bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5778: Early age of onset of double germline DDR-mutated gastric cancer
Authors: Qu Yurong , Shi Min , Liang Yiming , Zhu Bowen
Published: June 2022

Background: Gastric cancer (GC) is one of the leading causes of cancer death in China. Approximately 10% of GC cases are associated with strong familial clustering and can be attributed to genetic predisposition. However, GC is biologically and genetically highly heterogeneous, the underlying genetic cause is complicated. DNA damage repair (DDR) genes play key roles in maintaining human genomic stability. Loss of DDR function, conversely, is an important determinant of cancer risk, progression, and therapeutic response.Our aim was to analyze the germline mutational pattern of DDR-mutated Chinese GC cohort and find possible genetic factors related to the early onset of gastric cancer.

Methods: In this analysis we defined a “core DDR” gene set with 10 homologous recombination deficiency-HRD gene (BRCA1, BRCA2, ATM, PALB2, BRIP1, CDK12,CHEK1, CHEK2,FANCA and FANCL) and 4 mismatch repair-MMR gene (MLH1,MSH2,PMS2 and PMS6). The panel of 14 core DDR genes was used to analyze the germline mutation profiling of DDR-mutated GC cohort which is consisted of 144 Chinese patients with at least one germline “core DDR” gene likely pathogenic/pathogenic (LP/P) mutations. LP/P mutations were called according to the classification criteria of the American College of Medical Genetics and Genomics.

Results: The DDR-mutated GC cohort was consist with 144 patients with at least one “core DDR” gene germline mutations, and the median age of this cohort was 63 years. In this cohort, eighty-three of 144 patients carried only one HRD gene P/LP mutations (median age at onset:63), forty-two patients of 144 patients carried only one MMR gene P/LP mutation (median age at onset:65.5). Nineteen of 144 (13.2%) patients had two “core DDR” germline mutation, and the median age of these patients with double germline mutations was 49. The double DDR-mutated GC had a significantly younger median age of onset than one HRD-mutated GC (log-rank test, P =0.00746) as well as one MMR-mutated GC (log-rank test, P =0.00849). Three of the double DDR-mutated patients had family histories of gastrointestinal cancer.

Conclusion: Our data suggests that GC patients harboring any two germline mutations in the “core DDR” gene may have an earlier age of onset.

Citation Format: Yurong Qu, Min Shi, Yiming Liang, Bowen Zhu. Early age of onset of double germline DDR-mutated gastric cancer [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 5778.
Abstract 5781: Molecular positive margin of surgical resections is a strong biomarker for tumor recurrence in pIIIA-N2 NSCLC patients
Authors: Li Li , He Kewen , Pang Jiaohui , Xu Yang , Shao Yang , Yuan Shuanghu , Yu Jinming
Published: June 2022

Background: The high recurrence rate of stage pIIIA-N2 NSCLC patients may reflect inadequate removal of all residual tumor cells despite conventional histologic negative surgery margin. The NGS-detected BRM status was possible to serve as a more accurate examination to identify those patients with a high-risk of postoperative recurrence.

Methods: We retrospectively studied 119 stage IIIA-N2 NSCLC patients who received curative-intent surgery plus adjuvant chemotherapy/chemoradiotherapy, and all of the patients were classified with negative resection margin by the conventional histologic method. Each patient had paired tumor and bronchial resection margin (BRM) samples, which were analyzed using next-generation sequencing (NGS) of 474 cancer-related genes, and we explored the prognostic values of various clinical and molecular features.

Results: Among the 119 stage IIIA-N2 NSCLC patients with histologic negative resection margins, the BRM samples from 56 patients (47.1%) were positive for tumor mutations, including multiple lung cancer driver mutations. The number and the variant allele frequency of genetic alterations in BRM samples were generally lower than that of the paired tumor samples. Notably, patients who were positive for NGS-detected BRM mutations had significantly shorter disease-free survival (DFS) than the negative patients (p=0.001, HR 2.18, 95%CI 1.37~3.47). Several other clinical/molecular features were also found to be significantly associated with DFS, including the metastatic lymph node ratio (MLNR), smoking history, and KRAS mutation status, and NGS-assessed BRM status remained to be statistically significant in multivariable analysis by including all of these prognostic factors (p =0.020, HR 1.82, 95%CI 1.10~3.02).

Conclusions: We demonstrated that the molecular positive margin of surgical resections was a strong and independent biomarker for disease recurrence in pIIIA-N2 NSCLC patients. Our results emphasized the clinical utility of molecular diagnostic approaches to detect minimal residual disease after surgical resection, which could potentially facilitate the stratification of high-risk patients for personalized and appropriate treatments.

Citation Format: Li Li, Kewen He, Jiaohui Pang, Yang Xu, Yang Shao, Shuanghu Yuan, Jinming Yu. Molecular positive margin of surgical resections is a strong biomarker for tumor recurrence in pIIIA-N2 NSCLC patients [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 5781.
Abstract 5825: Reduced miR-371b-5p expression drives tumor progression via CSDE1/RAC1 regulation in triple-negative breast cancer
Authors: Park Jong Hoon , Kim Yesol , Ko Je Yeong , Lee Soo-Been , Park Minah
Published: June 2022

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer; however, specific prognostic biomarkers have not yet been developed. In this study, we identified dysregulated microRNAs (miRNAs) in TNBC by profiling miRNA and mRNA expression. In patients with TNBC, miR-371b-5p expression was reduced, and miR-371b-5p overexpression significantly mitigated TNBC cell growth, migration, and invasion. In addition, we found that expression of cold shock domain-containing protein E1 (CSDE1), a direct target gene of miR-371b-5p, was upregulated in TNBC cells, and inhibition of CSDE1 expression alleviated TNBC cell growth by regulating RAC1 transcription. Mechanistically, CSDE1, phosphorylated C-terminal domain (p-CTD) of RNA polymerase II (RNAPII), and CDK7 form a complex, and downregulation of CSDE1 leads to weak interaction between RNAPII p-CTD and CDK7, resulting in a decrease in RNAPII p-CTD expression to reduce RAC1 transcript levels in CSDE1-deficient TNBC cells. Our data demonstrate that miR-371b-5p is a tumor-suppressive miRNA that regulates the CSDE1/Rac1 axis and could be a potential prognostic biomarker for TNBC.

Citation Format: Jong Hoon Park, Yesol Kim, Je Yeong Ko, Soo-Been Lee, Minah Park. Reduced miR-371b-5p expression drives tumor progression via CSDE1/RAC1 regulation in triple-negative breast cancer [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 5825.
Abstract 5826: Autophagy regulates cancer stem cell properties in triple negative breast cancer via miR-181a-mediated regulation of ATG5/ATG2B
Authors: Park Jong Hoon , Park Jee Won , Kim Yesol , Jun Jaehee , Ahn Yejin
Published: June 2022

Autophagy has a dual role in the maintenance of cancer stem cells (CSCs), but the precise relationship between autophagy and cancer stemness requires further investigation. In this study, it was found that luminal and triple-negative breast cancer require distinct therapeutic approaches because of their different expressions of autophagy flux. We identified that autophagy flux was inhibited in triple-negative breast cancer (TNBC) CSCs. Moreover, miRNA-181a (miR-181a) is upregulated both in TNBC CSCs and patients. ATG5 and ATG2B participate in the early formation of autophagosomes and were revealed as targets of miR-181a. Inhibition of miR-181a expression led to attenuation of TNBC cancer stemness and an increase in autophagy flux. Furthermore, treatment with curcumin led to attenuation of cancer stemness in TNBC CSCs; the expression of ATG5 and ATG2B was enhanced and there was an increase of autophagy flux. These results indicated that ATG5 and ATG2B are involved in the suppression of cancer stemness in TNBC. In summary, autophagy inhibits cancer stemness through the miR-181a-regulated mechanism in TNBC. Promoting tumor-suppressive autophagy using curcumin may be a potential method for the treatment of TNBC.

Citation Format: Jong Hoon Park, Jee Won Park, Yesol Kim, Jaehee Jun, Yejin Ahn. Autophagy regulates cancer stem cell properties in triple negative breast cancer via miR-181a-mediated regulation of ATG5/ATG2B [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 5826.
Abstract 5844: A comprehensive pan-cancer analysis of MDM2/MDM4 gene amplification in Chinese solid cancer patients
Authors: sun xiangyu , Fu Zhichao
Published: June 2022

Background: Many patients with cancer have benefited from immunotherapy represented by the blockade of immune checkpoint PD-1/PD-L1. However, about 4-29% of cancer patients treated with immunotherapy developed hyper-progressive diseases(HPD) with accelerated tumor growth. MDM2/MDM4 amplification was suggested as genomic correlates for elevated risk hyperprogression. The objective of this study was to evaluate the frequency of amplification of MDM2/MDM4 in the Chinese solid tumor patients and to provide advice on the selecting of optimal treatment decisions.

Methods: Tumor or blood samples were collected from 2,937 patients with solid cancer, genetic mutations and amplification was detected using the next-generation sequencing(NGS).

Results: A total 112 patients with MDM2/MDM4 amplification were identified, including lung cancer 50.9% (57/112), colorectal cancer 14.3% (16/112), gastric cancer 8.0% (9/112), liver cancer 5.4% (6/112), Biliary tract cancers 4.5% (5/112), breast cancer 2.7% (3/112), and pancreatic ductal adenocarcinoma 2.7% (3/112). TMB value was identified, The median TMB for lung cancer was 9.13 mutations/Mb, median TMB for colorectal cancer was 13.8 mutations/Mb, a high TMB value in gastric cancer (median TMB=20.22 mutations/Mb), and median TMB for liver cancer was 17.9 mutations/Mb. Meanwhile, MSI was detected in 8% of patients with MDM2/MDM4 amplification, of which 3 in lung cancer, 5 in colorectal cancer, and 1in gastric cancer.

Conclusions: Although amplification of MDM2/MDM4 was observed only in a small proportion of patients, it demonstrated an association with high TMB in several common cancer types. In addition, our data indicate that amplification of MDM2/MDM4 in different types of cancer is heterogeneous and that an appropriate immunotherapy strategy for patients with solid cancer should be noted.

Citation Format: xiangyu sun, Zhichao Fu. A comprehensive pan-cancer analysis of MDM2/MDM4 gene amplification in Chinese solid cancer patients [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 5844.
Abstract 5890: The effect of healthy eating on breast cancer-specific outcomes: A systematic review and meta-analysis
Authors: Han Eric , Kady Vanessa , Montan Kayla , Normuminova Marjona , Eum Soomin , Rovito Michael , Lee Eunkyung
Published: June 2022

Background:  Breast cancer (BC) survivors attempt to change their diet after diagnosis to improve cancer-specific outcomes; however, there are many sets of guidelines available, and cancer survivors are not sure which ones are best to follow. Therefore, we examined the effect of different dietary quality indices on BC-specific outcomes in BC survivors.

Methods:  Web of Science and EBSCOhost were searched for relevant publications using the key terms in June 2021. Covidence software was then used for the screening and extraction of these publications. Characteristics for the included studies such as, participants, and dietary quality index were examined, and summary effect sizes were estimated for BC recurrence and BC-specific mortality using a random-effects model.

Results: Across the 10 included studies (9 BC-specific mortality and 1 Recurrence; 8 Post-diagnosis and 3 pre-diagnosis diet studies), a total of 25,194 BC survivors were included in the meta-analysis, and 2,550 BC-specific deaths and 461 recurrences were observed over a follow up period of 6-17.2 years. The dietary indices evaluated were ACS (n=2), CHFP (n=2), MDS (n=2), DASH (n=3), HEI (n=8), DQIR (n=1), and RFS (n=1). Meta-analysis showed that adhering to dietary guidelines after diagnosis was associated a 4~36% reduction in BC-specific mortality with varying degrees of significance: ACS (HR=0.96, 95% CI=0.72-1.29), CHFP (HR=0.64, 95% CI=0.49-0.83), MDS (HR=0.93, 95% CI=0.70-1.24), DASH (HR=0.79, 95% CI=0.64-0.98), and HEI (HR=0.93, 95% CI=0.70-1.24). Subgroup analysis with DASH guidelines showed that the strength of the association was greater for those with ER-positive, PR-negative, or HER2-positive cancer, physically active, and older survivors compared to their respective counterparts. Only one study evaluated BC recurrence, which was insufficient to perform meta-analysis, and pre-diagnosis adherence to dietary guidelines was not associated with BC-specific mortality (HR=0.98, 95% CI=0.81-1.17).

Conclusions:  Healthcare providers may find it best to encourage BC survivors to comply with the DASH or CHFP dietary guidelines to improve cancer-specific mortality. Additional research should be performed to strengthen the relationship found between adherence to dietary indices and breast cancer-specific outcomes.

Keywords: dietary guidelines, diet quality, breast cancer mortality, DASH, meta-analysis

Citation Format: Eric Han, Vanessa Kady, Kayla Montan, Marjona Normuminova, Soomin Eum, Michael Rovito, Eunkyung Lee. The effect of healthy eating on breast cancer-specific outcomes: A systematic review and meta-analysis [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 5890.
Abstract 5900: Integrating prior knowledge of transcription factor occupied elements with transcriptome-wide association analysis identifies 153 breast cancer susceptibility genes
Authors: Guo Xingyi , He Jingni , Beeghly-Fadiel Alicia , Chen Zhishan , Cao Chen , Shu Xiao-ou , Zheng Wei , Long Quan
Published: June 2022

Transcriptome-wide association studies (TWAS) have been successful in uncovering large numbers of putative disease susceptibility genes. TWAS approaches such as S-PrediXcan, FUSION and TIGAR, show comparable overall performance for susceptibility gene discovery; however, integrating prior disease-specific regulatory information is lacking. To improve accuracy of gene expression prediction by integrating information on susceptible transcription factor (sTF) occupancy in target cells and tissues, we developed an analytical framework, called sTF-TWAS. We evaluated six sets of putative regulatory variants selected from sTF-occupied sites, and performed generalized Berk-Jones (GBJ) analysis to combine sets and quantify overall associations. We demonstrated that sTF-TWAS outperforms S-PrediXcan in both simulation and real data analyses. Using summary statistics data from the Breast Cancer Association Consortium (BCAC), we also incorporated alternative splicing (sp) data in TF-TWAS and identified 76 and 88 significant genes for breast cancer risk at a Bonferroni-corrected P <0.05 from sTF-TWAS and sp-sTF-TWAS, respectively. Of 153 putative susceptibility genes from both sTF-TWAS and sp-sTF-TWAS, 14 genes in 12 loci had novel associations with breast cancer risk and 90 genes were previously unreported by breast cancer GWAS. We also provide strong evidence for 15 previously unreported genes, including 11 essential for breast cell proliferation and five suggested cancer predisposition or driver genes: RAD50, IGHMBP2, ATXN3, KANSL1, and IL6ST. Overall, we demonstrated that our approach has significant advantages over regular TWAS and our findings provide additional insights into the genetic susceptibility of breast cancer.

Citation Format: Xingyi Guo, Jingni He, Alicia Beeghly-Fadiel, Zhishan Chen, Chen Cao, Xiao-ou Shu, Wei Zheng, Quan Long. Integrating prior knowledge of transcription factor occupied elements with transcriptome-wide association analysis identifies 153 breast cancer susceptibility genes [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 5900.
Abstract 5923: Rapid spectroscopic liquid biopsy for the early detection of brain tumors
Authors: Sala Alexandra , Theakstone Ashton G. , Brennan Paul M. , Jenkinson Michael D. , Mills Samantha J. , Syed Khaja , Rinaldi Christopher , Xu Yun , Goodacre Royston , Butler Holly J. , Palmer David S. , Smith Benjamin R. , Baker Matthew J.
Published: June 2022

To support the early detection and diagnosis of brain tumors we have developed a rapid, cost-effective and easy to use spectroscopic liquid biopsy based on the absorbance of infrared radiation. We have previously reported highly sensitive results of our approach which can discriminate patients with a recent brain tumor diagnosis and asymptomatic controls. Other liquid biopsy approaches (e.g., based on tumor genetic material) report a lower classification accuracy for early-stage tumors. In this manuscript we present an investigation into the link between brain tumor volume and liquid biopsy test performance. In a cohort of 177 patients (90 patients with high-grade glioma (glioblastoma (GBM) or anaplastic astrocytoma), or low-grade glioma (astrocytoma, oligo-astrocytoma and oligodendroglioma)) tumor volumes were calculated from magnetic resonance imaging (MRI) investigations and patients were split into two groups depending on MRI parameters (T1 with contrast enhancement or T2/FLAIR (fluid-attenuated inversion recovery)). Using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy coupled with supervised learning methods and machine learning algorithms, 90 tumor patients were stratified against 87 control patients who displayed no symptomatic indications of cancer, and were classified as either glioma or non-glioma. Sensitivities, specificities and balanced accuracies were all greater than 88%, the area under the curve (AUC) was 0.98, and cancer patients with tumor volumes as small as 0.2 cm3 were correctly identified. Our spectroscopic liquid biopsy approach can identify gliomas that are both small and low-grade showing great promise for deployment of this technique for early detection and diagnosis.

Citation Format: Alexandra Sala, Ashton G. Theakstone, Paul M. Brennan, Michael D. Jenkinson, Samantha J. Mills, Khaja Syed, Christopher Rinaldi, Yun Xu, Royston Goodacre, Holly J. Butler, David S. Palmer, Benjamin R. Smith, Matthew J. Baker. Rapid spectroscopic liquid biopsy for the early detection of brain tumors [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 5923.
Abstract 5967: ROSA: An ambassador program facilitating bidirectional partnerships between communities and basic scientists
Authors: Ruiz Gabriela , Lee Amanda
Published: June 2022

Background: Community Outreach and Engagement (COE) is integral in NCI-designated Cancer Centers. COEs work with community stakeholders identifying community needs, communicating research, and catalyzing significant activities to Cancer Center’s catchment areas. To facilitate this, the University of Arizona Cancer Center (UACC) Office of COE established the Research Outreach for Southern Arizona (ROSA) program, supporting bidirectional partnerships between basic scientists and underrepresented communities in catchment areas.

Objective: To describe a community and student ambassador program developed as ROSA, bridging gaps between basic science programs and community needs in UACC catchment areas.

Methods: The UACC catchment areas include five southern Arizona counties where 40% of residents are Hispanic, compared to 18.3% in the US. Moreover, ambassadors were bilingual/bicultural Hispanic undergraduate students (n=4) and Hispanic community members (n=4). The ambassador program held weekly cancer educational discussions, research methods, monthly Meet the Scientist events, and presentations on experiences. Evaluations for ROSA were completed by all affiliates.

Results: Overall, ROSA ambassadors reported increased knowledge of research and increased confidence sharing cancer information. Facilitators of ROSA community members included a bilingual/bicultural team, outreach collaborations, and participant compensation. Barriers included payments for undocumented members, lack of Spanish-speaking scientists, and reduced in-person activities. As a result of ROSA partnerships, scientists, healthcare professionals, and stakeholders is developing Scientific Cafes where scientists present research proposals for community feedback. The workgroup will select a community-driven project to implement in the future.

Discussion: Based on positive ambassador evaluations and working group collaborations, ROSA is successful in growing authentic partnerships between scientists and communities. Recently, a community-based survey was developed by members to examine perceptions of cancer and willingness of clinical research participation. This survey will inform how basic scientists align research within community needs. ROSA will continue to be valuable in providing bidirectional engagement from basic scientists and community members in cancer research.

Citation Format: Gabriela Ruiz, MEd., Amanda Lee. ROSA: An ambassador program facilitating bidirectional partnerships between communities and basic scientists [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 5967.
Abstract 6026: A novel humanized mouse model based on NOG-FcgR-/-mice recapitulates anti-tumor immune reactions by human immune systems in response to anti-PD-1 antibody (Nivolumab)
Authors: Katano Ikumi , Hanazawa Asami , Otsuka Iyo , Yamaguchi Takuya , Mochiduki Misa , Kawai Kenji , Ito Ryoji , Goto Motohito , Kagawa Takahiro , Takahashi Takeshi
Published: June 2022

Humanized mice with human hematopoietic and immune systems have been frequently used for examining in vivo anti-cancer effects of various drugs, including immune checkpoint inhibitors (ICIs) like anti-PD-1 or anti-CTLA-4 antibodies, yet the reliability of the mouse models to be improved. We have recently developed NOD-scid, IL-2Rγ KO (NOG) mice deficient for the mouse FcεRI and FcγIIb genes, thus lacking the expression of functional mouse FcγRs, (NOG-FcγR-/-) and the activity of endogenous antibody-dependent cellular cytotoxicity (ADCC). Reconstitution experiments with human hematopoietic stem cells (HSC) showed that NOG-FcγR-/- mice had higher engraftment capacity for human leucocytes than NOG mice, namely the numbers of HSC-derived human CD19+ B cells and CD33+ myeloid cells, but not CD3+ T cells, were higher in the various tissues in NOG-FcγR-/- mice than those in NOG mice. In tumor-bearing experiments using those reconstituted mice, it was of interest that humanized NOG-FcγR-/- mice (huNOG-FcγR-/-) could invoke strong tumor growth suppression or rejection in response to anti-PD-1 antibody (Nivolumab) treatment in several cancer cell lines, which was absent in conventional huNOG mice. Accordingly, Nivolumab treatment in huNOG-FcγR-/- mice induced a significant increase of human T cells in number in the spleen and infiltration of human T cells with Granzyme B and Perforin-expression into tumor. Furthermore, the composition of activated T cells was different between huNOG-FcγR-/- and huNOG mice. HuNOG-FcγR-/- mice had elevated numbers of activated T cells, both T central memory cells (TCM) and T effector memory cells (TEM), whereas huNOG mice showed an opposite trend, reduced TCM and TEM and increase of naïve T cells. Our results suggest that the novel NOG-FcγR-/- mice become a good model for elucidating the cellular and molecular mechanisms of human tumor rejection by human T cells, and that they will provide a superior in vivo platform for evaluation of anti-cancer drugs, especially, in combination with ICIs like Nivolumab.

Citation Format: Ikumi Katano, Asami Hanazawa, Iyo Otsuka, Takuya Yamaguchi, Misa Mochiduki, Kenji Kawai, Ryoji Ito, Motohito Goto, Takahiro Kagawa, Takeshi Takahashi. A novel humanized mouse model based on NOG-FcgR-/-mice recapitulates anti-tumor immune reactions by human immune systems in response to anti-PD-1 antibody (Nivolumab) [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 6026.
Abstract 6030: Reconstructed Pancreas: A tumor-specific 3D culture platform for accurate evaluation of therapeutic agents in pancreatic cancer
Authors: Kirshner Eleanore J. , Ahlawat Aayushi , Ryou Matthew
Published: June 2022

As it is rarely diagnosed early, the prognosis for patients with pancreatic cancer is grim. The average 5-year survival rate is 10% and only 3% for patients with metastatic disease. Partially because of the late diagnosis and partially because of its biology, treatment options for patients with pancreatic cancer are limited and new interventions are desperately needed to gain the upper hand on this disease. One of the challenges faced by the drug developers looking for agents against pancreatic cancer is capturing the elements of the tumor microenvironment, which provides both a physical barrier and stroma-driven resistance to therapeutic agents. We developed a tumor-specific Reconstructed Pancreas (r-Pancreas) model, which recapitulates the cellular and extracellular elements of the pancreatic tumor microenvironment. In the r-Pancreas model, tumor and stromal cells are embedded in a dense extracellular matrix (ECM) characteristic of pancreatic tumors. Pancreatic tumor cell lines, MiaPaca-2, Panc-1, and Bx-PC3 robustly proliferate and survive for 14 days providing an extended therapeutic window to test anti-tumor compounds in the context of pancreas-specific ECM. Mimicking clinical response pancreatic tumor cells grown in r-Pancreas are sensitive to gemcitabine (IC50=0.4-0.6µM) but are resistant to 5-fluorouracil (IC50=not reached). These cell lines were also 5-10 times less sensitive to gemcitabine when cultured in Matrigel (IC50=3-6µM), soft ECM rich in collagen IV/laminin neither of which is abundant in the pancreas. Incorporating a collagen-rich capsule into the r-Pancreas model further expands its physiological relevance as human pancreatic tumors have been shown to have an outer layer of stiff ECM, which provides a physical barrier that impedes drug access to the tumor. Finally, establishing a co-culture of pancreatic tumor cell lines with primary pancreatic stromal cells creates a complete model enabling testing of novel therapeutic agents within the pancreatic tumor microenvironment. Taken together these data suggest that to be clinically useful in vitro tumor models not only need to allow for 3-dimensional cell growth but also have to incorporate tumor-specific elements of the microenvironment.

Citation Format: Eleanore J. Kirshner, Aayushi Ahlawat, Matthew Ryou. Reconstructed Pancreas: A tumor-specific 3D culture platform for accurate evaluation of therapeutic agents in pancreatic cancer [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 6030.
Abstract 6062: Radiosensitizing head and neck squamous cell carcinoma using isothiocyanates
Authors: Wicker Christina Ann , Thompson Samuel , Dubey Poornima , Takiar Vinita
Published: June 2022

Head and neck cancer kills over 400,000 people each year with the majority of cases being head and neck squamous cell carcinoma (HNSCC). Despite major advances in cancer treatment, radiation resistance contributes to increased morbidity and mortality of patients with HNSCC. Few FDA-approved radiosensitizers exist for the treatment of HNSCC and the majority are associated with severe adverse effects. Therefore, there is a clear need to examine novel treatment combinations to improve radiosensitivity and HNSCC outcomes. Isothiocyanates enhance response to cytokines, chemotherapy, and radiation in other in vitro and in vivo cancer models, including pancreatic and breast cancer. Isothiocyanates are antioxidants found in cruciferous vegetables such as watercress and broccoli. Phenethyl isothiocyanate (PEITC) was well tolerated by patients in chemopreventative clinical trials and was thus selected for this study. We hypothesize that PEITC radiosensitizes HNSCC cells through increasing DNA damage, apoptosis and reactive oxygen species (ROS). Non-human papilloma virus or P16 negative HNSCC are associated with increased radioresistance and as such human HNSCC cell lines HN5 and CAL27 were selected. Combination of PEITC and photon radiation (XRT) decreased cell survival by half as compared to cells treated with PEITC or XRT alone for both HN5 and CAL27 cells as determined by clonogenic assay (n≥3). PEITC enhanced XRT-induced apoptosis in HN5 and CAL27 cells as indicated by increased cleavage of effector caspases 3 and 7, which was reversed upon treatment with pan-caspase inhibitor, QVD-OPH. Preliminary comet assays identified that combination of PEITC with XRT significantly increased Tail DNA % relative to vehicle (p<0.001), PEITC alone (p<0.0001), or XRT alone (p<0.0001) in HN5 cells. Preliminary data in CAL27 cells identified significantly increased signal of y-H2Ax in cells treated with both PEITC and XRT was 2.2 fold higher than XRT alone (p<0.001) and 12.1 fold higher than PEITC alone (p<0.001) in CAL27 cells. PEITC increased XRT-induced ROS generation in CAL27 cells relative to independent treatment as determined by 2′,7′ dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Taken together, these results support that PEITC synergistically enhances HNSCC cell response to XRT. The results of this study warrant further investigation into the potential of PEITC to improve radiation efficacy in pre-clinical HNSCC models with the long-term goal of testing this well-tolerated compound in clinical trials.

Citation Format: Christina Ann Wicker, Samuel Thompson, Poornima Dubey, Vinita Takiar. Radiosensitizing head and neck squamous cell carcinoma using isothiocyanates [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 6062.
Abstract 6079: Spatial deconvolution from bulk DNA methylation profiles determines intratumoral epigenetic heterogeneity
Authors: Xie Yumo , Zhang Yu , Tang Guannan , Wang Xiaolin , Huang Meijin , Luo Yanxin , Yu Huichuan
Published: June 2022

Purpose: Intratumoral heterogeneity emerges from accumulating genetic and epigenetic changes during tumorigenesis, which may contribute to therapeutic failure and drug resistance. We aimed to develop a tool that can evaluate the intratumoral epigenetic heterogeneity using the DNA methylation profiles from bulk tumors.

Methods: Ggenomic DNA of three laser micro-dissected tumor regions, including digestive tract surface (DTS), central bulk (CB), and invasive margin (IM), was extracted from formalin-fixed paraffin-embedded (FFPE) sections of 98 colorectal cancer patients. The genome-wide methylation profiles were generated with methylation array. The most variable methylated probes were selected to construct a DNA methylation-based heterogeneity (MeHEG) estimation tool that can deconvolve the proportion of each reference tumor region with the support vector machine model-based method. A PCR-based assay for quantitative analysis of DNA methylation (QASM) was developed to specifically determine the methylation status of each CpG in MeHEG assay at single-base resolution to realize fast evaluation of epigenetic heterogeneity.

Results: In the discovery set with 79 patients, the differentially methylated CpGs among the three tumor regions were found. The 7 most representative CpGs were identified by random forest analysis and subsequently selected to develop the MeHEG algorithm. We validated its performance of deconvolution of tumor regions in an independent cohort with 19 patients. In addition, we showed the significant association of MeHEG-based epigenetic heterogeneity with the genomic heterogeneity in mutation and copy number variation in our in-house and TCGA cohorts. Finally, we found that the patients with higher MeHEG score had worse disease-free and overall survival outcomes.

Conclusion: By constructing a 7-loci panel with a machine learning approach and QASM assay to facilitate its use in a PCR manner, we developed a valuable method to evaluate the intratumoral epigenetic heterogeneity. The MeHEG algorithm provides innovative insights into the intratumoral heterogeneity from the epigenetic perspective that may add valuable sources to current knowledge about tumor heterogeneity.

Citation Format: Yumo Xie, Yu Zhang, Guannan Tang, Xiaolin Wang, Meijin Huang, Yanxin Luo, Huichuan Yu. Spatial deconvolution from bulk DNA methylation profiles determines intratumoral epigenetic heterogeneity [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 6079.
Abstract 6110: Immune cell infiltrative characteristics reveals the superior efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in a real-world cohort of resectable non-small cell lung cancer
Authors: Cai Wenhan , Jing Miao , Wen Jiaxin , Gu Yajun , Zhao Xiaochen , Xue Zhiqiang
Published: June 2022

We aimed to analyze the efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in the real-world settings, and to further explore tumor immune microenviroment (TIME), as well as its influence on response of neoadjuvant therapy in patients with NSCLC. Fifty-three patients with neoadjuvant therapy (immunochemotherapy, n=22; chemotherapy alone, n=31), resectable stage I~III, age≥18 years, and ECOG performance status 0-1 were recruited in the study. Fluorescent multiplex immunohistochemistry was performed by the automated quantitative pathology imaging system with tumor samples obtained in radical surgery. The major pathologic response (MPR) rate was significantly higher in patients with neoadjuvant immunochemotherapy than chemotherapy alone (p=.025; OR=4.222, 95% CI: 1.292~13.800). Patients received immunochemotherapy had higher pathologic complete response (pCR) rate than those with chemotherapy (p=.168; OR=3.150, 95% CI: 0.792~12.535). Compared with chemo alone, the tumor to stroma ratio of CD68+CD163- density was significantly elevated in patients subjected to immunochemotherapy (p=.0399). When patients were stratified by the pathologic response to neoadjuvant immunochemotherapy, the CD56dim in stroma significantly increased in patients achieved pCR than non-pCR (p=.038). The density of CD3+CD4+ cells (stroma, p=.039; total, p=.027) and CD20+ (total, p=.027) immune cells was significantly higher in patients achieved MPR than non-MPR. In patients administered with neoadjuvant chemotherapy alone, the expression level of PD-1 (p=.036), the density of FoxP3+ (stroma, p=.025; total, p=.013) and CD3+CD4+FoxP3+ (total, p=.042) cells significantly reduced in patients reached pCR. The density of CD20+ cells in stroma (p=.034) and the number of tertiary lymphoid structures (TLS; p=.006) were significantly higher in patients reached MPR. In conclusion, the therapeutic efficacy was improved by neoadjuvant immunochemotherapy in patients with NSCLC, which may be associated with the TIME remodeling, especially the migration of M1 macrophage from stroma to tumor islet. Clusters of NK, Th, Treg and B, PD-1, and TLS also play important role in response to neoadjuvant therapy.

This work was supported by National Natural Science Foundation of China (NO. 62076254)

Citation Format: Wenhan Cai, Miao Jing, Jiaxin Wen, Yajun Gu, Xiaochen Zhao, Zhiqiang Xue. Immune cell infiltrative characteristics reveals the superior efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in a real-world cohort of resectable non-small cell lung cancer [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 6110.
Abstract 6114: Prognostic value of the tumor-infiltrating lymphocytes in Miller-Payne grade 4 triple-negative breast cancer following neoadjuvant chemotherapy
Authors: Ma Jianli , Deng Yuwei , Chen Dawei , Li Xiaomei , Yu Zhiyong , Wang Haibo , Zhong Lei , Li Yingjie , Wang Chengqin , Zhou Xiaoping , Li Xiang , Zhang Qingyuan , Yu Jinming
Published: June 2022

Background Triple-negative breast cancer (TNBC) with pathological complete response after neoadjuvant chemotherapy (NACT) has better prognosis, but there remain uncertainties upon the prognostic judgement for Miller-Payne 4 patients. We evaluated the prognostic correlations with the tumor-infiltrating lymphocytes (TILs) status in Miller-Payne 4 patients.

Methods A total of 272 TNBC patients with NACT were assessed as Miller-Payne grade 4/5. Pre-treatment core biopsies from Miller-Payne 4 patients were specifically assessed for TILs with prognostic relevance using standardized methods. The corresponding spatial distributions and components of the TILs were thoroughly analyzed by IMC and proteomic.

Results The 5-year disease-free survival (DFS) was 63.8% for Miller-Payne 4 and 83.0% for Miller-Payne 5 (p=0.003), and overall survival (OS) was 71.0% and 85.5% respectively (p=0.007). High TILs were significantly associated with longer DFS (p=0.007) and OS (p=0.004) in Miller-Payne 4/5 patients, and also in the Miller-Payne 4 subgroup (both p=0.016). Spatially, Miller-Payne 4 with good prognosis had an inflamed signature, included dominant T cells surrounding tumor cells with focal infiltrations, limited scattered myeloid-derived cells which were separated from T cells, and reduced suppressive cytokines. Functionally, 109 immunologically effective proteins were upregulated and 76 immunosuppressive components were downregulated, indicating more immunological effective activities. By contrast, Miller-Payne 4 with poor prognosis had an excluded signature. We also observed similar immune signatures in Miller-Payne 5.

Conclusion Miller-Payne 4 combined with immunotyping of the TILs could be powerful prognostic indicators for Miller-Payne 4 TNBC with NACT.

Citation Format: Jianli Ma, Yuwei Deng, Dawei Chen, Xiaomei Li, Zhiyong Yu, Haibo Wang, Lei Zhong, Yingjie Li, Chengqin Wang, Xiaoping Zhou, Xiang Li, Qingyuan Zhang, Jinming Yu. Prognostic value of the tumor-infiltrating lymphocytes in Miller-Payne grade 4 triple-negative breast cancer following neoadjuvant chemotherapy [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 6114.
Abstract 6121: Correlation of tumor immune microenvironment status and driver genes alterations in Chinese non-small-cell lung cancer patients
Authors: Guo Jindong , Xiong Liwen , Yuan Haibin , Hu Mengna , Zhang Bei , Zhang Ding
Published: June 2022

Background: Patients with different driver genes show a variety of immunotherapy efficacy for non-small-cell lung cancer (NSCLC). In addition to PD-L1, the evaluation of the immune microenvironment contributes to a deeper understanding of the mechanisms of immunotherapy resistance.

Methods: Tumor tissues from 2674 NSCLC patients were collected. Genetic alterations were profiled using targeted next-generation sequencing with 733 cancer-related genes panel. Immunohistochemistry was used to evaluate the PD-L1 tumor proportion score, (TPS) expression on the surface of tumor cells. Tumor-infiltrating immune cells of 120 tumor samples were labeled with multiple immunofluorescence staining.

Results: Overall, CD8+ T cell infiltration level was negatively associated with both EGFR copy number gain (CNG, p < 0.001) and ERBB2 CNG (p = 0.021). Also, the presence of EGFR or ERBB2 CNG was related with fewer natural killer cell infiltration (EGFR: p < 0.001; ERBB2: p = 0.036) and a lower M1/M2 tumor-associated macrophages ratio compared to wild-type tumors (EGFR: p = 0.051; ERBB2: p = 0.036), suggesting a relatively weaker anti-tumor ability. In addition, we noted that KRAS CNV was negatively related to M2 macrophages (p = 0.027). Patients carrying ALK translocation (p < 0.001), ROS1 translocation (p = 0.006), KRAS mutations (p < 0.001) and MET (p < 0.001) mutations had the elevated PD-L1 TPS expressions, while those harboring EGFR (p < 0.001) and ERBB2 mutations (p = 0.001) had lower PD-L1 expression. Compared to the other EGFR mutations, PD-L1 expression in EGFR CNG tumors was higher, and no significant differences were found between CNG and other types of mutation in patients harboring ERBB2, KRAS, MET alterations.

Conclusion: NSCLC patients with EGFR CNG and ERBB2 CNG had fewer invasion of cytotoxic T cells and NK cells and a lower M1/M2 macrophages ratio. EGFR CNG may intensively modify the tumor immune microenvironment, which is a possible mechanism contributing to EGFR-TKI resistance.

Citation Format: Jindong Guo, Liwen Xiong, Haibin Yuan, Mengna Hu, Bei Zhang, Ding Zhang. Correlation of tumor immune microenvironment status and driver genes alterations in Chinese non-small-cell lung cancer patients [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 6121.
Abstract 6182: A comprehensive panel of reporter cell lines to accelerate immune-checkpoint antibody discovery
Authors: Wang Guoqian , Guo Zhengcheng , Chen Hongling , Liu Chang , Ning Jinying , Hao Feng
Published: June 2022

Anti-tumor immune therapy has achieved great success. Antibody drugs targeting PD1/PD-L1 have brought significant benefits for cancer patients. In the post-PD1/PD-L1 era, many novel targets for tumor-related immune modulation have been discovered, and tremendous efforts have been put to develop new biologics for these targets. There is an urgent need for a high-throughput functional system that mimics tumor immune microenvironment to screen antibodies. Equipped with expertise in tumor immunology and cell biology, KYinno has generated a panel of reporter cell lines to accelerate immune-checkpoint antibody discovery. The reporter system includes two types of engineered cell lines, one is CHO-K1 or 293T based aAPC (artificial antigen presenting cell) which provides both stimuli and inhibitor (ligand) signals, and the other one is Jurkat-NFAT-luciferase reporter cell line that over-expresses the drug target (receptor). In this co-culture system, the ligand-receptor complex can induce NFAT inhibitory signals. The functional antibodies can rescue the inhibitory signal by blockage of the ligand-receptor interaction. All the reporter cell lines have been well validated with benchmark antibodies. Currently, the systems cover immune modulation for TIGIT, LILRB1, LILRB2, PVRIG, Lag3, TIM3, NKG2a, NKp30, PD1, NKp46, etc.

Citation Format: Guoqian Wang, Zhengcheng Guo, Hongling Chen, Chang Liu, Jinying Ning, Feng Hao. A comprehensive panel of reporter cell lines to accelerate immune-checkpoint antibody discovery [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 6182.
Abstract 6189: Development of an anti hepatocellular carcinoma CAR T strategy targeting PDL1
Authors: Lee Kyung-Sik , Park Hye-Seong , Park Guk-Yeol , Lee Gi-Chan , Choi Eun-Ji , Yu Jae-in , Yang Seung-Joo , Kim Mihwa , Choi Yoonjoo , Lee Je-Jung , Rhee Joon Haeng , Park Bum Chan , Park Jae Eun
Published: June 2022

[Purpose] Immunosuppressive tumor microenvironment (TME) is the major hurdle to cancer immunotherapy. Advanced hepatocellular carcinoma (aHCC) is one of the representative cold tumors with immunosuppressive TME and presents obvious correlation between immune check point expression, such as programmed cell death ligand 1 (PD-L1), and poorer prognosis. In aHCC patients, cancer cells and stellate cells in TME appeared to express high level of PD-L1, which should suppress activities of antitumor immune cells. In this context, the combination of PD-1/PD-L1 inhibitors and other therapeutic modalities are tried to treat aHCC. The chimeric antigen receptor (CAR) T cell therapy is a potent way of eradicating cells expressing targetable antigens. Removal of PD-L1 expressing cells in the aHCC TME will improve the clinical outcomes of current therapies against aHCC. In the present study, we developed an autologous anti-PD-L1 CAR T strategy and show high efficacy of tumor suppression using an HCC xenograft model.

[Result] We constructed second generation CAR lentiviral vector expressing an unique anti-PD-L1 scFv manifesting moderated affinity. The scFv was specifically generated by phage display technique using human B cell-derived naïve cDNA library, which targets PD-L1 with intermediate affinity in solid tumor TME. As the secondary signaling motif, CD28 was chosen and tested along with CD3 zeta chain. The effector CAR T, named VPC1, cells specifically recognized PD-L1 expressing HCC cells and exhibited rapid and robust cytotoxic activity in 2D and 3D culture experiments. In an HCC xenograft NSG mouse model, VPC1 CAR T cells significantly suppressed the tumor growth. More importantly, VPC-1-treated animals have well tolerated the CAR T therapy with no significant adverse manifestations during one month observation period and exhibited gradual weight gains since 3 days after CAR T cell injection.

[Conclusion] We hereby report that a new autologous PD-L1 CAR-T therapeutic is capable of eradicating solid tumors expressing PD-L1, which would significantly potentiate efficacies of current conventional and immunotherapeutic strategies.

Citation Format: Kyung-Sik Lee, Hye-Seong Park, Guk-Yeol Park, Gi-Chan Lee, Eun-Ji Choi, Jae-in Yu, Seung-Joo Yang, Mihwa Kim, Yoonjoo Choi, Je-Jung Lee, Joon Haeng Rhee, Bum Chan Park, Jae Eun Park. Development of an anti hepatocellular carcinoma CAR T strategy targeting PDL1 [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 6189.