bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT121: Demographics of clinical trial participants for new molecular entity (NME) oncology drugs and biologics approved by FDA CDER in 2015
Authors: Wright Hilary , Elahi Merina , Igun Ayomide , Soon Greg , Chen Alice , Pariser Anne , Fadiran Emmanuel 
Published: July 2016

Abstract
Background: In 2015, approximately 810,100 new cancer cases were diagnosed in females in the US. To facilitate the assessment of efficacy and safety of medical products in the diverse populations who might use them after approval, the Food and Drug Administration (FDA) has implemented guidance and regulations to encourage greater participation of women and minorities in clinical trials (CTs).
Objectives: To assess demographics in oncology CTs submitted in support of “new drugs” (i.e., New Molecular Entity New Drug Applications (NME NDAs) and original Biologics License Applications (BLAs)) approved by the FDA's Center for Drug Evaluation and Research (CDER) in 2015.
Methods: Participation by sex, race, and age (&lt;65 years, ?65 years) and presence of sex-based efficacy and safety analyses were assessed from sponsors’ final clinical study reports for new oncology drugs for adult indications approved in 2015. Sex-based analyses were coded as exploratory or conclusive as previously reported.,
Results: Fourteen new oncology drugs were approved by CDER in 2015. One BLA and one NDA were excluded from the analysis because they were for pediatric or sex-specific indications. For the 12 remaining drugs, there were 188 trials (phase 1, 2, or 3) that included a total of 17,702 subjects, 48.1% of whom were women. Of the subjects for which race was reported (94.2% of the total), 78.0% were Caucasian, and of those for which age group was reported (75.3% of all subjects), 33.4% were ?65 years of age. Women were 43.1%, 53.2%, and 53.9% of subjects in phase 1, 2, and 3 CTs, respectively. PPR, defined as the Ratio of the Proportion of women in the indicated disease population in the CTs to the Proportion of women in the disease population, was ?0.8 for 11 new drugs and &lt;0.8 for one new drug. Eleven new drugs included both efficacy and safety sex-based analyses, and one new drug included only efficacy sex-based analysis.
Conclusions: Relative to their proportion in the disease population, female participation was comparable to (i.e., PPR between 0.8 and 1.2) or greater than men's in late-phase trials for 11 of the 12 oncology drugs examined. Female participation in early-phase CTs was lower than in late-phase CTs; however, late-phase clinical trials are typically where FDA's risk-benefit assessments are made.
Citation Format: Hilary Wright, Merina Elahi, Ayomide Igun, Greg Soon, Alice Chen, Anne Pariser, Emmanuel Fadiran. Demographics of clinical trial participants for new molecular entity (NME) oncology drugs and biologics approved by FDA CDER in 2015. [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 CT121.
Abstract CT127: Results from a phase II clinical study in Chinese population: treatment with Chinese medicine cocktail LQ for patients with stage IIIB/IV advanced non-small cell lung cancer
Authors: Zhang Lei , Wu Chengyu 
Published: July 2016

Abstract
OBJECTIVES: To estimate the response of Chinese medicine “cocktail” LQ in patients with advanced non-small cells lung cancer, a phase II multicenter, double-blind, randomized clinical trial was conducted. Patients with IIIB/IV stage received LQ and natural product control Spirulina. The end points for this study included overall survival (OS), progression free survival (PFS), safety of the regimen, disease control rate (DCR) and other criteria.
METHODS: Patients with stage IIIB/IV advanced NSCLC cancer received LQ treatment and Spirulina. Toxicity was assessed. Quality of life was assessed. The primary objective was overall survival.
RESULTS: A hundred and twenty patients were enrolled and 80 were treated. Median age was 60 years (range, 42-75). The median overall survival rate in LQ group and Spirulina group is 10.9 months vs 7.4 months respectively (p&lt;0.0001). Median progression survival free survival is 3.84 months vs 1.97 months in LQ and Spirulina group (p&lt;0.01). There is no side effect were found in there. There were 42 patients with stable disease with the disease control rate of 59.15% in LQ treatment group, Compare with Spirulina group, there were only 4 standard disease, for disease control rate of 11.76% (p&lt;0.001). There are no notable toxicities were found in LQ treatment group.
CONCLUSIONS: This first-in-human phase II study of Chinese medicine cocktail LQ used as first-line therapy in patients with advanced NSCLC. LQ, a promising new drug, provides a safer and high effective therapy for late-stage lung cancer patients.
Citation Format: Lei Zhang, Chengyu Wu. Results from a phase II clinical study in Chinese population: treatment with Chinese medicine cocktail LQ for patients with stage IIIB/IV advanced non-small cell lung cancer. [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 CT127.
Abstract CT154: Phase I dose-escalating PoC study to evaluate the safety and tolerability of LiPlaCis (liposomal cisplatin formulation) in patients with advanced or refractory tumors
Authors: Lassen Ulrik , Mau-Sørensen Morten , Hald Buhl Ulla , Madsen Mogens W. , Balslev Eva , Pluim Dick , Schellens Jan H. M. , Knudsen Steen , Jensen Peter B. 
Published: July 2016

Abstract
LiPlaCis is a novel liposomal formulation of cisplatin, designed to be specifically degraded by secretory phospholipase A2 (sPLA2) which is over-expressed in tumor tissue. sPLA2 has been shown to be present in a number of different tumor tissues - e.g. prostate, lung, ovarian, breast etc. (T. Abe 1997). Thus, LiPlaCis is intended to improve the therapeutic index due to an improved therapeutic efficacy and possibly also an improved safety and tolerability profile. Objectives: The primary objectives were safety and determination of MTD. Secondary objectives were evaluation of PK, clinical activity, and PD. This included two PoC cohorts to study platinum-DNA adducts in tumor compared to normal tissue following administration of LiPlaCis. Methods: A standard 3+3 design was used to include patients with advanced solid tumors and PS 0-1. LiPlaCis was administered weekly on day 1, day 8 and possibly day 15 every 3 wks. CTCAE v4.03 and RECIST were used to assess safety and tumor activity. Paired tumor and normal tissue biopsies obtained pre-treatment and on day 2 were used to assess sPLA2-IIA protein levels and platinum-DNA adducts (by 32P-postlabeling assay) in two PoC cohorts of 60 and 90 mg LiPlaCis. Results: A total of 16 patients were included at dose levels of 60, 90 and 120 mg. At 120 mg two DLTs were observed and an intermediate dose level of 90 mg Day 1 and 8 and 45 mg Day 15 was explored. After 1 DLT, this dose level was halted and the PoC cohorts were initiated sequentially. The observed DLTs included renal toxicity and infusion reactions. Most frequent AEs of all grades were fatigue, hypomagnesemia and vomiting. The most common (&gt;10%) grade 3-4 AEs were hypomagnesemia, hypokalemia and anemia. Clinical activity was observed in a patient with H&N cancer; 60 mg (PR), SCC skin;120 mg (PR), BC; 60 mg (SD-ongoing), CRC; 90 mg (SD -18 wks) and gastric cancer; 90 mg (SD-21 wks). In the 60 mg PoC cohort of 3
pts the tumor- to normal tissue ratio of platinum-DNA adducts was from 5.7 to 8.3 fold. Conclusion: MTD has not yet been determined, but ongoing PoC cohorts indicate that LiPlaCis is preferably released in tumor by sPLA2 compared to normal tissue which potentially could improve the therapeutic index of cisplatin.
Citation Format: Ulrik Lassen, Morten Mau-Sørensen, Ulla Hald Buhl, Mogens W. Madsen, Eva Balslev, Dick Pluim, Jan H. M. Schellens, Steen Knudsen, Peter B. Jensen. Phase I dose-escalating PoC study to evaluate the safety and tolerability of LiPlaCis (liposomal cisplatin formulation) in patients with advanced or refractory tumors. [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 CT154.
Abstract CT160: Clinical application of a natural polypeptide, poly-γ-glutamic acid, which has immunotherapeutic efficacy
Authors: Lee Jae-Kwan , Min Kyung-Jin , Kim Kwang , Poo Haryoung , Sung Moon-Hee 
Published: July 2016

Abstract
Poly-gamma-glutamic acid (γ-PGA) is known as viscous component of Korean chungkookjang and a natural polypeptide consisting of only glutamic acid with gamma-amide linkages. High molecular weight γ-PGA was isolated and mass-produced from Bacillus subtilisChungkookjang. Previously, accumulating evidences indicate that the γ-PGA inducesinnate immune response including natural killer (NK) cell activation and interferon secretion throughtoll-like receptor 4 (TLR4). To evaluate the immunotherapeutic effects, we’ve investigated the effect of γ-PGA on human NK cell activity and antiviral effect. First human study involving 99 healthy volunteers revealed thathigh-dosage γ-PGA group were significantly higher cytotoxic activities of NK cells than the low dosage and placebo groups at weeks 4 and 8 after the treatment. Furthermore, westudied the effect of γ-PGA on the treatment of vaginal intraepithelial neoplasia (VAIN). A retrospectiveobservational study on γ-PGA therapy for biopsy-proven VAIN suggest that γ-PGA may be helpful for the cytological regression and reduction of viral load in patients with high-risk HPV-positive VAIN. Since previous human studies showed the possibility of drug, we have accomplished a phase I dose escalation study to determine the safety, tolerance and pharmacokinetics of γ-PGA in healthy adult male subjects. The phase I study of oral γ-PGA was conducted in 20 healthy volunteers. There was no any significant difference in abnormal diagnoses or clinically relevant changes in laboratory parameters, vital signs, or other safety parameters. Currently, we have initiated a phase II trial to determine the efficacy and safety of γ-PGA compared with placebo in patients with cervical intraepithelial neoplasia grade 1 (CIN1). Total 200 patients with CIN1 will be administered with γ-PGA or placebo for 4 weeks followed by 8 weeks observation and compare the regression rate of CIN1.So far there was no serious adverse event (SAE) during phase II study. These results indicate that the oral administration of γ-PGAcan serve as treatment option that are safe and clinical efficacy via inducing NK cell activity and anti viral effect.
Citation Format: Jae-Kwan Lee, Kyung-Jin Min, Kwang Kim, Haryoung Poo, Moon-Hee Sung. Clinical application of a natural polypeptide, poly-γ-glutamic acid, which has immunotherapeutic efficacy. [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 CT160.
Abstract LB-001: Functional role of Pak1/Erk signaling in Rac1-related diseases
Authors: Araiza-Olivera Daniela , Chernoff Jonathan 
Published: July 2016

Abstract
The RAS/MAPK signaling pathway regulates key cellular processes, including proliferation, differentiation, and survival. Somatic mutations of the RAS pathway are found in 30% of human cancers, including pancreatic, colon, thyroid, lung and melanoma. Furthermore, germ-line mutations in this pathway, collectively termed Rasopathy syndromes, cause abnormal development. Affected patients often present with cognitive defects, heart problems, facial aberrancies, skin abnormalities and in some cases a predisposition to cancer.
As p21-activated kinases (Paks) have been shown to be required for the activation of ERK by Ras, we evaluated Pak1 and its activator Rac1 as potential therapeutic targets in both Rasopathies and in melanoma. Using a zebrafish model, we first asked if the phenotypic consequences of Ras pathway overactivation during development could be blocked by Pak small molecule inhibitors. Introducing gain-of-function genes such as BRAF V600E, KRAS 4AG12V, and Rac1 P29S into one-cell zebrafish embryos produced a Rasopathy phenotype, characterized by abnormal head and heart development. These phenotypes were suppressed by a Pak-specific small molecule inhibitor. pERK and pPAK levels were increased in embryos expressing BRAF V600E, KRAS 4AG12V, or Rac1 P29S, and were restored to baseline upon addition of Pak1 or Rac1 small molecule inhibitors. We then studied the effect of these small molecule inhibitors in human malignant melanoma cell lines bearing activating mutations in BRAF, PREX (an activator of Rac1), and/or RAC1. Treatment with PAK or RAC inhibitors decreased the migration and proliferation of cells with mutant PREX or RAC1 mutations, but not those with BRAF mutations; the reverse was true when these cells were treated with a BRAF inhibitor. These data suggest that Pak1 might serve as a useful therapeutic target in PREX- or RAC1-driven cancers such as malignant melanoma.
Citation Format: Daniela Araiza-Olivera, Jonathan Chernoff. Functional role of Pak1/Erk signaling in Rac1-related diseases. [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 LB-001.
Abstract LB-007: Interaction between integrin α4β1 and IGF1 and its role in IGF signaling in hematologic malignancies
Authors: Cedano Prieto Dora M. , Yu Jessica , Takada Yoko , Takada Yoshikazu 
Published: July 2016

Abstract
Integrins are transmembrane αβ heterodimers that function as cell adhesion receptors. Integrins are aberrantly overexpressed in cancer cells and also in tumor-associated cells. They are involved in cancer cell proliferation, invasion and survival. It has been proposed that the interaction between integrin α4β1, a major integrin in hematologic cancer, and VCAM-1 and fibronectin is responsible for drug resistance in these malignances, since antagonists to this integrin reduce drug resistance. However these results are based on the assumption that VCAM-1 and fibronectin are the only ligands for α4β1. Insulin-like growth factor 1 (IGF1) signaling plays a critical role in drug resistance and radio resistance hematologic cancer. IGF1 is a polypeptide hormone that binds to tyrosine kinase receptor IGF1R and activates the PI3K/Akt signaling pathway. This pathway is involved in cell proliferation, survival, and inhibition of apoptosis. In various types of cancer IGF1 is over expressed and the PI3K/Akt pathway is activated at a much higher rate than in normal cells. This results in the growth of cancer cells and resistance to chemotherapy. IGF1 signaling is implicated in drug resistance, and is a good therapeutic target in hematologic cancers. It is unclear if α4β1 and IGF signaling work independently in drug resistance. Recently we established that IGF1 binds to integrins αvβ3 and α6β4, and subsequent integrin-IGF1-IGF1R ternary complex formation is a critical step in IGF signaling in non-hematologic cancer. We developed the R36E/R37E IGF1 mutant that is defective in integrin binding and a dominant-negative antagonist of IGF signaling. Here we show that IGF1 is a ligand for integrin α4β1 and induces a ternary complex with IGF1R and α4β1. Antagonists to integrin α4β1 and the R36E/R37E IGF1 mutant reduced intracellular signaling in Chinese hamster ovary cells expressing human integrin α4 (α4-CHO cells) and also in different hematologic cancer cells such as Reh, Molt-4, U937 and JY cells. These results suggest that integrin α4β1 is involved in IGF signaling through direct binding to IGF1 in hematologic cancer. The α4β1-IGF1 interaction is a novel therapeutic target for drug resistance in hematologic cancer.
Citation Format: Dora M. Cedano Prieto, Jessica Yu, Yoko Takada, Yoshikazu Takada. Interaction between integrin α4β1 and IGF1 and its role in IGF signaling in hematologic malignancies. [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 LB-007.
Abstract LB-008: KRAS engages AGO2 to enhance cellular transformation
Authors: Shankar Sunita , Pitchiaya Sethuramasundaram , Malik Rohit , Kothari Vishal , Hosono Yasuyuki , Yocum Anastasia K. , Gundlapalli Harika , White Yasmine , Firestone Ari , Cao Xuhong , Dhanasekaran Saravana M. , Stuckey Jeanne , Bollag Gideon , Shannon Kevin , Walter Nils , Kumar-Sinha Chandan , Chinnaiyan Arul M. 
Published: July 2016

Abstract
Oncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Approximately 30% of all cancers harbor activating mutations in the RAS family of small GTPase proteins, making it one of the most common oncogenic aberrations in humans. Normal RAS proteins (H, K or N-RAS) localize to the inner cell membrane and transduce extracellular growth signals by cycling between an “active” GTP-bound state and “inactive” GDP-bound state. Our understanding of RAS biology is primarily from RAS protein-effector interactions that activate a variety of effectors at the plasma membrane like RAF/PI3K/RalGDS. Yet, targeting mutant RAS proteins or its effectors / pathways remains a challenging endeavor for treating RAS driven cancers.
For a comprehensive identification of RAS interactors, we recently performed co-immunoprecipitation (Co-IP) Mass Spectrometric analysis of RAS immunoprecipitates from multiple cancer cell lines with differing KRAS mutation status. In all the cell lines studies, we uncovered an interaction between RAS and the core component of the RNA silencing machinery, Argonaute 2 (AGO2). Endogenously expressed RAS and AGO2 co-sediment and co-localize in intracellular membrane bound endoplasmic reticulum. AGO2 binds the Switch II region in KRAS, irrespective of GDP/GTP bound to RAS. Both endogenous and overexpressed mutant forms of KRAS, attenuate AGO2 related gene silencing function. Using NIH3T3 AGO2-/- cells, we demonstrate that the RAS-AGO2 interaction is required for maximal mutant KRAS expression and cellular transformation. Overall, our studies suggest that through its interaction with AGO2, RAS function extends well beyond its canonical role in intracellular signaling. We will present detailed characterization of the RAS-AGO2 interaction and its functional aspects that we have discovered so far.
Citation Format: Sunita Shankar, Sethuramasundaram Pitchiaya, Rohit Malik, Vishal Kothari, Yasuyuki Hosono, Anastasia K. Yocum, Harika Gundlapalli, Yasmine White, Ari Firestone, Xuhong Cao, Saravana M. Dhanasekaran, Jeanne Stuckey, Gideon Bollag, Kevin Shannon, Nils Walter, Chandan Kumar-Sinha, Arul M. Chinnaiyan. KRAS engages AGO2 to enhance cellular transformation. [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 LB-008.
Abstract LB-011: PAK1 inhibitor FRAX1036 sensitizes ovarian cancer cells with amplified 11q13 to cytotoxic effect of rottlerin
Authors: Prudnikova Tatiana , Chernoff Jonathan 
Published: July 2016

Abstract
p21-activated kinases (PAKs) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt, and Wnt/b-catenin. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate, and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. In our previous in vitro and in vivo studies we have shown that ovarian cancer cells with amplified/overexpressed Pak1 were significantly more sensitive to pharmacologic or genetic inhibition of Pak1 compared to cells without 11q13 amplification. In the present study we examined the combination effect of the Pak1 inhibitor FRAX1036 in ovarian cancer cells using ICCB Known Bioactives Library (Enzo). We found that the cytotoxic effect of FRAX1036 was significantly higher when combined with the PKC delta inhibitor, Rottlerin.
We tested FRAX1036 alone and in combination with Rottlerin on 11q13-amplified human ovarian cancer cell lines with respect to cell proliferation, migration and apoptosis. FRAX1036 alone inhibited cell proliferation and migration in 11q13-amplified ovarian cancer cell lines. Co-administration of FRAX1036 with Rottlerin further synergized the inhibition of cell proliferation in vitro and decreased tumor growth in vivo. To explain the synergistic inhibition of cell proliferation induced by the FRAX1036/Rottlerin combination we analyzed Pak1 and PKC delta down-stream signaling molecules. Western blot data indicated that FRAX1036 and Rottlerin synergistically inhibited phosphorylation of critical signaling molecules such as MEK, ERK1/2, b-Catenin, and 4EBP1.
Our findings suggest that Pak1 small molecule inhibitors in combination with Rottlerin hold potential clinical value as chemotherapeutic drugs for the ∼25% of ovarian cancers characterized by PAK1 gene amplification.
Citation Format: Tatiana Prudnikova, Jonathan Chernoff. PAK1 inhibitor FRAX1036 sensitizes ovarian cancer cells with amplified 11q13 to cytotoxic effect of rottlerin. [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 LB-011.