bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3928: Therapeutic targeting of NOTCH1 and neddylation pathway in T cell acute lymphoblastic leukemia
Authors: Bertulfo Carla , Perez-Duran Pablo , Palomero Teresa , Ferrando Adolfo
Published: April 2023

T-cell Acute Lymphoblastic Leukemia (T-ALL) is hematologic tumor characterized by the diffuse infiltration of the bone marrow by malignant hematopoietic cells expressing immature T cell markers. Although T-ALL currently has better cure rates primarily due to multiagent or intensified chemotherapy, the prognosis for patients who are resistant or develop relapse to therapy remains very poor. Aberrant Notch homolog-1 (NOTCH1) signaling is a major driver of T-ALL pathogenesis as more than 60% of T-ALL cases harbor activating mutations in the NOTCH1 gene. Gamma Secretase Inhibitors (GSIs) which effectively block the activation of oncogenic protein NOTCH1 are potential candidates for the treatment of T-ALL. However, the clinical application of GSIs is hampered by severe gastrointestinal toxicity due to the inhibition of NOTCH1 signaling in the gut. Here we demonstrate that combination therapy of GSIs and a small molecule inhibitor of the neddylation pathway circumvents the GSI-induced gut toxicity in vitro and in vivo. Genome-wide CRISPR loss-of-function screen in LS174T adenocarcinoma cells revealed neddylation pathway as a main regulator of massive goblet cell differentiation upon NOTCH1 inhibition. Genetic and pharmacologic inhibition of the neddylation pathway in LS174T cells rescued GSI-induced differentiation and cell death. Mechanistically, neddylation inhibition increases the protein stability of Hairy and enhancer of split-1 (HES1), a known regulator of absorptive and secretory cell fate decisions. Combination treatment of GSI and neddylation inhibitor in C57/BL6 mice showed a profound decrease in the number of goblet cells and maintained HES1 protein levels in the intestinal epithelium compared to GSI treatment alone. Remarkably, combined treatment of GSI and neddylation inhibitor in NOTCH1-induced T-ALL mice showed leukemia regression and improved overall survival without any associated gut toxicity. Overall, these results substantiate the potential of targeting NOTCH1 and neddylation pathway in the treatment of NOTCH1-induced T-ALL.

Citation Format: Carla Bertulfo, Pablo Perez-Duran, Teresa Palomero, Adolfo Ferrando. Therapeutic targeting of NOTCH1 and neddylation pathway in T cell acute lymphoblastic leukemia. [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 3928.
Abstract 3973: Precision RNAi using synthetic shRNAmir target sites
Authors: Neumüller Ralph , Hoffmann Thomas , Hörmann Alexandra , Corcokovic Maja , Zuber Johannes
Published: April 2023

Genetic loss-of-function methods including short-hairpin RNAs (shRNAs) and CRISPR are key methods for target gene validation across a variety of different disease areas. While these methods have revolutionized target gene discovery and characterization, both methods suffer from limitations in the context of in vivo target validation due to off-target effects and insufficient knock-down for shRNAs and resistant clones for CRISPR. In this study, we describe a method, artificial RNA interference (ARTi) that overcomes these limitations by fundamentally changing the basic experimental strategy of RNAi-based loss-of-function studies. Instead of newly designing gene-specific shRNA for individual target genes, ARTi utilizes ultra-effective and selective artificial miRNA-based shRNAs that do not match any transcribed gene in the target genome. In addition, these sequences are optimized for ultra-efficient miRNA processing and knockdown of synthetic target genes, and are deeply characterized to not trigger major off-target effects, enabling highly stringent target validation in vivo with unprecedented temporal control, selectivity and potency. We validate the approach by studying the in vitro and in vivo phenotypes of EGFR, KRAS and STAG1, genes relevant to cancer biology. This loss-of-function strategy will enable novel experimental strategies in therapeutic target validation and will be instrumental in guiding the lead optimization process by establishing genetic benchmark phenotypes.

Citation Format: Ralph Neumüller, Thomas Hoffmann, Alexandra Hörmann, Maja Corcokovic, Johannes Zuber. Precision RNAi using synthetic shRNAmir target sites. [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 3973.
Abstract 3987: Targeting nucleotide synthesizing enzyme dUTPase (DUT) represents a metabolic weakness and therapeutic opportunity in liver cancer
Authors: Liu Yue , Xu Mingjing , Wan Ho Lee , Wong Alissa M. , Ding Xiaofan , Ng Kelvin K. , Wong Nathalie
Published: April 2023

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, has an overall 5-year survival rate of around 20%, making it the third leading cause of cancer-related death worldwide. Upregulated nucleotide metabolism is frequently identified in HCC and represents a metabolic weakness of tumor cells. The enzyme dUTPase (DUT) catalyzes the synthesis of nucleotide precursor and prevents undesired uracil misincorporation into DNA, and thus plays an important role in the maintenance of DNA integrity and cell viability. Although common upregulation of DUT has been reported in cancers, its role in HCC remains largely unknown. In this study, we investigated the mechanism underlying DUT biology in HCC and tumor susceptibility to drug targeting dUTPase. Overexpression of DUT was found in 42% of HCC cases and significantly correlated with advanced stage tumors. CRISPR-Cas9 mediated knockout of DUT resulted in growth retardation, cell cycle arrest and a spontaneous induction of DNA damage in multiple HCC cell lines. A protective effect from oxidative stress was also demonstrated in both knockout and overexpression DUT assays. Metabolomics analysis showed altered DUT expression in HCC cells resulted in profound impact on pyrimidine and purine metabolism. In addition, levels of DUT protein strongly correlate with cellular level of dUTP and dTDP, which suggested its critical role in dNTP homeostasis. Interestingly, hepatic organoids overexpressing DUT showed drug resistance to tyrosine kinase inhibitor (TKI) Sorafenib. Both in vitro and in vivo assays confirmed that targeting dUTPase activity with TAS-114 synergized the effect of Sorafenib in suppressing HCC growth. In conclusion, our study showed that upregulated DUT conferred growth advantage to HCC cells by reducing uracil misincorporation and favoring nucleotide synthesis. Targeting DUT with its first-in-class inhibitor TAS-114 in combination with Sorafenib represents an effective treatment regime for HCC.

Citation Format: Yue Liu, Mingjing Xu, Ho Lee Wan, Alissa M. Wong, Xiaofan Ding, Kelvin K. Ng, Nathalie Wong. Targeting nucleotide synthesizing enzyme dUTPase (DUT) represents a metabolic weakness and therapeutic opportunity in liver cancer. [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 3987.
Abstract 4021: CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors
Authors: Shi Hui , Wang Meng , Huang Jiaxin , Ouyang Qiugeng , Guo Jiannan , Wang Youzhen , Mi Yuan , Wu Haiping
Published: April 2023

We identified CTS2016 as a novel, selective, orally bioavailable small molecule inhibitor with single-digit nanomolar enzymatic activity to AXL and FLT3. Overexpression of AXL is associated with metastasis, drug resistance, and poor prognosis of various hematological and solid tumors, which are all broadly modulated with epigenetic regulation. In addition, inhibition of AXL phosphorylation may overcome drug resistance to current FLT3 inhibitors in FLT3-ITD+ Acute Myeloid Leukemia (AML) (Park et al., 2015). We tested CTS2016 as a single agent or in combination with either venetoclax, a Bcl-2 inhibitor, or azacitidine, a hypomethylating agent (HMA) and an epigenetic modulation drug, in a series of in vitro and in vivo studies using various AML models

CTS2016 resulted in a potent growth inhibitory effect with strong induction of cell death in a spectrum of AML cell lines carrying FLT3 mutations (FLT3-ITD and/or FLT3-TKD)

CTS2016 orally administered once daily, demonstrated potent and dose-dependent antitumor responses in a variety of AML xenograft mouse models. The anti-tumor activity was correlated with the inhibition of receptor tyrosine kinase signaling, as measured by decreased phosphorylation of key downstream signaling targets of FLT3. In a tail vein injection of mouse LLC-Luciferase model, CTS2016 treatment could significantly reduce tumor metastasis. A combination of CTS2016 with venetoclax or azacitidine provides a therapeutic benefit over monotherapy and supports a rationale for testing these combination therapies in patients with relapsed or refractory (R/R) AML and myelodysplastic syndromes (MDS). In addition, CTS2016 significantly reduced the tumor burden of a leukemia model harboring FLT3-ITD-F691L, a drug-resistant mutation of FLT3. Notably, the selectivity of CTS2016 over other kinases (such as c-KIT) mitigates the off-target toxicity effects on normal hematological differentiation which is common in clinics for other FLT3 inhibitors. These data demonstrate that CTS2016 could be a promising therapy for treating patients diagnosed with AML and MDS harboring FLT3 mutations and solid tumors such as NSCLC and TNBC with high-expression of AXL. More proof-of-concept data would come from the ongoing clinical trial.

Citation Format: Hui Shi, Meng Wang, Jiaxin Huang, Qiugeng Ouyang, Jiannan Guo, Youzhen Wang, Yuan Mi, Haiping Wu. CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors. [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 4021.
Abstract 4102: attIL12-T cell therapy destructs cancer-associated fibroblasts and extracellular matrix in heterogenous osteosarcoma xenograft models
Authors: Hu Jiemiao , Lazar Alexander , Ingram Davis , Wang Wei-Lien , Zhang Wendong , Jia Zhiliang , Ragoonanan Dristhi , Wang Jian , Xia Xueqing , Mahadeo Kris , Gorlick Richard , Li Shulin
Published: April 2023

The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to immunotherapy. CAF-targeted CAR-T cell therapy does not impair ECM components such as collagen. In this study, we investigated whether the recently invented attIL12-T cells could destroy CAFs to disrupt the ECM and uncovered the underlying mechanism by which attIL12-T cells penetrate stroma-enriched osteosarcoma tumors. RNA sequencing demonstrated that attIL12-T cell treatment altered ECM-related gene expression. Immunohistochemistry staining revealed disruption or elimination of high-density CAFs and ECM in osteosarcoma xenograft tumors following attIL12-T cell treatment and that CAF/ECM density was inversely correlated with T-cell infiltration. Other IL12-armed T cells, such as wild-type IL12-T or ttIL12-T cells, did not disrupt the ECM because this effect depended on the engagement between cell-surface vimentin (CSV) on the tumor cell surface and its ligand on the attIL12 -T cells. Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production upon interacting with CSV+ tumor cells to suppress TGFβ secretion and in turn upregulate FAS-mediated CAF apoptosis. CAF destruction reshaped the tumor stroma to favor T cell infiltration and tumor destruction. Thus, this study unveiled a novel therapy—attIL12-T cells—for targeting CAFs/ECM. These findings are highly relevant to humans because CAFs are abundant in human osteosarcoma.

Citation Format: Jiemiao Hu, Alexander Lazar, Davis Ingram, Wei-Lien Wang, Wendong Zhang, Zhiliang Jia, Dristhi Ragoonanan, Jian Wang, Xueqing Xia, Kris Mahadeo, Richard Gorlick, Shulin Li. attIL12-T cell therapy destructs cancer-associated fibroblasts and extracellular matrix in heterogenous osteosarcoma xenograft models. [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 4102.
Abstract 4116: Modulating gut microbiota to improve intrahepatic immunity against hepatocellular cancer
Authors: Qi Xiaogiang , Yang Ming , Ma Lixin , Mitchem Jonathan , Kaifi Jussuf , Chen Shiyou , Ericsson Aaron , Kimchi Eric , Staveley-O’Carroll Kevin , Li Guangfu
Published: April 2023

Gut microbiota plays a pivotal role in the pathogenesis of hepatocellular cancer (HCC), significantly affecting the HCC treatment. It has been reported that the HCC patients’ response to the immunotherapy of PD-1/PD-L1 blockade was associated with their gut microbiota profiles. However, the impact of gut microbiota on anti-HCC immunity and its underlying mechanism are poorly understood. Treating HCC-bearing mice with a specific and non-hepatotoxic antibiotic cocktail caused the increased relative abundance of specific commensal bacteria such as Bacteroides, resulting in suppression of HCC growth and development which was involved in the activation of intrahepatic antitumor immune responses. Gut microbiota recolonization of Bacteroides thetaiotaomicron (B. th) in gut-sterilized HCC-bearing mice significantly improved the therapeutic efficacy of anti-PD-1 antibody (αPD-1 Ab) against HCC. Fecal microbiota transplantation (FMT) from HCC patients who received and responded to αPD-1 Ab treatment improved the efficacy of αPD-1 Ab treatment against HCC in mice model. Mechanistic studies demonstrated that the modulation of Krüppel-like factor 2 (KLF2)/Toll-like receptor 9 (TLR9) signaling and the accumulation of CpG-enriched genomic DNAs of B. th in livers/tumors activated the tumor antigen-specific CD8+ T cells through the dendritic cell in a TLR9-dependent manner. In conclusion, gut microbiota as a causative factor can be targeted to improve anti-HCC immunotherapy.

Citation Format: Xiaogiang Qi, Ming Yang, Lixin Ma, Jonathan Mitchem, Jussuf Kaifi, Shiyou Chen, Aaron Ericsson, Eric Kimchi, Kevin Staveley-O’Carroll, Guangfu Li. Modulating gut microbiota to improve intrahepatic immunity against hepatocellular cancer. [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 4116.
Abstract 4134: Boosting anti-tumor immunity by promoting high endothelial venule and tertiary lymphoid structure formation in solid tumors via LTBR agonism
Authors: An Disi , Chen Guoying , Wang Wei , Mohrs Katja , DiLillo David , Daly Christopher , Thurston Gavin , Lin John , Gupta Namita , Atwal Mickey , Kuhnert Frank
Published: April 2023

High endothelial venules (HEV) are specialized blood vessels that mediate lymphocyte trafficking to lymph nodes. Tertiary lymphoid structures (TLS) are ectopic lymphoid formations that develop in inflamed, infected or tumoral tissues. TLS contain HEV and B cell follicles surrounded by a T-cell zone and are characterized by abundant chemokine expression. The presence of TLS and HEV in solid tumors is positively correlated with patient survival in many cancer types, and may even be predictive of better response to immune-checkpoint blockade. However, the molecular mechanisms underlying the intratumoral HEV and TLS formation remain unclear. Using murine syngeneic tumor models, we found that systemic activation of lymphotoxin beta receptor (LTBR) with an agonistic antibody induced tumor-specific HEV formation, increased dendritic cell (DC) and T cell infiltration, and enhanced T cell activation in the tumor. In vitro assays revealed that LTBR agonism directly upregulated activation and maturation markers in bone marrow-derived DCs and promoted DC-mediated CD4 and CD8 T cell activation. Single agent LTBR agonist treatment attenuated Colon26 tumor growth in a CD8 T cell-dependent manner. In combination treatment studies, LTBR agonism further augmented anti-tumor efficacy of anti-PD1 and of CAR-T therapy. Notably, LTBR agonist mAb treatment upregulated the expression of TLS-related chemokines and induced TLS-like structures in approximately 20% of treated tumors. To enhance TLS induction, we generated syngeneic tumor models engineered to express several cytokines/chemokines and performed an in vivo screen for tumor-associated TLS formation. We identified some factors that in combination with LTBR agonism induced B cell enrichment and immature TLS formation, while others promoted robust TLS induction and anti-tumor effect. TLS formation induced by combined LTBR agonism and cytokine expression is associated with augmented anti-tumor responses to anti-CTLA-4 treatment. By studying anti-tumor mechanisms of LTBR agonism-mediated HEV and TLS formation, this work informs the future therapeutic strategies to boost T cell infiltration and activation in solid tumors.

Citation Format: Disi An, Guoying Chen, Wei Wang, Katja Mohrs, David DiLillo, Christopher Daly, Gavin Thurston, John Lin, Namita Gupta, Mickey Atwal, Frank Kuhnert. Boosting anti-tumor immunity by promoting high endothelial venule and tertiary lymphoid structure formation in solid tumors via LTBR agonism. [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 4134.
Abstract 4186: Underrepresentation of low- and middle-income country affiliated authors in NCI-supported cancer research
Authors: Eldridge Linsey , Garton Elise , Duncan Kalina , Gopal Satish
Published: April 2023

Introduction: We conducted a bibliometric analysis to assess authorship of recent publications involving collaborations in low- and middle-income countries (LMICs) supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH).

Methods: We identified active NCI grants awarded directly to LMIC institutions or to US institutions with a collaborator site or sites exclusively in LMICs between 2015-2019 in NIH Query View Report (QVR). Grants were linked to resulting publications using Dimensions for NIH. Because grants may have been active in 2015 while beginning in earlier years, we analyzed any linked publications from 2011 to 2020. Publications with missing author information were excluded. Author institutional affiliation was used to classify author country income level as defined by the World Bank. Authors with multiple institutional affiliations from a high-income country (HIC) and LMIC were classified as such. Relative citation ratio (RCR) and Altmetric data from Dimensions were used to compare citation impact measures using the Wilcoxon rank sum test.

Results: NCI funded 159 grants to US institutions exclusively with LMIC collaborators and five awards directly to institutions in LMICs from 2015 to 2019, resulting in 2,428 publications between 2011 and 2020, of which 49% had at least one author affiliated with an LMIC institution. Of all publications, 78% and 83% had a first and last author with high-income country (HIC) affiliation, respectively. Publications with HIC-affiliated last authors had significantly higher median RCR and Altmetric attention scores than publications with LMIC-affiliated last authors (p=0.0134 and p=0.0004, respectively). Publications with HIC-affiliated first authors had significantly higher Altmetric scores than publications with LMIC-affiliated first authors (p=0.001).

Conclusion: LMIC-affiliated authors are represented on only approximately half of publications resulting from NCI grants awarded directly to LMIC institutions or to US institutions with LMIC collaborators, and rarely in the first or last author position. LMIC-affiliated authors also receive less bibliometric attention when represented. Increased scientific capacity and more equitable collaboration should be critical priorities for the cancer research community working in LMICs moving forward.

Citation Format: Linsey Eldridge, Elise Garton, Kalina Duncan, Satish Gopal. Underrepresentation of low- and middle-income country affiliated authors in NCI-supported cancer research. [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 4186.
Abstract 4221: Aflatoxin exposure in a population-based representative sample of adults in Mexico in 2018
Authors: Monge Adriana , McGlynn Katherine , Santiago-Ruiz Luis , Remes-Troche Jose Maria , Hernandez-Flores Karina , Villapando-Hernandez Salvador , Romero Martin , Groopman John , Lajous Martin
Published: April 2023

Importance: Southern Mexico and Guatemala, together represent the region with the highest liver cancer burden in the Americas. There is a higher burden of liver cancer in rural regions in eastern and southern Mexico and remarkably there is an equal number of cases in men and women. Reasons for this increased burden are not clear, but previous studies of food samples have found that contamination of maize with aflatoxin B1 (AFB1), a potent liver carcinogen, is common in the region while HBV and HCV seroprevalence is less than 0.5%. Few examinations of AFB1 levels in persons have been conducted.

Objective: To estimate the prevalence of exposure and circulating levels AFB1 in a representative sample of adults living in five regions across Mexico.

Study Design: We randomly selected a subsample of 955 adults ≥40 years who participated in Mexico’s National Health and Nutrition Survey 2018 (ENSANUT). These residents were from five states in eastern and southern Mexico and all provided a venous blood sample. We assessed AFB1 levels as pg AFB1-lys/µL in serum using mass spectrometry. The limits of detection and quantification were both 0.010 pg/μL.

Results: The mean age of participants was 56 years (± SD 11.7) and 54% were female. The overall prevalence of AFB1-lys detection was 92% (95% confidence intervals; 95%CI 88, 94%). The region with the lowest prevalence, 88% (95%CI 78, 94%), was Chiapas and the region with the highest prevalence was Veracruz 95% (95%CI 84, 98). Median AFB1 was 0.127 pg AFB1-lys/µL (interquartile range; IQR 0.054, 0.446) with a range from 0.066 (IQR, 0.033, 0.147) in Yucatán to 0.476 (IQR, 0.199, 1.355) in Veracruz. AFB1 exposure levels were higher in persons aged ≥60 years, men, and participants living in rural areas. We observed decreasing levels of AFB1 exposure with increasing socioeconomic status.

Conclusions: In a representative sample of adults in eastern and southern Mexico we observed a high prevalence of exposure to AFB1. For certain regions, AFB1 levels are comparable to those in Guatemala. These results suggest that AFB1 may be related to the increased burden of liver cancer in eastern and southern Mexico.

Citation Format: Adriana Monge, Katherine McGlynn, Luis Santiago-Ruiz, Jose Maria Remes-Troche, Karina Hernandez-Flores, Salvador Villapando-Hernandez, Martin Romero, John Groopman, Martin Lajous. Aflatoxin exposure in a population-based representative sample of adults in Mexico in 2018. [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 4221.
Abstract 4242: High sugar food consumption and breast cancer risk in a prospective cohort study
Authors: Shin Woo-Kyoung , Huang Dan , la Torre Katherine De , Min Sukhong , Shin Aesun , Lee Jong-koo , Han Wonshik , Lee Jung Eun , Kang Daehee
Published: April 2023

Background: The association between excessive sugar intake and the risk of breast cancer has been considered in epidemiologic studied, however, the results are unclear. This study examined to evaluated between high-sugar food intake and breast cancer in a prospective cohort study.

Methods: This prospective cohort study included a total of 71,266 women aged 40-69 years from the Health Examinees-Gem (HEXA-G) study between 2004 and 2013. Information on cancer diagnosis was retrieved from the Korea Central Cancer Registry until 31 December 2018. Multivariate hazard ratios (HRs) and 95% of confidence intervals (CIs) for the risk of gastric cancer according to the consumption of high-sugar food were estimated using Cox proportional hazards models with age as the time scale.

Results: A total of 713 incident cases of breast cancer occurred over an average follow-up period of 9.20 years. The top food contributing to total sugar intake was fruit (42.89%). We found that increased consumption of sugary cereal was associated with increased risk of breast cancer; HR for sugary cereal consumption of more than one servings/two months vs. almost never consumed was 1.34 (95% CI: 1.08, 1.65; p for trend = 0.01). Also, consumption of loaf bread (p for trend = 0.03), ice cream (HR for ice cream consumption of more than one servings/week vs. almost never consumed = 1.26; 95% CI: 1.00, 1.58; p for trend = 0.03), and added sugar food (HR for all sugary food groups consumption of more than two servings/week vs. less than one serving/month consumed =1.28; 95% CI: 1.02, 1.61; p for trend = 0.05) was associated with increased risk of breast cancer.

Conclusion: Our results suggest that a high-sugar food consumption was associated with an increased risk of breast cancer among Korean women.

Key words: Sugar, High-sugar foods, Breast cancer, the Health Examinees (HEXA) study, prospective cohort study.

Citation Format: Woo-Kyoung Shin, Dan Huang, Katherine De la Torre, Sukhong Min, Aesun Shin, Jong-koo Lee, Wonshik Han, Jung Eun Lee, Daehee Kang. High sugar food consumption and breast cancer risk in a prospective cohort study. [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 4242.
Abstract 4338: Response to neoadjuvant targeted therapy in operable head and neck cancer confers survival benefit
Authors: Mascarella Marco Antonio , Olonisakin Tolani , Rumde Purva , Vendra Varun , Nance Melonie , Kim Seungwon , Kubik Mark , Sridharan Shaum , Ferris Robert , Fenton Moon , Clayburgh Daniel , Ohr James , Sen Malabika , Joyce Sonali , Herman James , Grandis Jennifer , Zandberg Dan , Duvvuri Umamaheswar
Published: April 2023

Purpose: Neoadjuvant targeted therapy provides a brief, preoperative ‘window of opportunity’ that can be exploited to individualize cancer care based on treatment response. We investigated whether response to neoadjuvant therapy during the preoperative window confers survival benefit in patients with operable head and neck squamous cell carcinoma (HNSCC).

Patients and Methods: A pooled analysis of treatment naïve patients with operable HNSCC enrolled in one of three clinical trials from 2009-2020 (NCT00779389, NCT01218048, NCT02473731). Neoadjuvant regimens consisted of EGFR inhibitors (n=83) or anti-ErbB3 antibody therapy (n=9) within 28 days of surgery. Clinical to pathologic stage migration was compared to disease-free survival (DFS) and overall survival (OS) while adjusting for confounding factors using multivariable Cox regression. Circulating tumor markers validated in other solid tumor models were analyzed.

Results: 92 of 118 patients were analyzed; all patients underwent surgery following neoadjuvant therapy. Clinical to pathologic downstaging was more frequent in patients undergoing neoadjuvant targeted therapy compared to a historic cohort without neoadjuvant therapy (P=0.048). Patients with pathologic downstage migration had the highest OS (89.5%, 95% CI 75.7-100) compared to those with no stage change (58%, 95% CI 46.2-69.8) or upstage (40%, 95% CI 9.6-70.4, P=0.003). On multivariable analysis, downstage migration remained a positive prognostic factor for OS (hazard ratio 0.22, 95% CI 0.05-0.90) while adjusting for measured confounders. Downstage migration correlated with decreased circulating tumor markers, SOX17 and TAC1 (P=0.0078).

Conclusion: Brief neoadjuvant therapy achieved pathologic downstaging in a subset of patients and was associated with significantly better DFS and OS as well as decreased circulating methylated SOX17 and TAC1.

Citation Format: Marco Antonio Mascarella, Tolani Olonisakin, Purva Rumde, Varun Vendra, Melonie Nance, Seungwon Kim, Mark Kubik, Shaum Sridharan, Robert Ferris, Moon Fenton, Daniel Clayburgh, James Ohr, Malabika Sen, Sonali Joyce, James Herman, Jennifer Grandis, Dan Zandberg, Umamaheswar Duvvuri. Response to neoadjuvant targeted therapy in operable head and neck cancer confers survival benefit. [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 4338.
Abstract 4370: How much time is needed to complete quality of life assessments in oncology trials? - Metadata analysis
Authors: Marszewska Jowita , Hughes Lindsay
Published: April 2023

Introduction: Digitalization in clinical trials introduced electronic data collection. Participants in diverse environments can use electronic devices to report their experiences with the drug by completing patient reported outcome assessments (ePROs). Quality of life (QOL) reports describe how a patient feels or functions during a treatment with a new drug. For oncology trials, QOL data is needed to prove the treatment effect and support a labeling claim.

Methods: The literature search in the Web of Science for articles containing QOL keyword found ten articles with the highest number of citations. QOL instruments relevant to cancer research were identified based on the literature search. Form completion times corresponding to the cancer-specific instruments were identified and analyzed using a metadata of 948 instruments and 17,234,458 assessment submissions.

Results: Three general QOL measures in oncology trials were identified: the EORTC Quality of Life Questionnaire - Core Questionnaire (EORTC QLQ-C30), Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F), and SF-36 Health Survey (SF-36). Median times of form completion in seconds (s) increased in the following order: FACIT-F < EORTC QLQ-C30 < SF-36v2 and were equal to 105 s < 213 s < 386 s. Metadata analysis showed that participants spent less than two minutes on completion of the FACIT-F assessment, which is only 18% of the estimated completion time of 10 minutes. Metadata analysis showed that it took participants three and a half minutes to complete the EORTC QLQ-C30 assessment, which is roughly one third of the estimated completion time of 11 minutes. The completion time for SF-36v2 fell within the estimated range of 5 to 10 minutes.

Conclusions: Properly selected QOL instruments facilitate collection of the right data for demonstration of a treatment benefit. It is recommended to include a general oncology and a disease specific QOL instrument to show the treatment’s success of improving patient’s QOL. At the same time, the completion of the instruments should not be burdensome considering disease progression characteristic for oncology studies.

Citation Format: Jowita Marszewska, Lindsay Hughes. How much time is needed to complete quality of life assessments in oncology trials? - Metadata analysis. [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 4370.
Abstract 4381: Predictive risk factors for cancer thrombosis in gastric cancer patients
Authors: Park Song Ee , Jung Moon Ki , Hwang In Gyu
Published: April 2023

Background Gastric cancer is strongly associated cancer thromboembolism. We aimed to identify the Khorana risk score (KRS) and other risk factors for cancer thromboembolism in patients with gastric cancer after gastrectomy.

Methods We reviewed 610 gastric patients, who had undergone D2 radical gastrectomy between January 2005 and December 2017. Kaplan-Meier survival analysis and Cox regression models were used to evaluate for independent predictor of cumulative incidence of cancer thromboembolism and survival.

Results The median follow up was 67.0 months. There were 35 (5.7%) caner thromboembolism. The cumulative incidences of thromboembolism were 6.1%, 3.1%, 3.3%, and 20.7% in stages I, II, III, IV. 181 (29.7%) patients were relapsed cancer and 159 (26.1%) patients were died. A high KRS (cumulative incidence 5.8%) was not associated with cancer thromboembolism compared to an intermediate KRS (cumulative 5.7%) (HR=1.005, 95% CI = 0.540-2.061, P= 0.876). After gastrectomy, recurrent cancer (cumulative incidence 9.9%) was associated with cancer thromboembolism compared to no recurrence (cumulative incidence 4.0%) (HR 3.713, 95% CI 1.879-7.335, P < 0.001).

Conclusions Recurrent gastric cancer patients after gastrectomy were significantly increased cancer thromboembolism risk compared to no recurrent cancer patients. Among patients with gastric cancer after gastrectomy, KRS did not stratify the patients at high risk of cancer thromboembolism.

Citation Format: Song Ee Park, Moon Ki Jung, In Gyu Hwang. Predictive risk factors for cancer thrombosis in gastric cancer patients. [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 4381.
Abstract 4404: Survival impact and trends of immunotherapy use in metastatic merkel cell carcinoma in the checkpoint era: analysis of a large database
Authors: Grant Christopher R. , Hagopian Garo , Brazel Danielle , Kumar Priyanka , Moyers Justin
Published: April 2023

Introduction: Merkel Cell Carcinoma (MCC) is an aggressive skin cancer that has typically been treated with conventional chemotherapy in the metastatic setting. In 2017, metastatic MCC treatment options expanded when the FDA approved immune checkpoint inhibitors based on single-arm uncontrolled studies. We utilized data from the National Cancer Database (NCDB) to examine the survival benefit of first line immunotherapy (IO) or chemotherapy (CT) in metastatic MCC.

Methods: The NCDB was analyzed to identify patients with metastatic MCC from 2017-2020. Patients who did not have data available on AJCC version 8 staging group, survival status, and treatment details (surgery, radiation therapy, CT, IO) were excluded from the analysis. Patients were divided into cohorts based on first line systemic therapy; those who received chemotherapy and those who received immunotherapy. Survival time was calculated from the time of initiation of systemic treatment to last contact or death. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-ranked method.

Results: We identified 648 patients with stage IV MCC between 2017-2020. Of those, 15.3% (n=99) received CT, 51.7% (n=335) received IO, and 32.9% (n=213) did not receive systemic therapy. Median OS was 13.2 (95% CI: 10.1-16.2) months for those receiving any systemic therapy. Median OS was 13.8 (95% CI: 7.9-19.7) months for CT and 12.9 (95% CI: 9.6-16.2) months for immunotherapy (p=0.379). In the first year of IO approval in 2017, only 37.4% of patients received IO which increased to 54.5% in 2018, 59.6% in 2019, and 54.9% in 2020. Chemotherapy use decreased throughout the same time period from 23.9% in 2017 to 12.4% in 2020. There was a notable difference in the number of patients less than 65 years old who received IO (66%) relative to the number of patients 65 years and older who received IO (80%) (p=0.006).

Discussion: Immunotherapy has supplanted chemotherapy as the first line treatment of choice in MCC, particularly in those 65 and older. However, we did not find first line use of immunotherapy to provide a statistically significant survival advantage over chemotherapy in stage IV Merkel cell carcinoma. Clinical equipoise exists, and a randomized clinical trial is needed.

Citation Format: Christopher R. Grant, Garo Hagopian, Danielle Brazel, Priyanka Kumar, Justin Moyers. Survival impact and trends of immunotherapy use in metastatic merkel cell carcinoma in the checkpoint era: analysis of a large database. [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 4404.
Abstract 4409: Survival determinants of aggressive adult T-cell leukemia/lymphoma (ATLL): analysis of a pooled database
Authors: Gupta Supriya , Graham Christopher , Haddad Philip A.
Published: April 2023

Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare Peripheral T-cell Lymphoma subtype caused by Human T-Lymphotropic Virus 1 (HTLV-1). The disease encompasses a vast phenotype ranging from the smoldering and chronic indolent subtypes to the lymphoma and acute aggressive subtypes. Aggressive ATLL which comprise acute/leukemic, lymphoma, and other indolent subtypes with aggressive transformation tend to have poor outcome with conventional chemotherapy rarely achieving durable lasting remission. We conducted this pooled database analysis to identify key factors that affect the clinical outcomes of aggressive ATLL subtypes.

Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 462 ATLL 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 the overall survival (OS).

Results: Three hundred and forty-seven aggressive ATLL patients with survival data were included in this analysis. The median OS of the whole group was 14 months, with a median OS of 12.8, 16, and 12 months for acute, lymphoma, and transformed subtypes. The median age was 54 years, with a M:F ratio of 1.1. SCT demonstrated superior OS compared to chemotherapy (28 vs. 10 months, p<0.0001). Similarly, LSG15 regimens were superior to no chemotherapy and other combinations (29 vs. 1 vs. 15 months, p<0.0001). Asians and Afro-Caribbeans lived longer than Whites, Indians, and Hispanics (15.7, 15, 10, 3, 1 months, p<0.0001, respectively). The presence of hypercalcemia (Ca>11 mg/dl, Anemia (Hgb<12 g/dl), elevated LDH (>1000 U/L), and effusions adversely effected OS. Moreover, visceral involvement generally and specifically GI, kidney, lung, and heart were significantly detrimental to OS. However, age, sex and the presence of constitutional symptoms or HAM/TSP did not impact the OS.

Conclusions: This study explored a wide array of clinical factors and their impact on the OS of aggressive ATLL. It identified race, types of treatment, the presence of hypercalcemia, anemia, elevated LDH, effusion and visceral metastases as significant determinants of OS in aggressive ATLL.

Citation Format: Supriya Gupta, Christopher Graham, Philip A. Haddad. Survival determinants of aggressive adult T-cell leukemia/lymphoma (ATLL): analysis of a pooled database. [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 4409.
Abstract 4452: FASN inhibition overcomes immune evasion by upregulating MHC-I in hepatocellular carcinoma
Authors: Huang Jiao , Tsang Wai Ying , Fang Xiaona , Zhang Yu , Luo Jie , Gong Lanqi , Zhang Baifeng , Wong Ching Ngar , Liu Beilei , Huang Jinlin , Yang Yuma , Liu Shan , Li Zhihong , Guan Xinyuan
Published: April 2023

Immune evasion is one of the important factors leading to the progression of hepatocellular carcinoma(HCC). Restricted antigen presentation by decrease of MHC-I remains a huge barrier to triggering an immune attack. However, knowledge is limited on how to enhance antigen presentation of cancer cells. Here we identify that FASN inhibition by shRNA and inhibitors could boost MHC-I level on HCC cell surface. FASN deficiency also promotes antigen presentation and augments CD8+ T cell cytotoxicity. Mechanistically, FASN knock-down decreases the degradation of MHC-I in lysosomes. Moreover, ZDHHC3-mediated palmitoylation participates in this process. In vivo, orthotopic HCC mouse model shows that Fasn knock-down greatly improves the cytotoxicity of tumor-infiltrating CD8+ T cells and suppresses HCC tumor growth, indicating that inhibiting FASN is a promising way to enhance the efficiency of immunotherapy in HCC.

Citation Format: Jiao Huang, Wai Ying Tsang, Xiaona Fang, Yu Zhang, Jie Luo, Lanqi Gong, Baifeng Zhang, Ching Ngar Wong, Beilei Liu, Jinlin Huang, Yuma Yang, Shan Liu, Zhihong Li, Xinyuan Guan. FASN inhibition overcomes immune evasion by upregulating MHC-I in hepatocellular carcinoma. [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 4452.
Abstract 4478: Up284, A small molecule inhibitor of ADRM1 demonstrates significant anti-tumor efficacy in preclinical models of aggressive breast cancer
Authors: Karanam Balasubramanyam , Anchoori Ravi , Chang Yung-Nien , Martini Rachel , Rowdo Florencia Madorsky , Davis Melissa B.
Published: April 2023

Quadruple-negative breast cancer (QNBCs) is a highly aggressive and metastatic disease and remains clinically challenging breast cancer subtype with worst prognosis. Due to its exceeding heterogeneity, absence of the AR, ER, PR, Her2 receptors and lack of established therapeutic targets, QNBC is hard to treat cancer and recurs rapidly with standard chemo regimen. QNBC demonstrated vulnerability to proteasome inhibition due to their higher metabolic needs. But FDA approved 20S proteasome inhibitors failed to treat solid tumors including QNBC. Hence, developing an effective strategy to overcome the limitations associated with current 20S proteasome inhibitors is mandated to provide alternate treatment options for QNBC patients. Preclinical, Up Therapeutics lead candidate small molecule inhibitor Up284 has shown significant tumor growth inhibition as a single agent in animal models. To explore potential synergy of Up284 with other therapeutic agents, we conducted the in vivo combination experiments. In this work, we present ADRM1 amplification in QNBC tumors, identification of a small molecule selective inhibitor of ADRM1, Up284 (Up Therapeutics), Up284 demonstrated efficacy against panel of BC cell lines and patient derived organoids. In vivo combination results for Up284 with widely used BC standard-of care chemotherapy regimen demonstrated strong in vivo synergy in tumor mouse syngeneic models. Taken together, these data demonstrated combination synergy of a small molecule ADRM1 inhibitor with other agents. These results pave the road for potential clinical evaluation of combination treatment of QNBC in patients.

Citation Format: Balasubramanyam Karanam, Ravi Anchoori, Yung-Nien Chang, Rachel Martini, Florencia Madorsky Rowdo, Melissa B. Davis. Up284, A small molecule inhibitor of ADRM1 demonstrates significant anti-tumor efficacy in preclinical models of aggressive breast cancer. [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 4478.
Abstract 4518: Highlighting the prenatal, natal, and early childhood risk factors of cancer: seeking better opportunities for cancer prevention
Authors: Elmoneim Abeer Abd , Roushdy Ayat , Metwally Ehab
Published: April 2023

Background: Fostering new public health approaches to cancer prevention is required to reduce the number of new cases. Early life exposures, to carcinogens may affect different phases of the multi-tage clonal expansion model of carcinogenesis. Critical development periods, in-utero and puberty, exposures may induce permanent changes in tissue differentiation, metabolism, and gene expression that influence cancer risk. Epigenetic modifications are also critical for regulating cellular processes and responses during development that are maintained overtime. Therefore, promising strategies should develop for cancer prevention mainly on environmental approaches. We aim in this study to assess the prevalence of risk factors of childhood cancer in Almadinah City, a local community in Saudi Arabia, and to address cancer prevention opportunities during prenatal, natal and early children life.

Patients and Methods: The study is a cross section observational study. The population includes convenient samples of pregnant mothers, neonates and preschool children. Data regarding natal, prenatal and early childhood risk factors of cancer collected using a predesigned questionnaire.

Results: Early life exposure to cancer risks increases prevalence of cancer. Risk factors like high birth weight, maternal obesity and smoking are the most frequent risks followed by chromosomal anomalies and genetic syndromes. Prenatal use of folic acid, breastfeeding and allergy, respectively, are the most frequent protective factors against cancer development.

conclusions: Strict approaches should be designed for preventing early life exposures and their cumulative effect that can lead to cancer development.

Citation Format: Abeer Abd Elmoneim, Ayat Roushdy, Ehab Metwally. Highlighting the prenatal, natal, and early childhood risk factors of cancer: seeking better opportunities for cancer prevention. [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 4518.