bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B231: Potent in vivo activity of the Aurora kinase inhibitor ABT-348 in a broad spectrum of histological types: Evaluation of efficacy, dosing/scheduling, and PK/PD.
Authors: Donawho Cherrie K. , Montgomery Debra , Rodriguez Luis E. , Wang Yi-Chun , Ellis Paul E. , Kaleta Lance , Bukofzer Gail , Bouska Jennifer , Clarin Jerry , Schlessinger Sally , Wang Baole , Glaser Keith , Michaelides Mike , Albert Daniel , Tse Chris , Frost David J. , Palma Joann P. 
Published: June 2012

Abstract
The Aurora kinases are a family of serine/threonine kinases that mediate multiple essential functions in cell division. Aurora A depletion results in accumulation of cells in the G2/M phase and apoptosis. Inhibition of Aurora B/C results in abnormal cell division, polyploidy, followed by apoptosis, therefore, Aurora kinases present an attractive target for chemotherapy. Cells treated with aurora inhibitors enter mitosis with normal kinetics but fail to undergo cytokinesis due to a disruption of the mitotic spindle checkpoint. ABT-348 is a novel adenosine triphosphate (ATP)-competitive inhibitor of Aurora A, Aurora B, and Aurora C (Enzyme IC50 A=116, B=5, C= 1 nM) and a potent inhibitor of all members of the VEGF and PDGF family of receptor tyrosine kinases (RTK). Here we demonstrate profound in vivo efficacy (with regressions) in a broad spectrum of histological types (breast, colon, NSCLC, HNSCC, melanoma, ovarian, pancreatic, prostate, leukemia, lymphoma and renal; 50–94% TGI, tumor growth inhibition). The treatment was well tolerated with no animal health concerns observed. In addition, ABT-348 was also efficacious in tumor xenografts overexpressing P-gp and provided significant in vivo efficacy in comparison to competitor compounds in colon, NSCLC and ovarian xenograft models. Various dosing schemes to achieve optimal efficacy (IV, OMP and PO) were investigated. The anti-tumor efficacy of ABT-348 was not affected by the route of administration. Similar efficacy was achieved by IV, OMP or PO administration, once weekly in a dose-dependent manner. Pharmacokinetic/pharmacodynamic biomarker analysis in select tumor xenograft models were evaluated by phospho-H3 (an Aurora B substrate, proliferation marker) and cleaved caspase-3 (apoptosis marker) by IHC at various timepoints post single dose (6 hr to 9 days). Significant levels of ABT-348 were detected in the plasma and tumor. A general decrease in proliferation and increase in apoptosis consistent with the mechanism of action was observed and coincide with the potent in vivo efficacy in xenograft models. Overall, ABT-348 is a potent, oral Aurora kinase inhibitor, demonstrating robust in vitro and in vivo antitumor activity with a good safety profile that warrants investigation in the clinic. ABT-348, is currently undergoing Phase I clinical trials in both solid and hematologic malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B231.
Abstract B240: Combined gefitinib and API-2 induced interaction of DNA-PK with EGFR and Akt, leading to impaired DNA-PK-mediated DNA repair and increased autophagy.
Authors: Kang Khong Bee , Zhu Congju , Wong Yin Ling , Yong Sook Kwin , Wong Meng Cheong 
Published: June 2012

Abstract
Resistance to epidermal growth factor receptor (EGFR) inhibitors and pro-apoptotic agents frequently occurs in malignant glioma due to excessive stimulation of growth factor receptors (eg. EGFR) and up-regulation of PI3K/Akt pathway. We aimed to overcome resistance of glioblastoma cells to gefitinib (an EGFR inhibitor) with API-2 (a selective Akt inhibitor) by increasing autophagy cell death. We investigated whether combined gefitinib and API-2 induced interaction of DNA-PK with EGFR and Akt, leading to impaired DNA-protein kinase (DNA-PK)-mediated DNA repair and autophagy.
Methods: U251MG, MO59J (DNA-PKcs-deficient) and MO59K (DNA-PKcs-proficient) cells treated with gefitinib, API-2 or both for 72 hours were analyzed by cell viability (MTT assay) and autophagy (FACS of acridine orange staining and LC3 expression) assays. U251MG cells treated with gefitinib and API-2 were assayed for nuclear expression of phosphorylated and native DNA-PKcs, Akt and EGFR, as well as DNA repair activity (immunostaining of γ-H2AX, a marker of DNA damage). Interaction of DNA-PK and EGFR/Akt in gefitinib and API-2-treated cells were analyzed by proximity ligation assay.
Findings: Combined gefitinib and API-2 significantly reduced viability of U251MG and MO59J cells (but not MO59K cells), compared with gefitinib alone. Single treatments of gefitinib and API-2 increased acridine orange staining and LC3-II expression in U251MG cells, with further increase by combined gefitinib and API-2. Increased acridine orange staining by combined gefitinib and API-2 was greater in MO59J than MO59K cells. In U251MG cells, combined gefitinib and API-2 significantly inhibited nuclear phosphorylation of DNA-PKcs (S2056), EGFR (T1173) and Akt (S473), compared with single therapies. Gefitinib and API-2 independently impaired DNA repair (time-dependent increase of γ-H2AX immunostaining) of U251MG cells, with further inhibition by combined gefitinib and API-2. There was an increased binding of DNA-PKcs with EGFR and Akt following combined gefitinib and API-2 treatment (compared to single agents) in U251MG cells.
Conclusion: Our findings reveal that API-2 enhances chemosensitivity of gefitinib by inducing interaction of DNA-PKcs with EGFR and Akt, leading to impaired DNA-PK-mediated DNA repair and induction of autophagic cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B240.
Abstract B245: Synergistic antiproliferative effects of the P21-activated kinase (PAK) inhibitor, PF-03758309, and standard-of-care agents in colorectal cancer models.
Authors: McPhillips Kelly L. , Pitts Todd M. , Im Eun Kyung , Spreafico Anna , Tan Aik Choon , Tentler John J. , Arcaroli John J. , Pierce Erica L. , Murray Brion W. , Eckhardt S Gail 
Published: June 2012

Abstract
Background: The p21-activated kinase (PAK) family of serine/threonine kinases is overexpressed in multiple cancer types including breast, ovarian, colorectal, thyroid, and pancreatic. The two groups of PAK proteins, Group I (PAK 1–3) and Group II (PAK 4–6), are critical mediators of cell survival, motility, mitosis, transcription, and translation. The goal of this study was to assess the efficacy of a PAK inhibitor, PF-03758309, with irinotecan in colorectal cancer (CRC).
Methods: A panel of 27 colorectal cancer (CRC) cell lines were exposed to increasing doses of PF-03758309 (0.015–1 μM) for 72 hours and analyzed for inhibition of proliferation using the sulforhodamine B (SRB) assay. Cell lines were designated sensitive (S), intermediate (I), or resistant (R) based on IC50's &lt; 0.125 μM, ≥ 0.125 and ≤ 1 μM, or &gt; 1 μM, respectively. Two sensitive and two resistant cell lines were exposed to three different concentrations of either the PAKi, irinotecan or all possible combinations. Proliferation was assessed by the SRB assay and synergy was calculated using the Calcusyn software. Apoptosis was also assessed using the luminescent Caspase 3/7 assay. Athymic nude mice were injected with primary patient derived explants. Once the tumors reached 200–300mm3 the mice were dosed with PF-03758309, irinotecan, or cetuximab or the combination. Tumors were measured twice weekly and growth curves were analyzed.
Results: Synergy was observed in both PF-03758309 sensitive and resistant cell lines, though the greatest synergy was seen in one of the more sensitive lines. Apoptosis was also increased in the combination when compared to the single agents. Of the explants treated, one of them demonstrated a synergistic/super-additive effect when dosed with the combination of irinotecan. One of the explants also demonstrated an added benefit with the combination of PF-03758309 and cetuximab. Further investigation into the differential sensitivities seen with PF-03758309 revealed that the more resistant CRC cell lines had higher expression of MDR1. When this was modulated either by shRNA knockdown or by addition of verapamil, we saw a shift to a more sensitive phenotype.
Conclusions: The combination of the PAKi, PF-03758309 with irinotecan resulted in synergistic anti-proliferative effectsand apoptosis in CRC cell lines regardless of sensitivity. Similar effects were observed in patient-derived CRC explants with PF-03758309 and standard of care agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B245.
Abstract B35: Hyaluronan (HA) accumulation in tumors predicts response to pegylated rHuPH20 hyaluronidase (PEGPH20) in human tumors: A biomarker strategy.
Authors: Jiang Ping , Ramanathan Ramesh , Infante Jeffrey , Thompson Curts B. , Maneval Daniel C. , Dychter Samuel , Frost Gregory I. , Shepard Michael H. 
Published: June 2012

Abstract
Increasing evidence suggests that the tumor microenvironment (TME) is a potential source of novel anti-tumor targets. Extracellular matrix components in the TME include the matrix glycosaminoglycan, hyaluronan (HA), which accumulates in 20–30% of solid tumors. HA functions to increase water content of HA-rich stroma, thereby creating high tumor interstitial fluid pressure (IFP) characteristic of many tumors. Cells engineered to overexpress hyaluronan synthase form tumors more readily in mouse models, and HA accumulation has been associated with disease progression and poor prognosis in human cancers. Enzymatic degradation of HA with hyaluronidase can reduce IFP and facilitate delivery of anti-tumor agents. We have previously presented data that demonstrate the therapeutic potential of PEGPH20 in tumor xenografts derived from a spectrum of human malignancies. Here we highlight the utility of HA detection methods that use aggrecan-derived HA binding region (HABR). Accumulation of HA was measured in tumor tissues from 14 different xenografts and compared with anti-tumor activity of PEGPH20. When cell line-derived tumors were classified according to HABR staining intensity as HA+1,2,3 (low to high staining), the anti-tumor activity of PEGPH20 correlated with higher accumulation of HA in tumor specimens (r=0.8). To more rigorously test the hypothesis that HA-depletion is an effective candidate therapeutic approach for cancer, we utilized non-small cell lung cancer (SCC) patient tumor explants which were characterized for HA accumulation in advance of implantation into immunodeficient mice. Three SCC explants (HA+1,2,3) were treated with PEGPH20 and tumor growth was measured over a 2-week interval. Tumor growth inhibition corresponded to HA accumulation status, with the most dramatic reduction (97%; 4/10 regressions) observed in the HA+3 SCC explants. We have extended this work and detected tumor HA in pre- and post-treatment tumor biopsies collected from two patients enrolled in a Phase 1 study with PEGPH20. In both sets of specimens, a reduction in HA accumulation was demonstrated following PEGPH20 treatment. These results provide a rationale to assess tumor HA staining as a promising biomarker for clinical investigation with PEGPH20 for the treatment of solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B35.
Abstract B47: EGCG induces apoptosis and inhibits proliferation of nasopharyngeal carcinoma cells in vitro and in vivo.
Authors: Chen Jen-Yang 
Published: June 2012

Abstract
(−)-Epigallocatechin-3-gallate (EGCG), a major green tea catechin, can effectively inhibit proliferation of a variety of tumor cells and has been considered as a chemopreventive agent for cancers. In this study, EGCG was tested on the EBV latently-infected nasopharyngeal carcinoma (NPC) cells line, NA, which corresponds to the in vivo situation in NPC patient. Treatment of EGCG induces growth arrest in the S phase of cell cycle in NA cells. In vitro spheroid formation assay indicated that EGCG can induce growth inhibition in NA cell at relative low concentration (CC50=2 μM). At higher concentration (&gt;25 μM), EGCG induces cellular DNA breakage and apoptosis via caspase activation. Moreover, cells exhibited reduction in migration and invasiveness after EGCG treatment. The expression of matrix metalloproteinases (MMP)-2 and MMP-9 was reduced after EGCG treatment. In a mice xenograft model with NA cells inoculation, oral administration of EGCG was able to inhibit the proliferation of tumors in vivo. These results indicate that EGCG is able to inhibit proliferation even at low concentration and can further induce apoptosis of NPC cells at high concentration, which make EGCG a promising candidate for chemoprevention of NPC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B47.
Abstract B53: Multicenter phase Ib study of the safety and efficacy of palifosfamide plus carboplatin/etoposide (PaCE) in patients with small cell lung cancer or other selected cancers.
Authors: Harb Wael A. , Govindan Ramaswamy , Fisher William B. , Buck Jill Y. , Lewis Jonathan J. , Youssoufian Hagop , Einhorn Lawrence H. 
Published: June 2012

Abstract
Palifosfamide (Pa) is a novel DNA cross linker molecule that consists of the active anti-tumor metabolite of ifosfamide (I). Potential advantages over I include the abrogation of I-metabolite related toxicities, increased activity by virtue of increased dose delivery over time, and overcoming resistance mediated by aldehyde dehydrogenase (ALDH) overexpression. ALDH overexpression is associated with cancer cell stem-like potential in several tumor types. Pa has broad activity in vitro and in vivo preclinical models and has shown early activity in humans. A previous randomized study evaluating the addition of I to cisplatin and etoposide (E) in small cell lung cancer (SCLC) demonstrated improved survival, but with disabling increase in toxicity with the three-drug combination. We hypothesized that the substitution of Pa for I could increase the therapeutic advantage of a similar three-drug regimen. We initiated a multicenter phase I, open-label, dose-escalation study assessing the safety and efficacy of Pa in combination with carboplatin and E (PaCE regimen) in SCLC and in other cancers in which C+E is considered an appropriate therapeutic option. Tumor responses were assessed by RECIST 1.1 and relevant tumor markers. A total of 15 patients (8 females and 7 males) have been treated to date: 5 with SCLC, 2 with NSCLC, 2 with ovarian, 1 with testicular and 5 with other cancers. Serious adverse events have been reported in six patients, including, thrombocytopenia (4), leukopenia (2), and neutropenia (2). The maximum tolerated dose of Pa was determined to be 130 mg/m2 when administered in combination with E 90 mg/m2 and C AUC4. The dose limiting toxicity was neutropenic fever. To date, two radiological partial responses in five patients with SCLC and one complete response assessed by tumor markers in a patient with testicular cancer have been noted.
Conclusion: This study is ongoing, and an additional cohort evaluating Pa 130 mg/m2 in combination with E 100 mg/m2 and C AUC 4 is being evaluated. Further clinical data will be presented. The PaCE combination appears to be tolerable and has demonstrated clinical activity. Based on these data, a confirmatory study in SCLC is planned.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B53.
Abstract B55: A study of REOLYSIN in combination with gemcitabine in patients with advanced pancreatic adenocarcinoma.
Authors: Mita Monica M. , Wang Yubao , Sarantopoulos John , Vemulapalli Sushma , George Benjamin , Mita Alain , Coffey Mattew , Gill George , Mahaligam Devaligam 
Published: June 2012

Abstract
Background: Pancreatic cancer (Pca) continues to have a dismal prognosis and very little progress has been made in finding new efficacious treatments. Oncolytic viruses have demonstrated cytotoxic effect in several tumor xenografts, particularly in cells with RAS pathway activation. REOLYSIN (Reovirus serotype 3) has shown extensive antitumor activity in preclinical models, as well as synergistic activity with cytotoxics including gemcitabine in various cancers. Several phase 1 and 2 clinical trials demonstrated tolerability and promising activity of REOLYSIN administered as a single agent in patients with solid tumors. Due to the high frequency of Kras pathway activation in Pca, we hypothesized that REOLYSIN may enhance the anticancer activity of chemotherapy in this tumor type. Therefore, this study was initiated to test the safety and efficacy of a combination of REOLYSIN with gemcitabine in previously untreated patients with Pca.
Methods: Patients with diagnosis of chemotherapy-naïve, surgically unresectable or metastatic Pca are eligible for the study. The primary objective is Clinical Benefit Rate (CBR=CR+PR+SD≥12 weeks). Secondary objectives include progression-free survival (PFS), toxicity, tolerability as well as pharmacokinetics (PK) and pharmacodynamics (PD). Patients are treated with gemcitabine at 800 mg/m2 day 1 and 8, and REOLYSIN administered IV at day 1, 2 and 8, 9. Tumor assessment is performed every 2 cycles (6 weeks). A two stage design is used for this study. In stage 1 at least 3/17 patients must achieve CBR in order to proceed to stage 2.
Results: Fourteen patients were enrolled in the study and 10 are evaluable for efficacy. Age ranged from 48 to 82 years, mean 67 years. All patients except one reported symptomatic improvement. No CR were reported. Two patients have SD for ≥36 weeks and one patient continues on study with SD at 39 weeks. An additional patient had an unconfirmed PR of less than 6 weeks. Six patients had SD ≥ 12 weeks. The treatment was well tolerated with common non-hematological toxicities including grade 1 fever, chills, nausea and vomiting. Only two patients had grade 3 neutropenia lasting 1–2 days. No other grade 3 toxicities were seen.
Conclusion: The endpoint for the first stage of the study (≥3 CBR in the first 17 patients) has been reached and therefore enrollment will continue. REOLYSIN in combination with gemcitabine has demonstrated clinical benefit in patients with unresectable Pca with a tolerable toxicity profile.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B55.
Abstract B57: Cabozantinib (XL184) reduces pain symptoms in patients (pts) with castration-resistant prostate cancer (CRPC) and bone metastases: Results from a phase 2 nonrandomized expansion cohort.
Authors: Basch Ethan , Bennett Antonia V. , Scher Howard I. 
Published: June 2012

Abstract
Background: Cabozantinib is a potent inhibitor of MET and VEGFR2. Cabozantinib treatment (100 mg qd) of CRPC pts in a Phase 2 randomized discontinuation trial resulted in high rates of both disease control per RECIST and resolution of bone lesions on bone scans. In addition, the majority of pts with bone metastases and pain at baseline experienced pain improvement per post-hoc investigator survey. Based on these data, a non-randomized expansion cohort was initiated for CRPC pts that included prospective evaluation of changes in pain and analgesic use.
Methods: Eligible pts had CRPC metastatic to the bone and had progressed on prior docetaxel therapy. Pain at baseline was not required for study entry. Cabozantinib was administered open label at 100 mg free base equivalent qd, and pain and analgesic use were evaluated daily over 7-day assessment intervals at baseline and during Weeks 3, 6, 12, and every 6 weeks thereafter. Using an interactive voice-response system (IVRS) questionnaire, pts rated pain at its worst over the prior 24 hours on a scale of 0–10 (0=no pain, 10=pain as bad as you can imagine), and interference with sleep and daily activity caused by pain using items from the Brief Pain Inventory. Pts also rated pain at its worst relative to the most recent prior assessment. Daily analgesic use was self-reported by pt diary. Of 100 planned patients, 51 have been enrolled and are evaluable for pain changes in this interim analysis.
Results: For the 51 enrolled pts with a minimum of 6 weeks of follow-up, evaluable data were obtained for 183/201 (91%) assessment intervals. Changes in average worst pain are summarized in Table 1.

Among the 23 pts that had average daily worst pain at baseline ≥4, 20 reported regular use of narcotic analgesics during the baseline assessment interval. Changes in sleep and daily activity, as assessed by pain interference questions, were generally consistent with the effects observed in pain.
Conclusions: Docetaxel-pre-treated CRPC pts with bone metastases treated with cabozantinib completed IVRS pain questionnaires with a high rate of compliance (&gt;90%) in this prospective analysis. High rates of pain reduction that was often accompanied by a concomitant decrease in narcotic use were observed in pts with baseline pain, consistent with prior retrospective analyses.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B57.