bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3144: Mapping the functional interactions at the tumor-immune checkpoint interface
Authors: Bozorgui Behnaz , Kong Elisabeth K. , Luna Augustin , Korkut Anil 
Published: April 2023

Abstract
The interactions between tumor intrinsic processes and immune checkpoints can mediate the immune evasion by tumors and responses to immunotherapy. It is, however, challenging to identify functional interactions due to the prohibitively complex molecular landscape of the tumor-immune interfaces. We address this challenge with a statistical analysis framework, termed immuno-oncology gene interaction maps (ImogiMap). ImogiMap quantifies tumor-immune checkpoint interactions based on their co-associations with immune-associated phenotypes. The interactions are statistically validated for significance, robustness, and specificity. The outcome is a catalog of maps that quantify the interactions at the tumor-immune interface for diverse immune phenotypes and checkpoints. We demonstrate that applications of ImogiMap on immune checkpoints and T-cell dysfunction signatures genes recapitulates the previously reported interaction of SERPINB9 and immune checkpoints in the tumor microenvironment. Our analyses also suggest other immune checkpoint and T-cell dysfunction signatures interactions that are significantly associated with IFNγ expression in uterine corpus endometrial carcinoma and basal-like breast cancer. We also provide open-source software and a user-friendly web application to enable future applications and rapid adoption of ImogiMap. Such applications may guide the discovery of previously unknown tumor-immune interactions and help the identification of immunotherapy targets.
Citation Format: Behnaz Bozorgui, Elisabeth K. Kong, Augustin Luna, Anil Korkut. Mapping the functional interactions at the tumor-immune checkpoint interface [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3144.
Abstract 3173: Integrative structural models of oncogenic mutants within the trans- and juxta-membrane region of human epidermal growth factor receptors (HERs)
Authors: Mercado Christina , Mamun Abdullah Al , Park Younghee , Lovly Christine M. , Meiler Jens , Ledwitch Kaitlyn 
Published: April 2023

Abstract
The trans- and juxtamembrane domains (TMD/JMD) of human epidermal growth factor receptors (HER/EGFR/ErbB) regulate the helix-helix dimerization interface to control receptor tyrosine kinase (RTK) activation. Patient-identified non-small cell lung cancer (NSCLC) mutations occur all along the EGFR (HER1) and HER2 TMD and JMD, but our structural understanding of how these patient-derived TMD/JMD mutations hijack wild-type RTK function to drive cancer is lacking. In this work, we integrate tools in experimental biophysics and computational modeling to evaluate the structural mechanism(s) driving these interactions in atomic detail. We use nuclear magnetic resonance (NMR) spectroscopy to assess how oncogenic mutations within the TMD/JMD perturb the architecture/interactions of the dimer interface. NMR-derived models are used to seed molecular dynamics (MD) simulations to probe how mutations affect TMD association and activation/stabilization via dimerization in a realistic membrane environment. We apply this strategy and focus our initial efforts on the EGFRA647T variant. We computed the free energy landscape from our simulations and show that the active state for the EGFRA647T-HER2WT heterodimer is stabilized by 10 kcal/mol. Conversely, the wild-type EGFR-HER2 heterodimer is stabilized by 5 kcal/mol for the inactive state suggesting the propensity of the EGFRA647T mutant favors the active state. These results are part of a multidisciplinary collaboration that share the common goal of constructing holistic models that detail how TMD/JMD variants are aberrantly activated in cancer.
Citation Format: Christina Mercado, Abdullah Al Mamun, Younghee Park, Christine M. Lovly, Jens Meiler, Kaitlyn Ledwitch. Integrative structural models of oncogenic mutants within the trans- and juxta-membrane region of human epidermal growth factor receptors (HERs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3173.
Abstract 3216: Comparative characteristics of stage I non-small cell lung cancer (NSCLC) patients segregated by quality of surgery and survival in a population-based cohort
Authors: Shao Huibo , Lee Yu-Sheng , Fehnel Carrie , Akinbobola Olawale , Saulsberry Andrea , Dortch Kourtney , Matthews Anberitha T. , Faris Nicholas R. , Smeltzer Matthew , Ray Meredith A. , Osarogiagbon Raymond U. 
Published: April 2023

Abstract
Introduction. Poor quality NSCLC resection impairs survival, but some patients survive irrespective. We explored characteristics of patients in 4 cohorts defined by surgery quality and survival.
Methods. We analyzed stage I resections in a population-based cohort surviving &gt;120 days post-op from 2009-2018. Using the International Association for the Study of Lung Cancer’s stringent definition of ‘complete resection’ and 3-year survival as ‘good’, we categorized patients into 4 dyads: 1) Good surgery/good survival; 2) Good surgery/poor survival; 3) Poor surgery/good survival (reference); 4) Poor surgery/poor survival. We used Chi-square and Kruskal-Wallis test for description, multivariable multinomial logistic regression to estimate Odds Ratio (OR) of surgery quality and survival.
Results. Of 1,515 patients, 31%, 7%, 51%, and 12% were in Groups 1-4, respectively. In the ‘mis-match dyads’ (Groups 2 and 3), Group 2 was more likely to be elderly (70 vs. 66, p&lt;0.01), on Medicaid (p=0.01), have ever smoked (96% vs. 85%, p&lt;0.01), have squamous cell carcinoma.
Older (OR=1.06), male (OR=1.78), Medicaid patients (OR=2.16) with smoking history (OR=3.25) had poorer survival despite good surgery rather than survival despite bad surgery. With poor surgery, male (OR=2.01) patients tumor 2-3 and &gt;3 cm (OR=1.77 and 1.64) had poorer survival; commercially insured patients had 36% reduced risk of poor survival. Compared to open thoracotomy, patients with robotic-assisted surgery were &gt;4-fold more likely to have good surgery rather than poor surgery but good survival.
Conclusion. Differentiating characteristics associated with good/bad survival after good/bad quality lung cancer surgery provide opportunity to compare biomarker profiles between dyads.
Citation Format: Huibo Shao, Yu-Sheng Lee, Carrie Fehnel, Olawale Akinbobola, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Matthew Smeltzer, Meredith A. Ray, Raymond U. Osarogiagbon. Comparative characteristics of stage I non-small cell lung cancer (NSCLC) patients segregated by quality of surgery and survival in a population-based cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3216.
Abstract 3217: Risk of thromboembolism in patients with non-small lung cancer (NSCLC) treated with immune check point inhibitors (ICIs) versus chemoimmunotherapy (ChemoIO)
Authors: Attia Doaa , Zhao Ran , Khorana Alok A. , Patil Prandya 
Published: April 2023

Abstract
Background: Immune checkpoint inhibitors with or without chemotherapy form the backbone of treatment for patients with advanced NSCLC without an actionable driver mutation. Emerging literature shows that ICIs increase the risk of venous thromboembolism (VTE), which is a major cause of death in patients with NSCLC. The mechanism is yet to be elucidated but is likely secondary to inflammation. Since chemotherapy is immunosuppressive, we sought to understand if the addition of chemotherapy to ICIs impacted the incidence of VTEs.
Methods: We performed a retrospective cohort study to evaluate thromboembolic outcomes in patients diagnosed with advanced NSCLC between 2012 and 2018 and treated with either ICIs or chemo immunotherapy at Cleveland Clinic Foundation. Diagnosis of thrombotic events (TE) (arterial/deep vein thrombosis and/or pulmonary embolism) was confirmed by imaging. Overall survival (OS) was estimated by Kaplan-Meier and compared using log rank test. Odds of developing TE was estimated and compared between ICI and ChemoIO groups, using Fisher's Exact Test.
Results: A total of 367 NSCLC patients (242 pts on ICI only and 125 pts on ChemoIO regimen), were identified with a median age 65 years ( range 58-72), 52% were men, 82% white, 85.3% smokers, 91.8% had ECOG ≤2, 73 % had adenocarcinoma and 18% had squamous cell carcinoma, 34% with brain metastasis and the distribution of PDL1expression was as follows- &lt;1 (26.4%), 1-49% (48%) and ≥50% (25.6%). Adjusted response rates to treatment were (N, %): Complete Response (CR) (6/367, 1.9%), Partial Response (PR) (96/367, 30%), Stable Disease (SD) (76/367, 24%) and PD (143/367, 45%). TE was detected in 19% of the cohort (n=70) (8.4% DVT, 4.9% PE, 5.2 % both, and 0.5 % arterial TE. Rate of TE in NSCLC pts on ICI alone was 18% (44/242) Vs. 21% (26/125) for those on ChemoIO (OR 1.5, 95% CI 0.66-2.1, P 0.6). Development of TEs was not associated with survival differences with either regimen (P &gt;0.05).
Conclusion: Rates of TE were high in patients with advanced NSCLC who received ICI therapy, but no different if treated with ICIs alone or ChemoIO. Further studies to better understand the pathophysiology of TE in patients treated with ICIs might allow us to identify subgroups of patients that are at the highest risk for TEs.
Citation Format: Doaa Attia, Ran Zhao, Alok A. Khorana, Prandya Patil. Risk of thromboembolism in patients with non-small lung cancer (NSCLC) treated with immune check point inhibitors (ICIs) versus chemoimmunotherapy (ChemoIO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3217.
Abstract 3233: A novel triple humanized B-hPD-1/hPD-L1/hCCR8 mouse model to evaluate in vivo efficacy of combination therapies
Authors: Wang Linlin , Liu Xiao , Jin James , Yu Yuxiang 
Published: April 2023

Abstract
Regulatory T cells (Tregs) play an immunosuppressive role in the tumor microenvironment (TME), such that altering or depleting Treg function has emerged as an important anti-tumor strategy. Targeting CCR8, which is highly expressed in tumor-infiltrating Tregs, has shown its potency in reducing tumor burden and increasing responsiveness to immune-checkpoint blockade therapy. Collectively, this suggests a need for preclinical models that support Treg-targeted therapies. To address this, Biocytogen developed a triple humanized (B-hPD-1/hPD-L1/hCCR8) mouse model to evaluate in vivo efficacy of combination therapies. In this model, the full coding sequence of murine Ccr8 was replaced by the full coding sequence of human CCR8, while murine Pd-1 and Pd-l1 IgV domains were replaced by their human counterpart gene sequences. Human PD-1 and PD-L1 protein expression was confirmed in B-hPD-1/hPD-L1/hCCR8 mice by flow cytometry, and human CCR8 protein expression was observed in MC38 tumors harvested from B-hPD-1/hPD-L1/hCCR8 mice. Finally, combination therapy using anti-human PD-1 and anti-human CCR8 antibodies were effective in controlling B-hPD-L1 MC38 tumor growth in B-hPD-1/hPD-L1/hCCR8 mice. Altogether, this line provides a powerful preclinical model for in vivo evaluation of therapeutic antibodies.
Citation Format: Linlin Wang, Xiao Liu, James Jin, Yuxiang Yu. A novel triple humanized B-hPD-1/hPD-L1/hCCR8 mouse model to evaluate in vivo efficacy of combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3233.
Abstract 3242: Efficacy evaluation by novel humanized mouse models for preclinical study of ADCs combined with immunotherapy
Authors: Zhu Fang , Sun Hongyan , Lu Qian , Fang Yuan , Xu Jianming , Ju Cunxiang , Wang Hongyu , Chen Santi Suryani , Li Zhiying , Moore Mark Wade , Zhao Jing , Gao Xiang 
Published: April 2023

Abstract
Antibody-drug conjugates (ADCs) are effective anti-tumor therapies with high specificity, with little toxicity and side effects. Xenograft tumor models based on immunodeficient mice have been used for evaluating the human anti-tumor efficacy of ADCs. However, the antibody-mediated immune response of ADCs is not well evaluated in immunodeficient mice. To this end, we have developed BALB/c-hPD1 humanized mouse model to evaluate the efficacy of ADCs in combination with immunotherapy.
Trastuzumab deruxtecan (T-DXd, DS-8201a) is a HER2-targeting ADC. In vitro efficacy studies showed that T-DXd effectively bound to the HER2-positive cell line SK-BR-3, resulting in strong endocytosis and induction of apoptosis. It has also been shown to kill HER2-negative MDA-MB-468 cells through a bystander effect both in vitro and in vivo. In vivo efficacy studies have demonstrated that ADCs can effectively inhibit human tumor cell growth in immunodeficient mice. In addition to human tumor cell lines, the efficacy of ADCs was also studied in BALB/c-hPD1mice engrafted with murine colon cancer cells model, and the results showed that T-DXd and Keytruda could significantly inhibit CT26-hHER2 tumor growth, with the tumor growth inhibition rates being 57% and 66%, respectively, Tumor growth inhibition rate of the combined treatment group was about 91%, which was superior compared to the efficacy of single drug treatment. The evaluation of Fc segment-mediated effect (such as ADCC, CDC and ADCP) of ADCs antibodies was carried out in humanized immune system mouse models, such as NCG-hIL15 and NCG-hSGM3. In summary, we have established a drug evaluation platform using various humanized mouse models to study the synergistic anti-tumor effects of ADCs combined with immune checkpoint blockade antibodies.
Citation Format: Fang Zhu, Hongyan Sun, Qian Lu, Yuan Fang, Jianming Xu, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. Efficacy evaluation by novel humanized mouse models for preclinical study of ADCs combined with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3242.
Abstract 3254: Combination of palbociclib, a potent CDK4/6 inhibitor, with anti-PD1 drug pembrolizumab treatment to promote T-cell mediated glioblastoma tumor cell death under hypoxia
Authors: Xia Yutong , Zhou Lanlan , Zhao Shuai , El-Deiry Wafik S. 
Published: April 2023

Abstract
Glioblastoma (GBM) is the most common malignant brain and other central nervous system (CNS) tumor, which comprises 47.7% of all cases. The standard treatment options are surgery, radiation therapy, and chemotherapy using temozolomide. GBM is fast-growing, aggressive, and results in poor overall survival, approximately 40% in the first year and 17% in the second year. Hypoxia, the lack of sufficient oxygen in tissues, is the hallmark of GBM and can induce drug resistance and inhibit anti-tumor immune responses. Previous studies show that CDK inhibitors can destabilize HIF1, a key regulator of hypoxia induced apoptosis and p53 stabilization. Palbociclib, a potent oral inhibitor of CD4/6, is undergoing clinical trials for GBM treatment. However, it was not an effective treatment for recurrent GBM when used as alone in a Phase II study. Thus, we are exploring the cytotoxicity of palbociclib in combination with an anti-PD1 drug pembrolizumab, which is proven to be highly effective in other cancer types. Preliminary studies use CellTitlerGLO viability assay to determine the IC50s for Palbociclib at 24, 48, and 72 hours in both normoxia and hypoxia conditions. Immune cell co-culture, comprising of GBM cell lines plus TALL104 human leukemia T cells, was used to determine the amount of tumor cell death with palbociclib, pembrolizumab and a combination at different time points in both normoxia and hypoxia conditions. Our results are providing insights into improving immune checkpoint therapy for GBM patients.
Citation Format: Yutong Xia, Lanlan Zhou, Shuai Zhao, Wafik S. El-Deiry. Combination of palbociclib, a potent CDK4/6 inhibitor, with anti-PD1 drug pembrolizumab treatment to promote T-cell mediated glioblastoma tumor cell death under hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3254.
Abstract 3428: Discovery of a highly potent and selective dual PROTAC degrader of CDK12 and CDK13
Authors: Chang Yu , Yang Jianzhang , Tien Jean Ching-Yi , Wang Zhen , Zhou Yang , Zhang Pujuan , Huang Weixue , Vo Josh , Apel Ingrid J. , Wang Cynthia , Zeng Victoria Zhixuan , Cheng Yunhui , Li Shuqin , Wang George Xiaoju , Ding Ke , Chinnaiyan Arul M. 
Published: April 2023

Abstract
Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound 7f effectively degraded CDK12 and CDK13 with DC50 values of 2.2 nM and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of 7f. In vitro, 7f suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, 7f markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC50 value of 47 nM. Importantly, 7f displayed a significantly improved anti-proliferative activity compared to the structurally similar inhibitor 4.The 2nd generation CDK12/13 degrader 9069 was further developed, which showed more potent degradation on both CDK12 and CDK13. Interestingly, multiple prostate cancer cell lines were sensitive to 9069, such as VCaP, 22RV1 and LAPC4 with IC50 values of 22.9, 90.3 and 152.1 nM, respectively. In vivo studies showed a potent tumor growth inhibition in both VCaP CRPC xenograft and PC310 PDX prostate cancer models. These results suggest the potential application of a CDK12/13 degrader for the treatment of TNBC and prostate cancer.
Citation Format: Yu Chang, Jianzhang Yang, Jean Ching-Yi Tien, Zhen Wang, Yang Zhou, Pujuan Zhang, Weixue Huang, Josh Vo, Ingrid J. Apel, Cynthia Wang, Victoria Zhixuan Zeng, Yunhui Cheng, Shuqin Li, George Xiaoju Wang, Ke Ding, Arul M. Chinnaiyan. Discovery of a highly potent and selective dual PROTAC degrader of CDK12 and CDK13 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3428.
Abstract 3525: VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis
Authors: Watson Sarah , LaVigne Collette A. , Xu Lin , Surdez Didier , Cyrta Joanna , Calderon Delia , Cannon Matthew V. , Kent Matthew R. , Silvius Katherine M. , Kucinski Jack P. , Harrison Emma N. , Murchison Whitney , Rakheja Dinesh , Tirode Franck , Delattre Olivier , Amatruda James F. , Kendall Genevieve C. 
Published: April 2023

Abstract
Clinical sequencing efforts are rapidly identifying sarcoma gene fusions that have not been functionally validated for their transformation capacity and biological activity. An example is the new fusion of transcriptional coactivators, VGLL2-NCOA2, found in infantile rhabdomyosarcoma. To delineate VGLL2-NCOA2 tumorigenic mechanisms and identify therapeutic vulnerabilities, we implemented a cross-species comparative oncology approach with zebrafish, mouse allograft, and patient samples. We found that in our transgenic zebrafish and mouse allograft models, VGLL2-NCOA2 is sufficient to generate mesenchymal tumors that display features of immature skeletal muscle. Zebrafish and mouse VGLL2-NCOA2 tumors are consistent with the human disease histologically and transcriptionally, and express diagnostic rhabdomyosarcoma markers. We found a shared molecular feature of these tumors was a suppression of myogenic differentiation pathways and reactivation of developmental programs. To identify impacted developmental programs, we transcriptionally clustered zebrafish VGLL2-NCOA2 tumors with the trajectory of early zebrafish development. A subset of VGLL2-NCOA2 zebrafish tumors cluster with embryonic somitogenesis and pinpoint VGLL2-NCOA2 developmental targets, including a RAS family GTPase, ARF6. In VGLL2-NCOA2 zebrafish, mouse allograft, and patient tumors, ARF6 is highly expressed and is absent from mature skeletal muscle. ARF6 knockout in our C2C12-VGLL2-NCOA2 cell culture model suppresses VGLL2-NCOA2 soft agar colony formation capacity, suggesting a genetic cooperating event in the disease. Our data indicate that VGLL2-NCOA2 is an oncogene which leverages developmental programs for tumorigenesis, and that the reactivation or persistence of ARF6 could represent a therapeutic opportunity.
Citation Format: Sarah Watson, Collette A. LaVigne, Lin Xu, Didier Surdez, Joanna Cyrta, Delia Calderon, Matthew V. Cannon, Matthew R. Kent, Katherine M. Silvius, Jack P. Kucinski, Emma N. Harrison, Whitney Murchison, Dinesh Rakheja, Franck Tirode, Olivier Delattre, James F. Amatruda, Genevieve C. Kendall. VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3525.