bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB042: Sorting nexin-dependent therapeutic targeting of oncogenic epidermal growth factor receptor
Authors: Atwell Ben 
Published: June 2022

Abstract
Overexpression and/or overactivation of the Epidermal Growth Factor Receptor (EGFR) is oncogenic in several tumor types yet targeting the kinase domain of wildtype EGFR has had limited success. EGFR has numerous kinase-independent roles, one of which is accomplished through the Sorting Nexin-dependent retrotranslocation of EGFR to the nucleus, which is observed in some metastatic cancers and therapeutically resistant disease. Here, we have utilized the BAR domain of Sorting Nexin 1 to create a peptide-based therapeutic (cSNX1.3) that promotes cell death in EGFR-expressing cancer. We evaluated the efficacy of cSNX1.3 in tumor-bearing WAP-TGFα transgenic mice (an EGFR-dependent model of breast cancer), where cSNX1.3 treatment resulted in significant tumor regression without observable toxicity. Evaluation of remaining tumor tissues found evidence of increased PARP cleavage, suggesting apoptotic tumor cell death. To evaluate the mechanism of action for cSNX1.3, we found that cSNX1.3 binds the C-terminus of the EGFR kinase domain at an interface site opposite the ATP binding domain with a K d of ~4.0 µM. In vitro analysis found that cSNX1.3 inhibits both long-term EGF-dependent AKT and ERK activation, as well as nuclear localization of EGFR. To determine specificity, we evaluated cancer cell lines expressing wildtype EGFR (MDA-MB-468, BT20 and A549), mutant EGFR (H1975) and non-transformed lines (CHO and MCF10A). Only transformed lines expressing wildtype EGFR responded to cSNX1.3, while mutant EGFR and normal cells responded better to the EGFR kinase inhibitor (Sapitinib). Phenotypically, cSNX1.3 inhibits EGF-, NRG-, and HGF-dependent migration, but not HA-dependent migration. Together, these data indicate that targeting retrotranslocation of EGFR may be a potent therapeutic for RTK-active cancer.
Citation Format: Ben Atwell. Sorting nexin-dependent therapeutic targeting of oncogenic epidermal growth factor receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB042.
Abstract LB103: Novel DNA-based-T-cell-activation for the generation of chimeric antigen receptor T cells with enhanced anti-leukemia cytotoxicity
Authors: Benzaoui Mehdi , Achar Sooraj R. , Keskar Vandana , Sood Anup , Davis Brian M. , Highfill Steven L. , Altan-Bonnet Grégoire , Chien Christopher D. , Taylor Naomi 
Published: June 2022

Abstract
Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable results in the treatment of hematological malignancies. However, several challenges remain, including achieving predictable efficacy and safety profiles and extending this approach to solid tumors. As such, the development of approaches that generate engineered T cells with superior persistence and efficacy are needed. Currently, the generation of CAR-T requires that they be activated and expanded ex vivo, generally via beads coated with anti-CD3/anti-CD28 mAbs. T cell activation provides three fundamental signals; (i) primary triggering of TCR signals; (ii) secondary co-stimulatory signals and, (iii) synthesis of cytokines to direct T cell expansion and differentiation. We hypothesize that a CAR-T response can be modulated by tuning the: (i) pattern, (ii) magnitude and, (iii) duration of the input T cell activation signals. To this end, we used a novel, soluble, tunable activation platform based on DNA hybridization - utilizing concatenated single stranded DNA (ssDNA) polymers to cluster complementary oligonucleotide-modified antibodies targeted at T-cell surface receptors. This DNA-Based-T-cell-Activation (DBTA) platform was compared with conventional bead-bound CD3/CD28 antibodies (Dynabead) in the generation and function of T cells engineered to express a CD19-targeted CAR harboring a 4-1BB co-stimulatory domain. The two methods did not result in any significant differences in CAR-T expansion nor in memory/activation phenotypes. Notably, though, these cells exhibited higher cytokine secretion in response to CAR stimulation, and in vitro killing of DBTA-generated CART was significantly higher than that of bead-activated CART. Indeed, only the former showed cytotoxicity against Nalm6 leukemic cells expressing low levels of the CD19 target antigen CART. Furthermore, in an in vivo NSG model with Nalm6 leukemia, the adoptive transfer of low numbers of DBTA-generated CART (2e6) resulted in leukemia eradication and delayed leukemia relapse. Mechanistically, the enhanced function of DBTA-generated CAR was associated with increased metabolic activity in the pre-infusion product. These results suggest that calibrating the activation potential of CAR-T cells can result in the generation of a product with enhanced therapeutic potential.
Citation Format: Mehdi Benzaoui, Sooraj R. Achar, Vandana Keskar, Anup Sood, Brian M. Davis, Steven L. Highfill, Grégoire Altan-Bonnet, Christopher D. Chien, Naomi Taylor. Novel DNA-based-T-cell-activation for the generation of chimeric antigen receptor T cells with enhanced anti-leukemia cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB103.
Abstract LB119: Precision combination therapies based on recurrent oncogenic co-alterations
Authors: Korkut Anil , Li Xubin , Kong Elizabeth , Yan Gonghong , Dereli Zeynep , Bozorgui Behnaz , Imanirad Parisa , Elnaggar Jacob , Luna Augustin , Menter David , Pilié Patrick , Yap Timothy , Kopetz Scott , Sander Chris 
Published: June 2022

Abstract
Cancer cells depend on multiple driver alterations whose oncogenic effects can be suppressed by drug combinations. Discovering effective combination therapies and selecting patients to maximize therapeutic benefit are challenging due to the complexity of the molecular landscape of drug responses. Here, we provide a comprehensive resource of precision combination therapies tailored to oncogenic co-alterations that are recurrent across patient cohorts. To generate the resource, we developed REcurrent Features Leveraged for Combination Therapy (REFLECT), which integrates machine learning and cancer informatics algorithms. Based on multi-omic data, the method maps recurrent co-alteration signatures in patient cohorts to combination therapies. The resource matches &gt; 2,000 drug combinations to co-alteration signatures across 201 cohorts stratified from 10,392 patients and 33 cancer types. We validated the REFLECT pipeline using data from patient-derived xenografts (PDX), in vitro drug screens, and combination therapy clinical trials. These validations demonstrate that REFLECT selects combination therapies with significantly improved efficacy, drug synergy, and survival outcomes. In patient cohorts with immunotherapy response markers, HER2 activation, and DNA repair aberrations, we have identified therapeutically actionable and recurrent co-alteration signatures. REFLECT provides a resource and framework to design combination therapies tailored to tumor cohorts in data-driven clinical trials and pre-clinical studies.
Citation Format: Anil Korkut, Xubin Li, Elizabeth Kong, Gonghong Yan, Zeynep Dereli, Behnaz Bozorgui, Parisa Imanirad, Jacob Elnaggar, Augustin Luna, David Menter, Patrick Pilié, Timothy Yap, Scott Kopetz, Chris Sander. Precision combination therapies based on recurrent oncogenic co-alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB119.
Abstract LB136: Characterization of a novel PI3Kinase inhibitor for treatment of glioblastoma multiforme
Authors: Fonkem Ekokobe , Newell-Rogers M. Karen , Tobin Richard , Healey Debbie , Das Mita , Bowen Sara , Quarles Chad , Clark John 
Published: June 2022

Abstract
The purpose of this study was to test the effects of a novel small molecule inhibitor of phosphatidylinositol-3 kinase (PI3K) for the treatment of glioblastoma multiforme (GBM). The key hurdles to effective treatment for GBM, the “most deadly” form of brain cancer, are resistance to chemotherapy, to radiation, and to immune check point inhibitor therapy. The overarching goal of our experiments has been to determine if a well-characterized small molecule inhibitor of PI3K, GCT.Glio.1, would improve treatment outcomes for GBM patients. The PI3K pathway has been shown to confer both chemotherapy and radiation resistance in GBM. GCT.Glio.1 (NPT520-337), a small molecule compound known to cross the blood brain barrier (BBB), was developed to target PI3K to treat GBM. GBMs, like other “difficult to treat” tumors, often over-express and actively utilize the PI3K pathway for survival, cell growth, and cell division. We used this small molecule inhibitor to determine how targeting the PI3K pathway impacts treatment resistance in GBM. We hypothesized that targeting PI3K would result in growth arrest, increase cell surface expression of a key immune check-point inhibitor target PD-L1, and would sensitize the GBM to treatment with radiation. Treatment of GL261 mouse GBM and U251 human GBM cell lines with GCT.Glio.1 resulted in profound growth arrest at the G2/M checkpoint, increased the cell surface expression of PD-L1, and synergized with radiation to cause growth arrest and subsequent cell death. In conclusion, these results indicate that GCT.Glio.1 may be a strong candidate for treatment of GBM, and suggest that GCT.Glio.1 is a candidate for rationally designed combinations with currently available radiation and immune checkpoint inhibitor therapies. Currently, the animal studies using GCT.Glio.1 in the GL261 mouse model of GBM have been initiated. Based on our promising pre-clinical data and early encouraging results from pre-clinical pharmacology and safety studies, we anticipate filing a pre-Investigational New Drug application (pre-IND) as the next step toward our goal of a clinical trial using GCT.Glio.1 for GBM patients.
Citation Format: Ekokobe Fonkem, M. Karen Newell-Rogers, Richard Tobin, Debbie Healey, Mita Das, Sara Bowen, Chad Quarles, John Clark. Characterization of a novel PI3Kinase inhibitor for treatment of glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB136.
Abstract LB157: Prevalence of metabolic syndrome among cancer survivors in the US
Authors: Ezeani Adaora , Agurs-Collins Tanya 
Published: June 2022

Abstract
Background: The purpose of this study was to determine the prevalence of metabolic syndrome (MetS) and its components in cancer survivors (CS) compared to participants without a history of cancer who have at least one chronic disease (CD) and those without a chronic disease diagnosis (NCD).
Methods: Using National Health and Nutrition Examination Survey (NHANES) data from 2015 to 2018, the prevalence MetS was evaluated among participants 50 years and older (n= 5466). MetS was defined based on the National Cholesterol Education Program’s Adult Treatment Panel III. Weighted data were used to estimate the prevalence of MetS, stratified by cancer site, gender, sex, and race/ethnicity. Chi-square test and logistic regression was used to assess group comparisons and associations respectively.
Results: Prevalence of MetS was higher among CS (71.4%) and CD (75.1%) participants compared to NCD (45.7%). Compared to NCD, participants with uterine cancer (UCa) and non-melanoma skin cancer (nMSC) had higher odds of MetS, with and without adjusting for covariates (p&lt;0.05). Those with UCa had the highest odds of MetS (OR 3.49, CI 1.51 - 8.06, p&lt;0.01) among all cancer types and NCD respondents. Regarding individual components of MetS, PCa survivors had lower odds of having elevated WC (p&lt;0.01) and BrCa and UCa had higher odds of having elevated WC (p&lt;0.05) after adjusting for covariates, compared to NCD. nMSC had higher odds of reduced HDL, elevated TG, and elevated WC (p&lt;0.05) after adjusting for covariates.
Conclusions: This study indicates that UCa and nMSC survivors have a strong association with MetS. In particular, nMSC survivors demonstrated statistically significant odds of meeting 3 of the 5 risk factors for MetS after adjusting for confounding variables. A better understanding of the association between MetS, its components, and specific cancers can provide insight into providing complete clinical care to CS.
Citation Format: Adaora Ezeani, Tanya Agurs-Collins. Prevalence of metabolic syndrome among cancer survivors in the US [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB157.
Abstract LB162: Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers
Authors: Jenkins Frank J. , Minas Tsion Z. , Tang Wei , Dorsey Tiffany H. , Ambs Stefan 
Published: June 2022

Abstract
Background: Chronic inflammation as seen with chronic infections, has been proposed as a risk factor for prostate cancer. Numerous studies failed to identify a specific microbial agent associated with prostate cancer risk. We have previously reported that human herpesvirus 8 (HHV-8) is associated with increased prostate cancer risk in Tobago; a population that is 97% of African ancestry. This association was not found in several studies of US men, who were predominately of European American ancestry. It is unclear if the discrepancies between US and Tobago men are due to differences in HHV-8 seroprevalence rates or ancestry-related genetics. Previous studies have reported that the dinucleotide germline variant, rs368234815-ΔG, in the IFNL4 gene encoding interferon λ4 is more prevalent among individuals of African ancestry and impairs viral clearance. In this study, we investigated whether the association of HHV-8 with prostate cancer is IFNL4-ΔG-dependent.
Methods: We investigated the association of HHV-8 seropositivity with prostate cancer in 728 IFNL4-ΔG-genotyped cases and 813 genotyped population-based control men from the NCI-Maryland Prostate Cancer Case-Control study. Associations between HHV-8 and prostate cancer were assessed in multivariable unconditional logistic regression models. We calculated adjusted odds ratios (OR) and stratified the analysis into men harboring the IFNL4-ΔG-variant and non-carriers (ΔG/ΔG or ΔG/TT vs. TT/TT).
Results: HHV-8 seropositivity was higher in cases than controls (OR 1.76; 95%CI: 1.20 - 2.59). The association of HHV-8 seropositivity with prostate cancer was restricted to carriers of the ΔG allele (OR 2.19: 95%CI: 1.38 - 3.48). HHV-8 seropositivity did not associate with prostate cancer among TT/TT genotype carriers (OR 1.03: 95%CI: 0.51 - 2.11). Further stratification by race/ethnicity showed that HHV-8 is associated with prostate cancer exclusively among carriers of the ΔG allele in both European American (OR 2.59; 95%CI: 1.20 - 5.56) and African American men (OR 1.96; 95%CI: 1.08 - 3.56).
Conclusions: HHV-8 seropositivity is associated with increased odds of prostate cancer in men harboring the IFNL4 rs368234815-ΔG variant.
Impact: The study establishes IFNL4-ΔG as a candidate prostate cancer risk factor in men with an HHV-8 infection. This gene-environment association of IFNL4-ΔG with prostate cancer should be further evaluated using prospective study designs.
Citation Format: Frank J. Jenkins, Tsion Z. Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs. Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB162.
Abstract LB175: MicroRNA-138 suppresses glioblastoma proliferation through downregulation of CD44 and sensitizes to temozolomide
Authors: Lee Tae Jin , Yoo Ji Young , Nam Deokhwa , Shim Ji Seon , Bueso-Perez Alberto , Kaur Balveen 
Published: June 2022

Abstract
Tumor suppressive microRNAs (miRNAs) are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells. This study aimed to pinpoint tumor suppressive miRNAs with therapeutic potential against GBM, one of the most deadly cancers. Whole transcriptome and miRNA expression profiling analyses were performed on human GBM patient tissues. Transient transfection of miRNA mimics was used to investigate the tumor suppressive role of a miRNA (miR-138) in cell proliferation, cell cycle, migration, would healing, and chemosensitivity to temozolomide (TMZ). Orthotopic xenograft mice model using human patient-derived primary GBM cells was used for the survival studies. miR-138 was found as one of the most significantly downregulated miRNAs with an inverse correlation with CD44 expression. Functional studies unveiled that miR-138 negatively regulates the expression of CD44 at protein level by directly binding to the 3’ UTR of CD44. CD44 inhibition by miR-138 overexpression resulted in an inhibition of glioblastoma cell proliferation in vitro through cell cycle arrest as evidenced by a significant induction of p27 and its translocation into nucleus. Ectopic expression of miR-138 also increased survival rates in mice that had an intracranial xenograft tumor derived from human patient-derived primary GBM cells. In addition, miR-138 sensitized GBM tumor to TMZ in mice. We demonstrated a therapeutic potential of tumor suppressive miR-138 through direct downregulation of CD44 and sensitization to chemotherapy for the treatment of primary and even chemoresistant GBM
Citation Format: Tae Jin Lee, Ji Young Yoo, Deokhwa Nam, Ji Seon Shim, Alberto Bueso-Perez, Balveen Kaur. MicroRNA-138 suppresses glioblastoma proliferation through downregulation of CD44 and sensitizes to temozolomide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB175.
Abstract LB197: Tucatinib has selective activity in HER2-positive cancers and significant combined activity with approved and novel breast cancer targeted therapies
Authors: O'Brien Neil A. , Huang Holly K. , McDermott Martina S. , Madrid Athena , Luo Tong , Ayala Raul , Issakhanian Shawnt , Gong Ke Wei , Lu Ming , Zhang Jun , Slamon Dennis J. 
Published: June 2022

Abstract
Pharmacologically targeting the HER2 oncoprotein with therapeutics such as the monoclonal antibody (mAb), trastuzumab, provides clinical benefit for patients with HER2-positive (HER2+) cancers. However, a significant number of patients eventually progress on these therapies. Efforts to overcome therapeutic resistance through combination therapy with small molecule inhibitors of HER2 have been limited by toxicities associated with off-target activity and/or limited efficacy. In this preclinical study, we explore single-agent and combined activity of tucatinib, a novel HER2-selective small molecule inhibitor. Tucatinib demonstrated potent, selective activity in a panel of 456 human cancer cell lines, with activity restricted to cell lines (breast and non-breast) with HER2-amplification, including models of acquired resistance to trastuzumab. Within the HER2+ population, tucatinib response tracked strongly with HER2-driven signaling. Single agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab induced a complete and sustained blockade of HER2/PI3K/AKT-signaling. Efficacy of the tucatinib/trastuzumab combination matched that induced by current standard of care (SOC) trastuzumab/pertuzumab/docetaxel combination, with the exception that the chemotherapy-sparing tucatinib/trastuzumab combination did not require a dosing holiday to achieve the same efficacy. In xenograft models of HER2+ breast cancer that also express estrogen receptor (ER) (HER2+/ER+), tucatinib showed combined efficacy with inhibitors of CDK4/6 and ER, indicating potential novel therapeutic strategies for difficult-to-treat subtypes of HER2+ breast cancer. These data support expanded clinical investigations of tucatinib as a combination partner for other novel and approved targeted therapies for HER2-driven malignancies.
Citation Format: Neil A. O'Brien, Holly K. Huang, Martina S. McDermott, Athena Madrid, Tong Luo, Raul Ayala, Shawnt Issakhanian, Ke Wei Gong, Ming Lu, Jun Zhang, Dennis J. Slamon. Tucatinib has selective activity in HER2-positive cancers and significant combined activity with approved and novel breast cancer targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB197.
Abstract LB210: Preclinical development and evaluation of allogeneic CAR T cells targeting CD70 for the treatment of renal cell carcinoma
Authors: Panowski Siler , Srinivasan Surabhi , Tan Nguyen , Tacheva-Grigorova Silvia , Smith Bryan , Mak Yvonne , Ning Hongxiu , Villanueva Jonathan , Wijewarnasuriya Dinali , Lang Shanshan , Melton Zea , Ghosh Adit , Dusseaux Mathilde , Galetto Roman , Heyen Jonathan , Sai Tao , Van Blarcom Thomas , Chaparro-Riggers Javier , Sasu Barbra 
Published: June 2022

Abstract
CD70 is highly expressed on renal cell carcinoma (RCC), with limited normal tissue expression, making it an attractive CAR T target for an immunogenic solid tumor indication. Here we generated and characterized a panel of anti-CD70 scFv-based CAR T cells. Despite the expression of CD70 on T cells, production of CAR T from a subset of scFvs with potent in vitro activity was achieved. Expression of CD70 CARs was found to mask CD70 detection in cis and provide protection from CD70 CAR T-mediated fratricide. Two unique classes of CAR T cells were identified with differing memory phenotype, activation status, and cytotoxic activity. Epitope mapping revealed CARs binding to the membrane distal region of the CD70 extracellular domain (ECD) fall into the more active and differentiated class, as compared to CARs binding the membrane proximal region of the CD70 ECD. CD70 CAR T cells were evaluated with rituximab-based off switches to provide control over CAR T function and displayed robust antitumor activity against RCC cell lines and patient-derived xenografts in mouse models. Tissue cross reactivity studies to evaluate off-target binding with two lead CARs showed membrane staining in rare tissue-resident lymphocytes, thus matching the known expression pattern of CD70. Expected findings related to T cell activation, and elimination of CD70-expressing cells were observed in a cynomolgus monkey CD3-CD70 bispecific toxicity study and included cytokine release and loss of cellularity in lymphoid tissues. Lastly, highly functional CD70 allogeneic CAR T cells were produced at large scale through elimination of the T cell receptor by TALEN® gene editing. Taken together, these efficacy and safety data support the evaluation of CD70 CAR T cells for the treatment of RCC and led to the advancement of an allogeneic CD70 CAR T candidate into Phase I clinical trials.
Citation Format: Siler Panowski, Surabhi Srinivasan, Nguyen Tan, Silvia Tacheva-Grigorova, Bryan Smith, Yvonne Mak, Hongxiu Ning, Jonathan Villanueva, Dinali Wijewarnasuriya, Shanshan Lang, Zea Melton, Adit Ghosh, Mathilde Dusseaux, Roman Galetto, Jonathan Heyen, Tao Sai, Thomas Van Blarcom, Javier Chaparro-Riggers, Barbra Sasu. Preclinical development and evaluation of allogeneic CAR T cells targeting CD70 for the treatment of renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB210.