bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B177: RXDX-107, a dodecanol alkyl ester of bendamustine, demonstrates improved pharmacokinetic properties and significant anti-tumor efficacy in preclinical models of solid tumors
Authors: Martin Leenus , Patel Roopal , Drager Anthony , Roemmele Renee , McIntyre Bradley , McKean Robert , Patel Piyush , Chua Peter , Cao Jerry , Shoemaker Robert , Brown Peter , Multani Pratik , Wild Robert , Lin Ralph , Li Gang 
Published: May 2016

Abstract
Bendamustine is an alkylating agent that can form interstrand DNA crosslinks (ICLs) and cause cell death via several pathways, including intrinsic apoptosis. Bendamustine has proven to be a potent and effective treatment for patients with chronic lymphocytic leukemia (CLL) and rituximab-refractory indolent non-Hodgkin's lymphoma (NHL), with additional clinical activity seen in other B-cell malignancies and in multiple myeloma (MM). However, the activity of bendamustine in the treatment of solid tumor malignancies has been less impressive, possibly due to the pharmacokinetic and biodistribution properties of bendamustine.
RXDX-107 is a dodecanol alkyl ester of bendamustine, and the clinical drug product is encapsulated in human serum albumin (HSA) to form nanoparticles. RXDX-107 was designed to improve tissue biodistribution over bendamustine, which may result in superior efficacy and tolerability in patients with solid tumors. In in vitro anti-proliferative studies, RXDX-107 displayed dose-dependent cytotoxicity against multiple solid tumor cell lines, including non-small lung cancer (NSCLC), breast and ovarian cancer. While the IC50s of RXDX-107 were comparable to those of bendamustine, RXDX-107 displayed stronger induction of pH2AX (a biomarker for DNA damage) and more complete cell killing than bendamustine in multiple cell lines. Furthermore, RXDX-107 potently inhibited subcutaneous tumor growth in cell line-derived xenograft (CDX) models of human NSCLC and breast cancer. Importantly, RXDX-107 also showed single agent anti-tumor activities, including tumor regression in multiple patient-derived xenograft (PDX) models of advanced solid tumors, such as breast, lung, and ovarian cancer.
In conclusion, our preclinical data demonstrate potent and broad anti-tumor activity of RXDX-107 across a variety of solid tumor types, and support further clinical development of this novel drug candidate for the treatment of solid tumors.
Citation Format: Leenus Martin, Roopal Patel, Anthony Drager, Renee Roemmele, Bradley McIntyre, Robert McKean, Piyush Patel, Peter Chua, Jerry Cao, Robert Shoemaker, Peter Brown, Pratik Multani, Robert Wild, Ralph Lin, Gang Li. RXDX-107, a dodecanol alkyl ester of bendamustine, demonstrates improved pharmacokinetic properties and significant anti-tumor efficacy in preclinical models of solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B177.
Abstract B195: Serum levels of CXCL10 and CXCL11 elevate after skin rash induction, the commonest adverse event by bendamustine in the treatment of malignant lymphoma
Authors: Terui Yasuhito , Mishima Yuji , Hatake Kiyohiko 
Published: May 2016

Abstract
Introduction: Bendamustine has been recently approved for the treatment of low-grade malignant lymphoma. In spite of the better efficacy, skin rash is the commonest adverse event by bendamustine in the treatment of malignant lymphoma. To understand the mechanism of the skin rash, we prospectively examine the relationship between skin rash and cytokines/chemokines.
Methods: After informed consent to the patients, who would received bendamustine (B) or bendmustine+rituximab (BR), the sera were collected before and after the treatment of B or BR. The Cytokine/Chemokine array was performed by Bio-Plex system.
Results: 20 patients with FL (n = 18), MCL (n = 1), and low-grade B-cell lymphoma (n = 1) were enrolled in this study. All patients wee treated with B or BR regimen. Nine patients showed skin rash after the treatment of bendamustine. In Cytokine/Chemokine array, serum levels of CCL22 and CCL25 before the treatment were significantly higher in skin rash group (p = 0.010738476 and p = 0.030366028, respectively), and serum levels of CXCL10 and CXCL11 after skin rash were higher significantly (p = 0.000923527 and p = 0.014890795, respectively).
Conclusion: The commonest adverse event by bendamustine and CXCL10 and CXCL11might contribute to induction of skin rash by bendamustine, and inhibition of their receptor, CXCR3 may be helpful for the treatment of skin rash by bendamustine
Citation Format: Yasuhito Terui, Yuji Mishima, Kiyohiko Hatake. Serum levels of CXCL10 and CXCL11 elevate after skin rash induction, the commonest adverse event by bendamustine in the treatment of malignant lymphoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B195.
Abstract B22: Outcomes and genomic mutational profiling results in patients with cancers of the head and neck treated with dovitinib in the Signature Program
Authors: Piha-Paul Sarina A. , Knost James A. , Raez Luis E. , Cohn Allen L. , Tawbi Hussein A. , Parasuraman Sudha , Kang Barinder P. , Matys Renata M. , Slosberg Eric D. 
Published: May 2016

Abstract
In the Signature Program, patients with advanced solid and hematologic cancers without other standard treatment options are enrolled in 1 of 8 tissue-agnostic, mutation-specific protocols. With no predetermined study sites, the program is able to bring the protocol to the patient through local enrollment via physician-directed genomic profiling of tumors. The primary endpoint of each study is clinical benefit, including complete response, partial response, or stable disease [SD], at 16 weeks by investigator assessment using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or appropriate hematologic criteria. This novel design allows rapid matching of patients to a relevant targeted therapy. Dovitinib, a tyrosine kinase inhibitor with activity against multiple receptor tyrosine kinases, is currently in clinical development. Eighty patients were accrued in the dovitinib (TKI258) protocol from May 2013 to January 2015. Here, we describe a head and neck cancer subset of this population, including adenoid cystic carcinoma (ADC; n = 6), head and neck squamous cell carcinoma (HNSCC; n = 5), and salivary gland cancer (n = 1). The median age was 62 years, and patients had a median of 2 prior lines of therapy; 69% of patients were male, 85% were Caucasian, and 31% and 69% had an Eastern Cooperative Oncology Group performance status of 0 and 1, respectively. Patients met mutational inclusion criteria, with mutations in PDGFRα/β, c-KIT, VEGFR2, FGFR1/2, and RET. There were no confirmed responses; however, 5 patients had SD on study. Of the 5 patients with SD, 4 had clinical benefit at 16 weeks (1 patient with SD at 8 weeks discontinued before 16 weeks). Consistent with other studies of dovitinib monotherapy, gastrointestinal adverse events (fatigue [69%], nausea [69%], diarrhea [54%], and vomiting [54%]) were the most common. In addition, pretreatment tissue biopsies from all patients were analyzed by a large multigene next-generation sequencing assay. Results to date indicate that the ADC cohort has a lower mutational load and fewer prior therapies than the HNSCC cohort. Further analysis of a correlation between clinical benefit and specific mutational profile is ongoing.
Citation Format: Sarina A. Piha-Paul, James A. Knost, Luis E. Raez, Allen L. Cohn, Hussein A. Tawbi, Sudha Parasuraman, Barinder P. Kang, Renata M. Matys, Eric D. Slosberg. Outcomes and genomic mutational profiling results in patients with cancers of the head and neck treated with dovitinib in the Signature Program. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B22.
Abstract B49: Inhibition of β-catenin pathway to overcome endocrine resistance in tamoxifen-resistant breast cancer cell line
Authors: Won Hye Sung , Lee Kyoung Eun , Nam Eun Mi , Mun Yeung-Chul , Seong Chu-Myong , Lee Soon Nam 
Published: May 2016

Abstract
Background: It is well known that Wnt/β-catenin signaling pathway is involved in hormone receptor negative breast cancer, especially triple-negative breast cancer. In the case of hormone resistant breast cancer cells, they rarely showed hormone receptor expression. So we aimed to investigate whether the β-catenin pathway becomes activated in endocrine-resistant breast cancer cells and inhibition of β-catenin pathway can overcome endocrine resistance.
Methods: We have established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with gradually increasing 4-hydroxytamoxifen concentration till 3μM. The levels of protein expression and mRNA transcripts were determined using western blot analysis and real-time quantitative PCR. The transcriptional activity of β-catenin was measured using luciferase activity assay. We used ICG-001 as inhibitor of β-catenin transcription activity.
Results: The expression of estrogen receptor was significantly decreased in TamR cells. On the other hand, the expressions of HER2 and EGFR were increased in TamR cells than in control cells. The active (uncomplexed form) β-catenin level was increased in TamR cells, and also showed a significantly increased β-catenin transcriptional activity. The ICG-001, small-molecular inhibitor of Wnt/β-catenin pathway, treatment significantly reduced β-catenin transcriptional activity in TamR cells. The ICG-001 reduced cell viability fo TamR cells which showed resistance to tamoxifen by 65.3%, and also inhibited target gene cyclin D1 expression. The combination of ICG-001 and mTOR inhibitor, rapamycin reduced cell viability of TamR cells by 81.7% and there was an additive effect of two drugs as a combination index of 1.022.
Conclusions: The β-catenin pathway is activated in endocrine-resistant breast cancer cells and inhibition of that pathway would be a new therapeutic strategy which overcomes endocrine resistance in breast cancer.
Citation Format: Hye Sung Won, Kyoung Eun Lee, Eun Mi Nam, Yeung-Chul Mun, Chu-Myong Seong, Soon Nam Lee. Inhibition of β-catenin pathway to overcome endocrine resistance in tamoxifen-resistant breast cancer cell line. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B49.
Abstract B53: Dynamic evolution of resistance to EGFR blockade from drug tolerant cancer cells
Authors: Hata Aaron N. , Niederst Matthew , Gomez-Caraballo Maria , Archibald Hannah , Siddiqui Faria , Mulvey Hillary , Hu Haichuan , Sequist Lecia , Engelman Jeffrey 
Published: May 2016

Abstract
Despite the success of targeted cancer therapies, acquired drug resistance remains a significant clinical challenge, as in the case of EGFR mutant non-small cell lung cancers (NSCLC) treated with EGFR inhibitor therapy. Although molecular mechanisms of acquired resistance to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. In some cases, clones with clinically validated genetic resistance mechanisms may exist prior to drug exposure and are simply selected by treatment. Alternatively, it has been hypothesized that drug tolerant (or “persister”) cells without bona fide resistance mechanisms may survive initial drug treatment by epigenetic adaptations, and undergo further evolution over time to acquire validated genetic resistance mechanisms. Although this would have immediate implications for new therapeutic strategies to prevent resistance, there has not been any direct evidence that drug tolerant cells can undergo such evolution. Using EGFR mutant NSCLC models, we observe that acquired resistance caused by the T790M gatekeeper mutation, which is observed in 50% of patients with acquired resistance to EGFR inhibitor therapy, can occur by either selection of pre-existing T790M clones or via evolution of T790M-negative drug tolerant cells that develop the mutation during months of drug treatment. Additionally, the path to resistance impacts the biology of the resistant clone, as those that evolved from drug tolerant cells have a diminished apoptotic response to third generation EGFR inhibitors that target T790M EGFR and can be sensitized by BCL-XL inhibitors. In total, these findings provide evidence that clinically relevant drug resistant cancer cells can both pre-exist and evolve from drug tolerant cells, and point to new therapeutic opportunities to prevent or overcome resistance in the clinic.
Citation Format: Aaron N. Hata, Matthew Niederst, Maria Gomez-Caraballo, Hannah Archibald, Faria Siddiqui, Hillary Mulvey, Haichuan Hu, Lecia Sequist, Jeffrey Engelman. Dynamic evolution of resistance to EGFR blockade from drug tolerant cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B53.
Abstract B58: BIM, a key player in apoptosis induction and acquired venetoclax resistance in follicular lymphoma cells
Authors: Bodo Juraj , Zhao Xiaoxian , Souers Andrew J. , Phillips Darren C. , Smith Mitchell R. , Hsi Eric D. 
Published: May 2016

Abstract
The chromosomal translocation t(14;18) in follicular lymphoma (FL) cells is a primary oncogenic event resulting in BCL-2 over-expression. BCL-2 is not directly responsible for growth of tumor cells, but it protects them against death by binding pro-apoptotic proteins. This study investigates in vitro and in vivo activity of the BH3 mimetic venetoclax (ABT-199) and mechanisms of acquiring resistance in FL.
Primary FL cells with similar expression of anti-apoptotic proteins, such as BCL-2 and MCL-1, showed variable sensitivity to treatment, which correlated with expression of BIM. To further study this correlation we used two t(14;18)+ cell lines, WSU-FSCCL and FC-TxFL2. As with primary cells, FC-TxFL2 cells with higher expression of BIM protein were more sensitive to venetoclax-induced apoptosis. The treatment caused dissociation of BCL-2/ BIM complexes, decreased mitochondrial potential, activation of caspase-3 and caspase-7, and PARP cleavage. Interestingly the population of cells that survived venetoclax treatment showed an increase of phospho-ERK1/2 and phospho-BIM (S69), as well as a decrease of total BIM levels.
Venetoclax treatment of murine xenografts of FC-TxFL2 cells resulted in significant delay in tumor growth. However, viable cells isolated from treated tumors showed a decrease of sensitivity to venetoclax exposure (IC50 increased almost 10 times) in comparison with the cells from the mice treated with vehicle only. These cells contained higher levels of MCL-1 and lower levels of BIM protein compared to control cells. BCL-2 levels remained unchanged.
Venetoclax resistant cells prepared in vitro by continuous treatment with increasing concentrations of venetoclax initially showed elevated levels of p-AKT, p-FOX01/3a, MCL-1, dissociation of BIM/BCL-2/BECLIN1 complex, decrease of p62 level (a sign of an increased autophagy) together with a slight decline of BIM expression. After a stable resistant cell line was established, a significant reduction of BCL-2 levels and almost total absence of BIMEL, BIML and BIMS isoforms was observed.
Detailed knowledge of venetoclax action and the mechanisms for acquired resistance in t(14;18)+ cells may help inform biomarker strategies and dosing schedules in future clinical trials. Inhibition of pathways activated in order to protect the FL cells (e.g. by down-regulating BIM (ERK or AKT pathway) or by autophagy) can significantly augment venetoclax potency and decrease incidence of acquired resistance.
Citation Format: Juraj Bodo, Xiaoxian Zhao, Andrew J. Souers, Darren C. Phillips, Mitchell R. Smith, Eric D. Hsi. BIM, a key player in apoptosis induction and acquired venetoclax resistance in follicular lymphoma cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B58.
Abstract B61: Bcr-Abl1 V304D mutation in CML: friend or foe?
Authors: Pricl Sabrina , Laurini Erik , Fermeglia Maurizio , Storici Paola , Giabbai Barbara , Semrau Marta , De March Matteo , Donato Nicholas J. , Quintas-Cardama Alfonso 
Published: May 2016

Abstract
Background
Our recent work revealed that some chronic myeloid leukemia (CML) patients failing imatinib therapy carry the BCR-ABL1 V304D mutation, and is associated with poor clinical outcomes. BCR-ABL1 V304D variant has rarely been described in clinical specimens, and its location within the BCR-ABL1 Kinase Domain (KD) appears to be in an area of the protein not involved in the direct binding with tyrosine kinase inhibitors (TKIs) such as Imatinib and Ponatinib. The present study integrates computational, structural, and molecular biology techniques to investigate the role of the BCR-ABL1 V304D mutation in kinase activity and TKI resistance.
Materials and methods
In silico experiments are used to probe whether, compared to the wild type (wt), the V304D mutation i) directly affects the kinase domain fold and/or thermodynamic stability and ii) if/how these effects might eventually interfere with BCR-ABL1 binding to the TKIs. Small angle X-ray scattering (SAXS), fluorescence, and circular dichroism spectroscopy are employed for structural characterization of the wt/mutated kinase domain and their interaction with TKIs. Cell proliferation, protein phosphorylation, and kinase activity assays are performed (with/without) the TKIs to assess the effect of this mutation on BCR-ABL1 KD, its enzymatic and transforming activities.
Results
Our preliminary results show that BCR-ABL1V304D does not transform Ba/F3 cells, retains minimal kinase activity, and fails to activate downstream pathways. At the same time, the V304D BCR-ABL1 isoform partially protects cells from cytokine withdrawal and exhibits imatinib resistance. The SAXS-based structural model of the kinase domain mutant in complex with Ponatinib does not reveal major structural perturbations compared to the wild type protein. Molecular simulations on the SH2-linker-SH3-KD construct suggest a possible rationale for the TKI resistance seen in the clinic.
Conclusions
The preliminary results obtained indicate that BCR-ABL1V304D results in kinase inactivation, pan-TKI resistance mediated by lower control of protein autoinhibition via perturbation of the SH3 binding domain and very poor prognosis.
Citation Format: Sabrina Pricl, Erik Laurini, Maurizio Fermeglia, Paola Storici, Barbara Giabbai, Marta Semrau, Matteo De March, Nicholas J. Donato, Alfonso Quintas-Cardama. Bcr-Abl1 V304D mutation in CML: friend or foe? [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B61.
Abstract B74: Combined inhibition of ALK and CDKs involved in transcriptional regulation is synergistic in ALK-mutated neuroblastoma
Authors: Moore Nathan F. , Chipumuro Edmond , Hatheway Clark M. , Zhang Tinghu , Gray Nathanael S. , George Rani E. 
Published: May 2016

Abstract
Activating mutations in the anaplastic lymphoma receptor tyrosine kinase (ALK) represent important therapeutic targets in neuroblastoma (NB). One of the more common mutations, ALKF1174L, is sensitive to the FDA-approved ALK inhibitor, crizotinib, only at high doses and mediates acquired resistance to crizotinib in ALK-rearranged cancers. To identify compounds that would enhance the cytotoxic effect of crizotinib, we conducted a high throughput small molecule screen for compounds that synergize with crizotinib in NB cells expressing the ALKF1174L mutation. We identified two pan-selective cyclin dependent kinase (CDK) inhibitors, AT7519 and SNS-032, which have overlapping efficacy against the cell cycle-regulating CDK2 and transcriptional elongation-regulating CDK9. Both inhibitors demonstrated synergistic activity with crizotinib, leading to downregulation of pALK and downstream signaling and significantly increased apoptosis over that of either single agent alone. This effect was observed in NB cells expressing not only ALKF1174L, but also in the other commonly observed ALKR1275Q mutation. Synergy was also noted with ceritinib (LDK378), a structurally unrelated ALK inhibitor, in combination with both AT7519 and SNS-032. The combination of crizotinib and SNS-032 led to the inhibition of CDK9-mediated transcriptional elongation as indicated by downregulation of RNA polymerase II phosphorylation at serine 2. Additionally, the combination also induced proteolytic cleavage of elongation-regulating BRD4, suggesting alternative mechanisms contributing to transcriptional inhibition in addition to direct inhibition of CDK9 activity These findings were comparable with results obtained using compounds that were highly selective for CDK7, which has roles in transcriptional initiation as well as in CDK9 activation. Finally, in murine xenogaft models of ALK-mutated NB, the combination led to inhibition of tumor growth and prolongation of survival compared to single agents alone. Together, these data support further pre-clinical and clinical efforts to explore the therapeutic potential of combining ALK inhibitors with transcriptional CDK inhibitors in ALK-mutated NB.
Citation Format: Nathan F. Moore, Edmond Chipumuro, Clark M. Hatheway, Tinghu Zhang, Nathanael S. Gray, Rani E. George. Combined inhibition of ALK and CDKs involved in transcriptional regulation is synergistic in ALK-mutated neuroblastoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B74.
Abstract B80: New inhibitors of histone deacetylase 8 (HDAC8) as anticancer agents
Authors: Jung Manfred , Chakrabarti Alokta , Heimbach Tino , Sippl Wolfgang , Marek Martin , Romier Christophe , Oehme Ina , Witt Olaf 
Published: May 2016

Abstract
The protein deacetylase HDAC8 has been recognized to be a potential target for the treatment of certain types of cancer, e.g. CNS cancer or T-cell leukemia. Starting out froom HDAC8 inhibitors with potency in the low micromolar region we have prepared a series of analogues and subjected them to iterative cycles of in-vitro testing using a fluorescence based assay and subsequent synthetic variation. Molecular docking to available X-ray structures of human HDAC8 further supported the process. We have obtained potent HDAC8 inhibitors in-vitro (potency down to 26 nM) and high selectivity over hHDAC1 and 6(&gt;200fold). Selected inhibitors block the proliferation of different cancer cell lines in culture (SH-SY5Y glioblastoma, Jurkat T-cell leukemia) and show hyperacetylation (shown by Western blotting) of the HDAC8 target Ac-SMC3.
Thus, we have obtained potent and selective HDAC8 inhibitors with cellular activity and target engagement. Mechanistic studies are underway to further optimized selected compounds.
Citation Format: Manfred Jung, Alokta Chakrabarti, Tino Heimbach, Wolfgang Sippl, Martin Marek, Christophe Romier, Ina Oehme, Olaf Witt. New inhibitors of histone deacetylase 8 (HDAC8) as anticancer agents. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B80.