bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5833: Functional characterization of TP53 mutations in human fallopian tube secretory epithelial cells
Authors: Cheng Ya-Yun , Prosser Denise , Velikokhatnaya Liudmila , Lokshin Anna
Published: June 2022

Ovarian cancer is the fifth leading cause of cancer-related death in women and mainly develops in older women. High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer and recently has been shown to arise from the distal end of the fallopian tube. About 96% of HGSC cases were found to contain mutations in TP53 and missense mutation was the most frequent type. It is known that TP53 mutation is an early event occurred in HGSC and may drive tumorigenesis. Different TP53 mutations have been reported to promote cell survival, metastatic potential or tumorigenicity. However, the roles of TP53 mutations and the underlying molecular mechanisms have not been satisfactorily understood in HGSC. In order to functionally characterize TP53 mutations in a systematic approach, primary human fallopian tube secretory epithelial cells (FTSECs) from normal fallopian tube specimens were used. We isolated and transduced FTSECs with hTERT for extending cell lifespan. Afterwards, both overexpression and knock down experiments were performed. According to the IARC TP53 Database, we selected four TP53 hotspot mutations found in ovarian cancer patients for further investigation. The mutant TP53, including R175H, Y220C, R273C, and R273H, were expressed in FTSECs. Meanwhile, knock down was achieved by introducing shRNAs targeting TP53. The transduced cells were subjected to RNA sequencing experiments to identify the significantly influenced genes and signaling pathways. The candidate genes and pathways will be validated in FTSECs and a panel of ovarian cancer cell lines. Functional assays, such as cell viability assay, migration/invasion assay, and metabolism assay, will be performed to study the effects of TP53 mutations. The results can provide further understanding of TP53 mutations and the downstream signaling in HGSC tumorigenesis.

Citation Format: Ya-Yun Cheng, Denise Prosser, Liudmila Velikokhatnaya, Anna Lokshin. Functional characterization of TP53 mutations in human fallopian tube secretory epithelial cells [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 5833.
Abstract 5836: SMC4 promotes prostate cancer organ-specific metastasis by modifying cancer cell metabolism
Authors: Zhang Wei , Huang Xin , Li yueming , Gong yingxuan , Li xiuzhi
Published: June 2022

Structural maintenance of chromosomes 4 (SMC4), one subunit of condensin complexes, is a key structural component of mitotic chromosomes. Accumulating evidence has suggested that SMC4 regulates prostate carcinogenesis. However, its roles on regulation of prostate cancer development remain unclear. Our previous studies showed that the expression of SMC4 is increased in highly lung-metastatic prostate cancer cells, RM1-LM, an organ-specific metastasis cell line that we developed. To investigate the function of SMC4, SMC4 gene was knockdown in RM1-LM cells by CRISPR/Cas9 system. Knockdown of SMC4 significantly diminished the cancer cell growth in RM1-LM. In addition, transwell assay results showed that SMC4 knockdown in RM1-LM suppressed the cell migration and invasion. Furthermore, we observed that SMC4 protein is important in the non-dividing phase of the cell cycle. In particular, cell cycle flow cytometry analysis indicated that SMC4 knockdown leaded to cell arrest in S phase. Finally, RM1-LM cells showed increased lung metastases compared with RM1-SMC4+/- cells in a murine model. The H&E and IHC results confirmed that RM1-LM cells induced greater number of lung metastases and colonization than RM1-SMC4+/-cells, suggesting the loss of SMC4 suppressed prostate cancer metastasis. The interactome of SMC4 was uncovered through IP-MS and revealed that SMC4 may interacted with GLUT1, a key protein in glycolysis pathway. The ATP rate assay and Glycolysis rate assay illustrated a significantly metabolic switch existing in RM1-SMC4+/-cells compared with their parental cells. Collectively, our study suggested that the interaction between SMC4 and GLUT1, confirmed by Co-IP, promotes prostate cancer cells metastasis via modifying the cell metabolism. This work was supported by NSFC projects 81802949, 81773146, 81972766, 81972420, 82173336; Shenzhen Science and Technology Commission Project JCYJ20190809161811237, JCYJ2021032410424040; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research (2017B030301018);and College students' innovative entrepreneurial training program (S202114325028)

Citation Format: Wei Zhang, Xin Huang, yueming Li, yingxuan Gong, xiuzhi Li. SMC4 promotes prostate cancer organ-specific metastasis by modifying cancer cell metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5836.
Abstract 5840: The characteristics of TP53 germline mutations analyzed in a large-scale cohort of Chinese glioma patients
Authors: Hong Xinyu , Zhao Ximeng , Guo Zeshang , Yang Xiaochen , Guo Bella , Zhang Xiang , Ma Tonghui
Published: June 2022

Backgrounds:TP53 germline mutation is well known to be the cause of Li-Fraumeni syndrome (LFS), a rare autosomal dominant cancer syndrome, characterized by predisposition of breast cancer, soft tissue carcinoma, osteosarcoma, brain cancer and etc. LFS has been reported in cases or small-scale cohorts for decades, while the characteristics of TP53 germline mutations carried by glioma patients were still less studied due to rarity. We performed large-scale retrospective research to identify TP53 germline mutations in Chinese glioma patients, which would extend the genetic knowledge of LFS related glioma.

Methods:We enrolled 3325 glioma patients in this study (female=1423, male=1902). Next-generation sequencing panel targeting 825 genes was performed to identify TP53 germline mutations. Mutations were annotated pathogenic or likely pathogenic according to ACMG guidelines or referring to the literatures.

Results:After annotation, 20 pathogenic or likely pathogenic germline mutations (PGMs) in TP53 were found in 3325 glioma patients. There was no statistical significance of gender ratio between all glioma patients and mutation carriers (female=6, male=14, p=0.25). The highest incidence rate of PGMs occurred in glioblastoma (n=16, 80.0%), followed by anaplastic astrocytoma (n=2, 10.0%), oligodendroglioma (n=1, 0.5%) and diffuse midline glioma (n=1, 0.5%). Significant difference of onset age between TP53 mutation carriers and non-carriers was pronounced (22.90YO vs 43.35YO avg, p<0.0001). Furthermore, the carrier rate of PGMs was prone to decrease with increasing onset age (table 1).

Conclusions:This research indicated that TP53 PGMs were prone to occur in younger glioma patients, suggesting the importance of TP53 germline mutations being screened. It might be able to assist with early detection and treatment of glioma.

The carrier rate of TP53 PGMs in each onset age intervals onset age glioma patient number PGM carrier number carrier rate 0-18 444 10 2.25% 19-30 263 4 1.52% 31-45 826 4 0.48% 46-55 717 1 0.14% 56-65 687 1 0.15% 66-75 337 0 0.00% 76+ 51 0 0.00%

Citation Format: Xinyu Hong, Ximeng Zhao, Zeshang Guo, Xiaochen Yang, Bella Guo, Xiang Zhang, Tonghui Ma. The characteristics of TP53 germline mutations analyzed in a large-scale cohort of Chinese glioma 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 5840.
Abstract 5847: Normal mammary epithelium of BRCA1 mutation carriers demonstrates increased susceptibility to cell plasticity
Authors: Ben-Yishay Rakefet Ruth , Herman Naama , Noy Vered , Mor Eyal , Mansur Aiham , Ishay-Ronen Dana
Published: June 2022

Background: Epithelial-mesenchymal transition (EMT) in breast cancer drives tumor invasion, metastasis and drug resistance. BRCA1 mutation carriers have a high risk for developing aggressive basal-like triple-negative breast cancers with EMT characteristics. It has been described that normal mammary epithelium of BRCA1-mutation carriers is comprised of aberrant luminal progenitor cell population resembling basal-like breast cancer cells. Yet, the role of BRCA1 in regulating epithelial cell plasticity in normal mammary gland remains largely obscure. Aim: Here, we used patient-derived normal and cancer organoid cultures from BRCA1-mutation carriers and noncarriers, to examine the effect of the BRCA1 mutation background on epithelial cell plasticity and the susceptibility to EMT.

Methods and results: Mammary organoids were established from normal or cancer mammary tissues obtained from consenting patients undergoing lumpectomy or mastectomy. Isolated cells were plated in adherent basement membrane extract (BME) drops and overlaid with optimized organoid culture medium. EMT regulation in breast cancer is usually studied using cell lines and murine models. To determine the possibility to study EMT on patient-derived organoids, organoid culture media was optimized and established organoids were exposed to TGFβ to induce EMT. Morphological and phenotypic alterations were characterized using immunolabeling and visualization with confocal microscopy. Breast cancer organoids induced with TGFβ demonstrated EMT-like changes including the downregulation of E-Cadherin and upregulation of N-Cadherin. Moreover, breast cancer organoids showed typical cytoskeleton rearrangements. Here, the transformation from cortical actin into stress fibers formed in dedifferentiated mesenchymal cells, was visualized with actin staining. However, normal mammary organoids behaved differently. The cytoskeleton of BRCA-wild type (noncarriers) normal mammary organoids was not affected by the treatment. Curiously, normal mammary organoids derived from BRCA1-mutation carriers demonstrated EMT like changes upon exposure to TGFβ. To further determine mechanisms facilitating cell plasticity in BRCA1-mutation carriers, single cell RNA sequencing analysis on BRACA1-mutation carriers and noncarriers derived organoids is ongoing.

Conclusion: The results suggest that BRCA1 germline mutation predisposes normal mammary epithelium dedifferentiation due to increased susceptibility to EMT.

Citation Format: Rakefet Ruth Ben-Yishay, Naama Herman, Vered Noy, Eyal Mor, Aiham Mansur, Dana Ishay-Ronen. Normal mammary epithelium of BRCA1 mutation carriers demonstrates increased susceptibility to cell plasticity [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 5847.
Abstract 5849: Activation of STAT3 is mediated by FGFR4 induction via SRC signaling after H. pylori infection
Authors: Bhat Nadeem S. , Soutto Mohammed , Zhang Xing , Chen Zheng , Zhu Shoumin , Lu Heng , Peng Dunfa , Xu Zekuan , El-Rifai Wael
Published: June 2022

Background: Gastric cancer is considered the 5th most common form of cancer and 4th leading cause of cancer-related deaths worldwide. Due to the late stage of diagnosis, gastric cancer carries poor prognosis and poor overall survival. Infection with H. pylori is the strongest known risk factor. Fibroblast Growth Factor Receptor 4 (FGFR4) belongs to a family of highly conserved tyrosine kinases. This study investigated the molecular mechanism of FGFR4 regulation in response to H. pylori infection.

Methods and Results: Among all the FGFRs, FGFR4 mRNA expression level was the most significantly elevated in human gastric cancer samples as compared to normal samples, using Real-time qPCR. These results were confirmed using the TCGA and Geo database analysis, confirming that FGFR4 is highly expressed in gastric cancer. Using western blot, we found that FGFR4 is significantly expressed in dysplasia and adenocarcinoma lesions in the TFF1-KO gastric cancer mouse model. Following infection with H. pylori in in-vitro (J166, 7.13) and in-vivo (PMSS1) models, we detected a significant increase in the expression of FGFR4 at the protein and mRNA levels. We also detected activation of STAT3 in human gastric cell lines and mice gastric tissues. Furthermore, analysis of FGFR4 promoter revealed several putative binding sites for STAT3. To confirm that FGFR4 expression is dependent upon STAT3 activation, we performed ChIP assay and confirmed direct functional binding of STAT3 on FGFR4 promoter. Using the FGF19, the ligand for FGFR4, we found that FGF19-FGFR4 axis played a vital role in activating STAT3 through an SRC-dependent mechanism and discovered that there is a feedforward activation loop between FGFR4 and STAT3. Functionally, we found that FGFR4 protected against H. pylori-induced DNA damage and cell death.

Conclusion: Our study established a feedforward activation loop between FGFR4 and STAT3 in response to H. pylori infection and FGFR4 could be a possible druggable moiety for future therapies in gastric cancer.

Citation Format: Nadeem S. Bhat, Mohammed Soutto, Xing Zhang, Zheng Chen, Shoumin Zhu, Heng Lu, Dunfa Peng, Zekuan Xu, Wael El-Rifai. Activation of STAT3 is mediated by FGFR4 induction via SRC signaling after H. pylori infection [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 5849.
Abstract 5863: The ABID (Assessing the gut microbiota and Individual Diet) Study in the Navajo Nation
Authors: Pete Dornell , Phipps Amanda I. , Salama Nina R. , Lampe Johanna W. , Wu Michael C.
Published: June 2022

A substantial burden of stomach cancer continues to be observed in American Indians (AI) in the Southwestern United States. The Navajo Nation, the largest tribe in the Southwest, is experiencing higher incidence of stomach cancer compared to the general population in the region, possibly due to high prevalence of Helicobacter pylori (H. pylori) infection and other contributing factors, like diet. To learn about factors linked to stomach cancer, we initiated a cross-sectional study to determine the prevalence, virulence, and dietary correlates of H. pylori infection among Navajo adults. We hypothesized that H. pylori infections, particularly with the virulent cagA gene, would be highly prevalent in Navajo adults compared to other non-AI populations, and that diets high in salt, processed meats, and low in vegetables would be associated with prevalent H. pylori infection. Study recruitment occurred from January to October 2021 in two geographic areas of the Navajo Nation. Participants were recruited using online and offline platforms, including social media (Facebook, Instagram), study website (www.theabidstudy.com), newspapers, flyers, word of mouth, and community outreach events. Eligible, consenting study participants provided a stool sample, which was analyzed by droplet digital PCR assays for H. pylori 16S gene detection and cagA virulence gene typing. Participants also provided health and food information through two questionnaires.Preliminary data indicate that prevalence of H. pylori is high in the included regions of the Navajo Nation. The H. pylori prevalence (51.5%, 95% CI: 38.9-64.0) in this study is higher than the prevalence in the US population (35%). Moreover, the cagA virulence gene prevalence in the Navajo with H. pylori was 55.9% (95% CI: 37.9-72.8), which is comparable to the US prevalence of 50%. These early results point to a need of developing prevention strategies to reduce H. pylori infection in the Navajo Nation.

Citation Format: Dornell Pete, Amanda I. Phipps, Nina R. Salama, Johanna W. Lampe, Michael C. Wu. The ABID (Assessing the gut microbiota and Individual Diet) Study in the Navajo Nation [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 5863.
Abstract 5866: Racial ethnic variations in trajectory of health-related quality of life in older women with breast cancer
Authors: Rupesh Sushantti , Lee Eunkyung
Published: June 2022

The purpose of the research study was to explore the ethnic/racial variations in health-related quality of life (HRQoL) scores, and the trajectory of comorbidities in older women with breast cancer. This study analyzed data from the Surveillance, Epidemiology, and End-Results (SEER) – Medicare Health Outcomes Survey (MHOS) linked data resource. The study population consists of 982 women (≥ 65 years old at diagnosis) with primary breast cancer who were diagnosed in 1998-2012 and completed the MHOS survey within 24 months before diagnosis and completed at least one more survey after diagnosis. The study population was grouped into three ethnic/racial groups: Whites (n=791), Black/African American (n=104) and Hispanics (n=87). The mean age of the population was 74.8 ± 6.1. HRQoL was measured using SF-36/VR-12 questionnaire and summarized as Physical Component Summary (PCS) Score and a Mental Component Summary (MCS) Score. Results showed an increase in the PCS score at month 6 after diagnosis, and a decrease at month 12 was observed in Whites and Black/African Americans. A continuous decrease in the PCS score till month 12 and an increase at month 24 was observed in Hispanics. All three groups showed similar trends in MCS scores over time - the MCS score dropped at month 6 but was back at baseline by month 12. The Whites had the highest MCS score out of the three, and Hispanics had the lowest. The MCS score for Hispanics decreased by month 36, whereas it increased for Black/African Americans. The MCS score for Whites remained fairly the same. The results also showed an increase in the total number of comorbidities at month six after diagnosis, along with a decrease to the baseline comorbidities by month 12. Hispanics had the highest increase in comorbidities at month 6 and Whites had the lowest and most stable. The number of comorbidities remained fairly the same in Whites and Black/African Americans, whereas the number of comorbidities increased slightly at month 24 for Hispanics and drastically increased at month 36. Overall, changes in the total number of comorbidities had a negative correlation with the changes in MCS scores, therefore it can be concluded that the number of comorbidities have a negative effect on a patient’s mental health. Whites were observed to have less comorbidities and better MCS scores than Black/African Americans or Hispanics. The information gained from this study will help clinicians and patients in the shared treatment decision process and guide individualized survivorship care plans among older women with breast cancer.

Citation Format: Sushantti Rupesh, Eunkyung Lee. Racial ethnic variations in trajectory of health-related quality of life in older women with 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 5866.
Abstract 5888: Trends in incidence of gallbladder cancer in all 50 United States from 2001 to 2018
Authors: Raza Syed A. , Costa Wilson L. , Thrift Aaron P.
Published: June 2022

Background: Gallbladder cancer (GBC) is an aggressive malignancy of the gastrointestinal system that is historically more common among racial/ethnic minority populations in the US. We investigated trends in GBC incidence rates in all 50 states from 2001 to 2018, overall and stratified by race/ethnicity, sex, and different regions.

Methods: Age-standardized incidence rates and trends in adults aged ≥35 years were calculated using data from the U.S. Cancer Statistics registry. We used joinpoint regression to compute annual percent changes (APC) and average annual percent changes (AAPC) and corresponding 95% confidence intervals (CI) for both sexes and used eleven 5-year age groups (35-39 years through 85+ years). Race/ethnic groups were classified as non-Hispanic Whites and Blacks (NHWs and NHBs), Hispanics, American Indians/Alaska Natives, and Asians and Pacific Islanders.

Results: Overall, the age-standardized incidence rate for GBC decreased by 0.3% annually between 2001 and 2018 (95% CI -0.5%, -0.1%). However, secular trends varied by age-group, sex and race/ethnicity. APC increased among individuals aged 45-54 years from 1.2% to 1.4% but decreased among those who were ≥ 75 years (-0.7% to -1.6% per year). While GBC incidence rates were stable among men between 2001 and 2014, incidence rates decreased by over 2% per year between 2014 and 2018 (APC, -2.1%; 95%CI: -3.9, -0.3). GBC incidence remained relatively stable between 2001 and 2018 among women. While GBC rates declined in other racial/ethnic groups, the rates increased by 1.4% annually among non-Hispanic Blacks (NHBs) between 2001 and 2018 (APC=1.4%; 95%CI: 0.9%, 2.0%). Among NHBs, increasing trends were also noted in Northeast, Midwest, and South regions of US.

Conclusions: The study shows increasing incidence trends for GBC in the US among NHBs from 2001-2018 compared to decreasing trends among other race/ethnic groups. The results also point to the need for studying equitable detection and treatment of underlying risk factors for GBC.

Citation Format: Syed A. Raza, Wilson L. Costa, Aaron P. Thrift. Trends in incidence of gallbladder cancer in all 50 United States from 2001 to 2018 [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 5888.
Abstract 5928: MTA1-targeted interception by natural stilbenes in high-risk prostate cancer
Authors: Levenson Anait S.
Published: June 2022

Active surveillance subpopulation of patients with prostate cancer includes men with varying cancer risk categories of precancerous disease due to prostatic intraepithelial neoplasia (PIN) heterogeneity. Identifying molecular alterations associated with PIN can provide preventable measures through finding novel targets for cancer interception, specifically by active dietary polyphenols with potent biological properties including anti-inflammatory, anti-oxidant, and anticancer effects. A large volume of preclinical evidence shows that natural stilbenes produce anticancer responses in a variety of cell lines and animal models of different types of cancer, including solid tumors as well as hematological malignancies. However, identification of a particular target with clinical relevance is rare. I will discuss the potent MTA1-targeted anticancer effects of natural stilbenes (resveratrol, pterostilbene, and Gnetin C) observed in unique preclinical models of prostate cancer mimicking high-risk premalignant tumors with overexpressed MTA1. We have shown that MTA1 cooperates with PTEN deficiency to accelerate high-grade PIN development through MTA1-associated signaling. We further demonstrated that stilbene supplemented diets lead to more favorable histopathology with decreased severity and number of PIN foci accompanied with reduced proliferation, inflammation, and angiogenesis concomitant to reduction of MTA1-associated signaling, including specific miRNAs. Together, our preclinical data provide strong evidence for the potential of stilbenes as promising natural agents for MTA1-targeted interceptive strategy. Human cancer prevention trials for protecting select patients with high MTA1 from developing into full-fledged disease are urgently needed. This can be one extra forward step towards viable and successful interception/chemoprevention potential for prostate cancer with an implication for precision medicine. Supported by NCI/NIH R15CA216070 to ASL.

Citation Format: Anait S. Levenson. MTA1-targeted interception by natural stilbenes in high-risk prostate 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 5928.
Abstract 5941: A simulation modeling study to support personalized breast cancer prevention and early detection in high-risk women
Authors: Jayasekera Jinani , Zhao Amy
Published: June 2022

Purpose: To evaluate the impact of early detection with screening and primary prevention with risk-reducing medication to provide personalized data that will help identify women who are more likely to benefit from various interventions or combinations of interventions with the least harms.

Methods: We adapted the CISNET microsimulation model G-E of breast cancer natural history to evaluate the harms and benefits of annual mammography and risk reducing medication among high-risk women (i.e., 5-year risk greater than or equal to 3%). Model G-E is a discrete event microsimulation model that follows millions of women from birth to death and captures the variability in distributions of each event. Each simulated woman is assigned a cohort-specific life expectancy which is used to select a date of breast cancer death. For this study, we dynamically updated the risk of developing breast cancer for each simulated woman based on her family history, breast density, age and history of biopsy. We used large observational and clinical trial data to derive input parameters for cohort-specific birth rates, incidence and stage without screening, other cause mortality by age, screening performance (sensitivity/specificity), survival by age, stage, and subtype without treatment, treatment efficacy, and other cause mortality. We compared model outcomes for screening alone vs. screening with a 5-year course of risk reducing medication. We modeled various screening strategies including annual or biennial screening starting at ages 35, 40, 45 and stopping at ages 65 and 74 years. Model outcomes for each strategy included, the benefits of risk-reducing drugs (avoiding breast cancer) and screening (breast cancer stage, breast cancer-specific survival), and harms of screening (false positives, overdiagnosis). We also conducted sensitivity analysis to estimate the effects of uncertainty in model inputs or assumptions on results.

Results: We found that risk reducing medication could result in an additional 28% decrease in invasive breast cancer incidence, 20% decrease in stage IV diagnosis, and a 30% decrease in breast cancer death if screening started at age 35 in a high-risk woman. However, potential breast density changes due to risk reducing medication among high-risk women could result in a 19% increase in false positive screening results compared to screening alone. The results varied by the starting age of screening.

Conclusions: Simulation modeling is useful in assessing the relative benefits and harms of screening and risk reducing medication in high-risk women.

Citation Format: Jinani Jayasekera, Amy Zhao. A simulation modeling study to support personalized breast cancer prevention and early detection in high-risk women [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 5941.
Abstract 5945: Gnetin C for chemoprevention and chemotherapy of prostate cancer
Authors: Campanelli Gisella , Al Deabel Rabab , Puaar Anand , Parupathi Prashanth , Adhvaryu Amee , Kumar Avinash , Levenson Anait S.
Published: June 2022

Prostate cancer is common among aging men. No cancer treatment is provided during active surveillance for prostate cancer. Targeted nutritional interception may prove to be the most appropriate chemoprevention for intermediate- and high-risk patients. Here, for the first time, we investigate the efficacy of Gnetin C, a resveratrol-dimer found abundantly in melinjo (Gnetum gnemon) plant that is characterized with improved pharmacokinetics compared to other stilbenes, in a transgenic mouse model of prostate cancer. We have generated two prostate-specific mouse models, one overexpressing MTA1 on the background of Pten heterozygosity (R26MTA1; Pten+/f), and the other overexpressing MTA1 on the background of Pten loss (R26MTA1; Ptenf/f). Chemoprevention design included Gnetin C- dietary supplementation in the high-risk model while the therapeutic design included i.p. administration in the more aggressive R26MTA1; Ptenf/f genotype. Our results show that while MTA1 cooperates with PTEN deficiency to accelerate PIN development by increasing MTA1-associated signaling, Gnetin C intervention combats the progression of prostate cancer. We show that mice treated with Gnetin C (7 mg/kg bw, daily i.p.) exhibited more favorable histopathology with decreased severity and number of PIN foci (41.23% reduction) accompanied by reduced proliferation (Ki67, 57.43% reduction), angiogenesis (CD31, 86.91% reduction), AR (31.57% reduction), and MTA1 (27.94% reduction). Ongoing chemopreventive studies with four different diets [Control-diet; Gnetin C high dose (70 mg/kg diet); Gnetin C low dose (35 mg/kg diet); and pterostilbene (70 mg/kg diet)] are in progress. Altogether, these data provide an evidence for efficacy of Gnetin C in blocking prostate cancer progression and reveal its potential for novel chemopreventive and therapeutic implications in prostate cancer.Supported by NCI/NIH R15CA216070 to ASL

Citation Format: Gisella Campanelli, Rabab Al Deabel, Anand Puaar, Prashanth Parupathi, Amee Adhvaryu, Avinash Kumar, Anait S. Levenson. Gnetin C for chemoprevention and chemotherapy of prostate 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 5945.
Abstract 5965: The effectiveness of health care professional training on the legal issues impacting individuals diagnosed with cancer to improve patient quality of life
Authors: Ward Madison McMahon , Morales Joanna Fawzy , Bryant Monica Fawzy
Published: June 2022

A cancer diagnosis may carry with it a variety of legal issues, including navigating insurance, government benefits, employment, and consumer rights. These legal issues can cause people unnecessary worry, confusion, and stress, and can be overwhelming. The Insurance and Finance Intensive provides health care professionals tools to proactively identify the presence of cancer-related legal, 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 health care 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 taking time off work and accessing disability insurance, and managing finances. A follow-up survey was sent to past 2020 and 2021 Intensive attendees (n=126), to measure the effectiveness of the training and to address additional questions and difficult case studies. Ninety-four percent of survey respondents indicated that they changed their behavior or practice based on what they learned at the training. Ninety-four percent of survey respondents strongly agreed or agreed that the information provided by the training helped reduce the financial burden that their patients and families experience after a cancer diagnosis. Ninety-seven percent of respondents strongly agreed or agreed that the information provided by the training improved the quality of life of their patients and 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 health care professionals participate in this training to mitigate the financial burden of a diagnosis and improve the quality of life of their patients.

Citation Format: Madison McMahon Ward, Joanna Fawzy Morales, Monica Fawzy Bryant. The effectiveness of health care 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 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5965.
Abstract 5966: Melanoma revisited; The need for bio-banking and precision oncology, a study from a resource limited setting
Authors: Adoke Kasimu Umar , Haruna Sanusi Mohammed
Published: June 2022

Since the incidence of Malignant melanoma (MM) is rising, we propose high quality patient samples bio-bank for proper understanding of the disease and with time analyze on a large scale proteogenomics. There is increased need to support research and help improved patient care and outcome. Bio-banking in MM will provide high quality and well define tissue and bio-fluid specimens.

Materials and Methods: Large scale sample collection were done for 22 patients with histological diagnosis of MM. The patients consent and hospital ethical approval was sorted for the study, with patients' fresh frozen tissue and blood samples collected, fractionated and stored in an automated bio-bank. Five patients however did not consent for bio-banking of their samples.

Results: Patients that consented to sample collection had proteogenomic studies and other studies were done on their specimens with possibilities of new treatments for the patients and precision oncology for these patients tailored on their unique genomic landscape.

Conclusion: Bio -banking on a large scale is possible and helpful in MM patient especially in our environment where most patients are lost to follow up and have high degree of resistance and mortality during chemo radiation treatment.

Citation Format: Kasimu Umar Adoke, Sanusi Mohammed Haruna. Melanoma revisited; The need for bio-banking and precision oncology, a study from a resource limited setting [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 5966.
Abstract 598: A novel allosteric CBL-B inhibitor with differentiated immune enhancing activity in preclinical models
Authors: Qi Yilin , Kuai Jun , Bi Yingzhi , Sun Huadong , Conrady Deborah G. , Govindaraj Rajiv G. , Hone Graham , Denny Rajiah A. , Carson Ken , Reilly Timothy , Harriman Geraldine , Wang Fang
Published: June 2022

E3 ligase Casitas B-Lineage Lymphoma Proto-Oncogene B (CBL-B) is a key negative modulator of T-cell receptor and co-stimulatory regulation. CBL-B inhibition lowers the threshold of antigen-specific T cell activation, even in absence of co-stimulatory signaling or the presence of an immune suppressive environment. Genetic ablation of Cbl-b or functional inactivation of its E3 ligase activity in mice or primary human T cells enhances immune-mediated tumor growth control. Therefore, CBL-B inhibition may address the suboptimal response to current immunotherapies due to low inflammation, no/low co-stimulation signal or a high immune suppressive environment. We have identified a series of potent allosteric CBL-B inhibitors via the application of our proprietary Smart Allostery࣪ platform. Herein we demonstrate one of our lead CBL-B inhibitors showed superior activity compared to a competitor CBL-B inhibitor (NX-519) in both biochemical and cellular assays. At similar exposures in a syngeneic mouse tumor model (CT26), our CBL-B inhibitor also demonstrated an increase in tumor growth inhibition relative to NX-519. Mechanistically, our CBL-B inhibitor not only enhanced T cell activation, but also re-invigorated exhaustive T cells and caused resistance to T regulatory cell-mediated suppression, both in a concentration-dependent manner. We further demonstrated differentiation of CBL-B inhibition versus anti-PD1 and anti-CTLA4 in the mixed lymphocyte reaction (MLR) assay. Our CBL-B inhibitor significantly promoted T cell proliferation where anti-PD1 alone and anti-CTLA4 alone did not. Both anti-PD1 and CBL-B inhibition increased IFNγ production in this MLR assay, but that effect was further enhanced in combination. Together, the pre-clinical data presented here provided evidence of a differentiated profile of our allosteric CBL-B inhibitors to enhance key parameters associated with T cell activation and reduce susceptibility to immune suppression, supporting their further progression toward clinical development.

Citation Format: Yilin Qi, Jun Kuai, Yingzhi Bi, Huadong Sun, Deborah G. Conrady, Rajiv G. Govindaraj, Graham Hone, Rajiah A. Denny, Ken Carson, Timothy Reilly, Geraldine Harriman, Fang Wang. A novel allosteric CBL-B inhibitor with differentiated immune enhancing activity in preclinical models [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 598.
Abstract 5982: Single-cell RNA sequencing (scRNA-Seq) from mice model reveals metastatic and stemness signatures in esophageal squamous cell carcinoma (ESCC)
Authors: Wong Ching Ngar , Zhang Yu , Ru Beibei , Zhou Hong Yu , Lam Kwong Yiu , Guan Xin Yuan
Published: June 2022

Remote oligometastases are the predominant roots of the unsatisfactory 5-year survival rate in esophageal squamous cell carcinoma (ESCC) patients. The title of metastatic-initiating cells (MICs) has been designated to describe tumor subpopulation with heterogeneous genetic background and behaviors that potentially displays stemness features and favors metastatic lesion formation. However, preceding studies have overpassed the early surviving MICs due to limitations in bulk transcriptomic sequencing at macrometastatic stage. With the aim of denoting and characterizing MICs in ESCC, we established the pulmonary metastatic mice model via intravenous injection and followed by multiplex single-cell RNA sequencing (scRNA-Seq) of tumor cells collected from lung tissues along longitudinal end-points. The scRNA-Seq results uncover a 7-gene surface marker signature panel that could depict the early surviving MICs of ESCC, including CD44, TACSTD2, TM4SF1, S100A14, RHOD, CST6, and C19orf33. In silico gene ontology (GO) enrichment of the early surviving MICs subpopulation reveals numerous migration and adhesion-related biological processes (p<0.05). In addition to scRNA-Seq, immunohistochemistry (IHC) staining of tumor cells in mice lungs collected in sequential order evidenced the survival heterogeneity of tumor subpopulations. Likewise, flow cytometry fluorescence-activated cell sorting (FACS) of signature-enriched tumor cells was performed to resemble the target MICs. CD44Pos ESCC cells are found to show distinctively greater wound-healing (p<0.01), foci formation (p<0.05), migration (p<0.01) and invasion (p<0.01) ability than CD44Neg cells in vitro, and longer survival patterns (p<0.05) upon implantation in vivo. Multi-color immunofluorescence (mIF) staining of these gene signatures is underway in mice models and clinical samples for comprehensive validation. We anticipate this surface marker signature to accelerate development for clinical diagnosis together with molecular targeting in metastatic ESCC patients.

Citation Format: Ching Ngar Wong, Yu Zhang, Beibei Ru, Hong Yu Zhou, Kwong Yiu Lam, Xin Yuan Guan. Single-cell RNA sequencing (scRNA-Seq) from mice model reveals metastatic and stemness signatures in esophageal squamous cell carcinoma (ESCC) [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 5982.
Abstract 5995: Tumor genomic landscape in patients (pts) with and without liver metastasis in metastatic urothelial carcinoma (mUC)
Authors: Tripathi Nishita , Jo Yeonjung , Sayegh Nicolas , Chigarira Beverly , Nordblad Blake , Thomas Vinay Mathew , Haaland Benjamin , Nussenzveig Roberto , Gupta Sumati , Agarwal Neeraj , Swami Umang , Maughan Benjamin L.
Published: June 2022

Background: Presence of liver metastasis is associated with a poor prognosis in mUC. According to the prognostic model by Sonpavde et. al, post platinum treated mUC pts with liver metastasis had a 50% higher risk of death on immunotherapy compared to pts without liver metastasis (PMID 32552295). Herein, we hypothesize that pts with liver metastasis harbor a distinct tumor genomic landscape compared to pts without liver metastasis.

Methods: In this IRB-approved retrospective study, mUC pts with and without liver metastasis at baseline and available tumor comprehensive genomic profiling (CGP) from a CLIA-certified laboratory were included. Variants of unknown significance and mutated genes present in ≤ 5% of pts were excluded. A Chi-square test was used to compare the frequency of mutated genes between both groups. The p-value was adjusted for false discovery, significance was preset at 0.25.

Results: 114 pts were included. 16/114 pts had a liver metastasis. Median age was 69 and 67 years, male/female 12/4 and 72/26, smokers/non-smokers 6/10 and 46/52, for pts with and without liver metastasis respectively. The most frequent genomic alterations (GAs) were seen in TP53, CDKN2B and FGFR3. Pts with liver metastasis had significantly higher GAs in MYC (unadjusted p=0.009, adjusted p=0.24) compared to pts without liver metastasis. The median number of GAs per patient and the tumor mutation burden were not significantly different between groups.

Conclusion: Our results indicate GAs in MYC are significantly enriched in pts with liver metastasis compared to those without liver metastasis. These hypothesis generating data require external validation.

Genes Liver Metastasis: N=16 Non-Liver Metastasis: N=98 Adjusted P-value MYC 3(18.8%) 3(3.1%) 0.24 ERBB3 3(18.8%) 5(5.1%) 0.62 FGFR3 5(31.2%) 16(16.3%) 0.73 RICTOR 2(12.5%) 4(4.1%) 0.73 TP53 7(43.8%) 58(59.2%) 0.73 ERBB2 3(18.8%) 9(9.2%) 0.73 CDKN2B 7(43.8%) 31(31.6%) 0.73 ARID1A 3(18.8%) 21(21.4%) 0.90 RB1 3(18.8%) 24(24.5%) 0.90 KDM6A 2(12.5%) 19(19.4%) 0.90

Citation Format: Nishita Tripathi, Yeonjung Jo, Nicolas Sayegh, Beverly Chigarira, Blake Nordblad, Vinay Mathew Thomas, Benjamin Haaland, Roberto Nussenzveig, Sumati Gupta, Neeraj Agarwal, Umang Swami, Benjamin L. Maughan. Tumor genomic landscape in patients (pts) with and without liver metastasis in metastatic urothelial carcinoma (mUC) [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 5995.
Abstract 6012: Antitumor effect of natural killer cells on breast cancer cells in murine model
Authors: Yim Chaok , Lee Jun Woo , Kim Jin-Hee
Published: June 2022

Natural killer (NK) cells are play pivotal functions in the tumor microenvironment of cancer immune surveillance. The killing ability of NK cells is expected to contribute to death of cancer cell. To prove NK cells as a cell therapy, we frist manufactured NK cells from the peripheral blood of healthy donor who received informed consent in a GMP facility. And we verifed the killing ability of the NK cells by decreasing the size of the tumor in NOG mice inoculated with SKBR3, HER2-positive breast-cancer cell, into mammary fat pad (orthotopic models). In this study, sudden death of mice was not found even when 20 millions NK cells were injected into a NOG female with intravenous injection. Moreover, it was confirmed that the size of the tumor was significantly reduced after NK cell injection. It is necessary to study co-administration with a targeted therapy such as rastuzumab and pertuzumab, and NK cells as a cell therapy will help reduce the size of the tumor. In the future, additional research is needed on the combined administration of targeted therapeutics and NK cells.

Citation Format: Chaok Yim, Jun Woo Lee, Jin-Hee Kim. Antitumor effect of natural killer cells on breast cancer cells in murine model [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 6012.
Abstract 602: 23ME-00610 is a first-in-class monoclonal antibody that targets the CD200R1 immune checkpoint to enhance T cell-mediated antitumor activity
Authors: Fenaux Jill , Huang Yao-ming , Melero Cristina , Chung Wei-Jen , Lee Suk , Ayupova Dina , Poggio Mauro , Glatt Dylan , Yi Zuoan , Lay Cecilia , Schmidt Maike , Majeed Sophia R. , Fuh Germaine , Chen Alice , Kumar Sushil
Published: June 2022

In the 23andMe genetic database, associations were observed for CD200R1 variants and autoimmune and cancer traits with opposing directionality. These data suggest that CD200R1 may be a pivotal checkpoint in immunosurveillance of cancer and a promising therapeutic target. CD200R1 is expressed widely on human T cells and myeloid cells; and binds to its cognate ligand CD200 to suppress the activity of immune cells. Elevated expression of CD200R1 was observed on tumor-infiltrating lymphocytes relative to peripheral blood mononuclear cells (PBMCs) from cancer patients. While the expression of CD200R1 and its ligand CD200 are well characterized, the downstream immunosuppressive role for CD200R1 in human tumors or the potentiation of anti-tumor T cell function by targeting of CD200R1 is not well understood. To test the therapeutic potential of inhibiting the CD200R1 pathway we developed 23ME-00610, a fully humanized monoclonal antibody that binds to all functionally relevant isoforms and haplotypes of CD200R1 with high affinity (KD values < 0.1 nM), to target tumors that are reliant on the CD200R1 immunosuppressive pathway. 23ME-00610 completely displaced the ligand CD200 from CD200R1 in cell-based flow cytometry assays with blocking IC50 values that ranged from 0.32 to 1.04 nM depending on the concentration of CD200 ligand present, and inhibited downstream signaling through the adaptor protein DOK2 in a reporter-based assay. Functionally, 23ME-00610 reversed CD200-mediated suppression of chronically stimulated primary T cells. In addition, 23ME-00610 enhanced PBMC-mediated tumor killing with a mean EC50 of 2.09 nM using methods of real-time measurement of cytotoxicity of human CD200-expressing tumor cells when compared to control antibodies. Moreover, 23ME-00610 promoted IFNγ production, a key functional anti-tumor T cell cytokine, in cancer patients’-derived PBMCs. Taken together, these results demonstrate that 23ME-00610 has the potential to reverse CD200-mediated immunosuppression in the TME to enhance anti-tumor T-cell functions in cancer patients.

Citation Format: Jill Fenaux, Yao-ming Huang, Cristina Melero, Wei-Jen Chung, Suk Lee, Dina Ayupova, Mauro Poggio, Dylan Glatt, Zuoan Yi, Cecilia Lay, Maike Schmidt, Sophia R. Majeed, Germaine Fuh, Alice Chen, Sushil Kumar. 23ME-00610 is a first-in-class monoclonal antibody that targets the CD200R1 immune checkpoint to enhance T cell-mediated antitumor activity [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 602.