bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2540: Belief in research, religious coping, and willingness to participate in clinical trials among African Americans with hematologic malignancies: a pilot study
Authors: Petty Marjorie
Published: July 2021

Purpose: The purpose of the proposed prospective cohort, pilot study is to recruit 30 AAs with hematologic malignancies to determine if a relationship exists between belief in research and willingness to participate in cancer clinical trials. The secondary objective is to determine whether religious coping moderates the effect of belief in research on the relationship between willingness to participate.

Description: African Americans (AAs) are disproportionately affected by certain types of hematologic malignancies, yet despite the efforts of investigators, they remain grossly underrepresented in cancer clinical trials. Few studies have evaluated the underrepresentation in clinical trials in this subgroup, while studies evaluating the same problem in AAs with solid tumors is well documented. A known barrier to clinical trial enrollment is knowledge of clinical trials; however, knowledge does not necessarily mean one will participate. One has also to believe and be willing to participate in clinical trials. Even so, it is unknown if a relationship exists between belief in research and willingness to participate in clinical trials in AAs with hematologic malignancies. Similarly, it is unknown if religious coping influences the possible association between belief in research and willingness to participate in AAs with hematologic malignancies. Due to sparse literature showing the connection of the concepts within this subset of AAs, research investigating the relationship between belief in research and willingness to participate is warranted.

Summary: Data will be captured at one time using the validated Brief Religious Coping Scale and researcher generated questions that address belief in research and willingness to participate in cancer clinical trials.

Conclusion: Findings will help in the design of future studies and the feasibility of recruiting AAs with hematologic malignancies.

Citation Format: Marjorie Petty. Belief in research, religious coping, and willingness to participate in clinical trials among African Americans with hematologic malignancies: a pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2540.
Abstract 2556: The somatic variant of HLRCC, an unrecognized type of RCC
Authors: Merino Maria J. , Dikoglu Esra , Gurram Sandeep , Linehan Marston , Srinivasan Ramaprasad
Published: July 2021

Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome where affected individuals are predisposed to the development of multiple leiomyomas of the skin and uterus and aggressive forms of kidney cancer. Affected individuals harbor a germline heterozygous loss-of-function mutation of the fumarate hydratase (FH) gene. Diagnosis of these tumors is done on clinical, morphologic and immunohistochemical (IHC) determination of negative staining for FH and genetic testing considered the gold standard. Somatic mutations in HLRCC RCC are not well recognized, and the morphologic features of tumors associated with the somatically mutated tumors has not been described. We report the clinical, morphologically and genetic findings of 7 patients with HLRCC and somatic mutations.

Design: Clinicopathologic correlation was done in all cases. All patients (4 males and 3 females) denied family history of kidney cancer or skin lesions. Age range was from 27 to 77. All patients had metastatic disease when accepted for protocol. Genetic testing was performed in all cases and IHC for FH when material was available.

Results: The genetic testing was negative for a germline mutation in all cases; however a pathogenic somatic mutation was found in all of them. Some of the somatic mutations included two copy deletion of 1q43, multiple break points on chromosome 1, and loss of heterozygosity. Morphologically the predominant pattern was extensive dense tubular formation with small tubules lined by clear or eosinophilic cells in which some nuclear features suggestive of HLRCC were identified (4 cases) the other cases showed cystic and papillary features. The diagnosis of HLRCC was suggested and FH performed with negative results.

Conclusion: Pathologists need to be aware that HLRCC with somatic and no germline mutations may occur more frequently than suspected and that a negative family history is frequently obtained. Morphology is helpful. However, staining for FH with negative results should be suspicious of HLRCC and genetic testing repeated considering the possibility of a somatic mutation, so proper diagnosis is made, and patients receive proper therapies.

Citation Format: Maria J. Merino, Esra Dikoglu, Sandeep Gurram, Marston Linehan, Ramaprasad Srinivasan. The somatic variant of HLRCC, an unrecognized type of RCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2556.
Abstract 2561: Tumorigenic and metabolomic impacts of adipose-derived monocyte chemotactic protein-1 in a model of obesity-enhanced, male breast cancer
Authors: Yan Lin , Sundaram Sneha , Rust Bret M. , Picklo Matthew J. , Bukowski Michael R.
Published: July 2021

Breast cancer is a rare but aggressive disease in men. Approximately, 90% of all breast cancer in men are invasive carcinomas, 25% of which have distant metastasis at the time of clinical presentation. Obesity is a risk factor for breast cancer. Monocyte chemotactic protein-1 (MCP-1) is an adipose-derived cytokine whose concentrations are elevated by obesity. This study tested the hypothesis that adipose-derived MCP-1 contributes to male breast cancer. In a 2x2 design, male MMTV-PyMT mice with or without adipose specific Mcp-1 knockdown [designated as Mcp-1-/- or wild-type (WT)] were fed the standard AIN93G diet or an obesogenic, high-fat diet (HFD) for 25 weeks. The AIN93G diet and HFD contained 16% and 45% of energy from soybean oil, respectively. Mcp-1-/- mice had lower adipose Mcp-1 expression than WT mice. Adipose Mcp-1 deficiency reduced plasma concentrations of MCP-1 in mice fed the HFD. Mice fed the HFD had a greater tumor progression rate than mice fed the AIN93G diet (4679% vs 2430%), regardless of genotype. Mcp-1-/- mice, compared to WT mice, had a longer tumor latency (25.2 weeks vs 18.0 weeks) and lower tumor incidence (19% vs 56%), tumor progression rate (2317% vs 4792%), and tumor weights (0.23 g vs 0.64 g). Metabolomic analysis of plasma identified 87 metabolites, 56 of which differed among the four groups, including 24 that differed between the diets and 22 that differed between the genotypes. Sparse partial least squares-discriminant analysis identified 10 major metabolites that were altered the most among the four groups. These included amino acids (alanine, isoleucine, leucine, phenylalanine, threonine, and valine) and carbohydrate metabolites (fumaric acid, glucuronic acid, hexuronic acid, and malic acid). The integrated pathway analysis of the 87 identified metabolites showed that protein biosynthesis and carbohydrate metabolism pathways are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-derived MCP-1 contributes to mammary tumorigenesis and alters metabolism in male MMTV-PyMT mice.

Citation Format: Lin Yan, Sneha Sundaram, Bret M. Rust, Matthew J. Picklo, Michael R. Bukowski. Tumorigenic and metabolomic impacts of adipose-derived monocyte chemotactic protein-1 in a model of obesity-enhanced, male breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2561.
Abstract 2566: The potential role of licorice and its bioactive compounds in promoting a tumor preventive environment in the postmenopausal breast
Authors: Hajirahimkhan Atieh , Howell Caitlin , Chen Shao-Nong , Clare Susan E. , Pauli Guido F. , Bolton Judy L. , Dietz Birgit M. , Khan Seema A.
Published: July 2021

Introduction: our purpose was to define if licorice and its main bioactive compounds can suppress aromatase expression/activity and Nrf2 dependent detoxification pathways in the postmenopausal breast. This chemopreventive potential has not previously been reported in preclinical models of high-risk postmenopausal breast.

Methods: Inhibition of aromatase activity by three licorice extracts (Glycyrrhiza species), and their bioactive compounds, (liquiritigenin; LigF, isoliquiritigenin; LigC, 8-prenylapigenin; 8-PA, and licochalcone A; LicA) were evaluated fluorometrically, using aromatase supersomes. Computational docking was performed to assess the binding of the bioactive compounds to the binding pocket of aromatase crystal structure compared to the known aromatase inhibitors, letrozole (non-steroidal) and exemestane (steroidal). Using qPCR, the effects of treatments on the expression of aromatase (CYP19A1) mRNA and Nrf2 dependent detoxification enzyme NADPH:quinone oxidoreductase 1 (NQO1) in breast microstructures obtained from high risk postmenopausal women were evaluated.

Results: Among the three medicinally used licorice species, Glycyrrhiza inflata (GI) showed the highest aromatase inhibitory potency (IC50 ≈ 1 µg/mL). Licorice phytoestrogens, LigF (400 nM or 0.1 µg/mL), and 8-PA (IC50 ≈ 590 nM or 0.2 µg/mL) exhibited the highest potency compared to the other tested licorice compounds. Computational docking suggested that these phytoestrogens bind to the aromatase binding pocket like the aromatase inhibitor, letrozole. This effect was not observed with non-estrogenic bioactive compounds of licorice, LigC and LicA (specific to GI). In breast microstructures obtained from high risk postmenopausal women, expression of aromatase mRNA was suppressed by GI (30%, P < 0.05), LigF (20%, P < 0.05), and LicA (45%, P < 0.05), while the expression of NQO1 mRNA was enhanced by LicA (200%, P < 0.0001).

Conclusions: Licorice species, and their bioactive compounds inhibited aromatase activity in vitro. In the breast microstructures, GI, its compounds LigF and LicA suppressed aromatase expression, and LicA enhanced NQO1 induction, significantly. Further studies will further elucidate the potential of these natural products for promoting a breast tumor preventive environment in postmenopausal women.

Citation Format: Atieh Hajirahimkhan, Caitlin Howell, Shao-Nong Chen, Susan E. Clare, Guido F. Pauli, Judy L. Bolton, Birgit M. Dietz, Seema A. Khan. The potential role of licorice and its bioactive compounds in promoting a tumor preventive environment in the postmenopausal breast [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2566.
Abstract 2602: Leveraging cell-free methylome markers for early cancer detection
Authors: Cheng Nicholas , Skead Kimberly , Soave David , Meng Jocelyn , Gbeha Elias , Lungu Ilinca , Lam Bernard , Bratman Scott , De Carvalho Daniel , Awadalla Philip
Published: July 2021

Cancer survival rates are significantly improved when detected at early stages, particularly when the tumor is still localized to the tissue of origin. However, effective screening tools for early cancer detection is currently limited to a subset of cancer types. The early development of human malignancies are difficult to observe as cancers are often detected once it becomes symptomatic, as such many cancer biomarker and evolution studies to date have primarily examined the genomics from solid tumor or liquid biopsies following a diagnosis. Investigating early tumor evolution in the pre-diagnosis context could allow us to better understand how to prevent or detect cancers in the earliest stage when survival rates are significantly higher, however this requires application of new technologies to biologics collected prior to a cancer diagnosis. Here, we leverage blood samples collected from participants in the Canadian Partnership for Tomorrow Project (CPTP), a longitudinal population cohort, prior to the onset of a cancer. Specifically, we utilize hybrid capture approaches to enrich for and characterize early mutations and methylation changes in circulating tumor DNA (ctDNA) of pre-cancer plasma samples collected from patients several months to years prior to clinical diagnosis. Here, we identify the earliest detectability of aberrant genetic and epigenetic events in ctDNA and describe the molecular evolution of these events at various stages prior to clinical detection of cancers. Further, we develop molecular biomarkers and implement machine learning tools to classify individuals with early cancers, and to develop risk scores from survival analyses predictive of cancer development up to 5 years prior to diagnosis. In our current study, we focus specifically on breast, prostate, lung and pancreatic cancer cases, and are extending this to pan-cancer applications in subsequent studies.

Citation Format: Nicholas Cheng, Kimberly Skead, David Soave, Jocelyn Meng, Elias Gbeha, Ilinca Lungu, Bernard Lam, Scott Bratman, Daniel De Carvalho, Philip Awadalla. Leveraging cell-free methylome markers for early cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2602.
Abstract 2623: Investigation into factors influencing probability of success in oncology clinical trials and trends over time
Authors: Hinrichs Mary Jane , Chaudhuri Shomesh E. , Bowden Robert , Lo Andrew W. , Jenkins David W.
Published: July 2021

The regulatory approval process for new therapies in oncology involves costly clinical trials that can span multiple years and historically have had a low probability of success. To derive estimates of the probability of success and other related risk characteristics in oncology clinical trials, we searched Informa Pharma Intelligence's Trialtrove and Pharmaprojects databases for oncology-specific drug-indication programs between 2001 and 2020. In total, we identified 10,083 oncology-specific drug-indication programs, which included 2,800 therapeutic agents (excluding biosimilars) tested across 98 indications. The features we considered included indication and indication group, clinical phase, follow-on indication status, presence and type of patient selection biomarker, drug modality, and accelerated approval status. In several cases, clinical success rates were higher than the benchmark oncology historical average of the phase 1 to approval success rate of 4.1% found in our sample set. For example, the use of pre-selection biomarkers in early clinical development was associated with a greater than two-fold increase in probability of approval from phase 1. Moreover, drugs with prior approvals in another indication were more than three times more likely to be successful from phase 1 than a candidate targeting a novel mechanism. In addition, we found that monoclonal antibodies were numerically more successful than other modalities in the historical data, while oncolytic viruses, vaccines, and bispecific antibodies have been less successful. In all cases, concomitant with the emergence of genomic technologies, an improved scientific understanding of cancer biology, and an evolving regulatory environment that includes a higher number of accelerated approvals, success rates in oncology have improved during the time period of this analysis and particularly in the past 5 years.

Citation Format: Mary Jane Hinrichs, Shomesh E. Chaudhuri, Robert Bowden, Andrew W. Lo, David W. Jenkins. Investigation into factors influencing probability of success in oncology clinical trials and trends over time [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2623.
Abstract 2626: The effectiveness of healthcare professional training on the legal issues impacting individuals diagnosed with cancer to improve patient quality of life
Authors: Morales Joanna , Bryant Monica , Ward Madison McMahon
Published: July 2021

A cancer diagnosis may carry with it a variety of legal issues, including insurance coverage, government benefits, and consumer rights. These legal issues can cause people unnecessary worry, confusion, and stress, and can be overwhelming. The Insurance and Finance Intensive is focused on providing healthcare professionals tools to proactively identify the presence of cancer-related legal, health insurance, and financial issues facing their patients. Additionally, the training helps health care professionals to offer referrals to appropriate legal and related resources, once those issues are identified. Oncology healthcare professionals participated in an eight-hour comprehensive training. Attendees were provided with substantive information about cancer-related legal issues, such as identifying health insurance options, navigating disability insurance and appeals, and managing finances. A follow-up survey was sent to all past intensive attendees to measure the effectiveness of the training and to address any lingering questions and difficult case studies. Ninety-four percent of survey respondents strongly agreed or agreed that the information provided by the training helped them reduce the stress and anxiety of their patients and their families. Ninety-two percent of survey respondents strongly agreed or agreed that the information provided by the training improved the quality of life of their patients and their families. The Insurance & Finance Intensive successfully provided health care professionals with valuable information on the practical and legal issues that impact individuals diagnosed with cancer. It is recommended that more healthcare professionals participate in this training to improve the quality of life of their patients beyond diagnosis.

Citation Format: Joanna Morales, Monica Bryant, Madison McMahon Ward. The effectiveness of healthcare professional training on the legal issues impacting individuals diagnosed with cancer to improve patient quality of life [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2626.
Abstract 265: Evaluating variation in drug efficacy endpoints in a syngeneic mouse model (CT26.WT) under immune checkpoint blockade
Authors: Mao Binchen , Guo Sheng , Ouyang Davy , Li Henry
Published: July 2021

INTRODUCTION: Preclinical research into immune checkpoint blockade (ICB) requires in vivo models with fully functional immunity. Syngeneic mouse models are homografts derived by transplanting immortalized mouse cancer cell lines or tumor tissues into strain-matched mouse hosts, and are well suited for evaluating the efficacy of new immunotherapies due to retaining an intact mouse immune system. Tumor growth inhibition (TGI) is widely used to characterize drug efficacy, however, a considerable amount of heterogeneity among TGI is often observed for a given ICB treatment in the same syngeneic mouse model. It is of vital importance to understand the source of such variation. The present study sets out to systematically investigate the variation of TGI for ICB treatment in syngeneic mouse models, using tumor growth data of anti-PD-1 treatment in the CT26.WT syngeneic mouse model for 27 independent studies.

METHODS: For each study, we calculated TGI and median area under curve (AUC) ratio on the corresponding study day when tumor volume data was collected. We utilized standard deviation and inter quantile range to quantify the variation. We evaluated the relationship between TGI and the corresponding day, and also compared the variation between TGI and median AUC ratio. Furthermore, to better understand the source of drug efficacy variation, we utilized a Bayesian multilevel model to quantify the amount of tumor growth variation at both the study and mouse level.

RESULTS: We found that TGI variation was much higher at earlier stages of studies. In contrast, the median AUC ratio showed smaller variation across the duration of each study than TGI for the majority of studies. Additionally, we found neither TGI nor median AUC ratio had significant correlation with the number of mice used in the study. Based on a Bayesian multilevel model, we observed that drug efficacy had larger variation on the mouse level (i.e. within a study), than variation on the study level (i.e. observed between studies), which could indicate heterogeneity of the tumor microenvironment (e.g. TILs) among mice play a major role in the variation of ICB treatment efficacy among studies.

CONCLUSIONS: Response to ICB treatment among mice of the same syngeneic model is inherently heterogeneous. TGI of later time points should be favored to reduce variation, and generally median AUC Ratio is more stable than TGI.

Citation Format: Binchen Mao, Sheng Guo, Davy Ouyang, Henry Li. Evaluating variation in drug efficacy endpoints in a syngeneic mouse model (CT26.WT) under immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 265.
Abstract 2664: Mutation characteristics of histone modification related genes in cholangiocarcinoma
Authors: Li Yunfeng , Chen Huanwei , Xu Zanmei , Yao Libo , Li Junying , Cai Chengzhi , You Dong
Published: July 2021

Background and objective: Histone modification, as an important part of epigenetics researches, can cause tumorigenesis and development by changing chromatin status and regulating gene expression. Histone deacetylase (HDAC) inhibitors have made great progress as new drugs, and its mechanism is related to the mutation of HDAC family genes. However, mutations of other related genes lacked reports. Here, we analyzed the mutation characteristics of 13 histone related genes in patients with cholangiocarcinom.

Methods: 380 cholangiocarcinom patients were enrolled. Next generation sequencing targeting 450 cancer genes was performed in OrigiMed. Disease-free survival (DFS) curve after operation was drawn with Kaplan-Meier and compared with Log-rank. Fisher's exact test was adapted to perform other statistical analysis.

Results: 153 mutations were occurred in 13 histone modification related genes (HDAC1, HDAC7, HDAC9, KMT2A, KMT2B, KMT2C, KMT2D, KMT2E, KMT5A, KMT5B, EZH2, EP300 and CREBBP), and 66.7% (102/153) was substitution/indel, 31.4% (48/153) truncation and 2.0% (3/153) rearrangement. According to the mutation, patients were divided into histone gene wild type (WT) group and histone gene mutation type (MUT) group, patients with at least one mutation in 13 genes. Co-mutation analysis of 450 genes revealed that KTM2D and KTM6A tended to co-mutate with other genes, including FAT4, ATM, BRAF and ERBB3. KTM2C and KRAS mutation were mutually exclusive (P<0.01). 98 patients (25.8%) had at least one histone modification related mutation; Among them, KTM2C was the highest (10.5%, 40/380), followed by KTM2D (7.9%, 30/380), CREBBP (3.9%, 15/380), EP300 (3.4%, 13/380) , KTM2A (3.4%, 13/380) and HDAC9 (2.6%, 10/380). Furthermore, compared with WT group, patients in MUT group had a short DFS time after operation (mDFS: 7 vs 11.15 months, P=0.0139). Besides, the TMB had no significant difference between two groups, as well as the PD-L1 expression and microsatellite status.

Conclusion: We firstly exhibited 13 histone related mutations in Chinese patients with cholangiocarcinoma. Mutations of histone modification related genes suggested poor outcomes of cholangiocarcinom.

Citation Format: Yunfeng Li, Huanwei Chen, Zanmei Xu, Libo Yao, Junying Li, Chengzhi Cai, Dong You. Mutation characteristics of histone modification related genes in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2664.
Abstract 2677: Clinicopathologic significance of CXCR2-CXCL1 signaling in cholangiocarcinoma
Authors: Yamamoto Yurie , Tsujio Gen , Sera Tomohiro , Sugimoto Atsushi , Kushiyama Syuhei , Nishimura Sadaaki , Kuroda Kenji , Tanaka Ryota , Kimura Kenjiro , Amano Ryousuke , Ohira Masaichi , Yashiro Masakazu
Published: July 2021

Background: Cancer progression has been recognized as not only the proliferation of tumor cells but also an interaction between cancer cells and the surrounding stroma in the tumor microenvironment. Among the tumor stromal cells, cancer-associated fibroblasts (CAF) have been reported to be closely associated with tumor development in various solid carcinomas. We previously reported that chemokine (C-X-C motif) receptor 2 (CXCR2) signaling might play an important role for the pathogenic construction of CAF in the gastric cancer (GC) microenvironment, suggesting that GC cells might alter their adjacent stroma to form a permissive environment for tumor progression, and also we reported that chemokine (C-X-C motif) ligand 1 (CXCL1) from cells stimulated the recruitment of bone marrow cells into GC microenvironment via CXCR2 signaling, resulting in the malignant progression of GC. Following these findings, we reported that among the CXCR2 ligands, CXCL1 might play an important role in the malignant progression of GC via CXCR2 signaling. And then, some studies suggest that CXCR2-CXCL1 plays an important role in not only GC but also other solid cancer. However, there is no report about the clinicopathological significance of CXCR2-CXCL1 signal in cholangiocarcinoma. Then, we examined the clinicopathological significance of CXCR2-CXCL1 signal in cholangiocarcinoma in this study.

Patients and Method: We retrospectively analyzed the total cases of 168 patients with cholangiocarcinoma. The expressions of CXCR2 and CXCL1 were investigated by immunohistochemistry, and we then analyzed the correlation between the clinicopathological features of 168 patients and the CXCR2 and CXCL1 expression level.

Results: The CXCR2 and CXCL1 positive expression wad as follows: CXCR2 was 18.5% (31/168), CXCL1 was 72.8% (126/173), both CXCR2 and CXCL1 was 17.9% (30/168). Metastasis negative was correlated with CXCL1 expression. Low depth invasion was correlated with CXCR2 expression. The prognoses of the both CXCR2 and CXCL1 positive patients were significantly better than those of CXCR2 and/or CXCL1 negative patients (p<0.023, log rank).

Conclusion:CXCLR2 and CXCL1 expression might be a better prognostic factor of patients with cholangiocarcinoma, and CXCR2-CXCL1 signaling might play an important role for tumor-suppressing effects of cholangiocarcinoma.

Citation Format: Yurie Yamamoto, Gen Tsujio, Tomohiro Sera, Atsushi Sugimoto, Syuhei Kushiyama, Sadaaki Nishimura, Kenji Kuroda, Ryota Tanaka, Kenjiro Kimura, Ryousuke Amano, Masaichi Ohira, Masakazu Yashiro. Clinicopathologic significance of CXCR2-CXCL1 signaling in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2677.
Abstract 2679: Role of TH2 cells in pancreatic cancer progression
Authors: Alam Aftab , Bhatta Maulasri , Denz Parker , Levanduski Eric , Dey Prasenjit
Published: July 2021

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that remains largely incurable. Although the cause for this profound therapeutic resistance is poorly understood, it is however partly blamed on signaling factors present in the tumor microenvironment (TME), which supports the proliferation and survival of neoplastic cells. Apart from being stroma rich, PDAC TME is associated with a distinctive tumor immune infiltrate. Paradoxically, most immunotherapy trials using immune checkpoint inhibitors, either as monotherapy or combination, failed to increase patient survival motivating exploration of new therapeutic strategies. To that end, the cytokine mediated heterotypic interactions between cancer cells and immune cells remain largely unexplored. Here, we explored the role of oncogenic Kras (KrasG12D=Kras*) in pro-tumorigenic signaling interactions between cancer cells and host cells. We found that TH2 cells infiltrate the pancreas in the early stage of the tumorigenesis and secrete type 2 cytokines [interleukin (IL)4 and IL13]. Further, Kras* signaling is involved in establishing this paracrine circuit utilizing type 2 cytokines in the PDAC tumor microenvironment (TME)2. Integrated transcriptomic, chromatin occupancy and metabolomic studies identified cMyc, as a direct target of activated Stat6, and that cMyc drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the Kras*-driven metabolic reprogramming of PDAC. This study and the work of others expanded the role of immune cell derived cytokines in the context of Kras* driven PDAC through its promotion of cancer cell proliferation. Importantly, perturbation of the IL4 and/or IL13 mediated signaling restricts tumor growth and increases survival in a mouse model of PDAC. Notably, PDAC patients with predominantly TH2 (Gata3+) polarized lymphoid cell infiltration show reduced survival compared to tumors with higher TH1 (Tbet+) cells. Finally, the presence of TH2 cells in the PDAC TME might explain the immense immunotherapy resistance observed in PDAC patients and anti-TH2 treatment might sensitize these patients to immune checkpoint inhibitors. Our subsequent preliminary work identified a potent inflammatory cytokine, IL33 which is overexpressed and released by PDAC cells that attract and activate TH2 and other immune cells such as Tregs. Inhibition of IL33 leads to a decrease in the infiltration and activation of TH2 cells and Treg cells, accompanied by significant PDAC tumor regression.

Citation Format: Aftab Alam, Maulasri Bhatta, Parker Denz, Eric Levanduski, Prasenjit Dey. Role of TH2 cells in pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2679.
Abstract 2686: Preventive effects of saffron in a colitis mouse model
Authors: Banskota Suhrid , Khan Waliul , Singh Gulshan , Habtezion Aida , Brim Hassan , Ashktorab Hassan
Published: July 2021

Background: Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract with rising incidence and no effective cure. IBD increases the risk of colon cancer through a Colitis-Associated-Cancer (CAC) pathway. Despite available anti-inflammatory or immunosuppressive drugs, many patients fail or loose response over time and many others experience drug-induced adverse events. Natural plant products are increasingly used by IBD patients and reported to have some efficacy for IBD in experimental models and clinical trials. Saffron (Crocus sativus), has been reported to play a key role in treatment of different digestive system disorders but its preventive role in IBD has not been explored.

Aim: To establish whether saffron treatment modulates immunity in intestinal inflammation and ameliorates experimental colitis.

Methods: Mice were pre-treated with either saffron (10 or 20 mg/kg body weight) or vehicle through daily oral gavage for 4 days before dextran sulfate sodium (DSS) administration. Then, we induced acute colitis in C57BL/6 mice with 2.5% DSS. On day 11, mice were euthanized and analyzed for gross and microscopic inflammation. Distal colon segments were collected for protein expression from the colon for immunophenotyping using ELISA. TNF-a, IL-b, and IL6 expression was analyzed by immunoblot analysis.

Results: Saffron Pre-treatment improved gross and histopathological characteristics of colonic mucosa in experimental colitis mice. Saffron dose 10 and 20 mg/kg body weight showed a significant improvement in body weight, disease activity index (DAI), colon length, and histology score, when compared to vehicle treated DSS mice group. Immunoblot analysis showed saffron pre-treatment significantly decreases pro-inflammatory TNF-a, IL-b, and IL-6 in the colon tissues indicating saffron mediates its preventive effect through anti-inflammatory pathways.

Conclusion: These data suggest saffron therapeutic potential of saffron and its preventive role in treating experimental colitis in part via immune response modulation and a switch from pro- to anti-inflammatory profile. The study also gives insights in developing an alternative treatment for IBD-associated colitis.

Citation Format: Suhrid Banskota, Waliul Khan, Gulshan Singh, Aida Habtezion, Hassan Brim, Hassan Ashktorab. Preventive effects of saffron in a colitis mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2686.
Abstract 2688: The landscape of precision cancer combination therapy: a single-cell perspective
Authors: Ahmadi Saba , Sukprasert Pattara , Vegesna Rahulsimham , Sinha Sanju , Artzi Natalie , Khuller Samir , Schäffer Alejandro A. , Ruppin Eytan
Published: July 2021

The availability of single-cell transcriptomics data opens new opportunities for rational design of combination cancer treatments in a systematic manner. Mining such data, we explore the landscape of optimal combination therapy targets in solid tumors (including brain, head and neck, melanoma, lung, breast and colon cancers). To this end, we developed MadHitter (https://github.com/ruppinlab/madhitter), which analyzes tumor single-cell transcriptomics data using combinatorial algorithms to identify precision combination of treatment targets that are predicted to maximize the killing of cancer cells while minimizing the killing of noncancerous ones. We started with a predefined set of 533 proteins that are lowly abundant across healthy tissues and thus may have low off-tumor targeting and toxicity if targeted via chimeric antigen receptors (CAR) T cell therapy. In most cancer types analyzed, we find that combinations composed of a single-digit number of targets are sufficient to kill at least 80% of the tumor cells while killing at most 10% of the non-tumor cells in each patient. We identify targets that are shared across datasets of the same cancer type (e.g., TNR) or across different cancer types (the SOX family, MAGE family, and KRT16). Next, we expanded our search for a set of 1269 known cell surface receptors, which may be precisely targeted by antibody or nanoparticles delivering a toxin into cells via receptor mediated endocytosis. The resulting optimal target sets are encouragingly also in the single-digit size. The gene PTPRZ1, a tyrosine phosphatase receptor, is frequently found in the optimal combinations for brain and head and neck cancers, and EGFR is a high-coverage target in multiple tumor types. Notably, requiring more stringent levels of cancer killing, the number of targets that need to be combined rises sharply in both search spaces described above. In sum, this analysis provides the first systematic characterization of potential combinatorial targets in solid tumors, uncovering promising future targets for both CAR therapy and conjugated toxin delivering antibodies and nanoparticles.

Citation Format: Saba Ahmadi, Pattara Sukprasert, Rahulsimham Vegesna, Sanju Sinha, Natalie Artzi, Samir Khuller, Alejandro A. Schäffer, Eytan Ruppin. The landscape of precision cancer combination therapy: a single-cell perspective [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2688.
Abstract 2709: CD44 inhibits DCIS progression to invasive carcinoma
Authors: Liu Fang , Zhou Jun , Kundu-Roy Tanima , Wahler Joseph , So Jae Young , Lin Yong , Lou You-Rong , Barnard Nicola J. , Matsuura Isao , Suh Nanjoo
Published: July 2021

Ductal carcinoma in situ (DCIS) transition to invasive tumor is an important issue for breast cancer. The human MCF10DCIS.com cell line (abbreviated as MCF10DCIS) is derived from the spontaneously immortalized human MCF10A breast epithelial cell line. The MCF10DCIS xenografts are similar to human high grade comedo DCIS. In the xenograft assay, MCF10DCIS cells form DCIS-like lesion, remain as DCIS-like lesion in the first several weeks, and then progress into invasive carcinoma. Thus, it is an excellent model to study human breast cancer transition from DCIS to invasive carcinoma. To the best of our knowledge, it is the most commonly used model for DCIS transition to invasive carcinoma. We investigated the role of CD44 in breast cancer transition from DCIS to invasive carcinoma by knockdown the expression of CD44 in the MCF10DCIS xenograft model. Our results show that knockdown of CD44 expression in the MCF10DCIS cells enhances DCIS transition to invasive carcinoma. Our finding is supported by a previous study which showed that CD44 expression was lower in invasive human breast carcinomas than in DCIS, especially in the luminal A subtype. Our study uncovered an unexpected role of CD44 in the inhibition of DCIS transition to invasive carcinoma. We will also present a model for the underlying mechanisms for the protective role of CD44 in the inhibition of transition from DCIS to invasive carcinoma. Our findings have important implications for breast cancer.

Citation Format: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh. CD44 inhibits DCIS progression to invasive carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2709.
Abstract 2712: Donor selection strategies to optimize humanized mouse models for the evaluation of T cell engagers
Authors: Cheng Liqing , Chen Jane , Yu Qunyan , Malkova Natalia , Cortez-Retamozo Virna F. , Sun Fangxian , Sidhu Sukhvinder
Published: July 2021

The success of early cancer immunotherapies has led to the development of novel therapeutic approaches including multi-specific antibodies engaging innate and adaptive effector cells. To evaluate the antitumor potency of these multi-specific cell engagers, we have established a protocol to select human PBMCs from donors of a commercial frozen source by their potency to produce inflammatory cytokines and the capacity to engraft into NOD-Scid IL2Rgammanull (NSG)mice. The selected human PBMCs were used to reconstitute NSG mice, or as donors of effector cells that upon in vitro expansion were adoptively transferred to NSG mice for humanization. We have employed these humanization strategies to evaluate T cell engagers, which are typically multi-specific antibodies directed against the T cell and one or multiple tumor-associated antigen (TAA), whose therapeutic strategy is to 1) engage T cells, 2) activate the T cells and 3) engage tumor cells, and thus induce tumor cell killing. We will present representative data from several humanization approaches using liquid and solid orthotopic tumor models to assess the effectiveness of multi-specific T cell engagers in mediating antitumor responses. Thus, pre-clinical evaluations rely on the development of optimized tumor bearing humanized models that mirror key properties of a human setting, to assess the therapeutic potential of anti-tumor multi-specific biologics.

Citation Format: Liqing Cheng, Jane Chen, Qunyan Yu, Natalia Malkova, Virna F. Cortez-Retamozo, Fangxian Sun, Sukhvinder Sidhu. Donor selection strategies to optimize humanized mouse models for the evaluation of T cell engagers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2712.
Abstract 2714: Development of a phenotypically diverse model of sarcoma formation to identify key drivers of tumorigenesis across subtypes
Authors: Carr-Ascher Janai
Published: July 2021

Approximately 13,000 people this year in the United States alone will be diagnosed with sarcoma and nearly 5,000 will lose their lives to this devastating disease. Soft tissue sarcomas are a clinically and biologically heterogeneous group of tumors made up of approximately fifty subtypes that are classified by their presumed mesenchymal origin. The development of novel therapies for sarcoma has been hampered by the considerable heterogeneity of the disease and the limited understanding of the molecular mechanisms driving sarcoma formation and evolution. Due to this, clinically, the majority of patients with aggressive soft tissue sarcoma subtypes are treated similarly despite evidence these subtypes are unique. Our lab has focused on the development of a new model for the study of sarcoma subtypes using a primary human transformation system. Based on TCGA data, one characteristic that is shared between sarcoma subtypes is the loss or silencing of p53 and Rb1. We have started with immortalized mesenchymal stem cells (MSC), the presumed cell of origin for sarcoma and introduced lentiviral constructs targeting p53 and Rb1 by CRISPR technology to delete these genes. Following this, we have added a barcoded oncogene library with genes implicated in sarcoma specific biology or across cancer subtypes. Using this system, we have successfully transformed these MSCs into high grade soft tissue sarcomas. The current goal is to continue to manipulate this system to develop multiple soft tissue sarcoma subtypes. By starting with the same cell of origin and arriving at different sarcoma subtypes, we can begin to understand the relationship between these subtypes which will inform clinical trial design. Using this system, we can investigate the development of sarcoma, understand subtype heterogeneity, and utilize this tool to develop novel therapies for our patients.

Citation Format: Janai Carr-Ascher. Development of a phenotypically diverse model of sarcoma formation to identify key drivers of tumorigenesis across subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2714.
Abstract 2720: Perivascular accumulation of immunosuppressive cells in the stroma of human triple negative breast carcinomas: implications for immunotherapy
Authors: Moamin Mohammed Ridha , Allen Richard J. , Stavrou Nicholas , Nagy Mate , Juncker-Jensen Anna , Lewis Claire E.
Published: July 2021

A distinct subset of tumor-associated macrophages (TAMs) accumulate around blood vessels in mouse tumors where they stimulate tumor angiogenesis and various steps in the metastatic pathway. They also limit tumor responses to frontline anti-cancer therapies like irradiation and chemotherapy, and dampen anti-tumor immunity by recruiting regulatory T cells and suppressing the proliferation of T cells. However, the presence and phenotype of such perivascular (PV) TAMs have yet to be investigated in human tumors. In this study we have used MultiOmyx multiplex immunofluorescence coupled to advanced analytics to compare the distribution and phenotype of TAMs, CD4+ and CD8+ T cells, and CD4+FOXP3+ regulatory T cells (Tregs) in PV vs non-PV areas in the stroma and tumor cell islands (TCIs) of 40 human triple negative breast carcinomas (TNBCs) - and whether this was altered after neoadjuvant chemotherapy. Tregs along with distinct subsets of TAMs and CD4+ and CD8+ T cells were found to preferentially accumulate in PV areas (ie. within 50um of CD31+ blood vessels), especially in the tumor stroma. CD163+ TIM3+ TAMs often made direct contact with the abluminal surface of blood vessels in these sites, and at increased numbers in in chemotherapy-treated TNBCs. This suggests they may regulate the formation/function of blood vessels in relapsing tumors. In both untreated and chemotherapy-treated tumors, a major subset of CD163+ TAMs lacked PDL1 expression and also accumulated preferentially in stromal PV areas, where many made direct contact with PD1- CD4+ or PD1- CD8+ T cells as well as FOXP3+CD4+ Tregs. We are currently investigating whether such close contact of these subsets of T cells with two immunosuppressive cell types (ie. CD163+ TAMs and Tregs) inhibits their subsequent anti-tumor functions. Taken together, our study shows that, as T cells cross blood vessels into TNBCs, they encounter a high density of at least two immunosuppressive cell types in the perivascular niche. This could lead to the inactivation of T cells before they migrate further into tumors, thereby reducing anti-tumor immunity. It could also limit the efficacy of cancer immunotherapies mediated by activated T cells. Identifying and targeting the mechanism causing these suppressive cells to accumulate and interact in such sites could remove this inhibition.

Citation Format: Mohammed Ridha Moamin, Richard J. Allen, Nicholas Stavrou, Mate Nagy, Anna Juncker-Jensen, Claire E. Lewis. Perivascular accumulation of immunosuppressive cells in the stroma of human triple negative breast carcinomas: implications for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2720.
Abstract 2722: Reprogramming of tumor-associated macrophages to M1-like macrophages using M1 macrophage-derived exosomes engineered to target IL-4 receptor and enhance M1 polarization
Authors: Lee Byungheon , Gunassekaran Gowri Rangaswamy
Published: July 2021

Tumor-associated macrophages (TAMs) are M2-polarized protumoral macrophages, whereas inflammatory macrophages are M1-polarized antitumoral macrophages. Interleukin-4 receptor (IL-4R) is expressed in M2 macrophages at higher levels than M1 macrophages. In this study, we aimed to inhibit tumor growth using M1 macrophage-derived exosomes engineered to target IL-4R and reprogram TAMs into M1 macrophages. M1 exosomes were transfected with NF-κB p50 siRNA and miR-511-3p as cargoes to enhance M1 polarization (Exo-si/mi) and surface-modified with IL4RPep-1, an IL-4R-binding peptide, to target IL-4R of M2 macrophages (IL4R-Exo-si/mi). The engineered exosomes showed sizes similar with parental exosomes, and IL4RPep-1 was retained on the exosomes and not degraded in the presence of serum up to 24 h. IL-4R-targeted exosomes were internalized into M2 macrophages and delivered cargoes through IL-4R more efficiently than untargeted exosomes. Whole-body fluorescence imaging showed that IL-4R-targeted exosomes homed to tumors at higher levels than to liver unlike to untargeted exosomes. Intravenous administration of IL4R-Exo-si/mi decreased the levels of M2 markers and immune-suppressive cells including TAMs, while increasing the levels of M1 markers and immune-stimulatory cells including M1 macrophages in tumor and spleen and subsequently inhibited tumor growth more efficiently than Exo-si/mi as well as M1 exosomes. These results suggest that IL-R-targeted exosomes carrying NF-κB p50 siRNA and miR-511-3p inhibit tumor growth by reprogramming TAMs into M1 macrophages and increasing anti-tumor immunity and hold a potential for caner immunotherapy.

Citation Format: Byungheon Lee, Gowri Rangaswamy Gunassekaran. Reprogramming of tumor-associated macrophages to M1-like macrophages using M1 macrophage-derived exosomes engineered to target IL-4 receptor and enhance M1 polarization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2722.