bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5633: Unique modulation of estrogen-induced apoptosis with structural analogues of endoxifen in long-term estrogen-deprived (LTED) breast cancer cells
Authors: Abderrahman Balkees , Fanning Sean W. , Rincon Daniela Quintana , Greene Geoffrey , Maximov Philipp Y. , Jordan V. Craig 
Published: July 2017

Abstract
Endoxifen, a non-steroidal anti-estrogen is the active hydroxylated metabolite of N-desmethyltamoxifen. The structure is based on a synthetic triphenylethylene-type angular estrogen. Endoxifen is in clinical trials as a therapeutic agent to treat aromatase resistant breast cancer. Paradoxically, LTED breast cancer is known to respond to synthetic and natural estrogens through estrogen-induced apoptosis. A series of synthetic endoxifen analogs, were used to modulate estrogen-induced apoptosis in LTED breast cancer cells (MCF7:5C). X-ray crystallography was performed on endoxifen, bisphenol, and diethylstillbestrol (DES), bound to the ligand-binding domain (LBD) of the human estrogen receptor (ER). Cellular studies established that (MCF-7:5C) of estrogen-induced apoptosis was dependent on the LBD of the ER. Similarly, endoxifen blocked estrogen-induced apoptosis in a concentration and time-dependent manner. Apoptosis triggered by DES was blocked by endoxifen and was ER-dependent. X-ray crystallography of both endoxifen and DES illustrate the two extremes of estrogen-induced apoptosis, which is dependent upon the closure of helix 12 over the LBD to generate estrogenic activity. Despite the fact that bisphenol, an analog of endoxifen without the anti-estrogenic monomethylamino ethyl side chain, is an estrogen that causes breast cancer cell replication; bisphenol initially inhibits estrogen-induced apoptosis, but triggers estrogen-induced apoptosis itself after 7 days of treatment of LTED breast cancer cells. X-ray crystallography demonstrates that bisphenol can produce a unique complex with the ER:LBD, which is similar to the DES:LBD estrogenic complex. In both cases, the ligands are sealed into the LBD by helix 12. This delay in apoptosis caused by an analog of endoxifen, that is an angular estrogen, possess unique biological features. We hypothesize that in LTED cells the complex passes through an anti-estrogenic conformation to evolve into an estrogenic complex with helix 12 sealing the LBD. We describe a unique property of a ligand:receptor complex. For the first time we demonstrate that a ligand:receptor complex is slowly activated from an antagonist to an agonist complex over a period of days.
Citation Format: Balkees Abderrahman, Sean W. Fanning, Daniela Quintana Rincon, Geoffrey Greene, Philipp Y. Maximov, V. Craig Jordan. Unique modulation of estrogen-induced apoptosis with structural analogues of endoxifen in long-term estrogen-deprived (LTED) breast cancer cells [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 5633. doi:10.1158/1538-7445.AM2017-5633
Abstract 5635: Vitamin D supplementation decreases serum 27-hydroxycholesterol and expression of CYP27A1 in tumors of breast cancer patients
Authors: Going Catherine , Alexandrova Ludmila , Lau Ken , Yeh Christine , Telli Melinda , Jensen Kristin , Feldman David , Pitteri Sharon 
Published: July 2017

Abstract
The goal of this study was to investigate whether vitamin D regulates the conversion of cholesterol to 27-hydroxycholesterol (27HC), an endogenous selective estrogen receptor modulator (SERM) that can act as a driver of estrogen receptor positive (ER+) breast cancer, particularly in post-menopausal women with low circulating estrogen levels. The hypothesis of this study was that the active metabolite of vitamin D, calcitriol, can inhibit expression of CYP27A1, the synthesizing enzyme for 27HC, thereby decreasing the concentration of 27HC in the blood. Both 27HC and 25-hydroxyvitamin D (25OHD) were quantified by LC-MS/MS in the serum of 29 breast cancer patients, 26 of which had ER+ cancer, pre- and post-treatment with either a low dose (control) of 400 IU vitamin D or a high dose of 10,000 IU vitamin D per day during the neoadjuvant period, which ranged between 7 and 37 days. In addition to these blood samples, tissue biopsies pre-treatment and the excised tumor collected post-treatment were tested for gene expression by microarray analysis. A significant increase (p = 4.3E-5) was observed in serum 25OHD for patients who received the high dose vitamin D compared to those who received the low dose, whose 25OHD values remained stable. A greater decrease (p = 1.7E-1) was observed in serum 27HC for the high dose group compared to the low dose group, with greater decreases in 27HC on average for those with larger increases in 25OHD concentration. Gene expression measurements showed a decrease in CYP27A1 expression (p = 4.5E-1) in breast cancer tissue for the high dose group compared to the low dose group, with greater decreases in expression observed for patients on high dose vitamin D treatment for longer times. These preliminary data show good evidence that high dose vitamin D supplementation can decrease 27HC levels in the body by inhibiting expression of CYP27A1 and that the longer this treatment, the greater the effect. While larger scale studies are needed, the data in this study point to vitamin D supplementation as a possible simple method for inhibiting ER+ breast cancer growth and suggests this reduction in CYP27A1 expression as an additional pathway by which vitamin D can mitigate risk and improve outcomes for ER+ breast cancer patients.
Citation Format: Catherine Going, Ludmila Alexandrova, Ken Lau, Christine Yeh, Melinda Telli, Kristin Jensen, David Feldman, Sharon Pitteri. Vitamin D supplementation decreases serum 27-hydroxycholesterol and expression of CYP27A1 in tumors of breast cancer patients [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 5635. doi:10.1158/1538-7445.AM2017-5635
Abstract 5638: Combination use of EF2K and VPS34 inhibitors with anti-androgen against drug-resistant castration resistant prostate cancer
Authors: Yang Joy C. , Cucchiara Vito , Gao Allen C. , Evans Christopher P. 
Published: July 2017

Abstract
INTRODUCTION AND OBJECTIVES:
Modulating the activity of eukaryotic elongation factor 2 kinase (eEF2K) has been suggested to regulate protein elongation to block autophagy in the tumor microenvironment. Among inhibitors of eEF2K, one would also inhibit VPS34, a class III phosphatidylinositol-3 kinase, and abrogate autophage flux to impair the survival escape mechanism. We tested the eEF2K and VPS 34 inhibitors from Janssen alone or in combination with anti-androgens for their effects on proliferation of prostate cancer cell lines, especially some castration resistant PC (CRPC) lines.
MATERIALS AND METHODS:
Cell proliferation was assessed with various concentrations of the EF2K or VPS34 inhibitor on CRPC lines using WST-1 viability assay. Effect of combinations of EF2K or VPS34 inhibitor with anti-androgens abiraterone (Abi) or enzalutamide (Enza) on drug-resistant CRPC cells was further explored. Western blot analysis was performed to examine the response of key autophagic molecules, androgen receptor (AR) and variant. Real time RT-PCR (RT-qPCR) was used to elucidate the effect of EF2K or VPS34 inhibitor alone or together with anti-androgens on AR, AR variant and their downstream molecules.
RESULTS:
EF2K and VPS34 inhibitors suppressed CRPC cell growth in a dose-response manner with IC50 ranging from 1 to 5 µM. These inhibitors displayed synergy with Abi and Enza against drug-resistant CRPC cells; especially on the pair of enza + EF2K inhibitor with p = 0.02 for significant difference when compared to enza or EF2K inhibitor alone. To our surprise, no significant autophagy was induced by these two inhibitors according to the autophagy markers detected by Western blots. VPS34 inhibitor alone and when combined with Abi and Enza showed AR/variant degrading ability. This downregulation was at the expression level with significant change of AR and V7, together with their transactivation markers PSA, TMPRS2, NKx3.1 and FKBP5 detected by RT-qPCR.
CONCLUSION:
EF2K and VPS34 inhibitors when combined with anti-androgens may solicit profound inhibitory effect on drug-resistant CRPC cells. Molecular delineation demonstrated the direct target might be AR and its variants. These combinations offered a new therapeutic option for advanced PC treatments.
Citation Format: Joy C. Yang, Vito Cucchiara, Allen C. Gao, Christopher P. Evans. Combination use of EF2K and VPS34 inhibitors with anti-androgen against drug-resistant castration resistant 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 5638. doi:10.1158/1538-7445.AM2017-5638
Abstract 5641: Effects of G1T48, a novel orally bioavailable selective estrogen receptor degrader (SERD), and the CDK4/6 inhibitor, G1T38, on tumor growth in animal models of endocrine resistant breast cancer
Authors: Wardell Suzanne E. , Yllanes Alexander P. , Baker Jennifer G. , Baldi Robert M. , Krebs Taylor K. , Sorrentino Jessica , Bisi John , Strum Jay , Norris John D. 
Published: July 2017

Abstract
Background: The combination of targeting the CDK4/6 and ER signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here we report the preclinical characterization of G1T48, a novel, orally bioavailable, non-steroidal small molecule inhibitor of ERα, which is a potent, selective antagonist that down regulates ERα in vitro and in vivo in ER-positive models of breast cancer.
Methods: Breast cancer cells expressing clinically relevant ESR1 mutations (ER-Y537S, ER-D538G) were threated with G1T38, G1T48, and mechanistically distinct SERMs/SERDs and cellular proliferation was assessed by measuring DNA content (Hoechst dye). Ovariectomized nu/nu mice bearing xenograft tumors of clinically relevant tamoxifen (TamR) and aromatase (long term estrogen deprived) resistant ER+ breast cancer were treated with G1T38 and G1T48, alone or in combination, with clinically relevant comparators. Time to progression and tumor volume were assessed over a 4 week dosing period.
Results: G1T38 and G1T48 significantly inhibited cellular proliferation of MCF7 breast cancer cells bearing endocrine resistant ER mutations, ER-Y537S and ER-D538G. G1T48 treatment led to dramatic reductions in ER protein levels. Importantly, tumor growth inhibition was observed in mouse models of sensitive and resistant human breast cancer when G1T48 was dosed as a single agent or in combination with G1T38, a potent, selective CDK4/6 inhibitor.
Conclusions: G1T38, a novel CDK4/6 inhibitor, and G1T48, a novel SERD, either alone or in combination, demonstrated highly potent inhibition of tumor growth in animal models of tamoxifen and aromatase resistance. G1T48 also demonstrated activity in models of endocrine resistance mediated by ER mutation. G1T48 is currently completing IND enabling studies.
Citation Format: Suzanne E. Wardell, Alexander P. Yllanes, Jennifer G. Baker, Robert M. Baldi, Taylor K. Krebs, Jessica Sorrentino, John Bisi, Jay Strum, John D. Norris. Effects of G1T48, a novel orally bioavailable selective estrogen receptor degrader (SERD), and the CDK4/6 inhibitor, G1T38, on tumor growth in animal models of endocrine resistant 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 5641. doi:10.1158/1538-7445.AM2017-5641
Abstract 5642: Quantitative comparison of hydrocortisone and prednisone in the postoperative hormone therapy of hypercortisolism
Authors: Tang Kunlong , Huang Yuting , Dong Shangwen , Gao Peng 
Published: July 2017

Abstract
Tumors and several types of malignancies including lung cancer, pancreatic cancer, pituitary tumor, and most often adrenal adenoma, may cause hypercortisolism, which requires glucorticoid (GC) replacement following adrenalectomy and/or surgical resection of the tumor. Based on our previous report of a simplified GC therapy scheme and the perioperative observation, we further investigated its efficacy and safety up to 6 months post-surgery in this retrospective cohort study. All patients received no GC before surgery. The i.v. doses of hydrocortisone (HC) were 100 mg during surgery, 100 mg bid on day 0 and day 1, followed by 100 mg qd on the morning of day 2 post-surgery. Patients were grouped by oral reception of either HC or prednisone since day 2. The doses and the withdrawal schedule are shown in Table. We found in adrenal adenoma patients, the adrenocorticotropic hormone (ACTH) levels were normal, and sufficient to stimulate the recovery of the dystrophic adrenal cortex, thus exogenous supplemental ACTH might not be necessary. By 6 months post-surgery, prednisone and HC exhibited similar efficacy in correcting hypertension, hyperglycemia, and hypokalemia (p&gt;0.05). Most patients lost weight. Both groups reported significant improvement in a subjective evaluation questionnaire. HC showed advantages over prednisone in improving liver function (p=0.035), but also caused significant leg edema (p=0.034). Both groups developed adrenal insufficiency (AI) during GC withdrawal, with no significant difference regarding the incidence rate or severity. Most AI symptoms were relieved by resuming the prior oral doses, while the severe cases were treated in hospital. No particular variable was identified as risk factor for AI. The withdrawal process may last longer time for HC than prednisone. HC may be prioritized for patients with hyperglycemia or abnormal liver function, while prednisone may reduce the incidence of leg edema.
hydrocortisoneprednisonepathology2220adrenal adenoma14/2216/20Cushing's Disease8/224/20oral glucorticoid schemedose on day 240 mg, tid10 mg, tidwithdrawal20 mg/week5 mg/weekaverage length (month)6.64.9correction of symptomshypertension10/1512/19hyperglycemia6/117/10hypokalemia12/1211/11abnormal liver panel7/82/7 *weight loss20/2217/20adrenal insufficiency10/227/20severe case1/101/7leg edema6/220/20 *
Note: This abstract was not presented at the meeting.
Citation Format: Kunlong Tang, Yuting Huang, Shangwen Dong, Peng Gao. Quantitative comparison of hydrocortisone and prednisone in the postoperative hormone therapy of hypercortisolism [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 5642. doi:10.1158/1538-7445.AM2017-5642
Abstract 5643: Physical and functional interactions of exon-skipping variants of androgen receptor with the full-length counterpart
Authors: Uo Takuma , Sprenger Cynthia C. , Sun Shihua , Bradley Robert K. , Nelson Peter S. , Plymate Stephen R. 
Published: July 2017

Abstract
The androgen receptor (AR) is arguably the critical driver of not only early but also advanced prostate cancer. The recent comprehensive splicing landscapes revealed that metastatic castration resistant prostate cancer harbors multiple forms of AR variants (AR-Vs), many of which have diverse patterns of inclusion/exclusion of exons (E4-8) corresponding to the ligand-binding domain. We had used AR-negative M12 prostate cancer cell line and recently reported characteristics of AR-Vs with respect to their subcellular localization and transcriptional activation on luciferase reporter driven by probasin-based promoter (AR2PB-luc)(1). While ARv5es is predominantly nuclear and constitutively active like well-documented ARv567es, many others are castration -induced variants are inactive. As many AR-Vs and the full-length AR (AR-FL) are co-expressed in the same cell, it is important to determine how these inactive AR-Vs interact with active AR including AR-FL. To this end, we examined two inactive AR-Vs namely v7es and v56es in relation to AR-FL. ARv7es, which skips exon 7, is predominantly localized in cytoplasm. ARv7es physically interacted with AR-FL. Moreover, nuclear accumulation of ARv7es was promoted by the addition of dihydrotestosterone (DHT) only in the presence of AR-FL, suggesting that ARv7es and AR-FL heterodimerize in the nuclear compartment. However, DHT-dependent transactivation of AR-FL was not affected by the presence of ARv7es. More specifically, in M12 cells, AR2PB-luc was transactivated by AR-FL to the similar extents either in the presence or absence of ARv7es. In addition, in doxycycline (Dox)-inducible ARv7es stable LNCaP cell line (LNCaP/ARv7es), the presence of ARv7es did not affect DHT-induced expression of endogenous PSA and NKX3.1 transcripts as well as transactivation of AR2PB-luc. In the similar setting, when we examined ARv56es which also physically interacted with AR-FL, Dox-induced expression of ARv56es in LNCaP/ARv56es was sufficient to induce expression of endogenous PSA and NKX3.1 transcripts. Further, DHT-induced expression of these transcripts was enhanced by ARv56es in LNCaP/ARv56es. Accordingly, we propose that AR-Vs display differential modes of action on AR-FL as exemplified by ARv7es as the bystander and v56es as the effector. 1. Oncogene (PMID: 27694897)
Citation Format: Takuma Uo, Cynthia C. Sprenger, Shihua Sun, Robert K. Bradley, Peter S. Nelson, Stephen R. Plymate. Physical and functional interactions of exon-skipping variants of androgen receptor with the full-length counterpart [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 5643. doi:10.1158/1538-7445.AM2017-5643
Abstract 5646: Germline activating mutations in the proto-oncogene GCM2 in primary hyperparathyroidism
Authors: Guan Bin , Welch James M. , Sapp Julie C. , Ling Hua , Vemulapalli Meghana , Li Yulong , Johnston Jennifer J. , Kebebew Electron , Biesecker Leslie G. , Simonds William F. , Marx Stephen J. , Agarwal Sunita K. 
Published: July 2017

Abstract
Primary hyperparathyroidism (PHPT) is a common endocrine disease caused by parathyroid tumors (adenoma or hyperplasia). The hypersecreting parathyroid tumor elevates serum parathyroid hormone level, which causes hypercalcemia and the classical symptoms of PHPT, including kidney stones, osteoporosis, and neuromuscular symptoms associated with hypercalcemia, such as muscle weakness, drowsiness, and depression. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. We performed exome sequencing on germline DNA of eight index cases from eight unrelated kindreds with FIHP. Rare variants were identified (minor allele frequency &lt;1%), and selected variants were assessed for co-segregation in affected family members by Sanger sequencing. Candidate genes were then screened in an additional 32 kindreds with FIHP. The functional consequence of variants in one FIHP candidate gene (GCM2, a parathyroid tissue-specific transcription factor) was analyzed in a cell culture model. In eight kindreds with FIHP, we identified three rare GCM2 missense variants. Functional characterization of GCM2 variants and deletion-analyses revealed a small C-terminal Conserved Inhibitory Domain (CCID). Two of the three rare variants were recurrent, located in the CCID that enhanced the transcriptional activity of GCM2, and found in seven of 40 (18%) kindreds with FIHP. Functional assays for transcriptional activity demonstrated that these two rare variants acted as gain-of-function mutations, suggesting that GCM2 is a parathyroid proto-oncogene. We further investigated the ethnicity of individuals with GCM2 CCID activating variants in PHPT patient samples and in genome survey datasets. Our results demonstrate that germline activating mutations in the GCM2 CCID can cause FIHP, and specific activating mutations expose a large population at risk for PHPT. Our findings of the first gene with mutations specific for FIHP are expected to have an important impact on clinical practice, including treatment decisions and genetic testing of individuals with PHPT and family members.
Citation Format: Bin Guan, James M. Welch, Julie C. Sapp, Hua Ling, Meghana Vemulapalli, Yulong Li, Jennifer J. Johnston, Electron Kebebew, Leslie G. Biesecker, William F. Simonds, Stephen J. Marx, Sunita K. Agarwal. Germline activating mutations in the proto-oncogene GCM2 in primary hyperparathyroidism [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 5646. doi:10.1158/1538-7445.AM2017-5646
Abstract 5650: Enhancement of CAR-T cell activity via PD-1 knockdown by self-deliverable RNAi
Authors: Wolfson Alexey , Eliseev Alexey , Shmushkovich Taisia , Betancur-Boissel Monica , Betancur-Boissel Monica , Scholler Nathalie 
Published: July 2017

Abstract
Background: A growing body of evidence indicates that the blockade of PD-1 and other immunosuppressive receptors can increase the efficacy of adoptively transferred cells in immunotherapy for cancer. The expression of PD-1 can be suppressed by ex vivo treatment of transferred lymphocytes by self-deliverable RNAi (sd-rxRNA®) compounds. sd-rxRNAs are based on proprietary chemical modifications of siRNA compounds making them stable to nuclease degradation and capable of penetration into target cells without the use of transfection reagents or physical methods.
Aim: To determine whether the reduction of PD-1 by ex vivo treatment of mesothelin-targeting CAR-T cells with sd-rxRNA will improve the efficacy of meso-CAR-T cells in a mouse model of ovarian cancer.
Methods: Second-generation human CAR-T cells expressing P4 antibody fragments targeting mesothelin (meso-CAR-T) were treated ex vivo with PD-78, a self-deliverable siRNA silencing the PD-1 gene. The meso-CAR-T cells were then injected into tumors in a xenograft mouse model of human ovarian cancer (A1847 cell line expressing mesothelin and PD-L1) in NSG mice. The tumor volumes were monitored over the course of one month. After the animals were sacrificed, human CD45-containing cells extracted from the tumor were analyzed for PD-1 expression by flow cytometry.
Results: We observed a statistically significant reduction in tumor growth in the group of mice injected with meso-CAR-T cells pretreated ex vivo with PD-78. The post-mortem tumor analysis by flow cytometry showed that the expression of PD-1 in meso-CAR-T cells was significantly suppressed for the full duration of the experiment (one month).
Conclusion: Our results suggest that the silencing of immunosuppressive genes by ex vivo treatment with sd-rxRNA may improve efficacy of CAR-T cells in the treatment of solid tumors. A similar approach may be applied to other types of adoptive cell transfer.
Citation Format: Alexey Wolfson, Alexey Eliseev, Taisia Shmushkovich, Monica Betancur-Boissel, Monica Betancur-Boissel, Nathalie Scholler. Enhancement of CAR-T cell activity via PD-1 knockdown by self-deliverable RNAi [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 5650. doi:10.1158/1538-7445.AM2017-5650