bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B59: Preliminary clinical experiences of Phortress: Putative role for c-MET inhibition in antitumor activity
Authors: Bradshaw Tracey D. , Stevens Malcolm F.G. , Calvert Hilary , Plummer E. Ruth 
Published: June 2012

Abstract
Experimental antitumor agent Phortress elicits selective activity in vitro and in vivo in human breast, ovarian and renal carcinoma models via a novel mechanism(s) of action. Prodrug Phortress [2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) lysylamide dihydrochloride] liberates 5F 203 in the presence of cancer cells in vitro, and in plasma in vivo. 5F 203 is a potent aryl hydrocarbon receptor (AhR) ligand, resulting in induction of cyp1a1 transcription. CYP1A1-catalyzed biotransformation of 5F 203 to electrophilic species in sensitive tumor cells leads to cell death. Preclinical toxicokinetic studies in two rodent species led to a clinical starting dose of 3 mg/m2 Phortress.
Three and six patients have received 3 mg/m2 and 4.25 mg/m2 Phortress respectively, by intravenous injection over a 15 minute period on day 1 of consecutive 21 day cycles.
Phortress was generally well tolerated. Drug-related adverse reactions include fatigue and headache/arthralgia. In four patients, indications of stable disease have been achieved. One patient with colorectal carcinoma received nine 3 mg/m2 cycles before fatigue led to withdrawal. A mesothelioma patient received twelve 3 mg/m2 cycles; treatment was stopped after lung function tests revealed decreased TLco associated with disease progression. Two patients with renal cell carcinoma received four and sixteen 4.25 mg/m2 Phortress cycles before progressive disease led to withdrawal from trial.
Germline and somatic mutations in the MET oncogene encoding transmembrane hepatocyte growth factor receptor tyrosine kinase (HGFTK) are thought to play a key role in the pathophysiology of hereditary and sporadic renal cell carcinoma (RCC). Indeed, aberrant MET activation has been detected in many carcinomas including breast, ovary, gastric and metastatic colon, promoting aggressive invasive growth through stimulation of cell migration, and inhibition of apoptosis. MET-dependent signaling includes the Ras-Raf-Mek-Erk and PI3K-Akt cascades. Downregulation (85% and 69%) of MET (HGFTK) activity has been observed in protein isolated from MCF-7 and MDA 468 breast cancer cells treated for 24 h with 1 M 5F 203; downstream of MET, inhibition of Erk, MapK, Mek kinase activity was observed. Samples were subjected to antibody microarray which tracked phosphorylation status of cell signalling proteins that regulate cell proliferation, stress and apoptosis.
In scratch wound assays, 5F 203 (0.1 M) impeded renal TK10 as well as MCF-7 and MDA 468 cell motility.
Inhibition of MET signaling may afford an important 5F 203 target. Further translational research will more comprehensively elucidate mechanisms of action of Phortress. Such studies may ultimately guide patient selection and predict tumor response.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B59.
Abstract B88: A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding B-RafV600E mutation
Authors: Laquerre Sylvie , Arnone Marc , Moss Katherine , Yang Jingsong , Fisher Kelly , Kane-Carson Laurie S. , Smitheman Kimberly , Ward Jessica , Heidrich Bradley , Rheault Tara , Adjabeng George , Hornberger Keith , Stellwagen John , Waterson Alex , Han Chao , Mook Robert A. , Uehling David , King Alastair J. 
Published: June 2012

Abstract
Activation of the Ras-Raf-MEK-ERK pathway has been implicated in a large range of human cancers. Growth factor receptor stimulation by extracellular ligands activates Ras, which then sets in motion a signal transduction cascade through the Raf, MEK and ERK serine/threonine kinases. Mutation of the B-Raf kinase constitutively activates MAPK signalling, thus bypassing the need for upstream stimuli. This has been genetically associated with several human cancers, especially occurrence of the B-RafV600E mutant and its high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. The ability to selectively and potently inhibit B-Raf should provide a potential therapy for patients with mutant B-Raf tumors, for which addictive dependency on this pathway is observed. We have identified a novel, potent, and selective Raf kinase inhibitor that is capable of inhibiting the kinase activity of wild-type B-Raf, B-RafV600E and c-Raf with IC50 values of 3.2, 0.8, and 5.0 nM, respectively. Kinase panel screening for over 270 kinases has indicated that this inhibitor is selective for Raf kinase, with ∼400 fold selectivity towards B-Raf over 91% of the other kinases tested. Specific cellular inhibition of B-RafV600E kinase by this inhibitor leads to decreased ERK phosphorylation and inhibition of cell proliferation by an initial arrest in the G1 phase of the cell cycle, followed by cell death. This inhibition is selective for cancer cells that specifically encode the mutation for B-RafV600E. Oral compound administration inhibits the growth of B-RafV600E mutant melanoma (A375P) and colon cancer (Colo205) human tumor xenografts, growing subcutaneously in immuno-compromised mice. This cell-specific B-RafV600E inhibitor is currently being evaluated in a human Phase I clinical trial.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B88.
Abstract C31: Phase 1 study of AV-412, a novel irreversible EGFR inhibitor, administered daily in patients with advanced solid tumors
Authors: Bhargava Pankaj , Laheru Dan , Pupareli Carmen , Van Kooten Maximiliano , Martinez Justina L. , Varela Monica , Cotreau Monette M. , Credi Marc , Al-Adhami Mohammed , Wood Debra L. , Hidalgo Manuel 
Published: June 2012

Abstract
Background: Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib is a frequent clinical phenomenon in non-small cell lung cancer (NSCLC). Approximately 50% patients (pts) with acquired resistance to EGFR TKIs demonstrate the T790M mutation in EGFR gene. AV-412, an irreversible EGFR TKI, has demonstrated activity in chimeric mouse models with acquired resistance to EGFR TKIs (bearing the T790M mutation), and is being developed for treatment of NSCLC.
Methods: Pts with advanced, incurable solid tumors were enrolled in a phase 1 study and administered AV-412 orally once-a-day. Doses evaluated were: 50mg, 100mg, 150mg and 200mg. The goals of the study were to determine the maximum tolerated dose (MTD), safety, dose limiting toxicity (DLT), pharmacokinetics (PK) and activity of AV-412.
Results: 24 pts were treated: 13 males/11 females, median age 61 yrs (range 32–73). ECOG PS 0 (17 pts) or 1 (7 pts). Tumor types (No. of pts) were colorectal (5), NSCLC (3), pancreatic (3), uterine (3), melanoma (2), ovarian (2), hepatocellular (1), breast (1), head and neck (1) and other (3). Mean number of prior treatments were 6 (range 1–15). Five (20.8%) pts had received prior therapy with an EGFR inhibitor. The median duration of treatment was 32.5 days (range 7 – 214 days). Two pts experienced DLT at 200mg (grade 3 nausea and vomiting, and grade 3 diarrhea), following which anti-emetic premedications were instituted in the study. The MTD of AV-412 was 150mg; 11 pts were treated at this dose. The most common treatment-related adverse events (all grades) were nausea (54.2%), diarrhea (45.8%), and vomiting (41.7%); hematologic abnormalities included lymphopenia, increased INR, anemia, and leucopenia (12.5% each), hepatic and renal abnormalities included increased ALT, increased AST, and proteinuria (12.5% each). Drug-related laboratory abnormalities were generally mild to moderate in severity. Preliminary PK data indicate dose proportional exposure. Three patients had disease stabilization &gt; 16 weeks: 2 pts with colorectal cancer (116 days, 170 days) and a pt with ovarian cancer (172 days).
Conclusions: AV-412 is well tolerated at a dose of 150 mg/day. The most frequent toxicities were nausea and diarrhea, which could be controlled with standard medications. This study is currently enrolling a cohort of patients with NSCLC to evaluate clinical activity of AV-412 in patients with EGFR mutations, and updated results will be available for presentation. A phase 1 study of intermittent dosing of AV-412 is also being conducted.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C31.
Abstract A221: A phase II study of SB939 in patients with recurrent or metastatic castration resistant prostate cancer (CRPC).
Authors: Eigl Bernhard J. , North Scott , Murray Nevin , Heng Daniel YC , Winquist Eric , Powers Jean , Walsh Wendy R. , Eisenhauer Elizabeth , Squire Jeremy , Cox Michael , Chi Kim N. 
Published: June 2012

Abstract
Background: SB939 is a potent oral inhibitor of class I, II and IV histone deacetylases (HDACs) with high tumor tissue selectivity. These 3 classes of HDAC are highly expressed in prostate cancer and associated with poor clinical outcomes. HDAC inhibition has been shown to abrogate androgen receptor signaling via inactivation of HSP90, and may have relevance particularly in TMPRSS2-ERG fusion positive prostate cancer.
Methods: In this multicenter phase II study, pts with CRPC received SB939 60mg every other day 3 times per week × 3 weeks on a 28-day cycle. Primary endpoints were PSA response rate (RR) (&gt;50% decline from baseline for &gt; 4 weeks) and progression free survival (PFS). Secondary endpoints included objective response rate; response duration, overall survival; circulating tumor cell (CTC) enumeration at baseline, 6 and 12 weeks; TMPRSS2-ERG fusion analysis; correlative analysis of archival tissue; and safety. Planned sample size was 29 pts, the hypotheses (PSA RR &lt;2% vs. ≥15%) could be tested at 10% and levels.
Results: Twenty-nine pts have been accrued. Median age is 69, 25 pts had received no prior chemotherapy, ECOG performance status was 0/1 in 48%/52% of pts. Bone/lymph node/visceral metastases were present in 86%/69%/10% of pts. The median number of cycles of SB939 administered is 2 (range 1–6) with 7 pts still continuing treatment. Adverse events were generally grade 1–2, with 5 patients experiencing grade 3 events (fatigue (5 pts), vomiting (1 pt) and dyspnea (1pt)). To date, a confirmed PSA response has been noted in 2 pts (7%). In 8 RECIST-evaluable pts, there were no objective responses, and 3 pts had stable disease lasting from 3.4 to 5.6 months. CTC favorable conversion (from ≥5 at baseline to &lt;5 at 6 or 12 weeks) was observed in 9/14 evaluable patients (64%) and unfavorable CTC levels (&gt;5) at 6 weeks correlated with PSA progression. RT-PCR for presence of TMPRSS2-ERG transcripts from whole blood and FISH analyzes of CTC and archival tissue for TMPRSS2-ERG fusion and PTEN deletion status are ongoing.
Conclusion: SB939 is well tolerated and has shown early evidence of activity in CRPC. Analysis of more mature data will be required to determine whether this agent warrants further study, and whether TMPRSS2-ERG status might predict for response to SB939.
Supported by grants from the Canadian Cancer Society and the Ontario Institute for Cancer Research.
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 A221.
Abstract A230: Discovery and characterization of ARQ 092, an ATP-independent, potent and selective inhibitor of AKT kinases.
Authors: Chan Thomas C.K. , Lapierre Jean-Marc , Ashwell Mark A. , France Dennis S. , Chen Chang-Rung , Cornell-Kennon Susan , Bull Cathy , Eathiraj Sudhi , Palma Rocio , Liu Yanbin , Makhija Sapna , Waghorne Carol , Savage Ron , Fujiwara Kosaku 
Published: June 2012

Abstract
The AKT family of serine-threonine kinases is a critical signal transduction node serving a variety of cellular functions including survival, proliferation, protein synthesis, and glucose metabolism. Small molecule inhibitors of AKT are emerging as potential targeted agents to treat cancers that exhibit aberrant AKT pathway signaling. A screening strategy was employed to identify inhibitors which utilize the intrinsic negative regulatory function of hydrophobic clusters in the ATP-binding cleft to inhibit the kinase activity of AKT1. ARQ 092 was identified through this screening paradigm following in vitro and in vivo optimization and was selected for further development. Crystallographic studies provided evidence that this mechanism of inhibition of AKT had been achieved. ARQ 092 binds to inactive, unphosphorylated AKT1 with sub-nanomolar affinity (Kd = 0.28 nM measured by surface plasma resonance) and biochemically inhibits all three isoforms (IC50 values of 3 nM, 4.5 nM, and 5.5 nM respectively for AKT1, AKT2, and AKT3). ARQ 092 displayed inhibition kinetics against AKT1 which were not affected by ATP concentrations up to 1000 M. When screened against a panel of over 300 kinases, ARQ 092 inhibited only three kinases within 100-fold of its IC50 against AKT1. ARQ 092 potently inhibited AKT phosphorylation (Ser473 & Thr308) in AN3CA human endometrial carcinoma cells (EC50 values of 39 nM and 61 nM, respectively for p-Ser473 & p-Thr308) and demonstrated concentration-dependent inhibition of phosphorylation of the downstream AKT substrate PRAS40. ARQ 092 inhibited growth of AN3CA cells (GI50 = 555 nM), A2780 cells (GI50 = 400 nM), and IGROV-1 cells (GI50 = 66 nM), in addition to LNCaP, ZR-75–1, and BT-474 human cancer cell lines (GI50 values ranging from 1 to 4 μM). Following a single oral dose of ARQ 092, inhibition of AKT and PRAS40 phosphorylation was documented in vivo in both AN3CA human endometrial tumor and BT474 human breast tumor xenograft models. The growth of AN3CA tumor xenografts was markedly suppressed after daily oral administration of ARQ 092 for 10 days. Finally, ARQ 092 was shown to have good pharmaceutical properties and was advanced into preclinical development.
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 A230.
Abstract A66: Antiproliferative effects of CDK4/6 inhibition alone and combination with chemotherapy in KRAS-mutated NSCLC.
Authors: Hong Jihyung , Zhang Xiang-Hua , Shin Jung-Young , Kim Jeong-Oh , Oh Ji-Eun , Kang Jin-Hyoung 
Published: June 2012

Abstract
Background: Deregulation of the p16INK4A-cyclin D-cyclin-dependent kinases (CDK) 4/6-retinoblastoma (RB) pathway is a common paradigm in various solid tumors and represents one of the attractive targets in cancer treatment. KRAS mutation confers intrinsic resistance to cytotoxic chemotherapeutic agents, and to EGFR TKIs leading to treatment failure. An effective systemic treatment for adenocarcinomas harboring KRAS mutations are urgently needed to improve clinical outcomes.
Purpose: CINK4, a chemical inhibitor of cyclin-dependent kinase 4, has demonstrated effective anti-proliferative activity in vivo in the presence of pRb. Herein, we investigated that CINK4 may increase its anti-proliferative activity in the NSCLC cells harboring KRAS mutation
Methods: We measured the anti-proliferative activities of CINK4 in A549 (KRASG12S), H358 (KRASG12C), PC14 (KRASwild), and Calu-3 (KRASwild) cell lines using SRB assay, cell cycle distribution quantified by flow cytometry, and the expression of cell cycle regulators and apoptosis-related proteins was evaluated by Western blotting. Multiple drug effect was analyzed to study an interaction between two drugs. The nature of the interaction between two agents was calculated for the combination index (CI).
Results: Concentration- and time-dependent anti-proliferative effects of CINK4 (0.1∼40 μM concentration range) and pacitaxel (0.1∼300 nM) alone were seen in four NSCLC cell lines, and were not significantly different between each cell line (48 h IC50: 10.4 ± 0.2 μM and 5.5 ± 0.9, 10.1± 1.9 μM and 5.2 ± 0.9, 6.6 ± 0.8 μM and 3.6 ± 1.0, and 8.4 ± 0.2 μM and &gt; 10 nM, in A549, H358, PC14, and Calu-3, respectively). After 48 h CINK4 treatment alone, the G0/G1phase cell population increased with increment of subG1 faction in concentration-dependent manner. CINK4 reduced cyclinD1 and Rb phosphorylation and increase the expression of cleaved PARP in concentration-dependent manner in A549, H358, and PC14 cell lines. And CINK4 combined with paclitaxel in two KRAS mutated cell lines showed enhanced anti-proliferative activity of paclitaxel. The CI values of CINK4 and palitaxel combination in A549 and H358 were 0.51 ± 0.16 and 0.63± 0.12, respectively.
Conclusions: CINK4 showed promising anti-tumor activity in NSCLC cell lines. NSCLC harboring KRAS mutation may have clinical benefit from CDK4/6 inhibitor in combined with chemotherapy.
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 A66.
Abstract C202: Discovery and initial characterization of the clinical compound ABT-348, a potent inhibitor of the VEGF, PDGF, and Aurora kinase families.
Authors: Curtin Michael L. , Heyman Robin , Frey Robin R. , Soni Niru B. , Marcotte Patick A. , Pease Lori J. , Glaser Keith B. , Magoc Terrance J. , Tapang Paul , Albert Daniel H. , Osterling Donald J. , Olson Amanda M. , Bouska Jennifer J. , Guan Zhiwen , Martin Ruth L. , Stewart Kent D. , Tse Chris , Davidsen Steven K. , Michaelides Michael R. 
Published: June 2012

Abstract
The Aurora kinases are a family of serine/threonine kinases that mediate multiple events in cell division. Humans have three Aurora kinases, A, B and C, that are differentially localized and mediate distinct functions during mitosis. Because the Aurora kinases play a key role in mitosis and are overexpressed in multiple human tumor types, there has been considerable interest in developing Aurora kinase inhibitors as antitumor agents. A number of small-molecule Aurora kinase inhibitors have been reported and there are several compounds currently in Phase I/II clinical trials for cancer. ABT-348 is a novel, potent and orally bioavailable inhibitor of the Aurora kinases as well as the VEGF and PDGF families of receptor tyrosine kinases and is currently in Phase I clinical trials. Herein we describe the discovery and preparation of this molecule including the SAR work that provided improved Aurora kinase potency, aqueous solubility and oral bioavailability with reduced hERG and CYP liabilities relative to earlier analogs.
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 C202.
Abstract 1009: Leptin induces Src/Gbr2/Gab2/STAT3 activation and Rac-1 crosstalk to regulate VEGF/VEGFR2 in breast cancer
Authors: Fuller Miles , Byrd Manzy , Guo Shanchun , Gonzalez-Perez Ruben Rene 
Published: June 2012

Abstract
Leptin and its receptor, OB-R, are overexpressed in cancer cells and their levels correlate to worse prognosis of cancer patients. Leptin is an important inducer of VEGF/VEGFR2 in breast cancer under normoxia through the activation of several signaling pathways and HIF-1α/NFκB/SP1. However, the specific mechanisms of leptin-mediated regulation of VEGF/VEGFR2 genes are still partially unknown. VEGF/VEGFR2 directly regulates tumor angiogenesis and also works as an essential autocrine/paracrine process for cancer cell proliferation and survival. We have previously shown that disruption of leptin signaling with our novel antagonists, PEG-LPrAs, significantly impaired the growth of breast tumors and reduced the levels of VEGF/VEGFR2. We hypothesize that leptin regulation of VEGF/VEGFR2 in breast cancer involves the activation of Src and Gbr2/Gab2/STAT3 and crosstalk to Rho-GTPases. Methods: To test this hypothesis, VEGF/VEGFR2 expression and activation of signaling intermediaries were determined in mouse and human breast cancer cells challenged with leptin as well as genetic and pharmacologic kinase inhibitors. Results: Inhibition of JAK2 partially reduced leptin-induced pSTAT3 levels but increased VEGF protein and mRNA. Moreover, leptin-induced pSTAT3 was related to Src and Gab2. Inhibition of Src increased leptin-induced VEGF and dramatically reduced VEGFR2. Rac1 inhibition also abrogated leptin-induced pSTAT3 and decreased pGab2 and VEGF/VEGFR2 levels. Conclusions: Leptin activation of Rac1 upregulates VEGF/VEGFR2 and promotes a negative feed-back, which downregulates leptin activation of Src/Gbr2/Gab2/STAT3. In addition, leptin activation of Src/Gbr2/Gab2 and Rac1 are needed for the induction of VEGFR2. These data suggest a high complexity of signaling crosstalk is involved in leptin regulation of pro-angiogenic factors and breast cancer growth. Therefore, PEG-LPrA combined with inhibitors for leptin-sensitive regulatory signaling partners could provide novel multiple target therapies for breast cancer. This could be of paramount importance for the higher risk patients: obese and postmenopausal women who show highest leptin levels. Our proposed studies could also be relevant to patients having the very aggressive and difficult to treat triple negative breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1009. doi:10.1158/1538-7445.AM2011-1009