bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1763: BiTEs vs CAR-Ts: Preclinical targeting of CD133+ brain tumor initiating cells using immunotherapy-based treatment strategies
Authors: Vora Parvez , Adams Jarrett , Singh Mohini , Venugopal Chitra , Tatari Nazanin , Chokshi Chirayu , Qazi Maleeha , Salim Sabra , Mahendram Sujeivan , Bakhshinyan David , London Max , Savage Neil , Subapanditha Minomi , McFarlane Nicole , Pan James , Bramson Jonathan , Sidhu Sachdev , Moffat Jason , Singh Sheila 
Published: August 2018

Abstract
Glioblastoma (GBM) is a uniformly fatal primary brain tumor, characterized by extensive cellular heterogeneity. Numerous studies have implicated CD133+ brain tumor initiating cells (BTICs) as drivers of chemo- and radio-resistance in GBM. We have recently demonstrated that a CD133-driven gene signature is predictive of poor overall survival and targeting CD133+ treatment-refractory cells may be an effective strategy to block GBM recurrence.
Bispecific T-Cell engaging antibodies (BiTEs) and Chimeric antigen receptors (CARs) present promising immunotherapeutic approaches that have not yet been validated for recurrent GBM. Using CellectSeq, a novel methodology that combines the use of phage-displayed synthetic antibody libraries and DNA sequencing, we developed the CD133-specific monoclonal antibody ‘RW03'. We constructed CD133-specific BiTEs that consist of two arms; one recognizes the tumor antigen (CD133) and the second is specific to the CD3 antigen that binds to human GBMs and PBMC-derived T cells, respectively. We observed BiTEs redirecting T cells to kill GBMs, with greater efficiency observed in CD133high GBMs, validating BiTE target specificity. Incubating T-cells with BiTEs and the CD133high GBMs resulted in increased expression of T cell activation markers. In parallel, we derived the single chain variable fragment (scFv) from RW03 we engineered a second-generation CAR T cell. CD133-specific CAR-T cells were cytotoxic to CD133+ GBMs. Co-culturing CD133 CAR-T cells with GBMs triggered T cell activation and proliferation. Treatment of GBM tumor-bearing mice with CD133-specific CAR-T cells yielded extended survival in mice and significant reductions in brain tumor burden.
Furthermore, we uniquely adapted the existing chemoradiotherapy protocol for GBM patients for treatment of immunocompromised mice engrafted with human GBMs. Within this model, we have initiated treatment of recurrent GBM directed against CD133+ BTICs, to allow for a direct prospective comparison of toxicity and efficacy of BiTEs and CAR-T cell strategies.
Citation Format: Parvez Vora, Jarrett Adams, Mohini Singh, Chitra Venugopal, Nazanin Tatari, Chirayu Chokshi, Maleeha Qazi, Sabra Salim, Sujeivan Mahendram, David Bakhshinyan, Max London, Neil Savage, Minomi Subapanditha, Nicole McFarlane, James Pan, Jonathan Bramson, Sachdev Sidhu, Jason Moffat, Sheila Singh. BiTEs vs CAR-Ts: Preclinical targeting of CD133+ brain tumor initiating cells using immunotherapy-based treatment strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1763.
Abstract 1767: Synergy between intratumoral immunotoxin and systemic anti-CTLA-4 promotes massive inflammation and leads to complete regression of tumors in mice
Authors: Leshem Yasmin , O'Brien James , Reiter Yoram , Pastan Ira 
Published: August 2018

Abstract
Background: The immunotoxin SS1P consists of an anti-mesothelin Fv attached to Pseudomonas exotoxin A and kills tumor cells by inhibiting protein synthesis. Because of its unique mechanism of cell killing and unlike other anti-cancer drugs, SS1P does not suppress the immune system. Here we determined if SS1P can cooperate with anti-CTLA-4 to induce anti-tumor immunity and cause tumor regression.
Methods: A BALB/c breast cancer cell line was transfected with human mesothelin (66C14-M) and implanted in two different locations. SS1P was injected directly into one tumor and anti-CTLA-4 given IP. Twelve days after treatment initiation, the tumors were harvested and evaluated for immune related gene expression by Nanostring Technologies. A portion of each tumor was sent to pathology and stained for CD8.
Results: In mice treated with anti-CTLA-4 and SS1P, complete tumor regressions occurred in 25/30 (86%) SS1P injected tumors and in 16/30 (53%) tumors at the un-injected location. No complete regressions occurred with either drug given separately. This indicates that the combination therapy has a synergistic and systemic anti-tumor effect. Pathological evaluation of injected tumors from combination-treated mice revealed large central abscesses surrounded by a collar of inflammation, containing a mixture of lymphocytes and mononuclear cells. The collar of inflammation was unique to the combination treated mice. Only very small abscesses were observed in tumors from control mice. Immunohistochemistry of tumors from mice treated with SS1P and anti-CTLA-4 showed an increase in CD8+ cells located mainly in the inflammation collar. Analysis of gene expression in tumors from combination-treated mice, compared to PBS-treated tumors, showed that 341/747 (45%) immune transcripts were elevated by 2-fold or more including CD8a, PDL2 and CD56 (8, 15 and 24-fold, respectively). In mice treated with anti-CTLA-4 and PBS, the increase of transcripts was lower: 127/747 (17%) genes. Only 18 out of 747 transcripts (2%) were elevated in the SS1P-treated tumors. This suggests that SS1P by itself does not initiate an inflammatory process. However, SS1P greatly potentiates the inflammatory process initiated by anti-CTLA-4.
Conclusions: Combining local SS1P with anti-CTLA-4 promotes massive inflammation that cures injected and un-injected tumors and provides a strong rational to explore this combination therapy in patients.
Citation Format: Yasmin Leshem, James O'Brien, Yoram Reiter, Ira Pastan. Synergy between intratumoral immunotoxin and systemic anti-CTLA-4 promotes massive inflammation and leads to complete regression of tumors in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1767.
Abstract 1791: Evolutionary dynamics of non-Hodgkin's lymphoma CAR T cell therapy
Authors: Altrock Philipp M. , Kimmel Gregory , Locke Frederick L. 
Published: August 2018

Abstract
Non-Hodgkin Lymphoma (NHL) is the most common hematologic malignancy in the United States with an estimated 72,000 new cases (4.3% of all cancer cases) and 20,000 deaths (3.4% of all cancer deaths) in 2017; the median 5-year survival rate is 71%. Despite a possible cure, with front-line chemotherapy, there exist patients that do not response or relapse and develop refractory disease. These patients have a median overall survival of less than seven months. Chimeric antigen receptor (CAR) T-cell therapy for refractory NHL relies on expansion of engineered T- cells that specifically target tumor cells expressing CD19. Here we combine mathematical modeling with statistical data-analysis based on recent results of clinical studies of CAR T-cell dynamics in individual patients. We use statistical and mathematical modeling to elucidate the key mechanisms that drive evolutionary dynamics of anti-CD19 CAR T-cell therapy. To this end, we integrate patient specific tumor burden profiles, inflammatory cytokine profiles, and CAR T cell population dynamics into our model. We find that the success of therapy may depend on dynamic regulation of inflammatory cytokines in the tumor microenvironment, as well as on specific properties of the heterogeneous CAR T-cell population. Relative abundances of juvenile and effector T cells are key factors that drive the duration of treatment response, and the tumor-killing rate of this CD19-specific immunotherapy. Our modeling framework elucidates disease and treatment specific eco-evolutionary dynamical properties, but can also quantify genetically engineered T-cell population properties related to neurological toxicity and long-term homeostatic mechanisms that determine patient survival.
Citation Format: Philipp M. Altrock, Gregory Kimmel, Frederick L. Locke. Evolutionary dynamics of non-Hodgkin's lymphoma CAR T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1791.
Abstract 1808: The anti-estrogen endoxifen altered bone morphology and reduced muscle function in mice
Authors: Wright Laura , Mohammad Khalid , Guise Theresa 
Published: August 2018

Abstract
Endoxifen, the predominant CYP2D6 metabolite of the selective estrogen receptor modulator (SERM) tamoxifen, is currently being developed as a novel anti-estrogen therapy for the treatment of estrogen receptor (ER)+ breast cancer. Genetic polymorphism of CYP2D6 is a predictor of response to tamoxifen in patients, implicating endoxifen as one of the most active and relevant tamoxifen metabolites. Breast cancer patients treated with adjuvant endocrine therapies including aromatase inhibitors (AIs) and SERMs often report unmanageable musculoskeletal toxicities that can result in treatment discontinuation. While ER binding affinity and anti-tumor effects have been established in preclinical models, the effects of endoxifen on the musculoskeletal system are not fully known. Twenty-week female C57BL/6 mice underwent sham surgery or ovariectomy (OVX) and were treated daily with vehicle, the AI letrozole, or the SERM endoxifen. Body composition was assessed prospectively by DXA. Bone indices and marrow adipose tissue volume were measured by μCT and muscle contractility of the extensor digitorum longus (EDL) was measured ex vivo. After eight weeks, trabecular bone volume fraction (BV/TV) decreased by 50% in OVX-vehicle and OVX-letrozole mice, whereas BV/TV increased threefold in endoxifen mice relative to sham-vehicle. Despite the presence of significantly more trabecular bone following endoxifen treatment, cortical bone analyses revealed impaired periosteal and endosteal expansion of bone, resulting in reduced polar moment of inertia, which is a measure of resistance to fracture. Uterine weight increased significantly in endoxifen-treated mice relative to all OVX groups, similar to what is observed with tamoxifen treatment. Peripheral body fat, bone marrow adipose tissue, and circulating leptin were reduced by endoxifen, suggesting that the drug may elicit positive systemic metabolic effects. At the termination of the study, muscle-specific force was reduced in OVX-endoxifen mice relative to sham-vehicle, OVX-vehicle, and OVX-AI mice, despite no change in muscle mass. While endoxifen shows promise as a potent anti-estrogen therapy for the treatment of ER+ breast cancer, it may be important to monitor patients for endometrial proliferation, morphological changes in bone that increase fracture risk, and for musculoskeletal side effects that could reduce drug compliance.
Citation Format: Laura Wright, Khalid Mohammad, Theresa Guise. The anti-estrogen endoxifen altered bone morphology and reduced muscle function in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1808.
Abstract 1810: Stapled peptide inhibitors of mutant estrogen receptor/coactivator interactions
Authors: Speltz Thomas E. , Danes Jeanne M. , Fanning Sean W. , Mayne Christopher G. , Tajkhorshid Emad , Greene Geoffrey L. , Frasor Jonna M. , Moore Terry W. 
Published: August 2018

Abstract
A current limitation in treating estrogen receptor-positive breast cancer is the development of resistance to endocrine therapy. Among the many possible mechanisms of resistance, mutations in the estrogen receptor ligand binding domain have been recently shown to be a contributing factor. Specifically, estrogen receptor mutations Y537S and D538G have been reported to contribute to resistance by decreasing the efficacy of the clinically used drug tamoxifen. A standing hypothesis in estrogen receptor pharmacology is that coactivator binding inhibitors can be used in place of traditional endocrine therapy to block cellular proliferation mediated by estrogen receptor. To validate the coactivator binding inhibitor hypothesis within a cellular context, we have prepared cell-permeable stapled peptides to function as inhibitors of the estrogen receptor/steroid receptor coactivator interaction in both wild-type and mutant estrogen receptors. Guided by x-ray crystallography, we have applied molecular dynamics and structure-based rational design to develop stapled peptides with high affinity for the estrogen receptor. In targeting the wild-type receptor, we have found that stapled peptides mimicking steroid receptor coactivators have even higher affinity against mutant receptors Y537S and D538G. In addition to inhibiting the estrogen receptor/coactivator interaction in biochemical assays, we find inhibition of estrogen receptor function within multiple breast cancer cell lines. The stapled peptides reported in this research support the coactivator binding inhibitor hypothesis and shed light on estrogen receptor coactivator interactions in cells expressing both wild-type and mutant receptors.
Citation Format: Thomas E. Speltz, Jeanne M. Danes, Sean W. Fanning, Christopher G. Mayne, Emad Tajkhorshid, Geoffrey L. Greene, Jonna M. Frasor, Terry W. Moore. Stapled peptide inhibitors of mutant estrogen receptor/coactivator interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1810.
Abstract 1813: The role of androgen receptor variant AR-V9 in prostate cancer
Authors: Ho Yeung , Etten Jamie L. Van , Henzler Christine , Li Yingming , Yang Rendong , Tseng Elizabeth , Hon Ting , Clark Tyson , Dehm Scott M. 
Published: August 2018

Abstract
The expression of androgen receptor (AR) variants is a frequent, yet poorly-understood mechanism of clinical resistance to AR-targeted therapy for castration-resistant prostate cancer (CRPC). Among the multiple AR variants expressed in CRPC, AR-V7 is considered the most clinically-relevant AR variant due to broad expression in CRPC, correlations of AR-V7 expression with clinical resistance, and growth inhibition when AR-V7 is knocked down in CRPC models. Therefore, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The aim of this study was to understand whether other AR variants are co-expressed with AR-V7 and promote resistance to AR-targeted therapies. To test this, we utilized RNA-seq to characterize AR expression in CRPC models. RNA-seq revealed the frequent coexpression of AR-V9 and AR-V7 in multiple CRPC models and metastases. Furthermore, long-read single-molecule real-time (SMRT) sequencing of AR isoforms revealed that AR-V7 and AR-V9 shared a common 3'terminal cryptic exon. To test this, we knocked down AR-V7 in prostate cancer cell lines and confirmed that AR-V9 mRNA and protein expression were also impacted. In reporter assays with AR-responsive promoters, AR-V9 functioned as a constitutive activator of androgen/AR signaling. Similarly, infection of AR-V9 lentiviral construct in LNCaP cells induced androgen-independent cell proliferation. In conclusion, these data implicate co-expression of AR-V9 with AR-V7 as an important component of constitutive AR signaling and therapeutic resistance in CRPC.
Citation Format: Yeung Ho, Jamie L. Van Etten, Christine Henzler, Yingming Li, Rendong Yang, Elizabeth Tseng, Ting Hon, Tyson Clark, Scott M. Dehm. The role of androgen receptor variant AR-V9 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1813.
Abstract 1817: Establishment and characterization of non-small cell lung cancer cell line variants selected for resistance to osimertinib
Authors: Ferguson Peter J. , Vincent Mark D. , Koropatnick James 
Published: August 2018

Abstract
Many non-small cell lung cancers (NSCLC) are oncogenically driven by mutant epidermal growth factor receptor (EGFR). EGFR tyrosine kinase inhibitors (TKIs) are commonly used as a first-line treatment against such tumors, but NSCLC tumors often recur with a mutant EGFR (often with a T790M mutation in exon 20) that confers resistance to these drugs [Ther Adv Respir Dis 10(6): 549-565, 2016]. Third generation EGFR TKIs (e.g., osimertinib) have been designed that are highly active aganst both T790M EGFR and the original non-T790M-mutated, oncogenic EGFR. Clinical resistance to third generation TKIs has been observed, but model systems in which to study the mechanisms of resistance are few. The human NSCLC cell line H1975, derived from an EGFR-TKI-resistant tumor, contains EGFR mutations T790M and L858R (exon 21). To explore mechanisms mediating resistance to third generation TKIs, we selected variants of the H1975 cell line for resistance to osimertinib to create models in which mechanisms of resistance can be characterized and tested for potential methods to overcome that resistance. Cells were exposed continuously to a single concentration of osimertinib, in some cases with the inclusion of verapamil to avoid possible selection of multidrug resistant cells. After 4 weeks, with weekly changes of drug-medium, clonal cell lines were selected in the presence of 6 and 10 μM osimertinib (one each) or in 5 μM osimertinib plus 10 μM verapamil (3 cell lines). These clonal lines were, respectively, 90-, 95-, 38-, 227-, and 244-fold resistant to osimertinib. The RAD51 inhibitor 2-(benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2), which enhances cytotoxicity of several EGFR inhibitors against numerous cell lines (Ferguson et al., JPET 2017, doi.org/10.1124/jpet.117.241661), decreased osimertinib-resistance by up to 80% in these cell lines. Sequence analysis indicates that cell line H1975/osi-6b retained the same EGFR sequence as that in the parent cell line. H1975/osi-5b/VPL appears to have undergone epithelial-to-mesenchymal transition. Further analyses of the resistant cell lines are being undertaken. These cell lines are a valuable resource in which to test methods to circumvent resistance to third generation EGFR TKIs.
Citation Format: Peter J. Ferguson, Mark D. Vincent, James Koropatnick. Establishment and characterization of non-small cell lung cancer cell line variants selected for resistance to osimertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1817.
Abstract 1819: Acquired T790M mutation after first generation EGFR tyrosine kinase retreatment
Authors: Lee Sung Yong , OH Jee Youn , Shim Jae Jeong , Kang Kyung Ho , Min Kyung Hoon 
Published: August 2018

Abstract
Introduction The first or second generation EGFR TKI drugs showed good overall response and progression free survival rates in EGFR mutation positive patients. However, most of them progress within 12 months from treatment start due to acquired resistance. In clinical practice, many physicians frequently offer these patients retreatment with EGFR TKIs after a chemotherapy break, because EGFR TKI retreatment can reduce the regrowing EGFR TKI sensitive clones. We evaluated induction of T790M mutation in previously sensitive EGFR mutation positive cancer patients that repeatedly treated EGFR TKIs. Method We reviewed the medical records of patients who were rechallenged with first generation EGFR TKIs. Those patients were previously responded to gefitinib or erlotinib and progressed after several chemotherapies. We analyzed the clincopathological characteristics, treatment modality and their outcome, and development of T790M mutation. EGFR mutations in exons 18, 19, 20, and 21 were evaluated with PNA mediated PCR clamping method. Results Three patients showed acquired T790M mutation after first generation EGFR TKIs retreatment. The acquired T790M mutation was detected in the tumor tissue in two patients and in the bronchoalveolar lavage fluid in the other patient. Three patients were taking osimertinib or olmutinib, two patients showed good clinical efficacy and low adverse events, however the other patient showed serious adverse event (interstitial lung disease). Conclusions Re-treatment with first generation EGFR TKIs after drug holiday in sensitizing EGFR mutant patients are considered to be an effective option, because EGFR TKI retreatment can reduce the regrowing EGFR TKI sensitive clones. Moreover, retreatment of first generation EGFR TKI may also induce or expand EGFR TKI resistance by T790M mutation and it could be treated with third generation EGFR TKI.
Citation Format: Sung Yong Lee, Jee Youn OH, Jae Jeong Shim, Kyung Ho Kang, Kyung Hoon Min. Acquired T790M mutation after first generation EGFR tyrosine kinase retreatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1819.