tbuckley/cabot-search huggingface dataset:
Abstract 3850: Establishment of patient derived model of high-risk endometrial cancer for pre-clinical combined carboplatin and decitabine therapy
Authors: Weiwei Feng, Menghan Zhu, Yinhua Yu, Wei Jiang
Journal: Cancer Research (2017)

Abstract Objective: The high risk endometrial cancers (EC), including high grade EC, serous carcinoma (SC), clear cell carcinoma (CC) and carcinosarcoma, account for 50% of death. Therapies for them are limited and patient derived tumor xenograft (PDX) model become useful tools to predict response to treatment. Here we compared the two methods of establishment of PDX models and evaluated the efficacy of carboplatin and decitabine in two high grade EC PDX models. Methods: Fresh tumor tissues collected from 11 primary high risk EC patients (6 high grade ECs, 4 SCs, 1 CC and 1 carcinosarcoma) were engrafted subcutaneously and in subrenal capsule in SCID mice. For those subcutaneous models, tumors were then orthotopic transplanted into uterine cavity. Histology, vimentin, cytokeratin, ER, PR, P53 expression were evaluated, together with mutation profiles by next generation sequencing for 500 cancer-panel genes. The efficacy of carboplatin and decitabine were evaluated in two high grade EC models. Results: The total tumor take rate was 81.8% (9 /11), without regard to engraft methods. The tumor take rate was higher in subrenal capsule models than subcutaneous models (70% vs 54.5%, respectively). The time for tumor formation (from transplantation to 1 cm in diameter) varies greatly from 4 weeks to 5 months. We observed good similarity between primary tumors and corresponding different passage of xenografts. One high grade EC model was sensitive to carboplatin and decitabine treatment whereas another was drug resistant. Two models harbor different genetic mutation profiles. Conclusion: The high tumor take rate ensures the establishment of the high risk EC biobank which provides a powerful resource for pre-clinical drug-sensitive tests as well as identification of biomarkers of response or resistance. Note: This abstract was not presented at the meeting. Citation Format: Weiwei Feng, Menghan Zhu, Yinhua Yu, Wei Jiang. Establishment of patient derived model of high-risk endometrial cancer for pre-clinical combined carboplatin and decitabine therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3850. doi:10.1158/1538-7445.AM2017-3850
Abstract 801: A zebrafish model of <i>NF1</i>-mutant melanomas that lack activating mutations of <i>BRAF</i> or <i>NRAS</i>
Authors: Shuning He, Marc R. Mansour, Hillary M. Layden, Scott J. Rodig, E. Elizabeth Patton, A. Thomas Look
Journal: Cancer Research (2017)

Abstract Cutaneous melanoma is the most lethal type of skin cancer, with ~76,380 newly diagnosed melanoma and ~10,130 melanoma-associated deaths per year in the US. Thus, there is a need for improved understanding of the molecular pathogenesis and more effective targeted therapies for this devastating disease. The recent work of The Cancer Genome Atlas Network has defined melanoma as an RTK/RAS-driven solid tumor that can be classified into four genomic subtypes: BRAF-mutant, RAS-mutant, NF1-mutant, and triple-wild-type. This landmark study highlighted the important role of the previously understudied NF1 tumor suppressor in melanoma pathogenesis, especially for the 9% of melanoma patients who have acquired inactivating NF1-mutations, but lack hotspot mutations that activate BRAF or RAS. To date, animal models have not been developed for the NF1-mutant subtype of melanoma, which has significantly impaired the development of novel therapeutic strategies for this subtype. Here we report the first zebrafish model for NF1-mutant melanoma, which we generated by combining the loss of nf1 with loss of both pten and p53. The resultant compound mutant zebrafish develop aggressive melanomas from the age of 7 weeks and the tumor penetrance is 80% by the age of 18 weeks. We demonstrate further that these high-risk zebrafish melanomas were exclusive of hotspot mutations of braf and nras. Sustained inhibition of both MEK and PI3K suppressed tumor progression in vivo, whereas inhibition of MEK or PI3K alone was insufficient to suppress the growth of these tumors. Surprisingly, single agent therapy with rapamycin, an MTOR inhibitor, proved even better for short- and long-term suppression of tumor cell growth in nf1/pten-mutant melanomas. Thus our model appears ideal for the testing of drugs that will prove uniquely active for the significant subset of NF1-mutant, BRAF/NRAS-wildtype human melanomas. Citation Format: Shuning He, Marc R. Mansour, Hillary M. Layden, Scott J. Rodig, E. Elizabeth Patton, A. Thomas Look. A zebrafish model of NF1-mutant melanomas that lack activating mutations of BRAF or NRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 801. doi:10.1158/1538-7445.AM2017-801
The role of Beta2-microglobulin in immune evasion and metastasis of microsatellite unstable colorectal cancer
Authors: Sara Michel, Matthias Kloor, Yvette Schwitalle, Magnus von Knebel Doeberitz
Journal: Cancer Research (2008)

4558  The present study aimed to investigate the implications of Beta2-microglobulin (B2M) during the different steps of carcinogenesis in colorectal tumors with high level microsatellite instability (MSI-H) and to eludicate the role of B2M in the formation of distant metastasis in this cancer entity.  The high level microsatellite instability (MSI-H) phenotype in colorectal cancer (CRC) is caused by defects of the DNA mismatch repair (MMR) system that result in insertion/deletion mutations in repetitive DNA sequences termed microsatellites. MSI-H CRC are considered to be a highly immunogenic cancer entity that is characterized by a dense infiltration with lymphocytes. As a consequence of immunoselection, MSI-H CRC frequently display a loss of human leukocyte antigen (HLA) class I surface expression caused by mutations of the Beta2-microglobulin (B2M) gene. In a recent study, we observed that B2M mutation frequency increased with progression of the local disease (adenoma, UICC stages I to III). However, no B2M mutations were observed in a small collection of CRC that had developed distant metastasis (UICC IV). These preliminary data suggested a potential role of B2M in formation of distant metastases.  In the present study, we therefore evaluated the frequency of truncating B2M mutations in a larger set of metastasized MSI-H CRC by direct sequencing of the B2M coding region. Truncating B2M mutations were detected in 8/22 (36.4%) of UICC stage III and in 1/25 (4.0%) of UICC stage IV MSI-H CRC. The B2M mutation frequency was significantly lower in those CRC with distant metastasis (UICC IV, p=0.008), pointing towards a functional role of B2M in distant metastsasis formation of MSI-H CRC. In vitro experiments showed that B2M may enhance proliferation in different cancer cell lines. To further eludicate the potential contribution of B2M to organ metastasis formation, we examined the effects of stable retransfection of wild type B2M into B2M-deficient CRC cell lines SW48 and K073A. In detail, several immunological and tumor cell-inherent mechanisms potentially contributing to metastasis formation in MSI-H CRC were analyzed by cytotoxicity assays, proliferation and cell migration assays.  In summary, the results of our study suggest a pro-metastatic effect of B2M expression in colorectal cancer. This observation may be of high relevance for future therapeutic strategies in the management of colorectal cancer patients.
Abstract 5180: Effects of soy isoflavones and SRC inhibitors on metastatic activity in prostate cancer
Authors: Lori P. Rice, Dietmar W. Siemann
Journal: Cancer Research (2017)

Abstract Background: In advanced prostate cancer (PCa), cells escape from the primary tumor and enter the bloodstream, preferentially targeting the bone. This results in weakened bones, spinal compressions, fractures and intense pain. Efforts to interfere with early steps in the metastatic cascade by affecting the tumor microenvironment have led to the development of promising small molecule targeting agents. The tyrosine kinase inhibitors, saracatinib and dasatinib, have been shown to inhibit activation of Src and downstream effectors thought to be involved in cancer cell dissemination. Soy-derived isoflavones (ISFs) have been shown to have cytostatic effects on PCa cells without toxicity. Aim: The aim of these studies was to determine if ISFs enhance the effects of Src inhibitors on PCa cells, resulting in lower doses of these agents needed to produce optimum results. Methods: PC-3 ML and LNCaP cells were treated with either a Src inhibitor (dasatinib or saracatinib), a soy isoflavone extract (ISFs), or a combination. Modified Boyden transwell chambers were used to evaluate migration and invasion. Cell cycle and proliferation were measured using FACS analyses and trypan blue staining, respectively. Results: ISFs and Src inhibitors did not cause cytotoxicity or reduce proliferation. However, Src inhibitors produced an increase in cells in G1 phase, while ISFs increased cells in G2/M phase. When ISFs were combined with Src inhibitors, both phases were increased with a concomitant decrease in S phase cells. In transwell migration studies, all agents significantly decreased the number of cells found on the bottom of the membrane: dasatinib&amp;gt;saracatinib&amp;gt;ISFs. Lower doses of Src inhibitors were needed to produce inhibition of migration when ISFs were added to the treatment. Invasion studies with PC-3 ML and LNCaP cells suggest that ISFs can reduce metastatic activity by 39% and 35%, respectively. Therefore, by adding ISFs, lower doses of inhibitors might be used to achieve optimal response and decrease toxicity. Conclusions: In vitro studies suggested that a combination of a Src inhibitors and ISFs, at non-cytotoxic doses, results in greater inhibition of metastatic or invasion activity than either alone. Further studies are needed to determine if this strategy could be used clinically to treat patients with lower doses of small molecule inhibitors by including soy isoflavone concentrates in the treatment regimen. Citation Format: Lori P. Rice, Dietmar W. Siemann. Effects of soy isoflavones and SRC inhibitors on metastatic activity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5180. doi:10.1158/1538-7445.AM2017-5180
Abstract 1614: Intratumoral delivery of a P2A-linked bicistronic IL-12 construct leads to high intratumoral expression and systemic anti-tumor response
Authors: David A. Canton, Christoph Burkart, Shawna A. Shirley, Anandaroop Mukhopadhyay, Richard J. Connolly, Arya Bahrami, Jean S. Campbell, Robert H. Pierce
Journal: Cancer Research (2017)

Abstract The use of immunomodulatory cytokines has been shown effective in regressing a wide range of tumors. However, systemic delivery of recombinant cytokines can result in serious adverse effects, often life-threatening. DNA transfer via electroporation (EP) is a safe and effective method of delivering cytokines to target tissues. Intratumoral (IT) electroporation of Interleukin 12 (IL-12), a potent immunomodulatory cytokine, is well tolerated with an acceptable safety profile and objective response rates of 34-40% and 33% in Phase II clinical trials in advanced melanoma and Merkel cell carcinoma, respectively. We sought to improve the systemic anti-tumor response of IT pIL-12-EP by improving IL-12p70 expression and electroporation conditions, which were evaluated in vitro and in vivo with a two-tumor syngeneic mouse model of melanoma. As functional IL-12 p70 is a heterodimer, we compared different expression constructs to achieve high levels of IL-12 protein expression. IL-12p70 protein expression from a plasmid that incorporated a picornavirus-derived co-translational cleavage site (P2A) was higher than constructs with an internal ribosomal entry sequence (IRES) or a fusion of the p35 and p40 subunits. In functional in vitro assays, pIL-12(P2A) was superior to pIL-12(IRES) and the fusion protein. Using the murine B16.F10 tumor model, we show that IT EP of pIL-12 (P2A) plasmid regresses the treated lesions in a dose-dependent manner compared to control treatments. Systemic effects of IT-expressed IL-12 was assessed by monitoring generation of an antigen-specific CD8 T cell response and regression of B16.F10 contralateral (untreated) tumors following primary tumor electroporation. IT-pIL12-EP treatment with the P2A-linked construct resulted in a significant increase in antigen-specific CD8 T cells, as well as enhanced contralateral tumor growth inhibition suggesting the induction of strong systemic anti-tumor immune response. * Contributed equally to this work Citation Format: David A. Canton, Christoph Burkart, Shawna A. Shirley, Anandaroop Mukhopadhyay, Richard J. Connolly, Arya Bahrami, Jean S. Campbell, Robert H. Pierce. Intratumoral delivery of a P2A-linked bicistronic IL-12 construct leads to high intratumoral expression and systemic anti-tumor response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1614. doi:10.1158/1538-7445.AM2017-1614
Abstract 948: Characterization of the microenvironment of murine primary triple negative breast cancer
Authors: Kassondra Balestrieri, Keith Pittman, Mohamed Ramez, Nasreen Vohra, Kathryn Verbanac
Journal: Cancer Research (2017)

Abstract The purpose of this study was to investigate the role of inflammatory cells in the metastatic process using reliably metastatic murine models of Triple Negative Breast Cancer (TNBC). We have previously selected, developed and characterized two reliably metastatic TNBC mouse models for our investigations. The T11 (claudin-low) and 2225LM (basal-like) Balb/c-derived transplantable tumors display molecular profiles that mirror human TNBC. Here we report characterization of the inflammatory cells and microenvironment in these primary TNBC tumors and at metastatic sites in both heterotopic and orthotopic models. Tumors were implanted in the s.c. flank or mammary fat pad and resected 1-2 weeks later to promote the growth of seeded metastases, when volumes reached ~700 mm3 or 300 mm3, respectively. Both flow cytometric analysis and immunohistochemistry of primary tumors demonstrated high infiltration by myeloid-derived cells (CD11b+) and low levels of lymphoid cells (CD3+). Myeloid cells were also the major infiltrating cells in lung metastases and were significantly elevated compared to normal lung. The granulocytic subset (CD11b+Ly6G+) predominated, consistent with an immunosuppressive role for cells with this phenotype (N2, G-MDSC, etc.). Primary 2225LM and T11 tumors and metastatic lung tumor homogenates were assayed for immunomodulators and compared to normal breast and lung tissue from age-matched contemporary controls. G-CSF was significantly increased in tumors and levels (pg/mg protein) were correlated with tumor burden. VEGF was significantly elevated in all tumors, as were chemoattractants for granulocytic cells (KC/CXCL1, MIP-2/CXCL2), monocytic cells (MCP-1/CCL2), eosinophils (Eotaxin/CCL11) and T cells (MIG/CXCL-9). In the heterotopic model, lung levels of KC/CXCL1 and MCP-1/CCL2 were significantly increased prior to frank lung metastasis (5-30 days post-implant). These data suggest that TNBC-derived G-CSF may play a role in the mobilization of CD11b+Ly6G+ granulocytes and progenitors from the bone marrow and key chemokines may mediate migration of these cells to metastatic sites. Future studies will define phenotypic and functional characteristics of the G-MDSC that are promoting tumor progression in these murine TNBC models. Citation Format: Kassondra Balestrieri, Keith Pittman, Mohamed Ramez, Nasreen Vohra, Kathryn Verbanac. Characterization of the microenvironment of murine primary triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 948. doi:10.1158/1538-7445.AM2017-948
Abstract 1189: Enhanced YAP expression leads to EGFR TKI resistance in lung adenocarcinomas
Authors: Ting-Fang Lee, Yu-Chi Tseng, Cheng-Wen Wu
Journal: Cancer Research (2017)

Abstract Epidermal growth factor receptor (EGFR) mutation is prevalently expressed in lung adenocarcinoma cases and acts as one of the major driving oncogenes. EGFR tyrosine kinase inhibitors (TKIs) have been used in patients with EGFR-mutant as an effective targeted therapy in lung adenocarcinoma, but drug resistance and tumor recurrence inevitably occurs. Recently, Yes-associate protein (YAP) has been reported to promote multiple cancer cell properties, such as promoting cell proliferation, EMT and drug resistance. This study investigated the roles of YAP in TKI-resistant lung adenocarcinoma. In TKI-sensitive cells, enhanced YAP expression leads to TKI resistant. Also, upregulated YAP expression and activation were detected in long term TKI-induced resistant cells. With reduced YAP expression using shRNA or YAP inhibitors, TKI-resistant cells become TKI-sensitive. Moreover, combined EGFR TKI and an YAP inhibitor statin, prolonged survival among lung cancer patients analyzed by Taiwan National Health Insurance Research database. These observations revealed the importance of YAP in promoting TKI-resistance and combined YAP inhibition can be a potential therapy delaying the occurrence of TKI-resistance in lung adenocarcinoma. Citation Format: Ting-Fang Lee, Yu-Chi Tseng, Cheng-Wen Wu. Enhanced YAP expression leads to EGFR TKI resistance in lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1189. doi:10.1158/1538-7445.AM2017-1189
Abstract 425: SMRT® Sequencing of full-length androgen receptor isoforms in prostate cancer reveals previously hidden drug resistant variants
Authors: Manish Kohli, Yeung Ho, David W. Hillman, Jamie L. Van Etten, Christine Henzler, Rendong Yang, Yingming Li, Elizabeth Tseng, Ting Hon, Tyson A. Clark, Liguo Wang, Kevin Silverstein, Liewei Wang, Scott M. Dehm
Journal: Cancer Research (2017)

Abstract Prostate cancer is the most frequently diagnosed male cancer. For prostate cancer that has progressed to an advanced or metastatic stage, androgen deprivation therapy (ADT) is the standard of care. ADT inhibits activity of the androgen receptor (AR), a master regulator transcription factor in normal and cancerous prostate cells. The major limitation of ADT is the development of castration-resistant prostate cancer (CRPC), which is almost invariably due to transcriptional re-activation of the AR. One mechanism of AR transcriptional re-activation is expression of AR-V7, a truncated, constitutively active AR variant (AR-V) arising from alternative AR pre-mRNA splicing. Noteworthy, AR-V7 is being developed as a predictive biomarker of primary resistance to androgen receptor (AR)-targeted therapies in CRPC. Multiple additional AR-V species are expressed in clinical CRPC, but the extent to which these may be co-expressed with AR-V7 or predict resistance is not known. Here we utilized long read sequencing to identify and quantify AR isoforms expressed in CRPC. To unambiguously characterize all AR isoforms, we prepared Iso-Seq™ libraries via 3’ rapid amplification of cDNA ends (RACE) with RNA isolated from prostate cancer cell lines and xenograft tissues using a forward primer anchored in AR exon 1. 3’RACE reactions were subjected to single molecule, real-time (SMRT®) long-read sequencing with a Pacific Biosciences RSII System. Our work identified AR-V9 as a truncated isoform that is frequently co-expressed with AR-V7 in CRPC. Mechanistically, our work re-annotated AR-V7 and AR-V9 mRNAs, showing these two species shared a common 3’ terminal exon containing separate splice acceptor sites. Taking into account this new information, novel siRNAs and antibodies which could distinguish between AR-V7 and AR-V9 were designed, validated and used to measure the relative expression of these two AR isoforms in CRPC cells with a view to determining the potential of AR-V9 as a predictive biomarker of primary resistance to AR-targeted therapies. Citation Format: Manish Kohli, Yeung Ho, David W. Hillman, Jamie L. Van Etten, Christine Henzler, Rendong Yang, Yingming Li, Elizabeth Tseng, Ting Hon, Tyson A. Clark, Liguo Wang, Kevin Silverstein, Liewei Wang, Scott M. Dehm. SMRT® Sequencing of full-length androgen receptor isoforms in prostate cancer reveals previously hidden drug resistant variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 425. doi:10.1158/1538-7445.AM2017-425
Abstract 3210: Targeting PTP4A3 phosphatase in ovarian cancer with the potent noncompetitive inhibitor JMS-631-053
Authors: John S. Lazo, Paula Pekic, Alex Cheung, Kelley McQueeney, Joseph Salamoun, Peter Wipf, Charles N. Landen, Elizabeth R. Sharlow
Journal: Cancer Research (2017)

Abstract PTP4A3 is a highly attractive molecular target for ovarian cancer (OvCa). Elevated levels of PTP4A3 mRNA and protein in human ovarian tumors correlate with disease progression, poor prognosis and poor survival. Genetic depletion of PTP4A3 in OvCa cell lines diminishes their ability to migrate and reduces their in vivo tumorigenicity while PTP4A3 overexpression increases tumor cell migration, invasion, and dissemination. Together, these data suggest PTP4A3 is a novel molecular target for OvCa; however, the lack of potent and selective PTP4A3 small molecule inhibitors has hindered PTP4A3’s definitive validation in OvCa and in other cancers. To drive the pharmacological validation of PTP4A3, we developed JMS-631-053 (7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione), a potent (Ki=3 nM in vitro), specific, noncompetitive, PTP4A3 inhibitor. JMS-631-053 inhibited cellular migration, invasion, and colony formation in soft agar. Potent OvCa cell-based effects were observed by profiling JMS-631-053 against a panel of 8 OvCa cell lines using a 2D drug susceptibility assay, with EC50 values as low as 600 nM. Likewise, JMS-631-053 killed OvCa 3D spheroids, including those derived from high grade serous OvCa cell lines, with EC50 values as low as 300 nM. The OvCa drug resistant cell lines (i.e., A2780CP20 and HeyA8MDR) retained responsiveness to JMS-631-053 (using 2D and 3D culturing conditions) suggesting that inhibition of PTP4A3 may be a viable therapeutic strategy for chemoresistant OvCa. Preliminary data also suggests that JMS-631-053 synergizes with cisplatin when used in combination studies. Hence, JMS-631-053 will be a valuable chemical tool for further validation of PTP4A3 as an OvCa target as well as provide potential leads for future drug discovery. Citation Format: John S. Lazo, Paula Pekic, Alex Cheung, Kelley McQueeney, Joseph Salamoun, Peter Wipf, Charles N. Landen, Elizabeth R. Sharlow. Targeting PTP4A3 phosphatase in ovarian cancer with the potent noncompetitive inhibitor JMS-631-053 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3210. doi:10.1158/1538-7445.AM2017-3210