bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2988: Proteasomal deubiquitinases represent an attractive therapeutic target in head and neck squamous cell carcinomas (HNSCC)
Authors: Morgan Ethan L. , Toni Tiffany , Yang Xinping , Cheng Hui , Viswanathan Ramya , Chen Zhong , Van Waes Carter 
Published: June 2022

Abstract
Despite recent advances in treatment options for Human Papillomavirus (HPV)- head and neck squamous cell carcinoma (HNSCC), the overall survival (OS) rate for HNSCC is low, demonstrating the need for novel therapies for these cancers. Targeting the ubiquitin-proteasome system (UPS) has emerged as a potential target for the development of novel anti-cancer therapies. Bortezomib, a first generation proteasome inhibitor clinically approved for the treatment of Multiple Myeloma, has previously been demonstrated to induce tumor regression in a subset of HNSCC patients through the inhibition of canonical NFκB activity; however, the failure of Bortezomib to inhibit other pro-survival pathways such as MAPK and STAT3 signalling resulted in heterologous responses. A recently developed alternative to proteasome inhibitors is the small molecule b-AP15, which inhibits the proteasomal deubiquitinases USP14 and UCHL5, thus allowing more specificity and less toxicity than proteasome inhibitors.
Here, we show b-AP15 inhibits proliferation and colony formation in multiple HPV- and HPV+ HNSCC cell lines, with minimal effects in normal oral keratinocytes. Furthermore, b-AP15 induces significant caspase-dependent apoptosis. Using siRNA targetting USP14 and UCHL5, only USP14 depletion significantly reduced cell proliferation and colony formation. Mechanistically, b-AP15 treatment reduces TNFα-induced NFκB activity and the expression of pro-survival proteins such as cIAP2 and TRAF2, promoting the formation of the TNFR complex II and sensitizing cells to TNFα-induced cell death. Finally, TCGA data demonstrates that USP14 is highly expressed in HNSCC when compared with normal tissue and is significantly correlated with worse overall survival. Together, we have identified that inhibition of proteasomal deubiquitinases inhibits the proliferation and survival of HNSCC cells and enhanced TNFα-induced cell death via the inhibition of NFκB activity. Our data suggest that combination therapies with b-AP15 could potentially offer a clinical benefit in HNSCC patients by promoting TNFα-induced cytotoxicity. Further studies will focus on the mechanism by which USP14 regulates NFκB signalling in HNSCC cells and the effect of b-AP15 activity in combination with radiation treatment in in vivo mouse xenograft models.
Citation Format: Ethan L. Morgan, Tiffany Toni, Xinping Yang, Hui Cheng, Ramya Viswanathan, Zhong Chen, Carter Van Waes. Proteasomal deubiquitinases represent an attractive therapeutic target in head and neck squamous cell carcinomas (HNSCC) [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 2988.
Abstract 3157: KLF5 defines the secretory lineage and governs sphingolipid metabolism in the skin
Authors: Ge Yejing 
Published: June 2022

Abstract
Adult stem cells contribute to tissue regeneration and wound repair through cellular programs that can be hijacked by cancer cells. We previously reported such a phenomenon in skin, where squamous cell carcinomas adopt a plastic phenotype so called “stem cell lineage infidelity”, entailing a wide-spread co-expression of otherwise lineage restricted genes, exemplified by hair follicle factor SOX9 and interfollicular epidermal factor KLF5. Occurring transiently in wounds and persists in cancer, stem cell lineage infidelity is essential to drive wound repair and tumorigenesis. However, it remains unclear what were the functional mediators of lineage infidelity factors. We thus set out to investigate one of its defining factors, KLF5. Employing genome-wide transcriptome and epigenome profiling, we found KLF5 specifies the epidermal lineage in the skin and is essential for skin maturation in vivo. Strikingly, KLF5 binds to the genomic vicinity of, and transcriptionally controls, multiple key enzymes catalyzing rate-limiting steps of epidermal sphingolipid secretion, whose disruption led to loss of lipid ultrastructural integrity, compromised secretory machinery and selective decline of high complexity sphingolipids in the skin. Remarkably, lipid-rich dietary intervention was able to reverse skin defects caused by KLF5 ablation and KLF5 is prevalently disrupted in skin barrier and inflammatory diseases. Our findings suggest KLF5 serves as a master secretory lineage factor and a transcriptional governor of sphingolipid metabolism in the developing and diseased skin, warranting future investigation of its functional underpinning in wound repair and cancer.
Citation Format: Yejing Ge. KLF5 defines the secretory lineage and governs sphingolipid metabolism in the skin [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 3157.
Abstract 3208: Angiogenesis inhibitors strongly synergize with therapeutics targeting tumor metabolism
Authors: Khadka Sunada , Lin Yu-Hsi , Ackroyd Jeffery , Arthur Kenisha , Barekatain Yasaman , Poral Anton , Tran Theresa , Behr Eliot , Chen Yining , Georgiou Dimitra , Depinho Ronald , Muller Florian 
Published: June 2022

Abstract
Angiogenesis inhibition has become a mainstay of oncology despite having fallen short of its early promise. As originally envisioned, angiogenesis inhibition would cut off the blood supply, deprive tumor cells of key nutrients, leading to their demise. In practice, while there is evidence that tumors under angiogenesis treatment do in fact exhibit some degree of metabolic stress, this is stress is not sufficient to induce significant cancer cell death. We posit that the full potential of angiogenesis inhibition can be realized by the combination of angiogenesis inhibition with emerging tumor metabolism targeting therapies. Because tumors under angiogenesis inhibition are already in a state of nutrient stress, the effects of metabolically targeted therapies such as amino acid depletion (e.g. asparginase, methionine restriction), inhibitors of stress adaption (AMPK and GCN2 inhibitors) or energy metabolism (e.g. IACS-010759, Metformin, POMHEX) stand to dramatically increase in potency whilst remaining selective for (angiogenic) tumor versus (non-angiogenic) normal tissue. Here, we provide proof-of-principal for this thesis. First, we performed metabolomic profiling of angiogenesis-inhibited tumors, which corroborates a state of nutrient stress in angiogenesis-inhibited tumors. Second, we demonstrate dramatic anti-neoplastic synergy (effectively curing of xenografted tumor-bearing mice, irrespective of initial tumor size), without enhanced adverse toxicities, between the anti-VEGFA antibody Avastin and enolase inhibitor HEX. The same results were recapitulated with the VEGFR inhibitor Tivozanib and HEX and the enolase inhibitor could be substituted with the Oxphos inhibitor IACS-010759, with similar effects. The synergy was observed in a broad range of tumor types, even those without clear genetic susceptibilities. Together, these results suggest that angiogenesis inhibitors synergize broadly with cancer therapies targeting metabolism, allowing the realization of the full potential of these previously disappointing drugs. Our results warrant systematic combination clinical trials between angiogenesis inhibitors and established, as well as emerging anti-metabolic cancer therapies.
Citation Format: Sunada Khadka, Yu-Hsi Lin, Jeffery Ackroyd, Kenisha Arthur, Yasaman Barekatain, Anton Poral, Theresa Tran, Eliot Behr, Yining Chen, Dimitra Georgiou, Ronald Depinho, Florian Muller. Angiogenesis inhibitors strongly synergize with therapeutics targeting tumor metabolism [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 3208.
Abstract 3227: Prognostic role of systemic inflammation in colon and rectal cancer patients: Results from the ColoCare Study
Authors: Ose Jennifer , Lin Tengda , Himbert Caroline , Warby Christy A. , Hardikar Sheetal , Boehm Juergen , Gigic Biljana , Schrotz-King Petra , Schneider Martin , Ulrich Alexis B. , Shibata David , Figueiredo Jane C. , Siegel Erin M. , Li Christopher I. , Toriola Adetunji T. , Ulrich Cornelia M. 
Published: June 2022

Abstract
Purpose: Inflammation and angiogenesis are hallmarks of cancer development and progression. No studies have prospectively examined association of angiogenesis-related biomarkers with clinical outcomes in colon and rectal cancer.
Patients and Methods: In pre-surgery serum samples from n=426 non-metastatic colorectal cancer (CRC) patients (stage I-III), we investigated associations of inflammatory (e.g., CRP, SAA, sICAM-1, sVCAM-1) and angiogenesis biomarkers (VEGF-A, VEGF-D) with overall survival (OS), disease-free survival (DFS), and risk of recurrence. We computed hazard ratios (HR) and 95% confidence intervals (CI). Analyses were adjusted for age, sex, body mass index, stage, tumor site, and study site, and also exploratory stratified by tumor site (colon vs. rectum).
Results: N=65 patients (15%) were deceased and n=59 patients (15%) had a recurrence after a median follow-up of 31 months. Overall, doubling of CRP was associated with a ~24% increase in risk of death (OS: HRlog2: 1.24; 95% CI: 1.11-1.40), a 19% increase in risk of recurrence: HRlog2: 1.19; 95% CI: 1.08-1.32, and a non-statistically-significant 12% increase for DFS HRlog2: 1.12; 95% CI: 0.98-1.28. Similar associations were observed for SAA. Doubling of sICAM-1 was associated with a 4-fold increase in risk of death (OS: HRlog2: 4.05; 95% CI: 2.35-6.98). For the angiogenesis marker VEGF-D, significant heterogeneity was observed in analyses stratified by tumor site: doubling was associated with a 3-fold increase in risk of death for rectal cancer (OS: HR: 3.26; 95% CI: 1.58-6.70) and a 22% reduction in mortality for colon cancer (OS: HR: 0.78; 95% CI: 0.35-1.73; pheterogenity &lt;0.001). Similar heterogeneity was observed in associations of VEGF-D with DFS and risk of recurrence, although not statistically significant (pheterogeneity&lt;0.10).
Conclusion: Our data suggest that some biomarkers of inflammation and angiogenesis are prognostic markers for stage I-III CRC patients, with potential differences by tumor site for angiogenesis markers.
Citation Format: Jennifer Ose, Tengda Lin, Caroline Himbert, Christy A. Warby, Sheetal Hardikar, Juergen Boehm, Biljana Gigic, Petra Schrotz-King, Martin Schneider, Alexis B. Ulrich, David Shibata, Jane C. Figueiredo, Erin M. Siegel, Christopher I. Li, Adetunji T. Toriola, Cornelia M. Ulrich. Prognostic role of systemic inflammation in colon and rectal cancer patients: Results from the ColoCare Study [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 3227.
Abstract 3281: DNMT targeting enhances vulnerability of glioblastoma cells to MNK inhibition
Authors: Mazewski Candice , Eckerdt Frank , Baran Aneta , Fischietti Mariafausta , Vagadia Purav P. , Perez Ricardo E. , James Charles D. , Schiltz Gary E. , Platanias Leonidas C. 
Published: June 2022

Abstract
Many factors complicate therapeutic strategies for glioblastoma (GBM), including the existence of the blood brain barrier and a heterogenous population of difficult to treat glioma stem cells. Innovative strategies targeting novel pathways alone or in combination are needed for sustainable therapeutic improvements. The MAPK pathway has been implicated in many cancers. MAPK interacting kinases (MNK1 and MNK2) are downstream of MAPKs and phosphorylate the eukaryotic translation initiation factor 4E (eIF4E), a protein involved in translation of oncogenic mRNAs. We have previously established pharmacological MNK inhibition as a promising strategy for GBM. However, most currently available MNK inhibitors lack specificity and exhibit off-target effects. We developed novel selective MNK inhibitors that show MNK inhibition specificity in GBM established cell lines as well as patient-derived cell lines propagated under stem cell permissive conditions as 3-D neurospheres. MNK inhibitors reduced cell viability and neurosphere growth. Our previous work with MNK inhibitors showed involvement in negative feedback loops activated with treatment of other pharmacological agents, so we conducted a high-throughput screening to identify potential targets for combination treatment. One of the top hits was a DNA methyltransferase (DNMT) inhibitor that enhanced MNK inhibitor antineoplastic effects in GBM cells. Dual MNK and DNMT inhibition synergistically reduced neurosphere growth in 3-D glioma stem-like cells. The combination promoted apoptosis in the mesenchymal glioma stem-like cells as shown through flow cytometry and increased expression of cleaved PARP, cleaved caspase 3, and Bax. Also, DNMT targeting enhanced the viability reduction effects of siRNA mediated MNK1 knockdown in GBM cells. This combination of our novel MNK inhibitor with DNMT inhibition elicited antineoplastic benefits in both 2-D cultures and 3-D glioma stem cell-like populations, demonstrating a potential novel therapeutic strategy in GBM.
Citation Format: Candice Mazewski, Frank Eckerdt, Aneta Baran, Mariafausta Fischietti, Purav P. Vagadia, Ricardo E. Perez, Charles D. James, Gary E. Schiltz, Leonidas C. Platanias. DNMT targeting enhances vulnerability of glioblastoma cells to MNK inhibition [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 3281.
Abstract 3744: Differential Orthopedia Homeobox (OTP) expression in pulmonary carcinoids is associated with changes in DNA methylation
Authors: Moonen Laura , Mangiante Lise , Leunissen Daphne J. , Lap Lisa M. , Gabriel Aurelie , Hillen Lisa M. , Roemen Guido M. , Koch Alexander , van Engeland Manon , Dingemans Anne-Marie C. , Foll Matthieu , Alcala Nicolas , Fernandez-Cuesta Lynnette , Derks Jules L. , Speel Ernst-Jan M. 
Published: June 2022

Abstract
Introduction: Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms.
Methods: We analyzed publicly available multi-omics data (whole-exome-, whole-genome-, RNA sequencing, Epic-850K-methylation array) of 58 typical-, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K-methylation analysis was cross validated using targeted pyrosequencing on 35 carcinoids.
Results: Results showed bimodality of OTP expression in carcinoids (OTPhigh versus OTPlow group, likelihood-ratio test p=1.5x10-2), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (fdr&lt;0.05 & β-value effect size&gt;0.2). Overall, OTPlow carcinoids harbor a high DNA methylation level as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (logrank test p=0.0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, i.e., sustaining proliferative signaling, evading growth suppressor, and genome instability and mutation.
Conclusion: High OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis. In poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels.
Citation Format: Laura Moonen, Lise Mangiante, Daphne J. Leunissen, Lisa M. Lap, Aurelie Gabriel, Lisa M. Hillen, Guido M. Roemen, Alexander Koch, Manon van Engeland, Anne-Marie C. Dingemans, Matthieu Foll, Nicolas Alcala, Lynnette Fernandez-Cuesta, Jules L. Derks, Ernst-Jan M. Speel. Differential Orthopedia Homeobox (OTP) expression in pulmonary carcinoids is associated with changes in DNA methylation [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 3744.
Abstract 4027: Dual MEK and AKT inhibition suppresses pancreatic cancer growth and migration
Authors: Jack Jarrid , Pierce Alexandra , Bye Bailey , Walsh McKinnon , Chalise Prabhakar , VanSaun Michael N. 
Published: June 2022

Abstract
Pancreatic cancer is one of the deadliest cancers, due to late diagnosis and very few available therapeutic treatments. The Kras gene is frequently mutated in pancreatic cancer, but previous clinical trials using RAS inhibitors have proven ineffective. Additionally, many drug treatments targeting the MAPK pathway have shown little success due to the inherent drug resistance of pancreatic cancer cells and to acquired resistance through activation of alternative proliferative pathways such as JAK-STAT and PI3K-AKT. Our pathway analysis after MEK inhibition in pancreatic cancer cells displayed sustained and/or upregulation of AKT activity in multiple cell lines. Therefore, we hypothesize that a combination treatment of Trametinib and Omipalisib would block two prominent mitogenic pathways (MEK and AKT, respectively) to suppress cancer cell proliferation and migration. Multiple analyses including Western blot, clonogenic, 5-Ethynyl-2’-Deoxyuridine (EDU), and scratch migration assays were employed to determine the augmentation of cellular function in murine and anthropic pancreatic cancer cell lines after single or combination treatment with Trametinib and/or Omipalisib. Results demonstrated that application of Omipalisib alone was successful at blocking pAKT but failed to suppress pERK. Conversely, Trametinib alone selectively inhibited pERK but did not affect pAKT levels. The combination treatment successfully suppressed both pathways in relatively low quantities, indicating their efficacy as a dual therapeutic. Dual therapy was further effective at inhibiting cell growth as evidenced by clonogenic and EdU assays. Recovery and closure from an in vitro scratch wound was also significantly inhibited with combination of Omipalisib and Trametinib. In vivo studies demonstrated that both the pancreatic xenograft mean tumor growth and final tumor size were significantly reduced in response to the combination treatment compared to vehicle. In conclusion, dual therapy with Omipalisib and Trametinib showed a greater anti-tumor efficacy than treatment with either drug alone. Currently, we are determining the prolonged effectiveness of this combination treatment program in genetically-engineered mouse models. If successful, a pharmacological application of Omipalisib and Trametinib has the potential to provide a beneficial therapeutic option to pancreatic cancer patients.
Citation Format: Jarrid Jack, Alexandra Pierce, Bailey Bye, McKinnon Walsh, Prabhakar Chalise, Michael N. VanSaun. Dual MEK and AKT inhibition suppresses pancreatic cancer growth and migration [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 4027.
Abstract 4129: Descriptors of primary cutaneous follicular helper T-cell lymphoma (PCFHTCL): Analysis of a pooled database of a rare entity
Authors: Haddad Philip A. , Hammoud Dalia , Gallagher Kevin 
Published: June 2022

Abstract
Introduction: Primary Cutaneous Follicular Helper T-cell Lymphoma (PCFHTCL) is a rare cutaneous T-cell lymphoma that was recently described. PCFHTCL is comprised of small to medium lymphocytes that express CD4, CD19, Bcl6, PD1, ICOS, CXCR5, and CXCL13. While it tends to have mostly an indolent course, occasionally PCFHTCL may display a more aggressive pattern. We conducted this analysis to explore the key clinicopathologic characteristics of this rare and little-known entity.
Methods: In order to study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 57 cases. Kaplan-Meier survival curves were constructed. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival and disease-free survival.
Results: A total of 57 patients with confirmed PCFHTCL were identified. The median age was 57 years with a peak incidence between ages 53 and 64. There was a male predominance with an M:F ratio of 1.25. PCFHTCL commonly involved the head (54%), followed by the torso (24%) and limbs (12%). Sixteen percent of the lesions were solitary and mostly involved the head. The most common pattern was nodular/tumorous. Histologically, PCFHTCL involved mainly the dermis with occasional focal epidermotropism (27%), folliculotropism (43%), syringotropism (7%), and subcutaneous extension (14%). Extracutaneous involvement comprised lymph nodes (11%), bone marrow (4%), and the peripheral blood (2%). The median duration of symptoms prior to diagnosis was 5 months. The six-year disease-free survival is around 85%. Surgical resection alone resulted in durable remission in 40% of the cases. Recurrent disease was successfully salvaged with re-resection, radiation, and chemotherapy. While solitary lesions tended to have a better disease-free survival, it did not reach statistical significance.
Conclusions: This study represents the largest cohort of this rare cutaneous T-cell entity. It describes the demographic and clinical patterns of disease presentation and provides a detailed update on the clinicopathologic features PCFHTCL.
Citation Format: Philip A. Haddad, Dalia Hammoud, Kevin Gallagher. Descriptors of primary cutaneous follicular helper T-cell lymphoma (PCFHTCL): Analysis of a pooled database of a rare entity [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 4129.