bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5474: PD-L1 regulates cisplatin chemoresistance in head and neck squamous cell carcinoma
Authors: Ruffner Randall S. , Ramsey Andrew , O'Malley Bert W. , Li Daqing 
Published: August 2015

Abstract
PD-L1 has been known to play a major role in suppressing the immune system. The effect of PD-L1 has been clinically studied by inhibiting PD-L1 in tumor and tumor-infiltrating immune cells, thereby activating anti-tumor T cells and re-establishing anti-tumor immune responses. Little is known about a unique role of PD-L1 in cisplatin chemoresistance of head and neck squamous cell carcinoma (HNSCC). The aim of the current study is to investigate a novel finding that PD-L1 regulates DNA double strand break (DSB) repairs via the MRE11-RAD50-NBS1 (MRN) complex and contributes to cisplatin chemoresistance in HNSCC.
Well-characterized HNSCC tumor cell lines were used for this study. JHU 006 tumor cell line has a cisplatin resistant phenotype whereas JHU 020 is cisplatin sensitive. PD-L1 expression was determined by quantitative polymerase chain reaction (qPCR) and western blot before and after cisplatin treatment. The interactions between PD-L1 and MRN in DNA DSB mediated chemoresistant pathway were studied. PD-L1 siRNA was used to induce chemosensitization of HNSCC cells to cisplatin.
Our study demonstrates that treatment of HNSCC cells with cisplatin resulted in increased expression of PD-L1 in cisplatin resistant tumor cells, whereas chemosensitive tumor cells showed no change in PD-L1 expression. Additionally, knockdown of PD-L1 using siRNA resulted in downregulation of NBS1, a key protein of the MRN DNA DSB repair complex. However, NBS1 was able to modulate the levels of PD-L1 expression as the use of either NBS1 siRNA or cells that had been transfected with a dominant negative NBS1 mutant resulted in increased PD-L1 expression. The experimental data suggest that PD-L1 may act as an upstream regulator of NBS1 and may facilitate formation of the MRN complex, enhancing repair of cisplatin induced DNA damage, thereby increasing the cell's resistance to chemotherapeutics. Decreasing expression of PD-L1 via siRNA leads to increased sensitivity of HNSCC cells to cisplatin. This highlights the importance of PD-L1 in the development of chemoresitance and suggests a potential therapeutic strategy for patients with cisplatin-resistant HNSCC.
In conclusion, we have identified a novel role for PD-L1 in the development of chemoresistance through its interaction with the MRN complex, which plays a major role in the repair of chemo-induced DNA DSB. Therapies aimed at blocking PD-L1 show great promise because of their ability to enhance both chemotherapeutics and the anti-tumor immune response.
Citation Format: Randall S. Ruffner, Andrew Ramsey, Bert W. O'Malley, Daqing Li. PD-L1 regulates cisplatin chemoresistance in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5474. doi:10.1158/1538-7445.AM2015-5474
Abstract 5499: Necuparanib affects tumor progression and invasion in a 3D co-culture system of pancreatic cancer cells and stellate cells
Authors: Krause Silva , Weyers Amanda , Loveluck Katie , Schultes Birgit 
Published: August 2015

Abstract
Pancreatic cancer is one of the most aggressive and deadliest cancers, with only about 5% of patients surviving 5 years past the initial diagnosis. In over 80% of patients the cancer has already spread to distant organs at the time of diagnosis, making it difficult to treat. Most alarmingly, pancreatic cancer is the only cancer for which deaths are predicted to increase over the next few years. Despite advances with new chemotherapy combinations, overall survival outcomes are still dismal and require novel therapeutic approaches. Necuparanib (formerly M402) is a heparan sulfate-like molecule that binds and inhibits multiple heparin-binding growth factors, chemokines, adhesion molecules and enzymes involved in cancer progression and metastasis and as such modulates multiple elements of the tumor microenvironment. In order to further explore the mechanism of action for epithelial-stromal interactions affected by necuparanib, a 3-dimensional culture system mimicking pancreatic cancer was developed containing a co-culture of pancreatic tumor cells and pancreatic stellate cells, the most abundant stromal cell in the pancreas. In this culture system, pancreatic cancer cells form a tumor spheroid embedded in a matrix that is a mixture of type I collagen and basement membrane extract and contains pancreatic stellate cells. Notably, pancreatic cancer cells required the co-culture with pancreatic stellate cells to become invasive in vitro. Conditioned medium derived from pancreatic stellate cells could not mimic this effect indicating that soluble factors are not sufficient to cause invasion into surrounding matrix. Necuparanib inhibited the invasive behavior in a dose-dependent manner. The effect of pancreatic stellate cells on tumor cell invasion and the effect of necuparanib on stromal cells were further explored in this culture system. We showed an effect of necuparanib on proliferation, migration and invasion of pancreatic tumor cells. These studies aid in our understanding of the key biological targets and pathways responsible for necuparanib's anti-tumor effects and support biomarker discovery in the ongoing Phase 2 efficacy study in metastatic pancreatic cancer.
Citation Format: Silva Krause, Amanda Weyers, Katie Loveluck, Birgit Schultes. Necuparanib affects tumor progression and invasion in a 3D co-culture system of pancreatic cancer cells and stellate cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5499. doi:10.1158/1538-7445.AM2015-5499
Abstract 635: Development of anti-cancer ADCs with Concortis’ C-and K-lock technology
Authors: Chen Gang , Zhu Tong , Deng Dylan , Zhang Hong , Miao David 
Published: August 2015

Abstract
Antibody-Drug Conjugation (ADC) is a rapidly growing area and has been widely explored for cancer therapy. In the past decade, numerous progresses have been reported on the identification of proper antibodies, targets validation, discovery of novel payloads, improvement of linkers, as well as the development of new coupling techniques.
We have developed novel conjugation methods, C-lock, K-lock and the combination of the two. C-LockTM conjugation method utilizes a novel linker chemistry to re-connect the reduced disulfide bonds between antibody heavy and light chains, and in the meantime, to introduce a drug to each disulfide bond. While K-LockTM conjugation method is a linker-controlled conjugation technology highly selective on 1 or 2 particular sites among 80-90 Lys side chains of an antibody. The generated ADCs have fewer regioisomers and lower DAR (Drug-Antibody Ratio) while maintaining comparable potency to ADCs from regular conjugation methods. Further purification will give rise to site-specific homogeneous products without needs for cell engineering or enzymatic modification steps. The lead ADCs generated by these technologies showed improved activity both in vitro and in vivo in relevant tumor models, and also exhibited less toxicity compared to commercial standard.
To pursue to the next level, we are currently developing dual drug ADCs which have two different payloads conjugated to single antibody; as well as bi-specific ADCs with either single or dual drug conjugations (2nd generation or ADC-2X). Initial results indicated that these ADCs showed improved activity and specificity in relevant tumor cell lines compared to 1st generation ADCs. Detailed results will be reported. All these data proved that our ADC technologies are unique and superior in antibody drug conjugation and are promising for anti-cancer drug development.
Citation Format: Gang Chen, Tong Zhu, Dylan Deng, Hong Zhang, David Miao. Development of anti-cancer ADCs with Concortis’ C-and K-lock technology. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 635. doi:10.1158/1538-7445.AM2015-635
Abstract 637: Preclinical activity of hLL2-PBD, a novel anti-CD22 antibody-pyrrolobenzodiazepine (PBD) conjugate in models of non-Hodgkin lymphoma
Authors: Zammarchi Francesca , Williams David , Havenith Karin , D'Hooge Francois , Howard Philip W. , Hartley John A. , van Berkel Patrick 
Published: August 2015

Abstract
CD22 is a type I transmembrane sialoglycoprotein, which expression is restricted to the B-cell lineage. CD22 is also found highly expressed on most malignant mature B cells, including follicular non-Hodgkin lymphoma (NHL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL).
The differential and favorable expression profile of CD22 in normal and tumor tissues, together with its rapid internalization upon binding with a ligand or antibody, make CD22 an attractive target for an antibody drug conjugate (ADC) mediated treatment of B-cell malignancies. hLL2-PBD is an ADC composed of the humanized monoclonal antibody epratuzumab (hLL2) against human CD22 stochastically conjugated via a valine-alanine cleavable, maleimide linker to a PBD dimer. PBD dimers represent a novel class of payloads, which bind in the DNA minor groove and form highly cytotoxic DNA interstrand cross-links. The average drug to antibody ratio (DAR) of hLL2-PBD is 2.
In vitro, hLL2-PBD showed potent and specific cytotoxicity, as assessed by the MTS assay, in the CD22-positive human Burkitt's lymphoma-derived cell lines Ramos and Daudi and the human diffuse large B-cell lymphoma-derived cell line WSU-DLCL2.
In vivo, hLL2-PBD demonstrated potent anti-tumor efficacy in subcutaneously (s.c.) implanted Daudi and Ramos xenograft models. In the Daudi model, hLL2-PBD, administered as a single dose at either 0.1 or 0.3 mg/kg, achieved dose-dependent anti-tumor activity, resulting in significant increase in survival. At 0.3 mg/kg, hLL2-PBD induced complete tumor regression in all treated animals. In the Ramos xenograft model, a single dose of 1 mg/kg of hLL2-PBD achieved strong tumor regression. Moreover, hLL2-PBD achieved a superior anti-tumor activity compared to Hu10F4-vcMMAE, a CD22-targeting ADC with the auristatin payload vcMMAE and a DAR of 4 (Genentech Inc.), when tested at 1 mg/kg, single dose. Pharmacokinetic (PK) analysis of hLL2-PBD in CB.17 SCID mice showed a favorable PK profile, with a half-life of approximately 12 days.
In conclusion, these data demonstrate the potent in vitro and in vivo anti-tumor activity of hLL2-PBD against CD22-positive hematological tumors and warrant further development of this ADC into the clinic.
Citation Format: Francesca Zammarchi, David Williams, Karin Havenith, Francois D'Hooge, Philip W. Howard, John A. Hartley, Patrick van Berkel. Preclinical activity of hLL2-PBD, a novel anti-CD22 antibody-pyrrolobenzodiazepine (PBD) conjugate in models of non-Hodgkin lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 637. doi:10.1158/1538-7445.AM2015-637
Abstract 651: Superior anti-tumor activity compared to T-DM1 in preclinical studies of targeted therapies for her2-positive cancers by a novel her2-ADC ZV0201
Authors: Zhang Hong , Li Zhaohui , Zhu Tong , Cao Sheldon , Chen Gang , Miao David 
Published: August 2015

Abstract
ZV0201 is a her2-targeting ADC based on newly developed K-Lock technology at Concortis. Anti-her2 Antibody ZV02 was conjugated with highly cytotoxic auristatin analogue through a non-cleavable linker to form ZV0201,which mainly consists of DAR2 species. Biochemical analysis indicated that ZV0201 was homogeneous and displayed as a single population after purification. In cellular assay, enhanced anti-tumor activities were observed with this conjugate, compared to T-DM1 in a variety of tumor cell lines. ZV0201 was especially active in cells expressing medium to low level of Her-2. In PK study, ZV0201 had an IC50 about 3-4 days in mouse and was stable for up to 7 days in sera from different species. In xenograft models, a single dose of ZV0201 at low levels completely wiped out the tumors and kept it down for up to 100 days, outperformed T-DM1. Toxicity analysis in rats showed less or comparable toxic effect to that of T-DM1. ZV0201 is currently under further evaluation as a candidate for clinical treatment of her2-positive cancers.
Citation Format: Hong Zhang, Zhaohui Li, Tong Zhu, Sheldon Cao, Gang Chen, David Miao. Superior anti-tumor activity compared to T-DM1 in preclinical studies of targeted therapies for her2-positive cancers by a novel her2-ADC ZV0201. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 651. doi:10.1158/1538-7445.AM2015-651
Abstract 669: BGB-283 effectively enhances MEK inhibitor induced tumor suppression in RAS mutant cancers
Authors: Yuan Xi , Tang Zhiyu , Du Rong , Cheung Shing-Hu , Wei Jing , Zhao Yuan , Du Yunguang , Hao Rui , Hu Xiaoxia , Gong Wenfeng , Liu Yong , Gao Yajuan , Wei Min , Zhou Changyou , Wang Lai , Luo Lusong 
Published: August 2015

Abstract
Mutation in K-RAS, which drives constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway, is one of the most frequent genetic alterations in human cancers. Pharmacological targeting RAS mutants directly is extremely challenging and targeted inhibition of K-RAS downstream effector MEK has shown limited clinical activity in suppressing the progression of K-RAS mutant tumors. The reduced sensitivity of K-RAS-mutated cancer cells to MEK inhibitors (MEKi) is associated with feedback phosphorylation of MEK and rebound of phosphorylated ERK levels after prolonged treatment. A synthetic lethal screen provided the rational of targeting both RAF1 and MEK in K-RAS mutated cancers. In this study, we investigated whether combining BGB-283, a potent inhibitor to RAF dimers, and a series of MEKi could achieve better therapeutic effect of the latter. We confirmed that selumetinib (AZD6244) induced strong MEK phosphorylation in K-RAS mutated cancer cells. Either knockdown of B-RAF/C-RAF or addition of BGB-283 in the presence of selumetinib potently inhibited RAF-dependent MEK phosphorylation and led to sustained inhibition of ERK activity. Furthermore, BGB-283 and selumetinib showed synergistic effect in inhibiting proliferation of several non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cell lines harboring RAS mutations. In vivo, combined dosing of BGB-283 and AZD6244 also exhibited enhanced antitumor activity in K-RAS mutant NSCLC and CRC xenograft models compared to monotherapies. Pharmacodynamic (PD) analysis revealed improved inhibition of ERK phosphorylation in dually treated tumors. Together, these findings suggested that combining RAF dimer inhibitor BGB-283 and MEKi could be a promising strategy in treating RAS mutated cancers.
Citation Format: Xi Yuan, Zhiyu Tang, Rong Du, Shing-Hu Cheung, Jing Wei, Yuan Zhao, Yunguang Du, Rui Hao, Xiaoxia Hu, Wenfeng Gong, Yong Liu, Yajuan Gao, Min Wei, Changyou Zhou, Lai Wang, Lusong Luo. BGB-283 effectively enhances MEK inhibitor induced tumor suppression in RAS mutant cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 669. doi:10.1158/1538-7445.AM2015-669
Abstract 724: Anti-tumor effect of Dasatinib in HER2 positive breast cancer with Trastuzumab resistance
Authors: Takeda Tatsuaki , Kanzaki Hirotaka , Toyooka Shinichi , Watanabe Mototsugu , Ohtsuka Tomoaki , Suzawa Ken , Hashida Shinsuke , Maki Yuho , Yamamoto Hiromasa , Soh Junichi , Asano Hiroaki , Tsukuda Kazunori , Miyoshi Shinichiro , Kitamura Yoshihisa , Sendo Toshiaki 
Published: August 2015

Abstract
[Background]
Overexpression of human epidermal growth factor receptor 2 (HER2) was observed in approximately 20%-25% of breast cancers and they are classified in HER2-positive breast cancer. Trastuzumab is a therapeutic drug for the first choice for HER2-positive breast cancer, showing good response. However, acquired resistance to trastuzumab is one of the critical clinical issues in breast cancer treatment, especially in the patients with recurrent breast cancer. Therefore it is necessary to develop the effective therapy to overcome resistance. In this study, we established a trastuzumab-resistant breast cancer cell line from a trastumab-sensitive cell line with HER2 amplification (BT-474), and demonstrated anti-tumor effect of dasatinib in the breast cancer cell with trastuzumab resistance.
[Methods]
Trastuzumab-resistant breast cancer cell line (BT-474-R) was established by treating BT-474 cells for long-term exposing with trastuzumab. We performed cell viability assay to analyze drug sensitivity. Then, we performed quantitative PCR and western blotting to investigate expression and activation of HER2 and related molecules. Cell viability assay and signal analysis were performed with or without trastuzumab and/or dasatinib treatment.
[Results]
Proto-oncogene tyrosine-protein kinase Src was up-regulated and activated in BT-474-R. Signaling molecules, such as Akt and MAPK, were also activated. Dasatinib, which is known as a Src inhibitor, suppressed the activation of signal molecules and cell survival of BT-474-R. Moreover, dasatinib treatment recovered sensitivity to trastumab in the BT-474-R with down-regulation of Src phosphorylation.
[Conclusion]
Src plays an important role in acquired resistance to trastumab in breast cancer. Our data also suggest that inhibition of Src may become the new strategy to overcome trastuzumab resistance.
Citation Format: Tatsuaki Takeda, Hirotaka Kanzaki, Shinichi Toyooka, Mototsugu Watanabe, Tomoaki Ohtsuka, Ken Suzawa, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo. Anti-tumor effect of Dasatinib in HER2 positive breast cancer with Trastuzumab resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 724. doi:10.1158/1538-7445.AM2015-724
Abstract 792: ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity
Authors: Reddy Sanjeeva , Damle Nitin K. , Venkatesan Aranapakam M. , Thompson Scott K. , Rao Niranajan , Smith Roger A. , Gupta Sandeep 
Published: August 2015

Abstract
Spleen tyrosine kinase (SYK) and Janus kinase (JAK) play important roles in the pathogenesis of various types of lymphomas, solid tumors, myeloproliferative and inflammation disorders. Inhibition of these targets has been shown to suppress tumor growth in various preclinical and/or clinical studies. Most B-cell malignancies are driven by the B-cell receptor (BCR) pathway, and SYK plays a critical role in this pathway by initiating and amplifying the signal from the receptor. JAK kinases (JAK1, JAK2, JAK3 and TYK2), upon stimulation by various growth factors and cytokines, phosphorylate signal transducers and activators of transcription family proteins (STAT1 -5) which activate various downstream target genes. ASN002 is a novel and potent dual inhibitor of SYK and JAK kinases with IC50 values of 5-46 nM in biochemical assays. In mechanistic cell-based studies involving IgE and cytokine stimulations, ASN002 strongly suppressed the SYK and JAK family kinase signaling pathways measured as pLAT and pSTAT levels, respectively. The compound showed anti-proliferative activity in a broad panel of human cancer cell lines including DHL6, DHL4, OCI-LY10, H929, Pfeiffer, HT-1376, and Lovo, suggesting activity in both solid and hematological tumor types. In a multiple myeloma (H929) xenograft model, ASN002 exhibited significant efficacy in inhibiting tumor growth (&gt;95%). It also significantly delayed the onset of hind limb paralysis in the human erythroleukemia (HEL) mouse model. ASN002 has good oral bioavailability, metabolic stability, is not a Pgp substrate, and shows little to no inhibition of CYP450 isozymes. ASN002 showed a favorable safety profile in rat and dog toxicology studies. A Phase I/II clinical study is being planned for the evaluation of ASN002 in lymphomas (diffuse large B cell lymphoma, mantle cell lymphoma, follicular lymphoma) and solid tumors.
Citation Format: Sanjeeva Reddy, Nitin K. Damle, Aranapakam M. Venkatesan, Scott K. Thompson, Niranajan Rao, Roger A. Smith, Sandeep Gupta. ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 792. doi:10.1158/1538-7445.AM2015-792