed/refractory MCL or HL.