bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B269: Effects of blocking aberrantly expressed CSF-1R in Hodgkin lymphoma.
Authors: Campion Liam , Deangelis Nikki , Ferrante Catherine , Verona Raluca , Seetharam Shobha , Manthey Carl , Snyder Linda
Published: August 2014

The human genome contains a large number of repetitive elements that have been suspected to play a role in human diseases. Recent literature has shown that aberrant activation of one of these repetitive elements, a long terminal repeat (LTR), leads to lineage inappropriate expression of the CSF-1 receptor (CSF-1R) transcript in Hodgkin's lymphoma (HL) clinical samples and cell lines. CSF1-R, also known as Feline McDonough Sarcoma (FMS), is the receptor for CSF-1 and IL-34, and under normal circumstances it plays an important role in monocyte survival, proliferation, and differentiation as well as osteoclast generation. Aberrant expression of CSF-1R has been shown previously to support proliferation and survival in HL cells. To confirm the role of CSF-1R in HL, we determined that 17 of 17 HL clinical samples and 7 of 7 HL cell lines were positive for the aberrant CSF-1R transcript by TaqMan and traditional PCR, while non-HL cell lines were negative for the aberrant CSF-1R transcript. The HL lines were further characterized for surface expression of CSF-1R by flow cytometry and CSF-1 secretion by ELISA. L-1236 cells expressed the highest levels of CSF-1R and CSF-1. Treatment of the HL cell lines with CSF-1R-Fc, resulted in reduced viability in four of the five lines, consistent with the hypothesis that HL cell lines are sensitive to CSF-1 as a growth factor. Additionally, it was found that treating the L-1236 HL cell line with the CSF-1R small molecule inhibitor JNJ-40646527 had a significant effect on viability of the HL cell line L-1236, with an IC50 of 264 nM at 72 hrs. JNJ-40646527 did not have a significant effect on the viability of several other HL cell lines. These results indicate that aberrant LTR driven CSF-1R expression may play a role in the pathogenesis of Hodgkin's lymphoma (HL) and could be a potential target for Hodgkin's lymphoma therapy.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B269.

Citation Format: Liam Campion, Nikki Deangelis, Catherine Ferrante, Raluca Verona, Shobha Seetharam, Carl Manthey, Linda Snyder. Effects of blocking aberrantly expressed CSF-1R in Hodgkin lymphoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B269.
Abstract B55: Antitumor activity of the MDM2 antagonist RG7388.
Authors: Higgins Brian , Tovar Christian , Glenn Kelli , Walz Antje , Filipovic Zoran , Zhang Yu-E , Dangl Markus , Graves Bradford , Vassilev Lyubomir , Packman Kathryn
Published: August 2014

The p53 tumor suppressor is a transcription factor that inhibits tumor development by inducing cell cycle arrest or apoptosis in response to diverse stresses. In normal cells, p53 levels are tightly controlled by MDM2 which binds p53 and negatively regulates its activity and stability. MDM2 is overproduced in many human cancers, thereby impairing p53 function. Antagonists of p53-MDM2 interaction can reactivate p53 and offer a novel approach to cancer therapy. The first potent and selective small-molecule inhibitors of p53-MDM2 binding, the nutlins, provided preclinical proof-of-concept for MDM2 antagonists as therapeutics for patients with tumors expressing wild-type p53. Subsequently, a member of the nutlin family, RG7112, was the first small molecule inhibitor of MDM2 to be tested clinically. Here we describe, RG7388, a highly optimized agent with analogous mechanism of action representing an entirely new branch of the nutlin family of MDM2 antagonists. Like RG7112, RG7388 binds selectively to the p53 site on the surface of the MDM2 molecule, effectively displacing p53 from MDM2, and leading to p53 stabilization and activation of the p53 pathway. However, RG7388 is derived from a distinct chemical series that binds with higher potency and selectivity to the MDM2 protein. RG7388 has substantially improved pharmacological properties, resulting in superior preclinical efficacy at lower doses and exposures as compared with its predecessor, RG7112. RG7388 elicits growth arrest and apoptosis at approximately 10-fold lower concentrations in vitro and in vivo, has an improved CYP inhibition profile, and a 2.5- to 20-fold lower projected human efficacious dose as compared with RG7112. Tumors with functional p53 signaling and MDM2 over-expression or amplification are likely to be the most sensitive to RG7388, however preclinical studies indicate that tumors with normal MDM2 levels may also respond to this novel therapeutic strategy. Results from preclinical safety and toxicology studies support further exploration of this compound in cancer patients. RG7388 is a promising agent that may offer a new therapeutic option and is currently in clinical testing in both solid and hematologic malignancies.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B55.

Citation Format: Brian Higgins, Christian Tovar, Kelli Glenn, Antje Walz, Zoran Filipovic, Yu-E Zhang, Markus Dangl, Bradford Graves, Lyubomir Vassilev, Kathryn Packman. Antitumor activity of the MDM2 antagonist RG7388. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B55.
Abstract C120: Genomic landscape in advanced metaplastic breast cancer and outcomes with mTOR targeted therapy.
Authors: Janku Filip , Kurzrock Razelle , Helgason Thorunn , Valero Vicente , Esteva Francisco , Wheler Jennifer J. , Karp Daniel D. , Meric-Bernstam Funda , Moulder Stacy L.
Published: August 2014

Background: Metaplastic breast cancer (BC) is a treatment-refractory rare type of BC with characteristics similar to claudin-low tumors. Understanding the genomic landscape of metaplastic BC can lead to identification of new therapies.

Methods: Patients with metastatic metaplastic BC referred for experimental therapies, who had adequate archival tumor tissue for DNA extraction, had targeted next-generation sequencing (NGS) for 3,769 exons of 236 cancer-related genes and 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform (Foundation One, Foundation Medicine, MA).

Results: NGS results were obtained for 10 women with metaplastic BC (median age 60 years [39-73], median prior therapies for metastatic BC 0 [0-1]). NGS revealed a total of 41 aberrations in 25 genes and all 10 patients had at least 1 molecular aberration (range 1-7, median 4). Of 41 detected molecular aberrations, 17 (41%) included putative activation of the PI3K/mTOR and/or MAPK pathways (PIK3CA [6], PTEN [3], PIK3R1 [1], NF1 [1], EGFR [1], EPHB1 [1], FGF23 [1], FGFR2 [1], HRAS [1], PTPN11 [1]), 13 (32%) loss of cell cycle control (CCND2 [1], CCND3 [1], CCNE1 [1], CDK2 [1], CDKN2A [2], MYC [6], RB1 [1]), 6 (15%) loss of apoptosis (MCL1 [1], NFKBIA [1], TP53 [4]), 2 (5%) aberrant DNA repair (BRCA2 [1], FANCA [1]), 2 (5%) aberrant methylation (KDM6A [1], MLL2 [1]) and 1 (2.5%) aberrant SWI/SNF chromatin remodeling (ARID1A [1]). Of the 10 patients, 9 (90%) received an experimental mTOR targeting therapy combination with temsirolimus, bevacizumab, and liposomal doxorubicin and at the median follow up of 5.8 months, 2 (22%) patients attained a partial response and 3 (33%) had stable disease >/= 4 months. The median progression-free survival was 6.2 months (95% confidence Interval 3.4 - 9.0)

Conclusion: Genomic alterations putatively activating PI3K/mTOR and MAPK pathways are common in metastatic metaplastic BC. A combination therapy targeting mTOR demonstrated encouraging activity.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C120.

Citation Format: Filip Janku, Razelle Kurzrock, Thorunn Helgason, Vicente Valero, Francisco Esteva, Jennifer J. Wheler, Daniel D. Karp, Funda Meric-Bernstam, Stacy L. Moulder. Genomic landscape in advanced metaplastic breast cancer and outcomes with mTOR targeted therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C120.
Abstract C125: Development of gene signature profile predicting nodal metastasis in squamous cell carcinoma of tongue.
Authors: Nair Sudhir V. , Upadhyay Pawan , D'Cruz Anil , Dutt Amit
Published: August 2014

Background: In India, oral cancer is the leading cancer type among men and third most common cancer among women. While 70% of patients in T1 (< 2cm) and 30% in T4 primary tumor stage are clinically node negative (N0), at the time of treatment, studies carried out at Tata Memorial Center suggest that 27% of these N0 patients had microscopic nodal metastatic disease (occult metastasis). Metastases are missed because they are not detectable with the currently available techniques. Hence all patients with oral cancers have to undergo a selective neck dissection as a diagnostic and therapeutic tool. Whole transcriptome Sequencing and simultaneous miRNA expression profiling of primary tumor will be an effective molecular tool to detect occult nodal metastasis.

Material and Methods: Whole Transcriptome Sequencing and miRNA expression profiling on total RNA extracted from 100 primary tumors and normal samples collected prospectively from patients with squamous carcinoma of the tongue with a clinical stage of T1 or T2 with N0 or N+ histopathology is underway. The raw reads obtained are aligned to the genome using TopHat, which uses Bowtie aligner for the mapping of the raw reads. The Bam/Sam output files generated by Tophat is used as an input files for cufflinks to assemble transcripts and estimate their abundance. The GTF files generated by Cufflinks are used to run Cuffdiff to find significant changes in the transcript expression and splicing between N0 and N+ samples.

Results: The literature suggests clinical and histological parameters of the primary tumor can predict lymphatic metastasis with an accuracy of 60%, however molecular profiling has a predictive accuracy of 86% to 90% and if used in clinics, may reduce the requirement for unnecessary neck dissections in a number of patients significantly. 10 whole transcriptome sequencing and 15 miRNA profiling studies from N0 and N+ tumor and normal tissues have been completed so far in this study. Early analysis reveals encouraging molecular profiles to identify subtypes based on the nodal infiltration status of the tumors. Data from these samples and additional ongoing experiments will be presented.

Conclusion: This is the first ongoing study from India to allow identify molecular signature that can prognosticate and stratify tongue cancer patients with potential to inform designing of clinical trials.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C125.

Citation Format: Sudhir V. Nair, Pawan Upadhyay, Anil D'Cruz, Amit Dutt. Development of gene signature profile predicting nodal metastasis in squamous cell carcinoma of tongue. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C125.
Abstract C130: The Hsp90 inhibitor ganetespib promotes the degradation of FGFR3 in bladder cancer models and induces regression in tumors harboring oncogenic FGFR3 fusions.
Authors: Acquaviva Jaime L. , Zhang Chaohua , He Suqin , Jimenez John-Paul , Nagai Masa , Sang Jim , Sequeira Manuel , Smith Donald L. , Knowles Margaret A. , Proia David A.
Published: August 2014

Background: Fibroblast growth factor receptor 3 (FGFR3) is activated by point mutation, chromosomal rearrangement, and/or receptor overexpression in a high percentage of bladder cancers, making FGFR3 an attractive therapeutic target for bladder cancer. Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability of FGFR3 and hundreds of other kinases and oncoproteins (termed “client proteins”), many of which are known to support tumorigenesis. Ganetespib is a selective inhibitor of Hsp90 currently being evaluated in several clinical trials, including a pivotal Phase 3 study. Here, we investigated the preclinical activity of ganetespib in bladder cancer models expressing FGFR3, as monotherapy or in combination with an FGFR inhibitor.

Results: Ganetespib displayed strong anticancer activity across a panel of 20 bladder cancer cell lines with diverse genetic backgrounds (mean EC50 = 38 nM), including those overexpressing wt FGFR3 or FGFR3 fusions. Notably, ganetespib was 10 times more potent than the selective FGFR3 inhibitor BGJ398 in bladder cancer cells with activating mutations in FGFR3. At the molecular level, ganetespib induced the rapid destabilization of full-length FGFR3 and the FGFR3-TACC3 fusion protein within 4 hours suggesting that FGFR3 is a highly sensitive Hsp90 client. Consequently, MAPK and AKT/mTOR signaling were suppressed, resulting in apoptosis evident by decreased levels of P-BAD and an increase in BIM, cleaved Caspase-3, and PARP expression. In vivo, ganetespib treatment led to tumor regression in RT112 xenografts coordinate with the deactivation of FGFR3-TACC3, as well as numerous other client proteins and their downstream effectors, as determined by phosphoprotein array. Combining ganetespib with BGJ398 increased tumor regression 3-fold compared to monotherapy.

Conclusions: The Hsp90 inhibitor ganetespib elicits the rapid degradation of FGFR3 mutants and fusion proteins in bladder cancer cells resulting in tumor regression in animal models, which could be further enhanced by combination with an FGFR inhibitor. These results may provide a framework for the future treatment of FGFR3-dependent bladder cancer.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C130.

Citation Format: Jaime L. Acquaviva, Chaohua Zhang, Suqin He, John-Paul Jimenez, Masa Nagai, Jim Sang, Manuel Sequeira, Donald L. Smith, Margaret A. Knowles, David A. Proia. The Hsp90 inhibitor ganetespib promotes the degradation of FGFR3 in bladder cancer models and induces regression in tumors harboring oncogenic FGFR3 fusions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C130.
Abstract C14: Squamous non-small cell lung cancer (NSCLC-SCC) patient-derived xenografts (PDX) from Asian patients have high response rate (RR) to cetuximab than those of adenocarcinoma.
Authors: Yang Mengmeng , Cai Jie , Guo Sheng , Huang Xuesong , Yang Jie , Song Xiaoming , Chen Dawei , Zhang Likun , Jiang Jiahua , Wery Jean-Pierre , Li Henry
Published: August 2014

Cetuximab was approved for advanced colorectal carcinoma (CRC), but yet for NSCLC, although some trials [e.g. FLEX (1) and BMS099 (2)] demonstrated benefit in subsets of patients. Recent retrospective study on Caucasian patients among the FLEX study cohort revealed that high EGFR expressors, uniquely defined by high-IHC score, are likely to benefit from the treatment (3). In particular, this was confirmed in a 50-patient derived xenografts model trial, mouse clinical trial (MCT or “Patient Avatar Trial”), in a similar format of FLEX, first time demonstrating relevance of human trial and MCT. The goal of the present study is identify the subset of Asian NSCLC patients that respond to cetuximab in a MCT. We have established a large panel of PDXs from NSCLC Asian patients of different histology (4): squamous cell carcinoma (SCC), adenocarcinoma (ADC), pleiomorphic carcinoma (PLC), and large cell carcinoma (LCC). We tested cetuximab activity in a randomly selected 32 PDX in a MCT. While NSCLC had overall engraftment rate of 25%, SCC interestingly, had higher rate of ∼31%, near-double ∼17% of ADC, which may have metastasis and prognosis implications. A subset of PDXs were found to respond to cetuximab (10/32) (31%, defined by %ΔT/ΔC < 25%). Surprisingly, all 10 responders exclusively belong to SCC and PLC (9/10 and 1/10 respectively), contrasting none to ADC (0/10). Non-/poor-responders (%ΔT/ΔC > 25%) include ADC (7/22), LCC (2/22) and SCC (12/22). Among the 12 non-/poor-responsive SCC, one has KRAS-G12D mutation, one has ALK-EML4 fusion and one has c-MET gene amplification. Among the SCC responders are ones with activating EGFR mutations. SCC has strikingly higher cetuximab response rate (RR) than ADC, with possible positive factors of EGFR mutation and negative factors of KRAS mutation, ALK fusion and c-met amplification. If proven true clinically, cetuximab could become a new therapy for NSCLC-SCC.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C14.

Citation Format: Mengmeng Yang, Jie Cai, Sheng Guo, Xuesong Huang, Jie Yang, Xiaoming Song, Dawei Chen, Likun Zhang, Jiahua Jiang, Jean-Pierre Wery, Henry Li. Squamous non-small cell lung cancer (NSCLC-SCC) patient-derived xenografts (PDX) from Asian patients have high response rate (RR) to cetuximab than those of adenocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C14.
Abstract C167: Establishment of a cancer-specific anti-podoplanin antibody not reacting with lymphatic endothelial cells.
Authors: Kato Yukinari , Kaneko Mika K.
Published: August 2014

Podoplanin is a mucin-like sialoglycoprotein that is highly expressed in brain tumors, mesotheliomas, testicular tumors, and several squamous cell cancers. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. We previously established a neutralizing monoclonal antibody (mAb; NZ-1) and its human chimeric mAb (NZ-8), which inhibit the association between podoplanin and CLEC-2, block the podoplanin-induced tumor metastasis, and possess extremely high antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, those mAbs also react with normal cells including type I alveolar cells, podocytes, and lymphatic endothelial cells. Herein, we established the platform to produce cancer-specific mAbs (CasMabs) by combining glycobiology and cell engineering technologies, and successfully produced cancer-specific anti-podoplanin mAbs, which react with tumor cells but not with lymphatic endothelial cells in flow cytometry and immunohistochemistry. Both peptides and glycans of podoplanin were included in the epitopes of those mAbs. The CasMab-producing platform could lead to establishment of the side effect-reducing mAbs.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C167.

Citation Format: Yukinari Kato, Mika K. Kaneko. Establishment of a cancer-specific anti-podoplanin antibody not reacting with lymphatic endothelial cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C167.
Abstract C195: CD98hc (SLC3A2) is a central regulator of renal cancer cell behavior.
Authors: Prager Gerald W. , Poettler Marina , Unseld Matthias , Zielinski Christoph
Published: August 2014

CD98, a heterodimeric transmembrane protein, physically associates with certain integrin β subunit cytoplasmic domains via its heavy chain, CD98hc (SLC3A2). Thereby CD98hc regulates adhesion-induced intracellular signal transduction via integrins, thus, affecting cell proliferation and clonal expansion. Disruption of CD98hc led to embryonic lethality in mice (E3.5 and E 9.5) and CD98hc -/- embryonic stem cell transplantation failed to form teratomas, while over-expression of CD98hc in somatic cells resulted in anchorage-independent growth. Although, we and others identified CD98hc to be highly overexpressed in various cancer types, a functional role of CD98hc in tumor cell behavior is so far unknown. Here we demosntarte that the disruption of CD98hc interaction with integrins in clear cell renal cell cancer (ccRCC) leads to impaired tumor cell behavior such as cell spreading, migration, proliferation and survival in vitro and of tumor growth in vivo. CD98hc/integrin interaction was required for adhesion-induced sustained FAK phosphorylation and activation of the major downstream signaling pathways PI3k/Akt and MEK/ERK, while overexpression of a constitutive active form of FAK rescued for the CD98hc deficiency. Thus, we have identified the cell surface protein CD98hc as a critical mediator of integrin-dependent tumor cell functions. These studies suggest that interference with CD98hc might lead to a novel therapeutic strategy in renal cell cancer.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C195.

Citation Format: Gerald W. Prager, Marina Poettler, Matthias Unseld, Christoph Zielinski. CD98hc (SLC3A2) is a central regulator of renal cancer cell behavior. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C195.
Abstract C7: Inhibitory effects of flavonoid Apigenin by oral administration on angiogenesis of ovarian cancer through decrease VEGF expression in mouse model.
Authors: Alipour Majid
Published: August 2014

Diet can play a vital role in cancer prevention. Studies have shown that a diet high in fruits and vegetables is associated with a reduced risk of cancer. Apigenin is a non-toxic and non-mutagenic natural flavonoid. Our previous studies demonstrated the effects of apigenin on angiogenesis in CAM model is by two distintic parallel PI3K/AKT and jak/STAT pathways. Vascular endothelial growth factor (VEGF) is one of the most important of all known inducers of angiogenesis and in many cancers this protein is over-expressed. Studies confirm Apigenin efficient on reduction VEGF expression. In this study, as first time, effect of Apigenin is evaluated by oral administration on angiogenesis decreasing and VEGF expression levels were measured in creatures. After infection of mice's ovarian by A2780 cancer cell line, Apigenin (75/mg/kg/day) were fed once a day for 30 days to the animals and angiogenesis measured in vivo. Histological methods were used for counting blood vessels, ELISA analysis was used to measurement of VEGF protein in infected tissues. to confirm the effect of oral administration of Apigenin on VEGF expression, A2780 cells were infected by VEGF promoter reporter vectors then injected to the mice. Studies have shown that taking these orally, Apigenin reduced VEGF expression and ultimately leads to reduced angiogenesis.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C7.

Citation Format: Majid Alipour. Inhibitory effects of flavonoid Apigenin by oral administration on angiogenesis of ovarian cancer through decrease VEGF expression in mouse model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C7.
Abstract C79: TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs.
Authors: Huang Shar-Yin N. , Murai Junko , Dalla Rosa Ilaria , Dexheimer Thomas S. , Gmeiner William H. , Pommier Yves
Published: August 2014

Nucleoside analogs (NAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these chain-terminating NAs. Here we reveal the importance of tyrosyl-DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by chain-terminating NAs. Upon investigating the effects of four NAs: acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT) and zalcitabine (ddC), we show that TDP1 is capable of removing the covalently-linked corresponding NAs from DNA 3’-ends. We also show that Tdp1–/– cells are hypersensitive and accumulate more DNA damage when treated with ACV and Ara-C, implicating TDP1 in repairing NA-induced DNA damage. Since AZT and ddC are known to cause mitochondrial dysfunction, we examined whether TDP1 repairs the mitochondrial DNA damage they induced. We found that AZT and ddC treatment leads to greater depletion of mitochondrial DNA in Tdp1–/– cells. Thus, TDP1 appears critical for repairing nuclear and mitochondrial DNA damage caused by chain-terminating NAs.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C79.

Citation Format: Shar-Yin N. Huang, Junko Murai, Ilaria Dalla Rosa, Thomas S. Dexheimer, William H. Gmeiner, Yves Pommier. TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C79.
Abstract CN01-01: Opportunities for systemic treatment using siRNA in nanoparticles.
Authors: McCormick Frank
Published: August 2014

Systemic delivery of siRNA has the potential to revolutionize cancer therapy. This technology is indifferent to the “druggability” of the target, and therefore opens up opportunities to target cancers driven by mutant RAS genes, or by MYC, β-catenin, and so on. Furthermore, elimination of well-established drug targets such as EGF-R could circumvent the problem of drug resistance. Complex mixtures of siRNAs can be loaded into nanoparticles, facilitating knock-down of genes that confer adaptive resistance, as well as potentiating the effects of knocking down driver genes by eliminating passengers.

In addition to these opportunities, systemic delivery of siRNA has another major advantage, which could greatly accelerate the rate of drug development, while decreasing costs and risk of failure. One a system is proven safe and effective to deliver a specific siRNA or cocktail, the same system can be used repeatedly for different payloads. This is in marked contrast with the current approach of developing individual chemical entities, each with its own safety profile and its own ADME characteristics,

Effective delivery requires nanoparticles with certain physical and chemical properties, but these particles need to be internalized into cells through surface receptors. The physical properties and internalizing ligands add selectivity to the particles, in addition to the expected selectivity of the siRNA payload. Together these considerations raise the possibility of a new generation of safe and effective therapies for treating cancer.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN01-01.

Citation Format: Frank McCormick. Opportunities for systemic treatment using siRNA in nanoparticles. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN01-01.
Abstract PL01-04: Mechanisms of acquired resistance to ALK/ROS1 inhibitors.
Authors: Shaw Alice T.
Published: August 2014

Chromosomal rearrangements of ALK and ROS1 define two distinct molecular subsets of non-small cell lung cancer (NSCLC). The multitargeted tyrosine kinase inhibitor crizotinib is highly active in both ALK- and ROS1-rearranged NSCLC, inducing responses in approximately 60% of patients. However, most patients relapse within the first year or two of treatment due to the development of resistance. Multiple distinct mechanisms of crizotinib resistance have been discovered in resistant tumor specimens and subsequently validated in the laboratory. These include acquisition of secondary resistance mutations in the ALK or ROS1 tyrosine kinase domain, amplification of the target gene, and activation of alternative signaling pathways like EGFR. In this talk, we will review the data supporting these established mechanisms of resistance. In addition, we will describe emerging resistance mechanisms, including epithelial to mesenchymal transition and pharmacokinetic failure leading to both systemic and central nervous system relapses. We will also explore the potential basis for both the homogeneity and heterogeneity of resistance that has been observed in patients. Finally, we will delve into therapeutic strategies that are currently being developed based on our understanding of resistance. These include more potent and selective ALK/ROS1 inhibitors (so called next generation inhibitors), as well as a variety of different combination strategies. These strategies are being tested primarily in patients who have already developed resistance, but they may in fact have greater impact in sensitive, treatment-naive patients by thwarting or delaying the emergence of resistance.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL01-04.

Citation Format: Alice T. Shaw. Mechanisms of acquired resistance to ALK/ROS1 inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL01-04.
Abstract PL05-03: Phylogenetic quantification of intra-tumor heterogeneity predicts time to relapse in high-grade serous ovarian cancer.
Authors: Markowetz Florian M.
Published: August 2014

Intra-tumor genetic heterogeneity is the result of ongoing evolutionary change within each cancer. The expansion of genetically distinct sub-clonal populations may explain the emergence of drug resistance and if so would have prognostic and predictive utility. However, methods for objectively quantifying tumor heterogeneity have been missing and are particularly difficult to establish in cancers where predominant copy number variation prevents accurate phylogenetic reconstruction because of horizontal dependencies caused by long and cascading genomic rearrangements. To address these challenges we have developed MEDICC, a method for phylogenetic reconstruction and heterogeneity quantification, which determines optimal phasing of major and minor alleles, computes evolutionary distances between samples, and reconstructs ancestral genomes. Rigorous simulations and an extensive clinical study show the power of our method, which outperforms state-of-the-art competitors in reconstruction accuracy and additionally allows unbiased numerical quantification of tumor heterogeneity. Using MEDICC we investigated the relationship between tumor heterogeneity and patient outcome in high-grade serous ovarian cancer. We found that tumor heterogeneity in this cancer is driven by ongoing clonal evolution with fully branched evolutionary trajectories that do not have clock-like evolutionary rates. Quantitative measures of clonal expansion and temporal heterogeneity were the strongest predictors of progression-free survival. We show in 2 patients that clonal expansion of a minor subclone that was present prior to chemotherapy led to clinical relapse.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL05-03.

Citation Format: Florian M. Markowetz. Phylogenetic quantification of intra-tumor heterogeneity predicts time to relapse in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL05-03.
Abstract 1753: Comparison between early versus delayed treatment of breast cancer induced osteolytic bone metastasis by TGFβ inhibitors in a murine model
Authors: Bandyopadhyay Abhik , Agyin Joseph , Lopez-Casillas Fernando , Wang Long , Biswas Tanuka , Sun Lu-Zhe
Published: August 2014

In breast cancer patients the preferential metastasis to bone often causes considerable morbidity and mortality. Timely intervention is needed for the prevention and treatment of breast cancer-induced bone metastasis and osteolysis. Increased TGFβ signaling has been implicated to promote cancer cell invasion to bone and cause osteolysis. In this study we have evaluated the efficacy of the early and delayed start of treatment by TGFβ antagonists, TGFβ R1 kinase inhibitor (TβRI) and soluble TGFβ type III receptor (sRIII), in a murine bone metastasis model utilizing human breast cancer cells. The female athymic nude mice injected intracardiacally with human breast cancer MDA-MB-231 cells were divided into five groups (n=10). In the two early treatment groups, the i.p. treatment started on the same day of tumor cell inoculation and in the two delayed treatment groups, treatment started on the 8th day after tumor cell inoculation with TβRI (20 µg/mice) and sRIII (100 µg/mice) respectively and continued every alternate day. Control group of animals were injected with phosphate buffered saline. The experiment was terminated after 25 days. The incidence of osteolytic metastasis determined by Faxitron X-Ray of the legs and tumor burden by the histology of tibia was remarkably reduced in the early treatment group in comparison to the control group. On the other hand, the delayed start of the treatment showed little effect on the reduction of tumor burden and bone loss indicating better efficacy of early treatment by TGFβ inhibitors in preventing homing of the tumor cells into the bone. As a potential mechanism, we have investigated the role of TGFβ inhibitors in vitro on the bone marrow mesenchymal stem cell (BM-MSC) induced cancer cell invasion which has been implicated to facilitate early entry of breast cancer cell into bone marrow. We have observed that the medium conditioned by BM-MSCs stimulated the invasion of MDA-MB-231 cells, which was significantly inhibited by TGFβ antagonists. Our results point to the possible therapeutic utility of TGFβ inhibitors to prevent primarily the initiation of breast cancer-induced bone metastasis by the inhibition of homing of the tumor cells into the bone. The mechanism may involve the modulation of the bone marrow mesenchymal stem cell microenvironment.

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 1753. doi:10.1158/1538-7445.AM2011-1753
Abstract 1758: Influence of stromal microenvironment on rGel/BLyS-induced cytotoxicity in diffuse large B-cell lymphoma cells
Authors: Lyu Mi-Ae , Cheung Lawrence H. , Marks John W. , Rosenblum Michael G.
Published: August 2014

Diffuse large B cell lymphoma (DLBCL) is an aggressive sub-type accounting for 30-40% of non-Hodgkin's lymphoma. Despite recent advances in the understanding of the molecular and cellular basis for their pathogenesis, these tumors are still associated with poor response to treatment and a fatal outcome. The interactions of marrow stromal cells (MSCs) with tumor cells appear to be important in the development of tumor drug resistance through complex cytokine and adhesion-mediated mechanisms. We previously generated a highly cytotoxic growth factor fusion toxin designated rGel/BLyS for receptor-mediated delivery of the rGel toxin to malignant B cells. This fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA. In this study, we examined the impact of marrow stromal cells (MSCs) on rGel/BLyS-induced cytotoxicity in DLBCL cells. Treatment of tumor cell lines with dexamethasone and doxorubicine in the presence of MSCs was found to suppress the cytotoxic effect. In contrast, in vitro treatment with rGel/BLyS showed specific cytotoxic effects to DLBCL cell lines (IC50 ∼ 1-10 nM) in absence of MSCs or in presence of MSCs. At these doses, we found no cytotoxicity to MSCs. Treatment with rGel/BLyS induced down-regulation of Mcl-1, c-Myc, Bcl-xL, X-IAP, and Bcl-2 in DLBCL cells in absence of MSCs or in presence of MSCs. We also found that rGel/BLyS induced down-regulation of interleukin-6 receptor in DLBCL cells in absence of MSCs or in presence of MSCs. In addition, treatment of cells with rGel/BLyS induced apoptosis through caspase-9 activation, caspase-3 activation, and PARP cleavage. Our results demonstrate that rGel/BLyS can overcome stromal cell-mediated drug resistance which is a factor reducing the effectiveness of other conventionally-used agents for the treatment of this disease. This suggests that rGel/BLyS may be an excellent candidate for the treatment of DLBCLs which are resistant to conventional chemotherapeutic regimens. This research was conducted, in part, by the Clayton Foundation for Research and by Translational Research Award (LLS 6234-07) from the Leukemia and Lymphoma Society.

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 1758. doi:10.1158/1538-7445.AM2011-1758
Abstract 1761: Anti-tumor activity of trastuzumab-DM1 in combination with pertuzumab in a gastric cancer model
Authors: Yamashita-Kashima Yoriko , Fujimoto-Ouchi Kaori
Published: August 2014

Objective: Anti-HER2 therapy is considered to be important for gastric cancer as well as breast cancer. In a previous study, we showed the combinational efficacy of trastuzumab and pertuzumab (an anti-HER2 antibody which binds a different HER2 domain from trastuzumab) in HER2-positive gastric cancer models (AACR, 2010). In the present study, we investigated the usefulness of a HER2 antibody-cytotoxic drug conjugate, trastuzumab-DM1 (T-DM1) as monotherapy and in combination with pertuzumab for HER2-positive gastric cancer as a novel therapy.

Methods: A HER2 over-expressing human gastric cancer, NCI-N87 mouse xenograft model was used for examining the efficacy. T-DM1 was administered intravenously once every 3 weeks. Pertuzumab was administered intra-peritoneally once a week. Tumor growth inhibition (TGI) after 6 weeks of treatment was determined from tumor volume measurements. Apoptosis activity was measured with the activity of caspase 3/7. To measure ADCC activity, a real-time cell analyzer was used.

Results: T-DM1 (1.25, 2.5, 5, 10, 20, 40 or 80 mg/kg) as monotherapy showed tumor growth inhibition dose-dependently in the NCI-N87 model. The maximum effective dose was 10 mg/kg and TGI on day 42 after treatment started was 113%. T-DM1 (5 mg/kg) in combination with pertuzumab (40 mg/kg) in the NCI-N87 model showed significantly potent anti-tumor activity with a TGI of 113%. Both T-DM1 and pertuzumab as monotherapies showed significant anti-tumor activity, their TGI were 79% and 47%, respectively. To examine the mechanism of action of the combination of T-DM1 and pertuzumab, we analyzed apoptosis of NCI-N87 cells after treatment with T-DM1, pertuzumab or both under stimulation of EGF or heregulin. 24 h after treatment, the combination group had significantly enhanced caspase 3/7 activity compared with the monotherapy groups. We also examined ADCC activity of these agents. Both T-DM1 and pertuzumab showed ADCC activity and that activity was enhanced by the combination.

Conclusion: In this study, we showed that T-DM1 as monotherapy has significant anti-tumor activity in a mice model of HER2-positive gastric cancer. Furthermore, combining T-DM1 with pertuzumab significantly enhanced the anti-tumor activity compared with the efficacy of each agent used in monotherapy. The mechanism of this combination might be the potentiation of apoptosis induction and ADCC activity. The present study suggests that T-DM1 as monotherapy and in combination with pertuzumab would provide benefit for patients with HER2-positive gastric cancers.

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 1761. doi:10.1158/1538-7445.AM2011-1761
Abstract 1763: The discovery of novel non-RGD-containing αvβ3 ligands for molecular imaging
Authors: Cho Choi-Fong , Amadei Giulio , Breadner Daniel , Luyt Leonard , Lewis John
Published: August 2014

Metastasis is the cause of 90% of cancer deaths. The detection of neoplasms before they metastasize using non-invasive molecular imaging approaches can have a significant impact on patient survival. For many years it has been known that αvβ3 integrin, which is over-expressed on angiogenic endothelium and many tumours, associates with the extracellular matrix through an RGD tripeptide motif. RGD-mediated targeting has been utilized for a wide variety of peptide and nanoparticle molecular imaging agents that are in various stages of development and in clinical trials. As RGD peptide decreases cell adhesion, concerns regarding its utilization as a molecular imaging agent have been raised (Kiessling et. al., 2009 Radiology). RGD peptides exert an anti-angiogenic effect through their inhibition of αvβ3 integrin, raising the concern given recent studies (Ebos et. al., 2009 Cancer Cell v15; Paez-Ribes et. al., 2009 Cancer Cell v15) that this anti-angiogenic activity may result in increased tumour invasion and metastasis. We sought, therefore, to discover novel αvβ3 integrin-targeted peptides that do not contain RGD for the development of new molecular imaging agents. Using a recently developed “beads on a bead” approach, we screened a linear octapeptide one bead one compound library using purified αvβ3 integrin. Over one hundred peptides were isolated and sequenced “on bead” using a novel MALDI-TOF/MS technique and a number of non-RGD containing peptides were identified. Two of these peptides had a higher binding affinity for purified αvβ3 integrin than the linear RGD peptide (LCE62, KD = 4.7 nM and LCE64, KD = 16.3 nM) as determined by surface plasmon resonance. In contrast to peptides containing RGD, these peptides did not impact the morphology and adhesion of αvβ3 integrin-expressing MDA-435 cells, nor did they inhibit angiogenesis. The uptake of both fluorescein-labeled LCE62 and LCE64 by αvβ3 integrin-expressing breast cancer cells were significantly higher compared with a control AGD peptide. We have also demonstrated that this uptake was effectively blocked by an excess of free unlabeled peptide. These novel αvβ3 integrin-binding peptides could provide a basis for a new and potentially safer generation of molecular imaging agents for the early diagnosis of cancers.

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 1763. doi:10.1158/1538-7445.AM2011-1763
Abstract 1765: Inhibition of Notch signaling by a Notch1 monoclonal antibody induces robust anti-tumor efficacy in T-cell acute lymphoblastic leukemia and breast cancer
Authors: Wei Ping , Qiu Ming , Peng Qinghai , Lippincott John , Zachwieja Joseph , Kraynov Eugenia , Wu Aidong , Han Bora , Stone Donna , Zhai Wenwu , Rymer Isha , Yang Jennifer , Gajiwala Ketan , Yu Xiu , Gao Yijie , Tchistiakov Lioudmila , Ma Wenxue , Jamieson Catriona H. M. , Los Gerrit , Greenberg Norman , Li Kang
Published: August 2014

Notch signaling is deregulated in T-cell acute lymphoblastic leukemia (T-ALL) and advanced solid tumors, making it an attractive target for oncology drug development.

In this present report, we describe a novel mouse monoclonal antibody, Notch1 mAb, that specifically binds to the negative regulatory region (NRR) of human Notch1 receptor. Using a T-ALL cell line, HPB-ALL, that harbors mutations in Notch1 heterodimerization and PEST domains, we demonstrated that Notch1 mAb blocked Notch signaling by reduction of Notch1 intracellular domain (NICD) and down-regulation of Notch target genes, Hes-1 and cMyc. Notch1 mAb caused cell growth inhibition of HPB-ALL and several other T-ALL cell lines, via induction of cell cycle arrest and apoptosis. Notch1 mAb treatment resulted in robust NICD reduction and marked antitumor efficacy in HBP-ALL xenograft model. Additional mechanism-of-action studies revealed inhibition of tumor cell proliferation and induction of apoptosis in HPB-ALL tumors, suggesting that the anti-tumor activity of Notch1 mAb may be mediated by its direct effects on tumor cell growth or survival. Furthermore, this antibody led to a significant reduction in leukemia progenitor cells (LPCs) baring NOTCH1 mutation in bioluminescent humanized T-ALL LPC mouse models. In addition to its inhibitory effect on mutant Notch1, Notch1 mAb also displayed robust neutralization activity on wild type Notch1 and caused tumor growth inhibition in breast cancer models MDA-MB-231 and MX-1 by targeting the wild type receptor in these tumor types. Interestingly, using a gamma secretase inhibitor PF-03084014, we showed that Notch1 mAb and PF-03084014 elicited similar degree of biology responses in HPB-ALL cells. Our results indicate that antibodies that bind to NRR can act as potent inhibitors of Notch1 signaling and provide opportunities for development of novel cancer therapeutics for T-ALL and solid tumors.

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 1765. doi:10.1158/1538-7445.AM2011-1765
Abstract 177: Disruption of the MDM2-p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin resistant human testicular carcinoma cells via the Fas/FasL pathway
Authors: de Jong Steven , Koster Roelof , Timmer-Bosscha Hetty , Bischoff Rainer , Gietema Jourik
Published: August 2014

A major role for p53 in the response and execution of apoptosis after chemotherapy has been described for many cancers. Although testicular cancer (TC) often express high levels of p53 and almost no TP53 mutations are found, resistance to chemotherapy is still observed in a subgroup of TC patients. Therefore, the involvement of wild-type p53 in cisplatin sensitivity and resistance of human TC is not clear. In the present study, we demonstrate that in resistant human TC cells (Tera2-CP, Scha, 2102EP) p53 resides in a complex with murine double minute 2 (MDM2) even at higher cisplatin concentrations compared to cisplatin sensitive human TC cells (Tera2). Hyper-activation of the p53 pathway using the MDM2 antagonist Nutlin-3 in TC cells leads to nuclear localization of p53 and effective apoptosis induction as single agent. Targeting MDM2 with short interfering RNA extremely sensitizes TC cells in a similar way. The observed effects are dependent on the presence of wild-type p53, since mutant p53 expressing TC cells (NCCIT) or wild-type p53 suppressed TC cells are resistant to Nutlin-3. Specifically, we show that the Fas death receptor pathway, i.e. enhanced Fas expression (3-fold) and the induction of Fas/FasL interactions, plays an important role in MDM2 antagonist-induced apoptosis in TC cells as demonstrated by using FasL blocking antibodies and FasL small interfering RNA. Importantly, we have identified a similar mechanism in Hodgkin lymphoma cells (KM-H2 and L540) and acute myeloid leukaemia cells (MOLM-13), suggesting a common profile for Nutlin-3-induced apoptosis, which involves the Fas death receptor pathway. Finally, we combined nutlin-3 with cisplatin, which strongly sensitized TC cells, including cisplatin-resistant TC cells, to apoptosis via Fas pathway activation and reduced cell survival more than 8-fold. These results indicate that targeting the p53/MDM2 axis, in combination with standard treatment, appears to be a powerful strategy to pursue in cisplatin-resistant or -refractory testicular cancers.

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 177. doi:10.1158/1538-7445.AM2011-177