bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5586: Phase I study of PARP inhibitor ABT-888 and carboplatin with novel imaging in metastatic breast cancer (MBC) (NCI-8609)
Authors: Ramaswamy Bhuvaneswari , Lustberg Maryam B. , Wesolowski Robert , Layman Rachel M. , Mrozek Ewa , Olson Erin M. , Andreopoulou Eleni , Garcia-Villa Alejandra , Chalmers Jeff , Cotrill Jeffrey A. , Nutter Julie , Ledin Jamie , Schaaf Larry J. , Bajestani Saeed , Zhao Weiqiang , Geyer Susan , Chen Alice , Shapiro Charles L. , Villalona-Calero Miguel A. , Knopp Michael , Grever Michael R. 
Published: August 2012

Abstract
Purpose: ABT-888 is an oral inhibitor of PARP 1 and 2 and potentiates activity of platinums in preclinical models. We are conducting a phase I study of ABT-888 on 2 different schedules (7 and 14 day) plus q 3 week carboplatin (C) to identify the recommended phase II dose schedules (RPTD-7and 14 day) for this regimen in patients (pts) with MBC who are: (1) triple negative (TN); or (2) estrogen receptor positive (ER+) with defective Fanconi Anemia (FA) pathway (no FANCD2 foci in tumor). Study design: Eligible pts received C-AUC 5 Q 3weeks (except dose level 1-AUC 6) plus escalating doses of ABT-888 BID on a 7 or 14-day schedule using a 3+3 dose escalation design. Blood samples were collected during cycles 1 and 2 for PAR assay and CTCs isolated to measure gamma H2Ax. We performed 3′-[F-18] Fluoro-3′-deoxythymidine(FLT) PET scans to assess cellular tumor proliferation at baseline, cycle 1 day 7 and 14 and after cycle 3. FDG-PET-CT scans were used to assess response. Results: 22 pts (20-TN, 2-ER+ w/FA defect) with median age of 56.5 yrs (range 31-69) were enrolled on 5 dose levels. Dose level 1 with C at AUC 6 was too toxic with 3 DLTs (Table 1). Further dose escalations were performed with C at AUC-5. Dose reductions in C were made in subsequent cycles for thrombocytopenia, anemia and fatigue. Maximum reduction in thymidine uptake in tumors was seen on day 7 FLT scans. CTCs were isolated using an immunomagnetic negative depletion method on 8 pt samples to date (median-59, range 0-684 CTCs). Gamma H2Ax analysis on sequential samples is ongoing. Four pts have had an unconfirmed partial response (PR) with &gt; 50% tumor shrinkage; 2 of the 4 pts had a defective FA pathway. Conclusions: Thrombocytopenia is the major DLT when ABT-888 is given in combination with C, where lower AUC of C is better tolerated and shows promising activity of this combination. FA deficiency (5/14=27%) seen in this group is consistent with our previous reports. The study is supported U01 CA076576.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5586. doi:1538-7445.AM2012-5586
Abstract 5595: ALK mutant-driven cell lines develop crizotinib resistance by secondary mutations and ALK-independent means
Authors: Faber Andrew L. , Johnson Lori J. , Thomas James E. 
Published: August 2012

Abstract
The clinical success of crizotinib against mutant ALK-expressing cancers has generated great interest; however, the emergence of drug resistance is limiting its durability in some patients. In NSCLC, crizotinib resistance is linked to secondary mutations within EML4-ALK at amino acids L1196M, C1156Y, L1152R. A mutation at amino acid F1174L reduced the sensitivity to criozotinib in a patient with an inflammatory myofibroblastic tumor harboring a RANBP2-ALK translocation. The goal of our studies was to evaluate mechanisms of crizotinib resistance in a range of ALK-mutant expressing cell lines. Cells from ALCL (Karpas299), NSCLC (NCI-H3122 and NCI-H2228) or neuroblastoma (SKNSH and KELLY) developed resistance to crizotinib after being exposed to incremental increases in the compound over several weeks. NPM-ALK expressing Karpas299 cells independently acquired point mutations in ALK at amino acids N1178H and I1171N. As the concentration of drug was increased, cells that harbored the NPM-ALK N1178H mutation also expressed a mutation at G1269A. Each mutation enhanced the temperature dependent auto-phosphorylation activity of the kinase and diminished the inhibitory effect of crizotinib on downstream ALK signaling. Mutations in Karpas299 cells were also accompanied by up regulation of a drug efflux transporter, BCRP, whose heightened expression level was dependent on the presence of the compound. In contrast no additional mutations were discovered in ALK in crizotinib resistant NCI-H3122 and NCI-H2228 (EML4-ALK) or SKNSH and KELLY (ALK F1174L) cell lines. Instead both NCI-H3122 and NCI-H2228 resistant cell lines displayed increased levels of phospho-HER2 and HER3 and activation of AKT and ERK that may be due to autocrine secretion of a growth factor. NSCLC resistant lines also displayed an apparent change in phenotype with a mesenchymal-to-epithelial transition. SKNSH and KELLY are inherently less sensitive to crizotinib. We found that these cells may survive exposure to high levels of the compound by altering RET expression. Our observations represent potential mechanisms of resistance demonstrated in a small number of cell lines. It will be important to align these results with emerging data from drug-resistant patients to understand the multiple mechanisms by which resistance might develop.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5595. doi:1538-7445.AM2012-5595
Abstract 5604: Targeting survivin (BIRC5) with YM155 for the treatment of head and neck squamous cell carcinoma
Authors: Kumar Bhavna , Yadav Arti , Teknos Theodoros N. , Kumar Pawan 
Published: August 2012

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide and five-year survival rate (&lt;50%) is among the lowest of the major cancers. Treatment of advanced head and neck tumors remains a challenging clinical problem, due to the persisting high rate of local and distant failure. Currently, many advanced stage head and neck tumors are being treated with concurrent chemoradiation therapy but this treatment regimen is often associated with significant toxicity. Recent research efforts have attempted to develop targeted tumor-specific therapies to minimize normal tissue toxicity but maximize therapeutic benefits. One such potential target for HNSCC is survivin (a member of the inhibitor of apoptosis protein family), which is often overexpressed in HNSCC. Our results demonstrate that survivin is significantly upregulated in HNSCC cell lines as compared to normal oral keratinocytes. In this study, we used two cisplatin resistant cell lines; one naturally occurring cisplatin resistant cell line (UM-SCC-74A) and a second cell line (CAL27-PT) that was developed in the laboratory by subjecting a sensitive HNSCC cell line (CAL-27) to multiple rounds of cisplatin treatment. Interestingly, acquisition of cisplatin resistance by CAL27-PT resulted in further increase of survivin expression as compared to the parental cell line. Therefore, we hypothesize that targeting of survivin protein in advanced HNSCC could reverse the resistant phenotype in tumor cells thereby enhancing the therapeutic efficacy cisplatin treatment. We used both in vitro and in vivo models to test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with cisplatin treatment. YM155 treatment significantly decreased survivin expression in a dose-dependent manner and significantly inhibited cell proliferation, migration and colony formation ability of UM-SCC-74A and CAL27-PT cells. In addition, YM155 markedly enhanced the anti-proliferative and anti-migratory effects of cisplatin. This combination treatment was very effective in inducing tumor cell apoptosis as measured by Annexin V staining. In a SCID mouse xenograft model, YM155 significantly enhanced the anti-tumor and anti-angiogenic effects of cisplatin treatment with no added systemic toxicity. Taken together, our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells thereby enhancing the effectiveness of the chemotherapy in HNSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5604. doi:1538-7445.AM2012-5604
Abstract 5609: Mechanisms of acquired resistance to selective PI3K inhibitors in breast cancer cell lines
Authors: O'Brien Carol Lynn , Spoerke Jill , Lackner Mark , Sproul Scott , Haverty Peter , Hampton Garret 
Published: August 2012

Abstract
GDC-0941 is a class I PI3 kinase inhibitor of all 4 isoforms currently in phase II clinical trials in multiple indications, including ER+ breast cancer. The PI3 kinase pathway plays an important role in proliferation and survival and is known to be one of the most altered pathways in cancer. These alterations include PI3 kinase amplification, PI3 kinase mutations and PTEN loss, as well as numerous others. We have previously shown in-vitro and in-vivo data that alterations in this pathway can potentially help identify patients that are more likely to respond to a PI3 kinase inhibitor. A major outstanding question is mechanisms of intrinsic and acquired resistance to PI3K inhibitors. To address these questions we have selected multiple breast cancer cell lines harboring different pathway alterations (HER2, PIK3K mutations, PTEN loss) for resistance to PI3 kinase inhibition. Some of the resistant lines show cross resistance to inhibitors of mTOR and AKT (ie general pathway resistance), while others show specific resistance to PI3K or PI3K/mTOR inhibitors. We have characterized these resistant cell lines in detail at the molecular level and in terms of signaling pathway activation. Analyses performed include deep sequencing, reverse phase protein arrays, as well as focused Western blots and RTK arrays. We will discuss these results in detail and comment on candidate resistance mechanisms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5609. doi:1538-7445.AM2012-5609
Abstract 5623: Eliminating pancreatic cancer metastases through inhibition of hedgehog and RAS signaling
Authors: Gu Dongsheng , Zhang Xiaoli , Xie Jingwu 
Published: August 2012

Abstract
Pancreatic cancer is arguably one of the most challenging human malignancies, with the five year survival rate below 5%. Pancreatic cancer is often found in advanced stages, and is unresponsive to conventional cancer therapy. Thus, the need to develop novel treatment strategies targeting metastasis of pancreatic cancer has never been greater. The molecular hallmark of pancreatic cancer is an activating mutation in the small GTPase KRAS. Unfortunately, efforts to target RAS signaling are not very successful for pancreatic cancer treatment. Recently, inhibition of hedgehog (Hh) signaling emerges as a new cancer therapeutic option, but the available data from several current clinical trials in pancreatic cancer show only modest activity. At present, gemcitabine is the standard chemotherapy for metastatic pancreatic cancer but the response rate is less than 10%, with the median survival of only 6-7 months. A new chemotherapy combination of 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) was recently studied in Europe with a response rate of 30% and median survival of 11 months, but at a cost of significant toxicity. In order to design treatment strategies based on the molecular changes critical for cancer metastasis, we took the advantage of the knowledge recently generated in our laboratory and the newly developed molecularly targeted drugs currently in clinical trials. We compared primary pancreatic tumors with metastatic liver tumors for molecular alterations in an orthotopic mouse model, and discovered elevated expression of Indian hedgehog (Ihh) and ERK1/2 phosphorylation in liver metastases. Inhibition of Hh signaling or MEK activity alone reduced primary tumor size but did not significantly affect distal tumor metastases. In contrast, targeting Hh signaling and MEK activity in the orthotopic mouse model dramatically decreased the primary tumor size and nearly eliminated lung and liver metastases. Mice treated with two inhibitors lived two weeks longer than those in other groups. While MEK inhibition mainly interefered with cell proliferation, suppression of ligand-dependent Hh signaling affected the tumor microenvironment. These data indicate that simultaneous suppression of RAS and Hh signaling will be more effective in future pancreatic cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5623. doi:1538-7445.AM2012-5623
Abstract 5626: FKBP51 is a crucial modulator of melanoma plasticity and promising molecular target for preventing melanoma metastasis
Authors: Romano Maria Fiammetta , Romano Simona , Staibano Stefania , Greco Adelaide , Brunetti Arturo , Ilardi Gennaro , Mascolo Massimo , Bisogni Rita , Alfano Bruno 
Published: August 2012

Abstract
FKBP51, a protein with a relevant role in developmental stages in mammals and other organisms, is highly expressed in melanoma and correlates with tumor aggressiveness and resistance to therapy. We found that FKBP51 positively regulates melanoma cancer stem cell (CSC) phenotype at the transcriptional level. We also found that melanoma CSCs are endowed with epithelial to mesenchimal transition (EMT) traits. The immunochemistry study of 10 primitive cutaneous and 20 brain melanoma metastases showed that melanocytic cells capable of extravasation and subverting the architecture of metastatic tissue display intense FKBP51 nuclear signal and cytoplasmic positivity for the CSC marker nestin. These findings support the conclusion that the genetic programs of cancer stemness and invasiveness overlap in melanoma, and that FKBP51 plays a pivotal role in sustaining such a program. To confirm the role of FKBP51 in melanoma invasion, we utilized an experimental metastasis model. Animal studies were performed in accordance with NIH recommendations and the approval of the local institutional animal research committee. Injecting SAN melanoma cells into the tail vein of IL2γ-NOD-SCID mice produced prominent multifocal lesions in lungs and liver. We systemically administered two separate doses of FKBP51 siRNA to mice after the injection of melanoma cells. Organ colonization was evaluated both in live animals and post mortem. Qualitative PET/CT image analysis demonstrated low FDG uptake limited to small areas in lungs and liver. By contrast, untreated mice had diffuse metastatic liver and lung lesions and high FDG uptake in the same organs. Quantitative analysis performed on PET/CT images revealed that mean standardized uptake values (SUV) in treated mice were significantly lower than in untreated mice, both for lungs and liver. High Frequency Ultrasound examination revealed few or no liver metastases in treated mice versus untreated mice. Post-mortem organ examination showed a dramatic difference between the morphologically preserved organs dissected from treated mice, and severely compromised organs from untreated mice. The histological examination confirmed these findings. Most interestingly, invading cells co-expressed FKBP51 and nestin. Our study suggests a prominent role for FKBP51 in the pathogenesis of metastatic melanoma; we envision that targeting this protein for melanoma metastasis prevention may produce a successful outcome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5626. doi:1538-7445.AM2012-5626
Abstract 5641: Dual roles for ganoderic acid A in inducing apoptosis and enhancing HLA class II presentation in leukemia and lymphoma cells
Authors: Haque Azizul , Radwan Faisal F.Y. , Hossain Azim , God Jason M. 
Published: August 2012

Abstract
Ganoderic acid A (GA-A), a natural extract isolated from the medicinal mushroom Ganoderma lucidum, was found to induce a remarkable cytotoxicity in various leukemia and lymphoma cell lines and primary tumors, with a minor toxicity to nonmalignant B-cells. The GA-A cytotoxicity and growth inhibitory effects resulted from an induction of apoptosis, which was characterized by a dose-dependent increase in expression and activity of activated caspases 3, 8, and 9. Mechanistic studies showed that GA-A treatment upregulated pro-apoptotic protein Bax proteins while downregulating anti-apototic proteins Bcl-2 and survivin. Data also demonstrated that cytochrome c and apoptotic protease activating factor-1 (Apaf-1) were significantly elevated in the cytoplasmic fractions of GA-A-treated cells, which may have activated caspases for cell death. Despite GA-A's notable cytotoxic effects on leukemia and lymphoma cells, GA-A treatment enhanced HLA class II antigen (Ag) presentation and CD4+ T cell recognition of both malignant and nonmalignant B-cells. These data suggest that GA-A administration may play dual roles in inducing apoptosis and enhancing HLA class II Ag presentation, and could be used as novel adjunctive therapy for the treatment of hematological malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5641. doi:1538-7445.AM2012-5641
Abstract 5642: Wound-healing drainages contribute to triple negative breast cancers aggressiveness
Authors: Bianchi Francesca , Sasso Marianna , Turdo Federica , Agresti Roberto , Ghirelli Cristina , Cremona Mattia , Orlandi Rosaria , Tagliabue Elda , Campiglio Manuela 
Published: August 2012

Abstract
The triple negative breast cancers (TNBC) is an extremely aggressive cancer subtype that although account for only 10-17% of breast cancers carries the higher rate of distant recurrence and death than women with other breast cancer subtypes and, unfortunately has limited treatment options. The TNBC pattern of recurrence present a distant recurrence peak at approximately 3 years and then declines rapidly thereafter. It's now well known that growth-factors released during the healing process can accelerate the early recurrences in breast cancer patients. We speculate that wound healing drainages (WHD) stimulation may specifically contribute to TNBC early relapse. To this aim, a panel of TNBC cell lines (BT-549; HCC1937, MDA-MB-157; MDA-MB-231; MDA-MB-468; SUM159; SUM149) and the luminal cell lines MCF7 were treated with WHD. All breast carcinoma cell lines are induced to proliferate in response to more than 20 drainage fluids obtained from breast cancer patients, but median proliferation level was 3-folds higher in TNBC- compared to luminal-cell line. To identify which receptors/pathways can be activated and play a driving role in TNBC progression, a reverse phase protein microarray (RPMA) experiment on TNBC cells WHD stimulated was performed. We revealed a specific activation of PDGFR, VEGFR and their downstream pathways, whereas no significant changes were observed in other receptors, such as EGFR, IRS, Met and ERB3. Conversely, PDGFR and VEGFR pathways were not activated in MCF7. The type of activated receptors suggested the involvement of angiogenic properties, besides canonical proliferation pathways, upon WHD stimulation. To prove whether the receptors found activated by WHD play a key role in in vitro and in vivo TNBC progression, we targeted PDGFR, VEGFR and other receptors possibly involved in proliferation and angiogenic capabilities with sunitinib (targeting PDGFR, VEGFR, FGF and c-kit), anti-bFGF antibody (targeting the ligand bFGF) and bevacizumab (targeting the VEGF) in TNBC cells WHD-stimulated. Sunitinib and anti-bFGF antibody halved the proliferation of TNBC cell lines, whereas bevacizumab modestly affect proliferation. Notably, sunitinib and anti-bFGF antibody strongly inhibited MDA-MB-231 and MDA-MB-468 xenografts tumor growth (sunitinib: 80%, and 70% Growth Index (GI), respectively; anti-bFGF antibody 70% and 60% GI, respectively) whereas bevacizumab determined no more than 30% decrease of tumor volume. In conclusion, WHD promotes TNBC progression probably by sustaining both proliferation and angiogenic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5642. doi:1538-7445.AM2012-5642
Abstract 5650: Targeting siRNA to tumors and their stroma as a dual anticancer and anti-angiogenic therapy
Authors: Ofek Paula , Fischer Wiebke , Calderon Marcelo , Haag Rainer , Satchi-Fainaro Ronit 
Published: August 2012

Abstract
New targets for RNA interference (RNAi)-based cancer therapy are constantly emerging from the increasing knowledge on the molecular pathways involved in carcinogenesis. Nevertheless, in vivo delivery of small interfering RNA (siRNA) remains a crucial challenge for its therapeutic success. SiRNAs on their own are not taken-up by most mammalian cells in a way that preserves their activity. In order to circumvent these limitations, we developed a cationic carrier system, which can strongly improve its stability, intracellular trafficking and silencing efficacy. We have recently developed a polyglycerol (PG)-Amine, a water-soluble polyglycerol-based dendrimer that accumulates in the tumor environment due to the enhanced permeability and retention (EPR) effect, and therefore, represents an ideal delivery vehicle for antitumor biological agents. PG-Amine entrapment of siRNA neutralized its negative charge in a dose-dependent manner and significantly improved its cellular uptake. The luciferase gene, ectopically overexpressed in U87 human glioblastoma cell line was used as a model system and its silencing efficacy was extensively evaluated both in vitro and in vivo. Following encouraging results obtained from several cancer cell lines, the silencing efficiency of the nanocarrier luciferase-siRNA polyplexes was followed-up in vivo by non-invasive intravital bioluminescence imaging. A significant gene silencing effect was accomplished in vivo in both human glioblastoma and murine mammary adenocarcinoma mouse models following intravenous administration of our polyplexes. We further characterized the effect of silencing a few selected key proteins (e.g. Notch1) in vitro and achieved significant effects on the proliferation and migration of glioblastoma and neuroblastoma cell lines. In conclusion, we predict that specific delivery of siRNA to tumor epithelial and endothelial cells in vivo, and silencing of an important cell growth and angiogenesis regulator will warrant this approach as a successful anticancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5650. doi:1538-7445.AM2012-5650