tbuckley/cabot-search huggingface dataset:
Antitumor activity and suppression of AKT pathway activation by PDK1 inhibitor SNS-391.
Authors: Stig K Hansen, Nuzhat Pathan, Lihong Sun, Judith Ann Fox
Journal: Journal of Clinical Oncology (2014)

e13560 Background: 3-Phosphatidylinositide-dependent kinase 1 (PDK1) interacts with its substrate kinases after binding phosphatidylinositol (PI). PDK1 also affects downstream targets in a PI-independent manner, causing activation of additional pathways. PDK1 activation of AKT involves both PI-dependent and independent mechanisms, making PDK1 a challenging target for AKT pathway inhibition. Here we describe a novel PDK1 inhibitor, SNS-391, that is highly effective at inhibiting AKT activity with broad anti-tumor activity. Methods: SNS-391 was evaluated in the prostate cancer PC-3 cell line (PTEN null) for inhibition of several signaling pathways and was tested in proliferation assays in over 50 tumor cell lines of prostate, lung, colon, breast, melanoma, and pancreatic origin. Tumor xenograft studies were conducted in prostate, gastric, lung, pancreatic, and colorectal cancer models. Tumor samples were analyzed for pathway inhibition and compound exposure to develop PK/PD relationships. Results: SNS-391 (biochemical kinase assay IC50: 1.8 nM ) showed strong suppression of both AKT-308 (EC50: 87 nM) and AKT-473 phosphorylation in PC-3 cells. PDK1 autophosphorylation was reduced >50%, and downstream AKT pathway inhibition was indicated by suppression of PRAS-40 and S6K phosphorylation. Inhibition of phosphorylation of PI independent substrates IKKβ and RSK2 was observed. SNS-391 caused G1/S arrest and apoptosis. Inhibition of proliferation was seen across tumor cell lines of prostate, lung, colon, breast, melanoma, and pancreatic origin with EC50 < 1 μM. Many cell lines with mutations in PTEN, p53, PI3K, Ras, or Raf were sensitive to SNS-391 treatment. SNS-391 showed strong tumor growth inhibition (TGI 66%-95%) in gastric, lung, pancreatic, and colorectal cancer xenograft models. In the prostate PC-3 xenograft model, SNS-391 (TGI 82%) activity was superior to PI3K inhibitor pictilisib (TGI 58%) and AKT inhibitor MK2206 (TGI 40%). Conclusions: PDK1 inhibitor SNS-391 inhibits both PI-dependent and independent AKT pathways and has broad potential for the treatment of diverse cancers.
A randomized phase II trial of a vascular disrupting agent (VDA) fosbretabulin tromethamine (CA4P) with carboplatin (C), paclitaxel (P), and bevacizumab (B) in stage 3B/4 nonsquamous non-small cell lung cancer (NSCLC): Analysis of safety and activity of the FALCON trial.
Authors: E. B. Garon, F. F. Kabbinavar, J. A. Neidhart, J. D. Neidhart, N. Y. Gabrail, M. R. Oliveira, S. Lu, J. Balkissoon
Journal: Journal of Clinical Oncology (2011)

7559 Background: Inhibition of angiogenesis has clinical benefits in NSCLC. Depriving tumors of blood flow by adding bevacizumab (B) to other vasculature-directed agents has been hampered by toxicity. CA4P has shown additive effects with chemotherapy and antiangiogenic therapy. This phase II study evaluated the safety and activity of CA4P + carboplatin (C) + paclitaxel (P) + B in NSCLC. Methods: This is a randomized, open-label study in patients with untreated, Stage 3B/4 non-squamous NSCLC. 63 patients were randomized to receive up to 6 cycles of C + P + B with CA4P (CA4P Arm) or without CA4P (Control Arm). After 6 cycles of therapy, patients without progression continued to receive their randomized treatment (CA4P + B or B) until progression. Enrollment completed in June 2010. Results: 60 patients were treated (31 on the CA4P Arm and 29 on the Control Arm). This interim analysis (data cut-off 13Jan2011) has a median follow up 9.7 months. Responses were more frequent in the CA4P Arm, with partial responses in 55% of patients on the CA4P Arm vs. 38% on the Control Arm. Median time to progression is similar between the two arms (8.6 months in the CA4P Arm vs. 8.8 months in the Control Arm), hazard ratio (HR) and 95% CI of 0.89 (0.46, 1.73). Ten patients continue to be treated and have neither progressed nor died at the time of this analysis. With data continuing to mature, 49 patients have been followed for at least 12 months (the cut-off for efficacy analysis at ASCO 2010) and in these patients the median PFS is 8.6 months in the CA4P Arm vs. 7.9 months in the Control Arm, HR and 95% CI of 0.73 (0.35, 1.54). Grade 3 hypertension and neutropenia were more common on the CA4P Arm. There were three transient and reversible cardiac ischemia events in the CA4P Arm, none of which required hospitalization. Conclusions: The addition of CA4P to C + P + B continues to show clinical activity, with trends toward increased responses compared to C + P + B, without significant additional toxicity. This proof of concept trial shows that it is feasible to combine CA4P + B (two vascularly active drugs) with C + P therapy.
FOLFIRINOX as first-line therapy in patients with metastatic gastroesophageal cancers (GEC).
Authors: Albert C. Lockhart, Kenneth Anthony Krajewski, Andrea Wang-Gillam, Manik Amin, Steven Sorscher, Kian-Huat Lim, Benjamin R. Tan, Joel Picus, Anne Hecky, Kenisha Allen, Jaclyn D Peterson, Emily O'Day, Robert de Wilton Marsh, Mark Kozloff, Blase N. Polite, Hedy Lee Kindler, Manish Sharma, Daniel Virgil Thomas Catenacci
Journal: Journal of Clinical Oncology (2015)

177 Background: Adenocarcinomas of the distal esophagus, gastroesophageal junction and stomach (GEC) remain challenging cancers to treat. Unfortunately, 80-90% of newly diagnosed patients (pts) present with advanced disease where the overall median survival (mOS) is less than 1 year. Discouragingly, various common first-line metastatic regimens have similar overall response rates (ORR) (30-40%; and 47% for HER2+ with trastuzumab). Given results within other GI tumors, FOLFIRINOX was administered to pts with newly diagnosed advanced GEC. Methods: A pooled analysis from two independent ongoing clinical trials was conducted from: 1) the University of Chicago UC (NCT01643499) where pts received modified ‘mFOLFIRINOX’ with irinotecan dosing based on UGT1A1*28 genotyping; and 2) Washington University (WU) (NCT01928290) where pts received standard ‘sFOLFIRINOX’ as previously described, and HER2+ pts also received trastuzumab (sFOLFIRINOX-T). Both studies administered therapy every 14 days. Trastuzumab was administered as 6 mg/kg loading dose then 4 mg/kg every 14 days. mFOLFIRINOX used UGT1A1 genotype *1/*1, *1/*28, and *28/*28 to assign initial irinotecan doses of 180, 135, and 90 mg/m 2 , respectively. The mFOLFIRINOX 5-FU dose was 2400 mg/m 2 over 46 hours (no bolus) with leucovorin 400 mg/m 2 , and oxaliplatin 85 mg/m 2 . Outcomes included ORR, tolerability/safety, mPFS, and mOS for both trials. Results: In the pooled analysis, 18 pts with GEC were enrolled to date (11 at WU and 7 at UC), and 16 evaluable for response. ORR was 62.5% (10/16), (HER2- 58% (7/12), HER2+ 75% (3/4)). One HER2+ pt experienced a CR. mPFS was 8 months (range 1.5-18 months), however 10/16 pts have not progressed on first-line therapy to date. There were no unexpected toxicities for any of the regimens. Conclusions: ORR and PFS with first-line FOLFIRINOX were encouraging for metastatic GEC. sFOLFIRINOX was well tolerated in these patients, and sFOLFIRINOX-T was safely administered.mFOLFIRINOX consisting of genotype-directed irinotecan dose reductions and no 5FU bolus may limit toxicity yet retain similar benefit to sFOLFIRINOX. Continued investigation of this regimen is warranted given these encouraging preliminary results. Clinical trial information: 01928290.
Phase I study of immunization with the analogue peptide NY-ESO-1 157–165V in combination with CpG (PF-3512676) and Montanide ISA 720 in patients with stage III/IV melanoma
Authors: J. J. Fourcade, P. Kudela, P. A. Andrade Filho, B. M. Janjic, S. R. Land, C. Sander, A. M. Krieg, A. D. Donnenberg, H. Shen, J. M. Kirkwood, H. M. Zarour
Journal: Journal of Clinical Oncology (2008)

20011 Background: Analogue peptides represent a promising tool to further optimize peptide-based vaccines in promoting the expansion of tumor antigen-specific CTLs. Here, we report the results of a pilot trial designed to study the safety/toxicity and immunogenicity of the analogue peptide NY-ESO-1 157–165V in combination with CpG 7909/PF3512676 and Montanide ISA 720 in patients with NY-ESO-1- expressing melanoma. Methods: Eight HLA-A2+ patients with stage III/IV measurable melanoma were immunized with a stable emulsion composed of 3 ml Montanide in combination with either 2 mg CpG (arm 1), 400 μg analogue peptide NY-ESO-1 157–165V (arm 2) or CpG and peptide NY-ESO-1 157–165V (arm 3). Patients were vaccinated every other week for 8 immunizations prior to clinical and immunological evaluation. Results: In all patients, we observed grade I/II skin toxicity at the injection site with redness and pain. Only the three patients immunized with Montanide, CpG and peptide NY-ESO-1 157–165V in arm 3 developed a rapid and strong increase of effector- memory NY-ESO-1-specific CD8+ T cells that were detectable ex vivo. The majority of these T cells exhibited an intermediate/late-stage differentiated phenotype (CD28-). This study has further demonstrated that vaccination stimulated spontaneous tumor-reactive NY- ESO-1-specific CD8+ T cells in two patients with advanced disease, but failed to prime tumor-reactive NY-ESO-1-specific T cells in a patient without spontaneous tumor-reactive CD8+ T cells directed against NY-ESO-1. No objective clinical responses have been noted to date. Conclusions: Collectively, these data demonstrate that the peptide analogue NY-ESO-1 157–165V combined with CpG and Montanide promotes strong expansion of NY-ESO-1-specific CD8+ T cells in the blood of patients with advanced cancer. This study also demonstrates that the presence of tumor-induced NY-ESO-1-specific T cells of well-defined clonotypes is critical for expansion of tumor-reactive NY-ESO-1- specific CD8+ T cells following peptide vaccine strategies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Coley Pharmaceutical Group Coley Pharmaceutical Group
A phase II trial of neoadjuvant cisplatin (C), gemcitabine (G), and sunitinib (S) in muscle-invasive urothelial carcinoma (miUC): Results from Hoosier Oncology Group GU07-123 trial.
Authors: S. P. Lerner, T. Powles, N. M. Hahn, T. Gardner, L. Cheng, J. Green, D. Berney, D. Taber, J. Landgraf, S. S. Shen, G. Sonpavde
Journal: Journal of Clinical Oncology (2011)

e15173 Background: Neoadjuvant platinum-based chemotherapy has demonstrated survival benefits in miUC patients. Mediators of tumor angiogenesis including the vascular endothelial growth factor receptor (VEGFR) play a critical role in UC metastases. A phase II study of neoadjuvant cisplatin (C), gemcitabine (G), and the multi-targeted VEGFR tyrosine kinase inhibitor sunitinib (S) in miUC patients was conducted to determine the clinical efficacy and safety of the CGS regimen. Methods: Muscle-invasive UC patients with ECOG performance status (PS) 0-1 and creatinine clearance > 60 ml/min received C 60 mg/m2 iv d1, G 800 mg/m2 iv d1, 8, and S 37.5 mg po d1-14 on a q21d cycle for a maximum of 4 cycles followed by cystectomy. The primary endpoint was pathologic complete response rate (pCR). Results: 9 pts were enrolled and treated. Patient demographics included: median age – 70, M/F – 8/1, ECOG PS 0/1 – 6/3. Baseline tumor staging included: T2 – 4, T3 – 2, T4a – 3. All patients were clinically N0 M0. All 9 patients experienced at least one Grade 3-4 treatment related toxicity exceeding the pre-defined study toxicity stopping rule. Grade 3-4 hematologic toxicity included: perioperative bleeding 4 pts, neutropenia 2 pts, neutropenic fever 1 pt, thrombocytopenia 1 pt, anemia 1 pt. Grade 3-4 non-hematologic toxicity included: nausea/emesis 3 pts, syncope 2 pts, myocardial infarction 1 pt, fatigue 1 pt. No treatment-related-deaths were observed. Pathologic response data is available for 8 patients. 2 pCR’s (22%) were observed with full post-cystectomy staging summarized below. Conclusions: While pCR’s were observed, the excess toxicity of CGS in the neoadjuvant treatment of miUC precludes further development of the regimen in this population. Patient T-stage N-stage M-stage 1 T4 N3 MX 2 T3b N2 M0 3 T4a N0 M0 4 T0 N0 M0 5 T4a N3 MX 6 T0 N0 MX 7 T4a N1 MX 9 T3a N0 MX
BPS-001, a complex biologic agent extracted from the medicinal leech (<i>Huridinaria manillensis</i>) for treatment of metastatic castration-resistant prostate cancer.
Authors: M. Suzanne Stratton, Amr Ammar, Yuzhuo Wang, Mohamed Hessein, Emma Guns, Omer Kucuk, Ahmed Merzouk, David Kwok
Journal: Journal of Clinical Oncology (2016)

209 Background: We established that subcutaneous BPS-001 reduced tumor size and inhibited tumor growth in PC3, LNCaP and 22RV-1 mouse xenografts; and, tumor lHC demonstrated an increase in caspase-3 and decreases in expression of P21, Ki-67 and PCNA. We also showed that BPS-001 reduced PSA expression in both In vitro and in In vivo xenografts (LNCaP and 22RV1). We now demonstrate that BPS-001 inhibits angiogenesis in the xenografts; and, In vitro studies demonstrate that BPS-001 affects expression of adhesion molecules and the androgen receptor. In addition, BPS-001 inhibited tumor growth in a TRAMP allograft model. Methods: CD31 expression was measured using IHC of the previous mouse xenografts. In vitro androgen receptor and adhesion molecule expression were assessed by Western blot. Transplantable TRAMP-C2 mouse prostate cancer in B57CL allografts were grown to 5 mm prior to initiation of treatment. Immune markers in TRAMP allograft tumors were measured by IHC. Results: Mechanistic studies show BPS-001 acts by blocking angiogenesis demonstrated by a &gt; 50% decrease in expression of CD31 in the LNCaP and 22RV-1 xenografts. Furthermore, preliminary toxicology studies show similar efficacy to docetaxel with no weight loss in the longer-term PC3 xenograft study as was observed with docetaxel. Preliminary toxicology studies of BPS-001 also support a favorable toxicity profile, and the therapeutic dose (1-5 mg/Kg, QW or BIW) is well within the margin of safety. Dose limiting toxicity (bleeding) was observed at doses of 20mg/Kg daily. In vitro studies showed BPS-001 decreased expression of both N- and P- cadherins and the androgen receptor. BPS-001 inhibited tumor growth in the TRAMP allograft models. IHC analyses of the TRAMP allograft tumors suggest immunomodulation. Conclusions: BPS-001 exhibits anticancer activity with no observed toxicity in the therapeutic range. Effects of BPS-001 include inhibition of angiogenesis, downregulation of adhesion molecules associated with advanced prostate cancer and inhibition of androgen receptor signaling. Elucidation of the mechanism of action is ongoing.
Randomized phase III study of panitumumab (pmab) with FOLFOX4 compared with FOLFOX4 alone as first line treatment (tx) for metastatic colorectal cancer (mCRC): Results by Eastern Cooperative Oncology Group (ECOG) performance status (PS).
Authors: S. Siena, J. Cassidy, J. Tabernero, R. L. Burkes, M. E. Barugel, Y. Humblet, D. Cunningham, F. Xu, K. Krishnan, J. Douillard
Journal: Journal of Clinical Oncology (2011)

3567^ Background: Pmab is a fully human anti epidermal growth factor receptor (EGFR) monoclonal antibody. The primary analysis of this study (PRIME) demonstrated that pmab + FOLFOX4 significantly improved progression free survival (PFS) vs FOLFOX4 alone for 1st line mCRC in patients (pts) with wild-type (WT) KRAS. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg Q2W + FOLFOX4 (Arm 1) or FOLFOX4 alone (Arm 2). Pts had no prior chemotherapy for mCRC, ECOG ≤2, and tumor tissue for biomarker testing. Randomization was stratified by geographic region and ECOG ≤1 vs 2. The primary endpoint was PFS. Secondary endpoints included overall survival (OS) and safety. KRAS status was determined retrospectively using a validated testing kit (DxS, Manchester, UK) by a blinded central lab prior to the primary analysis. Here we present the prespecified descriptive analysis of efficacy by ECOG PS based on the primary OS analysis. Results: From 8/06 to 2/08, 1183 pts were randomized and received tx: 593 Arm 1, 590 Arm 2. In an evaluation of the effect of covariates on tx outcomes in the primary analysis using the Quantitative Interaction Test, the only significant treatment by covariate interaction was observed for ECOG PS. A significant difference between tx effects in pts with ECOG 0/1 and ECOG 2 was observed for both PFS (p = 0.003) and OS (p = 0.037). Efficacy results by ECOG PS are shown (Table). Conclusions: In pts with WT KRAS and ECOG 0/1, pmab improved OS and PFS when added to FOLFOX4. In pts with WT KRAS and ECOG 2, shortened OS and PFS were observed in pts receiving pmab + FOLFOX4. Detailed results, including safety data, will be presented. WT KRAS ECOG 0/1 (n = 616) Arm 1 (n = 305) Arm 2 (n = 311) HR (95% CI) Descriptive p value Median PFS - months (95% CI) 10.4 (9.4 – 11.3) 8.0 (7.5 – 9.3) 0.74 (0.60 – 0.91) p = 0.004 Median OS - months (95% CI) 25.8 (21.7 – Not Estimable) 20.7 (18.2 – 23.2) 0.77 (0.62 – 0.95) p = 0.018 WT KRAS ECOG 2 (n = 40) Arm 1 (n = 20) Arm 2 (n = 20) Median PFS - months (95% CI) 4.8 (2.7 – 5.3) 7.6 (5.3 – 11.1) 2.30 (1.08 – 4.89) p = 0.030 Median OS - months (95% CI) 7.0 (4.6 – 11.7) 11.7 (8.0 – 15.7) 1.83 (0.90 – 3.75) p = 0.097
Stem cell plasticity and microvesicles.
Authors: L. Goldberg
Journal: Journal of Clinical Oncology (2011)

e13504 Background: Marrow cells engrafted into irradiated mice form pulmonary epithelial type II pneumocytes. The capacity to do this is influenced by marrow cell cycle. Marrow derived pulmonary epithelial cells after transplantation are increased three fold at the G1/S interface. Methods: We have also shown that microvesicles derived from irradiated lung tissue enter marrow cells resulting in expression of mRNAs for surfactants A-D, clara cell-specific protein and aquaporin 5 and that cell entry is a prerequisite. Marrow cells interacted with lung-derived microvesicles also show an increased capacity for forming pulmonary epithelial cells after marrow transplantation. Results: We have also shown that marrow stem cells do not have a stable phenotype. They alter their phenotype continuously with cell cycle passage and that the most primitive marrow stem cells are an actively cycling population. Purified marrow stem cells, designated aslong-term hematopoietic stem cells (LT-HSC) are in fact mostly in G0, but when whole unseparated marrow is studied, using either Hoechst 33342/Pyronin Y separations or tritiated thymidine suicide followed by competitive engraftment into lethally irradiated mice, over 50% of these long-term engrafting cells are in S/G2/M. Given that these studies are at either an instantaneous point in time or over a 30 minute time interval, this indicates that the marrow stem cell population is a cycling population This explains the observations that marrow stem cell phenotype is continually changing with regard to marrow renewal, differentiation, marrow homing, and gene expression. Lung-derived microvesicles differentially enter marrow stem cells at different points in cell cycle adding another layer to the complexity of cell fate determination for marrow stem cells. Conclusions: Altogether, these observations indicate that microvesicle cell modulation probably explains the phenomena of stem cell plasticity. Furthermore, the marrow stem cell population is differentially modulated at different points in cell cycle by microvesicle exposure. These observations suggest a complex regulatory system for marrow stem cells with a stable population but continually changing individual components. This represents a new biology.
Prognostic significance of pre-treatment neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in locally advanced esophageal cancer.
Authors: Joseph A. Clara, Dae Won Kim, Puja Venkat, Jessica M. Frakes, Sarah E. Hoffe, Khaldoun Almhanna, Nishi Kothari, Luis Pena, Jose Mario Pimiento, Richard D. Kim
Journal: Journal of Clinical Oncology (2016)

172 Background: The prognosis for esophageal cancer remains poor despite advances in therapeutic modalities. Elevations of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been shown to be associated with poorer prognosis in several types of solid cancer. However, their prognostic value remains controversial in esophageal cancer. The aim of this study was to assess the prognostic value of NLR and PLR in esophageal and gastroesophageal junction (GEJ) cancer. Methods: We retrospectively reviewed the database of 77 patients who underwent neoadjuvant chemoradiation and potentially curative resection for esophageal cancer in our institute, between July 2006 and December 2011. NLR and PLR were calculated from laboratory data obtained prior to the start of chemoradiation. The predictive value of NLR and PLR was assessed using Kaplan-Meier curves and Cox regression models for an association with pathologic response to chemoradiation, relapse-free survival, and overall survival. Results: A total of 77 patients were identified with a median age at diagnosis of 62.5 years. In univariate analysis, neither NLR nor PLR were shown to be significantly associated with the pathologic response (p = 0.87, p = 0.89, respectively), relapse-free survival (p = 0.5, p = 0.4, respectively), or overall survival (p = 0.55, p = 0.44, respectively). Conclusions: The present study failed to confirm NLR and PLR as significant predictors of pathologic response to chemoradiation, relapse-free survival, and overall survival in patients with locally advanced esophageal and GEJ cancer undergoing neoadjuvant chemoradiation and surgical resection.
Primary small cell carcinoma of the esophagus: Retrospective analysis of the Veterans Affairs Cancer Registry.
Authors: Mahmoud Abu Hazeem, Ramya Thota, Shanmuga Subbiah, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2012)

e14641 Background: Small cell carcinoma (SCC) of the esophagus is a rare aggressive and rapidly fatal neoplasm, often diagnosed in late stages. Hence no prospective studies evaluating the most effective treatment strategies have been done. We aim to describe the clinicopathological features and treatment outcomes of this rare entity. Methods: Retrospective analysis of 49 patients diagnosed with SCC of the esophagus from 1995 to 2009 was done via the Veteran's Affairs Central Cancer Registry. Demographics, staging, treatment, and outcomes data was recorded. Staging was classified as limited (no distant metastasis) or extensive stage (metastatic disease). Results: Out of 10,540 patients with esophageal cancer, 49 were diagnosed with SCC (0.005%) and were mainly located in the middle and lower thirds of the esophagus (84%). Median age of diagnosis was 64.1 yrs (range: 26-90). 19 patients had limited disease, 26 patients had extensive disease and four patients who were not staged adequately were excluded. Patients received a variety of treatments (Table) with different survival outcomes. Limited stage SCC patients had a median survival of 6.3 mos with patients who received combined modality therapy showing a trend towards improved outcomes. Extensive stage patients who received no therapy had very poor outcomes compared to patients who received any therapy. Conclusions: SCC of esophagus should be considered a systemic disease and like pulmonary SCC, it is an aggressive tumor associated with a poor prognosis. Patient numbers are too low to draw definitive conclusions regarding choice of therapy. Extensive disease patients benefit from chemotherapy and combined modality therapy should be considered in limited stage disease. [Table: see text]