bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4780: RXDX-107 exhibits multiple mechanisms of intracellular delivery and results in extensive drug-induced interstrand crosslinks in solid tumor preclinical models
Authors: Martin Leenus , Patel Roopal , Johnson Michael , Cao Jerry , Chua Peter , Walsh Colin , Oliver Jennifer , Multani Pratik , Wild Robert , Lin Ralph , Li Gary G. 
Published: July 2016

Abstract
RXDX-107 is a dodecanol alkyl ester of bendamustine, which is then encapsulated in human serum albumin (HSA) to form nanoparticles. Bendamustine is an alkylating agent that induces interstrand DNA crosslinks (ICLs) and causes cell death via several pathways, including intrinsic apoptosis. The activity of bendamustine in the treatment of solid tumor malignancies has not been impressive, possibly due to the pharmacokinetic and limited biodistribution properties of bendamustine. RXDX-107 was designed to improve tissue biodistribution over bendamustine, which may result in superior efficacy and tolerability in patients with solid tumors. In preclinical studies, RXDX-107 displayed significant anti-tumor activity in multiple solid tumor cell lines, cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of advanced solid tumors, such as breast, lung, and ovarian cancer.
In this study, we further evaluated the mechanism of action of RXDX-107, particularly the means of entry and accumulation of drug into tumor cells. We have developed a novel analytical method to precisely quantify both dodecanol alkyl ester of bendamustine and released bendamustine in tissue culture medium and cells. Our data demonstrate that RXDX-107 is transported into cells in three active forms. Firstly, RXDX-107 slowly releases bendamustine into the extracellular medium, and released bendamustine then enters into cells. Secondly, the dodecanol alkyl ester of bendamustine is transported into cells and causes ICLs. And lastly, by measuring macropinocytosis, we also determined that human serum albumin nanoparticles mediate the intracellular entry of RXDX-107. Each of these mechanisms results in the formation of ICLs. In addition, comet assay data demonstrate that RXDX-107 displayed stronger induction of ICLs than bendamustine, and the induced ICLs persist over 48 hours in multiple solid tumor cell lines. Taken together, our data demonstrate that RXDX-107 enters and accumulates into cells via multiple mechanisms, and causes extensive and superior ICLs compared to bendamustine in several solid tumor cell lines, thereby providing a strong rationale for further investigation of this agent in solid tumor indications.
Citation Format: Leenus Martin, Roopal Patel, Michael Johnson, Jerry Cao, Peter Chua, Colin Walsh, Jennifer Oliver, Pratik Multani, Robert Wild, Ralph Lin, Gary G. Li. RXDX-107 exhibits multiple mechanisms of intracellular delivery and results in extensive drug-induced interstrand crosslinks in solid tumor preclinical models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4780.
Abstract 479: Detection and clinical significance of circulating tumor cells in squamous cell carcinoma of the head and neck
Authors: Chikamatsu Kazuaki , Takahashi Hideyuki , Sakakura Koichi , Toyoda Minoru 
Published: July 2016

Abstract
Background: With a developing tumor, tumor cells shed a variety of substances into the blood stream, such as tumor cells, tumor DNA, or exosomes, and these are considered to be as attractive circulating biomarkers to monitor disease progression in cancer patients. However, impact of circulating tumor cells (CTCs) in squamous cell carcinoma of the head and neck (SCCHN) is still not fully understood. In this study, we show that CTCs are present in the peripheral blood of patients with SCCHN, and then investigate the correlation with clinicopathological factors. Materials and Methods: 7.5mL of peripheral blood was obtained from 32 patients with pathologically and clinically confirmed SCCHN. Samples were run with a CellSieve™ Microfiltration Assay (Creatv MicroTech, Inc., Rockville, MD) using a low-pressure vacuum system. The CTCs captured by the filter were stained with an antibody mixture of FITC-conjugated anti-CK 8, 18, and 19, PE-conjugated anti-EpCAM, and Cyanine 5-conjugated anti-CD45. Cells that stained positive for DAPI and CK but negative for CD45, were identified as CTCs. Results: The CTCs were found in 29 (90.6%) of 32 patients. Although there was no association between the number of CTCs and tumor sites, the number of CTCs in patients with advanced disease (stage III/IV) was significantly increased, as compared with those with early disease (stage I/II) (p&lt;0.05). Furthermore, patients with T3/4 had higher number of CTCs compared to patients with T1/2 (p&lt;0.01). Meanwhile, nodal status was not significantly associated with the number of CTCs. In 12 of 32 patients tested, the number of CTCs after treatments was also evaluated. As expected, the number of CTCs was significantly decreased after treatments, regardless of the treatment modalities. Conclusion: Our results suggest that microfiltration is very efficient in capturing CTCs from SCCHN patients. Moreover, CTCs analysis in SCCHN may provide useful information for assessment of treatment efficacy.
Citation Format: Kazuaki Chikamatsu, Hideyuki Takahashi, Koichi Sakakura, Minoru Toyoda. Detection and clinical significance of circulating tumor cells in squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 479.
Abstract 4796: BTK inhibitor BGB-3111 synergizes with lenalidomide in MCL models
Authors: Hu Nan , Zhang Shuo , He Min , Zhang Jiye , Jiang Bin , Sun Zhijian , Luo Lusong , Wang Lai 
Published: July 2016

Abstract
Background
BGB-3111 is a novel, irreversible, second generation BTK inhibitor with better selectivity profile and DMPK property compared to ibrutinib. It has demonstrated promising anti-tumor activities in patients with advanced B cell malignancies, including mantle cell lymphoma (MCL). Lenalidomide is an immunomodulatory agent with single-agent activity in several histologic subtypes of B-cell non-Hodgkin lymphoma (NHL). It was approved for the treatment of patients with MCL whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. In this study, we sought to investigate the combination activities of BGB-3111 and lenalidomide in MCL models.
Methods
In vitro drug efficacy was determined using MCL cell lines including REC-1, MINO and JEKO-1. Cell viability was assessed with Cell Titer Glo® assay and half maximal inhibitory concentrations (IC50) were estimated upon exposure to single agents or drug combinations. In vivo activity was assessed in REC-1 and MINO subcutaneous mouse xenograft models. Treatments were administered by oral gavage when tumors were palpable and individual body weight and tumor volume was recorded twice weekly.
Results
The in vitro combination activity of BGB-3111 and lenalidomide was tested in MCL cell lines. Strong synergy was observed in REC-1 and MINO cells, but not in JEKO-1 cells. When tested in vivo, both BGB-3111 (7.5 mg/kg, BID) and lenalidomide (30 mg/kg, QD) significantly inhibited the REC-1 xenograft tumor growth with TGI of 86% and 56%, respectively. The combination treatment resulted in 100% TGI. In MINO xenograft model, combination treatment of BGB-3111 (30 mg/kg, BID) and lenalidomide (30 mg/kg, QD) was also more efficacious than either single agent.
Conclusions
In summary, BGB-3111 and lenlidomide showed interesting in vitro and in vivo combination activity in MCL models, providing rationale for testing this combination in clinic.
Citation Format: Nan Hu, Shuo Zhang, Min He, Jiye Zhang, Bin Jiang, Zhijian Sun, Lusong Luo, Lai Wang. BTK inhibitor BGB-3111 synergizes with lenalidomide in MCL models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4796.
Abstract 4803: A novel class of phenylacrylonitrile-based small molecules selectively induce double-strand DNA damage in breast cancer cells
Authors: Sakoff Jennette A. , Gilbert Jayne , De Iuliis Geoff , McCluskey Adam 
Published: July 2016

Abstract
We have discovered a class of phenylacrylonitrile-based small molecules that selectively target breast cancer cell lines while having little to no effect on normal breast cancer cells or on cell lines derived from other tumour types including colon, ovarian, lung, skin, prostate and pancreatic carcinomas, neuroblastoma and glioblastoma. Indeed these molecules show more than 200-fold selectivity towards breast cancer cells compared with other tumour types, while maintaining nM potency, as determined by the MTT growth inhibition (GI50) assay with GI50 values of 0.2-2.0μM (72h exposure). Moreover, the sensitive breast cancer cell lines represent tumour types from the four main breast cancer classifications including ER+ luminal A (MCF-7, T47-D and ZR-75-1 cells), ER+ luminal B (BT-474), HER2+ (SKBR-3), and most importantly the Basal (triple negative MDA-MB-468 and BT20) classification which traditionally carries a very poor prognosis. Our novel class of molecules also retain activity in MCF-7/VP16 cells (GI50 0.2μM) which overexpresses the drug resistance ABCC1 gene. Only one breast cancer cell line has shown insensitivity, MDA-MB-231 (Basal triple negative), which unlike all of the other breast cell types has amplifying mutations in KRas and BRaf activity, a genotype found in less than 5% of breast cancer tumours. Furthermore, our novel compounds induce minimal effects on the growth of normal MCF10A breast cells.
Analysis of our most sensitive breast cancer cell line (MDA-MB-468) shows a significant increase in gammaH2AX within 12h of exposure to our lead phenylacrylonitrile molecule, indicative of DNA double strand breakage. This response is concomitant with an increase in the phosphorylation of the cell cycle check point activator CHK2. Cell cycle analysis shows an increase in the proportion of cells in the S-phase of the cell cycle within 24h of exposure, concomitant with a decrease in the proportion of cells in the G1-phase, and preceding an increase in the sub-G1 cell death population. The ability to specifically target breast tumours, while having little or no effect on normal breast cells, or other tumour types is a unique finding. Elucidating the mechanism controlling this phenomenon is now the focus of our research efforts.
Citation Format: Jennette A. Sakoff, Jayne Gilbert, Geoff De Iuliis, Adam McCluskey. A novel class of phenylacrylonitrile-based small molecules selectively induce double-strand DNA damage in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4803.
Abstract 4807: Triphenylmethanol conjugates of triptorelin as anti-cancer prodrugs
Authors: Beni Ryan , Boadi William , Alnakhli Jawzah 
Published: July 2016

Abstract
Triptorelin (TRP) is an anti-cancer agent used for the treatment of a wide variety of hormone-responsive cancers, such as prostate cancer. The surge of testosterone, known as a flare effect, is the major side-effect of cancer chemotherapy using TRP in a combination regiment. Improving the biological activity of TRP by increasing the cellular uptake and retention is a remedy to this end. In this study, the hydrophobicity of TRP was optimized by using an appropriate hydrophobic linker attached to tris(4-methoxyphenyl)methanol (TPM) derivatives with the expectation to improve the cellular uptake. In this regard, a number of TRP conjugates of TPM derivatives with optimized hydrophobicity were synthesized by the reaction of 2-substituted methoxy benzenes (e.g. methyl 2-methoxybenzoate, 1,2-dimethoxybenzene, methoxy-2-methylbenzene, methoxy-2-nitrobenzene, chloro-2-methxyenzene), and 1,3,5-trioxane, followed by the conjugation with TRP and decanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields. Comparative antiproliferative assays between TPM-TRP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and TRP were performed against human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse pre adipocytes (3T3-L1) cells. TPM-TRP conjugates inhibited the cell proliferation of CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 55-92%, 24-73%, 37-56%, respectively, at a concentration of 10-50 μM after 24-72 h of incubation. These data suggest that TPM-TRP derivatives with optimized hydrophobicity can be used to improve the biological activity of TRP.
Citation Format: Ryan Beni, William Boadi, Jawzah Alnakhli. Triphenylmethanol conjugates of triptorelin as anti-cancer prodrugs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4807.
Abstract 4810: Histone deacetylase 2 is a potential determinant of the sensitivity of hepatocellular carcinoma cells to sorafenib
Authors: Kim Hyung Seok , Eun Jung Woo , Shen Qingyu , Shin Woo Chan , Yang Hee Doo , Kim Sang Yeon , Nam Suk Woo 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC) is the fifth frequently diagnosed cancer and is the second leading cause of cancer death worldwide. Many groups have suggested possible clinical applications for liver cancer therapy but sorafenib, an orally-available kinase inhibitor, is the only standard systematic therapeutics for treatment of hepatocellular carcinoma. However, survival benefit of sorafenib is unsatisfactory due to high level heterogeneity of individual response. We previously reported that histone deacetylase 2 (HDAC2) was deregulated in HCC, and thereby contributed to liver tumorigenesis by enhancing mitotic and metastatic potential of transformed cells. Targeted-disruption of HDAC2 suppressed in vitro and in vivo tumorgigenic potential of HDAC2 in liver cancer. The goal of this study was to investigate whether both sorafenib treatment and HDAC2 inhibition elicit synergistic anti-tumor effect against HCC cells. Here, we showed that sorafenib effectively blocked ERK/MEK and AKT signaling pathway upon EGF stimulation in liver cancer cell lines. Also, we found that valproic acid (VPA), a selective inhibitor of histone deacetylase family I, and sorafenib treatment synergistically evoked liver cancer cell growth retardation. This effect was recapitulated by HDAC2 knockdown with sorafenib treatment and exhibited synergistic effect on apoptotic cell death of liver cancer cell lines, Hep3B and Huh7, compared to single treatment of sorafenib. Our data suggest that combined sorafenib treatment with HDAC2 targeting may provide more benefits toward HCC therapy providing a novel approach for future application in patients with advanced HCC.
Citation Format: Hyung Seok Kim, Jung Woo Eun, Qingyu Shen, Woo Chan Shin, Hee Doo Yang, Sang Yeon Kim, Suk Woo Nam. Histone deacetylase 2 is a potential determinant of the sensitivity of hepatocellular carcinoma cells to sorafenib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4810.
Abstract 4828: Enhanced cytotoxicity following sequential treatment with filanesib and melphalan in human myeloma cell lines
Authors: Destephanis Darla , Norris Eric J. , Turnquist Brian , Usmani Saad , Ganapathi Mahrukh , Ganapathi Ram 
Published: July 2016

Abstract
As a single agent, melphalan is used as a preparative treatment prior to autologous stem cell transplant (ASCT) in patients with multiple myeloma (MM) given its myelosuppressive and anti-myeloma effects. While most patients achieve complete remission following ASCT, a majority will develop recurrent disease. Therefore, novel combinations that improve the anti-myeloma activity of melphalan may improve post-transplant outcomes. The first-in-class agent Filanesib (Fil) is a kinesin spindle protein inhibitor which induces mitotic arrest/apoptosis in proliferating cells and has demonstrated anti-myeloma activity in vitro and in vivo. In this study, we tested the effects of combination treatment with filanesib and melphalan in the human myeloma cell lines (HMCLs), U266, MM1S and NCI-H929. As single agents, melphalan and filanesib both inhibit myeloma cell proliferation as assessed by the MTS assay. However, when HMCLs were treated simultaneously with both drugs an antagonistic interaction was observed. This antagonism was in part due to cell cycle arrest in the S-phase, which prevented filanesib from downregulating the anti-apoptotic proteins, BCL-2 and MCL-1 and exerting its cytotoxic effect in the G2/M-phase.. To elucidate whether sequential treatment could enhance cytotoxicity, HMCLs were treated with either melphalan (1 hour) followed by filanesib (MelFil) for 48 hours or filanesib for 48 hours followed by 1 hour melphalan treatment (FilMel). Compared to the apoptosis observed with individual drugs, the MelFil sequence led to significantly lower apoptosis, whereas the the FilMel treatment led to enhanced apoptosis following 48 hours after drug washout. Furthermore examination of recovery of cell proliferation following seven days of recovery after drug removal revealed an increase in cell proliferation for the MelFil treatment compared to a decline in the number of viable cells for FilMel treatment. Taken together, our findings suggest that filanesib pretreatment prior to melphalan may be a clinically relevant therapeutic combination strategy. Moreover, our data underscore the importance of testing sequencing strategies for optimizing therapeutic efficacy of combination treatment.
Citation Format: Darla Destephanis, Eric J. Norris, Brian Turnquist, Saad Usmani, Mahrukh Ganapathi, Ram Ganapathi. Enhanced cytotoxicity following sequential treatment with filanesib and melphalan in human myeloma cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4828.
Abstract 4830: Preclinical anti-tumor activity of nanoliposomal irinotecan (Nal-IRI, MM-398) + 5-FU + oxaliplatin in pancreatic cancer
Authors: Gaddy Daniel F. , Lee Helen , Paz Nancy , Leonard Shannon C. , Kalra Ashish , Straubinger Ninfa L. , Straubinger Robert M. , Gillard Bryan M. , Moser Michael T. , Drummond Daryl C. , Klinz Stephan G. , Hendriks Bart S. , Fitzgerald Jonathan B. 
Published: July 2016

Abstract
Nanoliposomal irinotecan (Nal-IRI, MM-398) recently gained approval in combination with 5-fluorouracil/leucovorin (5-FU/LV) in post-gemcitabine metastatic pancreatic cancer based on results of the Phase 3 NAPOLI-1 trial. Nal-IRI, in combination with 5-FU/LV, improved overall survival in gemcitabine-refractory metastatic PDAC relative to 5-FU/LV alone with a well-defined and manageable toxicity profile in pretreated patients. FOLFIRINOX (5-FU/LV, irinotecan and oxaliplatin) is a chemotherapy regimen active in first-line metastatic PDAC. Herein, we evaluate the preclinical anti-tumor activity of a nal-IRI + 5-FU + oxaliplatin regimen relative to the FOLFIRINOX regimen. Using pancreatic cancer cell lines, we demonstrate enhanced cell death when nal-IRI treatment is simulated using prolonged exposure of SN-38 (the active metabolite of irinotecan) in combination with 5-FU and oxaliplatin. In cell line-derived and patient-derived xenograft models of pancreatic cancer we demonstrate improved anti-tumor activity of nal-IRI relative to exposure-matched doses of unencapsulated irinotecan. Further, nal-IRI consistently improved tumor growth inhibition and survival relative to unencapsulated irinotecan in preclinical models, both as a monotherapy and in combination with 5-FU and oxaliplatin. The addition of nal-IRI to 5-FU and/or oxaliplatin did not exacerbate the baseline toxicities of these agents, including weight loss and neutropenia, and tolerability could be further improved by delaying the administration of oxaliplatin to 1 day post-MM-398. These findings illustrate the therapeutic potential of nal-IRI in combination with 5-FU/LV and oxaliplatin and support an ongoing Phase 2 trial (NCT02551991) of this triplet regimen in first-line PDAC.
Citation Format: Daniel F. Gaddy, Helen Lee, Nancy Paz, Shannon C. Leonard, Ashish Kalra, Ninfa L. Straubinger, Robert M. Straubinger, Bryan M. Gillard, Michael T. Moser, Daryl C. Drummond, Stephan G. Klinz, Bart S. Hendriks, Jonathan B. Fitzgerald. Preclinical anti-tumor activity of nanoliposomal irinotecan (Nal-IRI, MM-398) + 5-FU + oxaliplatin in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4830.