bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 836: Immunologic markers and the progression of liver disease in HCV-positive individuals
Authors: Argirion Ilona , Pfeiffer Ruth M. , Liu Zhiwei , Hildesheim Allan , Pinto Ligia , McGlynn Katherine A. , Petrick Jessica L. , Lam Tram Kim , O'Brien Thomas R. , Yu Kelly , Chen Chien-jen , Yang Hwai-I , Lee Mei-Hsuan , Koshiol Jill
Published: July 2021

Background: Host immune response and chronic inflammation associated with chronic hepatitis C virus (HCV) infection play a key role in the progression of liver disease from cirrhosis to hepatocellular carcinoma (HCC). We evaluated a large panel of circulating immunologic markers to better understand the natural history of HCV-related liver disease.

Methods: We sampled 94 HCC, 68 cirrhotic and 100 non-cirrhotic controls from a Taiwanese prospective cohort study of chronically HCV-infected individuals. Multivariable polytomous logistic regression and canonical discriminant analysis (CDA) were used to compare baseline plasma levels for 102 markers in individuals who developed cirrhosis as compared to controls and those who developed HCC. P-values for individual markers were corrected for multiple testing using a false discovery rate of 10%; a p-value<0.05 was used to determine significance in CDA. Receiver operating characteristic curves were used to compare the predictive ability of marker groups from both analyses.

Results: After adjusting for age, sex, years of follow-up, serum alanine aminotransferase level, alcohol and smoking, DEFA-1 (p-trend: <0.0001), ITGAM (p-trend: <0.0001), CCL18 (p-trend: 0.002) and ARTN (p-trend: 0.003) were all found to be positively associated with the development of cirrhosis when compared to non-cirrhotic controls; the same four markers were shown to be associated with HCC when compared to cirrhotic participants. Taken together, these four markers predicted cirrhosis and HCC development with 79% and 88% accuracy, respectively in adjusted models. CDA models isolated a twelve-marker signature that included DEFA1, CCL18, and ARTN, improving predictability of cirrhosis development to 91% accuracy in adjusted models. Using the same methods, a fourteen-marker signature that included DEFA-1, ITGAM, CCL18 and ARTN was found to predict HCC development with 97% accuracy when compared to cirrhotic individuals in adjusted models.

Conclusion: To our knowledge, this is the first prospective study to assess immunologic markers in relation to liver disease progression in individuals chronically infected with HCV. While further validation is required, these findings highlight the importance of immunologic processes in HCV-related disease.  

Citation Format: Ilona Argirion, Ruth M. Pfeiffer, Zhiwei Liu, Allan Hildesheim, Ligia Pinto, Katherine A. McGlynn, Jessica L. Petrick, Tram Kim Lam, Thomas R. O'Brien, Kelly Yu, Chien-jen Chen, Hwai-I Yang, Mei-Hsuan Lee, Jill Koshiol. Immunologic markers and the progression of liver disease in HCV-positive individuals [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 836.
Abstract 84: Characterization of oncogenic KRAS A59 alleles and their cooperation with the MAPK signaling pathway
Authors: Johnson Christian W. , Terrell Elizabeth M. , Burd Christin E. , Morrison Deborah , Haigis Kevin M.
Published: July 2021

The Kirsten rat sarcoma (KRAS) proto-oncogene regulates signaling pathways that control proliferation (e.g. MAPK pathway), metabolism and survival (e.g. AKT pathway), and apoptosis (e.g. Hippo pathway). Mutations in KRAS are found in 40% of colorectal cancers (CRC). However, there are no FDA-approved drugs for CRC that target this oncogene. One reason why developing drugs against KRAS is difficult is because a number of different oncogenic alleles have been identified. Thus, an allele-specific approach to target KRAS is necessary. In turn, this approach requires a detailed understanding of their structure and function to drive cell transformation and tissue dysregulation. Our goal is to characterize the function of KRAS A59T in CRC. These alleles are interesting for a number of reasons. First, A59T discriminates retroviral homologues of mammalian RAS from their cellular counterparts. Second, unlike other oncogenic alleles, the KRAS A59T protein undergoes autophosphorylation, the biological function of which is unknown. Third, patient data show that A59 alleles of KRAS frequently co-occur with other genetic alterations in the MAPK signaling pathway, which is uncommon for other KRAS alleles. We hypothesize that KRAS autophosphorylation promotes CRC in a manner that is independent, but cooperative, with the MAPK signaling pathway. To test this hypothesis, we first characterized the function of KRAS A59T and its phosphomimetic A59E using in silico and biochemical techniques, along with classic assays of cell transformation. Next, we generated a new genetically engineered mouse model, K-Ras+/LSL-A59E, in order to test how KRAS autophosphorylation cooperates with other oncogenic mechanisms of MAPK pathway activation to alter colon homeostasis and model colon tumorigenesis. Consistent with our hypothesis, KRAS autophosphorylation and A59E inhibit KRAS-effector interactions that activate the MAPK, AKT, and Hippo signaling pathways. How this change in function alters the ability of K-RasA59E, versus K-RasG12D, to promote hyperproliferation and tumor development in combination with N-RasQ61K and Apc loss in the mouse colon, is currently underway. Ultimately, these studies bring us closer to discovering allele-specific vulnerabilities of KRAS and provide a means to test less understood aspects of oncogenic KRAS signaling.

Citation Format: Christian W. Johnson, Elizabeth M. Terrell, Christin E. Burd, Deborah Morrison, Kevin M. Haigis. Characterization of oncogenic KRAS A59 alleles and their cooperation with the MAPK signaling pathway [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 84.
Abstract 846: Associations of dietary and lifestyle oxidative balance scores with all-cancer, all-CVD, and all-cause mortality risk among older women: The Iowa Women's Health Study
Authors: Mao Ziling , Prizment Anna E. , Lazovich DeAnn , Bostick Boberd M.
Published: July 2021

Background: Substantial basic science evidence suggests that oxidative stress may play a role in aging-related health outcomes, including cancer and cardiovascular diseases (CVD), and oxidative stress markers were linked with all-cancer, all-CVD, and all-cause mortality in epidemiologic studies. However, the associations of many individual dietary and lifestyle anti-/pro-oxidant exposures with mortality are inconsistent. Oxidative balance scores (OBS) that incorporated multiple dietary and lifestyle factors were previously developed and reported to reflect the collective oxidative effects of multiple exposures.

Methods: We investigated associations of 11-component dietary and 4-component (physical activity, adiposity, alcohol, and smoking) lifestyle OBS (higher scores were considered more anti-oxidative) with all-cancer, all-CVD, and all-cause mortality among women 55 - 69 years of age at baseline in the prospective Iowa Women's Health Study (1986 - 2012). We assessed OBS-mortality associations using multivariable Cox proportional hazards regression.

Results: Of the 34,137 cancer-free women included in the analytic cohort, 18,058 died (4,521 from cancer, and 6,825 from CVD) during a mean/median 22.0/26.1 person-years of follow up. Among participants in the highest relative to the lowest lifestyle OBS quintiles, the adjusted hazards ratios and their 95% confidence intervals for all-cancer, all-CVD, and all-cause mortality were 0.47 (0.43, 0.52), 0.54 (0.54, 0.58), and 0.50 (0.48, 0.53) (all Ptrend < 0.001), respectively. The associations of the dietary OBS with mortality were close to null.

Conclusion: Our findings, combined with results from previous studies, suggest that a predominance of antioxidant over pro-oxidant lifestyle exposures may be associated with lower all-cancer, all-CVD, and all-cause mortality risk.

Citation Format: Ziling Mao, Anna E. Prizment, DeAnn Lazovich, Boberd M. Bostick. Associations of dietary and lifestyle oxidative balance scores with all-cancer, all-CVD, and all-cause mortality risk among older women: The Iowa Women's Health 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 846.
Abstract 850: Multivitamin use and risk of overall and site-specific cancer in the National Institutes of Health - AARP Diet and Health Study
Authors: Lim Jungeun , Weinstein Stephanie J. , Liao Linda M. , Huang Jiaqi , Albanes Demetrius
Published: July 2021

Although multivitamins are among the most commonly used supplements in the U.S., their effectiveness in preventing cancer and other chronic diseases is unclear. To help address this uncertainty, we prospectively investigated the association between multivitamin use and risk of overall and site-specific cancer in 489,640 participants enrolled in the National Institutes of Health (NIH) - AARP Diet and Health Study. We defined site-specific cancers using the Surveillance Epidemiology and End Results (SEER) incidence and the International Classification of Diseases for Oncology coding (3rd ed.). Multivitamin use was assessed by questionnaire at baseline and categorized as never, <3 times per week, 3-6 times per week, daily, and >1 per day. Cox proportional hazards regression models of multivitamin use estimated hazard ratios (HRs) and 95% confidence intervals (CIs) that adjusted for multiple potential confounders including gender, age, body mass index, smoking status, and Healthy Eating Index-2015 (HEI-2015) score. We observed no association between increasing multivitamin use and overall cancer risk (HRs 1.0 (reference, never use) 0.94, 0.96, 1.01, 1.00; trend P-value=0.42). Multivitamin use was, however, inversely associated with colon cancer risk: HR=0.79, 95% CI=0.70-0.89 (trend P-value<0.0001) among participants taking >1 multivitamin daily compared with never users, a finding that was identical in men and women (HR=0.79, 95% CI=0.68-0.92 and HR=0.79, 95% CI=0.65-0.95, respectively). Although there were some additional suggestive findings (e.g., for oropharyngeal cancer and leukemia), multivitamin use was not associated with the risk of cancer of the breast, prostate, or lung. In this study that comprehensively evaluated multivitamin use in relation to the risk of overall and site-specific malignancies in both men and women, we found little evidence to support beneficial associations, with the exception of colon cancer risk in both sexes.

Citation Format: Jungeun Lim, Stephanie J. Weinstein, Linda M. Liao, Jiaqi Huang, Demetrius Albanes. Multivitamin use and risk of overall and site-specific cancer in the National Institutes of Health - AARP Diet and Health 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 850.
Abstract 855: Is shift-work associated with increased risk of gastric cancer? A meta-analysis
Authors: Sun Chenyu , Cheng Ce , Bhan Chandur , Ahmed Mubashir Ayaz , Bheesham Nimararta , Lising Jannell F.
Published: July 2021

Introduction: Gastric cancer remains one of the most common cancers worldwide. Shift-work involving circadian disruption was designated as a probable cause of cancer by The International Agency for Research on Cancer. Several studies have investigated the impact of shift work on gastric cancer, however, most of them are with small sample size. Thus, this meta-analysis was conducted.

Method: A comprehensive literature search on PubMed was conducted to identify all relevant studies published prior to September 2020 according to the established inclusion criteria. The quality assessment was performed by the Newcastle-Ottawa Scale (NOS). The pooled relative risk (RR) and 95% confidence intervals (CI) were calculated to estimate the association between the shift-work and gastric cancer risk. A random-effect or fixed-effect model was used to calculate the pooled RR, based on heterogeneity significance. Subgroup analysis was performed based on rotating-shift versus permanent-shift. Sensitivity analysis and publication bias detection were also performed. All statistical analyses were performed using RevMan software (version 5.3; Cochrane library) and STATA 12.0 statistical software (Stata Corp., College Station, TX), and all P values were two-tailed, the test level was 0.05.

Result: 51 articles were obtained from the database search, and 7 articles obtained from other sources. 4 articles involving 36,574 participants were included. All studies were considered moderate to high quality. A non-statistically significant association between shift-work and increased gastric cancer risk was found (RR 1.15, 95%CI: 0.95, 1.37, P=0.14, I2=0%). In the subgroup analysis, neither rotating-shift (RR 1.24, 95%CI: 0.92, 1.67, P=0.16, I2=0%) nor permanent-shift (RR 1.13, 95%CI: 1.10, 0.90, P=0.12, I2=0%) were found to be associated with an increased risk of gastric cancer. Sensitivity analysis by changing fixed-effect models to random-effect models and by omitting each study at a time confirmed the stability of the result. Funnel plot, Egger's test (t=0.70, P=0.554), and Begg's test (z=0.68, P=0.497) found no publication bias of analysis.

Conclusion: The current meta-analysis demonstrates that shift-work is not associated with increased gastric cancer risk. However, only four studies were included. More original studies are needed to further explore shift-work impacts on gastric cancer risk.

Citation Format: Chenyu Sun, Ce Cheng, Chandur Bhan, Mubashir Ayaz Ahmed, Nimararta Bheesham, Jannell F. Lising. Is shift-work associated with increased risk of gastric cancer? A meta-analysis [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 855.
Abstract 883: Parsimonious model to predict length of stay following cystectomy
Authors: Pathak Rashmi , Perez-Morales Jaileene , Patel Sephalie Y. , Poch Michael A. , Schabath Matthew B.
Published: July 2021

BACKGROUND: The gold standard treatment for urinary bladder cancer is cystectomy, which can result in postoperative complications, patient morbidities, and lengthy hospital visits post-surgery. At present, there are limited models that can predict length of stay for patients post cystectomy. Identifying risk factors associated with increased length of stay could have translational implications in mitigating such risk factors. As such, the goal of this study was to generate parsimonious models to predict length of hospital stay (LOHS) following cystectomy in bladder cancer patients.

METHODS: Data from the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) was used to analyze patients who underwent cystectomy between 2014 and 2016. Modeling building approaches were used to identify the most informative preoperative and postoperative covariates to predict LOHS. Separate models were identified for preoperative covariates and for postoperative covariates and the most informative pre- and postoperative covariates were combined into a single model.

RESULTS: This analysis includes 6,074 patients (mean LOHS = 9.4 days). The preoperative (5 covariates; R squared= 0.245 and Adj R-squared = 0.240) and postoperative models (13 covariates; R squared= 0.237 and Adj R-squared = 0.236) were significantly better predictors compared to the ACS risk calculator model (19 covariates; R-square= 0.026 and Adj R-squared = 0.025). Likewise, the combined model (15 covariates) was a significantly better predictor (R squared= 0.241 & Adj R-squared = 0.239) when compared to the ACS risk calculator model. The combined model was subjected into CART analysis to stratify patients into five risk-groups based on ventilator over 48 hours, organ/space surgical site infection, wound disruption, and pneumonia. Patients in the high-risk group had significantly longer mean LOHS of 26.29 days compared to low-risk group of 8.4 days.

CONCLUSIONS: This study identified and validated a clinically important combined model that is to the ACS NSQIP surgical risk calculator to predict LOHS in patients who underwent cystectomy. Patients at high-risk may benefit from allocation of additional follow-up to prevent longer LOHS.

Citation Format: Rashmi Pathak, Jaileene Perez-Morales, Sephalie Y. Patel, Michael A. Poch, Matthew B. Schabath. Parsimonious model to predict length of stay following cystectomy [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 883.
Abstract 885: A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO
Authors: Blackford Amanda L. , Childs Erica J. , Porter Nancy , Petersen Gloria , Rabe Kari , Gallinger Steven , Borgida Ayelet , Syngal Sapna , Schwartz Ann , Cote Michele , Hruban Ralph , Goggins Michael , Klein Alison P. , Parmigiani Giovanni
Published: July 2021

Introduction: Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO), and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility.

Methods: We expanded the existing framework for PANCPRO and BRCAPRO to model underlying risk of pancreatic, breast, and ovarian cancer. We then validated this model on three datasets each reflecting the target populations for these models, including patients referred to a high-risk genetics clinic, patients with multiple family members with pancreatic cancer who underwent genetic testing for BRCA1/2, as well as a prospective registry of pancreatic cancer families. The new model is designated BRCAPANCPRO.

Results: BRCAPANCPRO yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUC = 0.84, 95% CI: 0.78, 0.87) and was reasonably well-calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.82 [0.69, 0.94]). In these families, BRCAPANCPRO outperformed both the prior BRCAPRO and PANCPRO models.

Discussion: The BRCAPANCPRO model improves the identification of families with a pathogenic variant in BRCA2 or BRCA1, particularly for families where there is the co-occurrence of pancreatic cancer in addition to breast and/or ovarian cancer. The model also improves the prediction of pancreatic cancer among families with a pancreatic cancer family history, with or without breast and/or ovarian cancer.

Citation Format: Amanda L. Blackford, Erica J. Childs, Nancy Porter, Gloria Petersen, Kari Rabe, Steven Gallinger, Ayelet Borgida, Sapna Syngal, Ann Schwartz, Michele Cote, Ralph Hruban, Michael Goggins, Alison P. Klein, Giovanni Parmigiani. A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO [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 885.
Abstract 895: Multi-trajectory models of multiple myeloma progression among patients with monoclonal gammopathy of undetermined significance
Authors: Avila Maira A. Castaneda , Lapane Kate L. , Pearson Sharina , Gurwitz Jerry , Zhou Yanhua , Epstein Mara
Published: July 2021

Background: Understanding the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma is needed to identify patients who would benefit from closer clinical surveillance. Given that two of the defining criteria of multiple myeloma are renal failure and anemia, we described the trajectories of creatinine and hemoglobin over time in patients with a diagnosis of MGUS.

Methods: We analyzed data from 429 patients who were diagnosed with MGUS at a large provider group in central Massachusetts between 2007 and 2015 and were followed up through 2018. Patients diagnosed with MGUS were identified by a previously validated case-finding algorithm using health claims and electronic health record data. Group-based trajectory modeling was used to identify groups of patients with distinct laboratory value trajectories of creatinine (mg/dL) and hemoglobin (mg/dL).

Results: The study sample was mostly non-Hispanic white (85.1%) with a mean age of 75 years at MGUS diagnosis. Three multi-trajectory groups were identified. Patients in Group 1 (54.3%) and Group 2 (43.1%) had increasing serum levels of creatinine and decreasing levels of hemoglobin over time, with group 2 having higher increments. Group 3 (2.6%) patients had increasing levels of creatinine and stable low levels of hemoglobin. Patients with MGUS in group 2 were older, less likely to have a prior cancer diagnosis, and had fewer comorbidities than other groups. Twenty-one patients (4.9%) developed multiple myeloma during the study period, with incidence proportions of 0.5%, 1.5%, and 1.6%, respectively for patients in groups 1, 2, and 3.

Conclusion: The data suggest that certain subpopulations of patients with MGUS can be characterized by biomarker trajectories over time. Future research should further investigate how these trajectories may be related to risk of progression to multiple myeloma.

Citation Format: Maira A. Castaneda Avila, Kate L. Lapane, Sharina Pearson, Jerry Gurwitz, Yanhua Zhou, Mara Epstein. Multi-trajectory models of multiple myeloma progression among patients with monoclonal gammopathy of undetermined significance [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 895.
Abstract 90: Fatty acid synthesis is required for breast cancer brain metastasis
Authors: Ferraro Gino B. , Ali Ahmed , Luengo Alba , Kodack David P. , Deik Amy , Abbott Keene L. , Bezwada Divya , Blanc Landry , Prideaux Brendan , Jin Xin , Possada Jessica M. , Chen Jiang , Chin Christopher R. , Amoozgar Zohreh , Ferreira Raphael , Chen Ivy , Naxerova Kamila , Ng Christopher , Westermark Anna M. , Duquette Mark , Roberge Sylvie , Lyssiotis Costas A. , Duda Dan G. , Golub Todd R. , Davidson Shawn M. , Fukumura Dai , Dartois Véronique A. , Clish Clary B. , Heiden Matthew G. Vander , Jain Rakesh K.
Published: July 2021

Brain metastases are refractory to therapies that otherwise control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the unique brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for breast cancer growth in the brain microenvironment may also introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors growing in the brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in the brain. We determine that this phenotype is an adaptation to decreased lipid availability in the brain relative to other tissues, which results in a site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reduces HER2+ breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.

Citation Format: Gino B. Ferraro, Ahmed Ali, Alba Luengo, David P. Kodack, Amy Deik, Keene L. Abbott, Divya Bezwada, Landry Blanc, Brendan Prideaux, Xin Jin, Jessica M. Possada, Jiang Chen, Christopher R. Chin, Zohreh Amoozgar, Raphael Ferreira, Ivy Chen, Kamila Naxerova, Christopher Ng, Anna M. Westermark, Mark Duquette, Sylvie Roberge, Costas A. Lyssiotis, Dan G. Duda, Todd R. Golub, Shawn M. Davidson, Dai Fukumura, Véronique A. Dartois, Clary B. Clish, Matthew G. Vander Heiden, Rakesh K. Jain. Fatty acid synthesis is required for breast cancer brain metastasis [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 90.
Abstract 907: XMT-1660, a B7-H4-targeted Dolasynthen antibody-drug conjugate for the treatment of breast cancer
Authors: Fessler Shawn P. , Wang Jason , Collins Scott D. , Qin LiuLiang , Avocetien Kenneth , Xu Ling , Eydelloth Ronald , Vonderfecht Steven , Chin Chen-Ni , Bradley Steven , Clardy Susan , Dirksen Anouk , Ditty Elizabeth , Du Bingfan , Kim Dokyong , Mosher Rebecca , Ter-Ovanesyen Elena , Slocum Kelly , Uttard Alex , Wongthida Phonphimon , Zurita Jeffrey , Toader Dorin , Damelin Marc , Lowinger Timothy B.
Published: July 2021

XMT-1660 is a novel Dolasynthen-based antibody drug conjugate carrying a DolaLock payload with controlled bystander effect and targeting B7-H4, a tumor antigen that is broadly expressed on the cell surface in breast, ovarian and endometrial cancers. B7-H4 (VTCN1) exerts immunosuppressive effects by suppression of T cell proliferation and is expressed on tumor-associated macrophages (TAMs) as well as epithelial tumor cells. XMT-1660 is comprised of an anti-B7-H4 antibody site-specifically conjugated to Dolasynthen, with a total of 6 DolaLock Auristatin F-HPA (AF-HPA) anti-tubulin payloads per antibody (DAR-6).

To select the optimal ADC, three ADCs using the same antibody and DolaLock payload were compared: site-specific Dolasynthen-based DAR-2 and DAR-6 ADCs, and a stochastically conjugated Dolaflexin-based DAR-12 ADC. In vitro, no significant differences were observed among the 3 ADCs: all exhibited specific recognition of B7-H4 and elicited potent cytotoxicity against B7-H4-expressing cancer cells. In vivo, XMT-1660 consistently exhibited more anti-tumor activity than the other ADCs in TNBC models and ER+/HER2- models after single, equivalent doses based on payload. XMT-1660 demonstrated dose-dependent anti-tumor activity and induced sustained tumor regressions after a single administration. XMT-1660 and the Dolasynthen DAR-2 ADC both exhibited improved pharmacokinetics in mouse relative to the Dolaflexin DAR 12 ADC.

These data indicate that XMT-1660 exhibited a superior preclinical profile to the other ADCs and more generally demonstrate the importance of DAR-ranging studies to identify the optimal antibody-drug conjugate for a given target. These results, as well as results from exploratory toxicology studies in non-human primates, strongly support the clinical development of XMT-1660.

Citation Format: Shawn P. Fessler, Jason Wang, Scott D. Collins, LiuLiang Qin, Kenneth Avocetien, Ling Xu, Ronald Eydelloth, Steven Vonderfecht, Chen-Ni Chin, Steven Bradley, Susan Clardy, Anouk Dirksen, Elizabeth Ditty, Bingfan Du, Dokyong Kim, Rebecca Mosher, Elena Ter-Ovanesyen, Kelly Slocum, Alex Uttard, Phonphimon Wongthida, Jeffrey Zurita, Dorin Toader, Marc Damelin, Timothy B. Lowinger. XMT-1660, a B7-H4-targeted Dolasynthen antibody-drug conjugate for the treatment of 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 907.
Abstract 914: Activity of SGN-B6A in patient-derived xenograft models of non-small cell lung cancer
Authors: Lyon Robert P. , Gosink John J. , Hale Christopher J. , Stilwell Jackie L. , Allred Sean , Hensley Kelly M. , Kumar Vineet , Patilea-Vrana Gabby , Nazarenko Natalya
Published: July 2021

The integrins are a large family of cell surface receptors with diverse roles in cellular adhesion, motility, and cytokinesis. Functional integrins exist as heterodimers consisting of single alpha and beta chains. Within this family, integrin beta-6, which dimerizes exclusively with isoform alpha-v, is expressed constitutively at low levels in numerous epithelial tissues and induced by tissue injury due to its role in tissue remodeling and wound repair. Numerous solid tumors, including non-small cell lung cancer (NSCLC), have been reported to overexpress integrin beta-6. Its role in tissue remodeling is believed to be the function that malignant cells exploit through its overexpression, allowing them to become more invasive into surrounding healthy tissue. Integrin beta-6 has also been reported to be among the integrins that can promote the epithelial to mesenchymal transition as well as provide resistance to anoikis, thus increasing the metastatic potential of malignant cells expressing it. SGN-B6A is an investigational antibody-drug conjugate (ADC) targeting integrin beta-6 to deliver the clinically validated payload monomethyl auristatin E (MMAE). We have previously presented data illustrating the antitumor activity of SGN-B6A in cell line-derived xenograft models originating from multiple carcinoma indications. Here we present results from a study of SGN-B6A activity dosed weekly at 3 mg/kg in patient-derived xenograft models of NSCLC, representing both squamous and adenocarcinoma histology. These results suggest that SGN-B6A is a promising ADC for the treatment of NSCLC and support further clinical investigation in the ongoing Phase I study (NCT04389632).

Citation Format: Robert P. Lyon, John J. Gosink, Christopher J. Hale, Jackie L. Stilwell, Sean Allred, Kelly M. Hensley, Vineet Kumar, Gabby Patilea-Vrana, Natalya Nazarenko. Activity of SGN-B6A in patient-derived xenograft models of non-small cell lung 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 914.
Abstract 929: A novel STAT3 inhibitor directly targeting STAT3 N-terminus simultaneously abrogates the nuclear and mitochondrial STAT3 activities leading to highly potent anti-cancer efficacy on the breast cancer
Authors: Kang Jinsuk
Published: July 2021

STAT3 functions are largely bifurcated: (1) STAT3 activated by Y705 phosphorylation (pY705) regulates target-gene expression in nucleus. (2) STAT3 activated by S727 phosphorylation (pS727) supports a electron transport complex (ETC) in mitochondria. Constitutive activation of STAT3 has long been considered to correlate with activation of diverse oncogenic pathways, which is a promising target for anti-cancer agents, but clinical therapeutic options are still unsatisfactory. Here we discovered a highly novel small-molecule inhibitor, JW-STAT3i directly binding to STAT3 N-terminal domain: 1) Through the cancer cell line panel screening, JW-STAT3i shows strong anti-cancer potency on various cancer cell lines including the breast cancer cell lines. 2) Anti-cancer mechanism of JW-STAT3i was elucidated: Firstly, the JW-STAT3i impairs pY705-STAT3 to abrogate pro-tumorigenic transcriptional programs mediated by STAT3. Secondly, JW-STAT3i also blocks pS727-STAT3 leading to mitochondrial dysfunction and AMPK activation. Consequently, JW-STAT3i treated cancer cells undergo growth arrest and apoptosis. 3) We further validated JW-STAT3i efficacy using cancer cell line- and patient-derived xenograft models whose response is well-correlated with the predictive biomarkers identified. Accuracy of in vivo efficacy in selected breast cancer PDX models based on predictive biomarker (estimated responders and non-responders) was very high. 4) We also demonstrated that JW-STAT3i shows a strong synergy with anti-PD-L1 antibody by induction of anti-tumorigenic immune environment. In conclusion, JW-STAT3i possesses both negative and positive effects on cancer cell proliferation and anti-immunity respectively. Currently, JW-STAT3i is under preclinical development and highly expected to be a promising anticancer therapeutic option in the near future.

Citation Format: Jinsuk Kang. A novel STAT3 inhibitor directly targeting STAT3 N-terminus simultaneously abrogates the nuclear and mitochondrial STAT3 activities leading to highly potent anti-cancer efficacy on the 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 929.
Abstract 941: TAM receptors as potential therapeutic targets in NF2-related schwannomas and meningiomas
Authors: Dave Foram , Ammoun Sylwia , Hanemann C Oliver
Published: July 2021

Background: Mutations in the NF2 gene, which codes for the tumor suppressor Merlin, is responsible for the development of all Neurofibromatosis Type 2 (NF2)-related tumors including schwannomas and meningiomas. These tumors can also occur spontaneously in non-NF2 patients. The only available treatments for this group of tumors are surgery and radiosurgery/radiotherapy. Therefore, in a search of effective drug-based treatments for NF2-mutated schwannomas and meningiomas, we are investigating TYRO3, AXL and MERTK (TAM) receptors as new therapeutic targets.

Methods: The expression and activation of TAM receptors were investigated using human Merlin-deficient meningioma and schwannoma tissues compared to control by Western blotting. Infiltration of tumor associated macrophages and their correlation to TAM family receptors were investigated using immunofluorescence double staining and flow cytometry. To understand the role of TAM receptors in the pathogenesis of schwannomas and meningiomas, in vitro shRNA knock-down and pharmacological inhibition analysis were conducted using patient-derived schwannoma and meningioma cells.

Results: The results revealed overexpression and hyper-activation of AXL, MERTK, TYRO3 in human Merlin-deficient meningiomas and schwannomas. Meningiomas and schwannomas show a varied level of infiltration by M2 macrophages (CD163+) and TAM receptors are expressed on these CD163+ macrophages in addition to the tumor cells. The expression of MERTK correlates to the level of infiltrated CD163+ macrophages. MERTK forms a complex with TYRO3 in both meningioma and schwannoma tissues, and its expression is mandatory to maintain AXL and TYRO3 levels in both cell types. MERTK and AXL contribute to the increased proliferation and survival of schwannoma and meningioma primary cells in vitro. Pathological proliferation and survival of both cell types were successfully reversed by AXL inhibitor BGB324 (BerGenBio, FDA approved for AML) and MERTK inhibitor UNC2025 (preclinical) in vitro, with UNC2025 being more effective. TYRO3 did not affect the proliferation of either schwannoma or meningioma primary cells.

Conclusion: Our findings suggest that TAM receptors are aberrantly expressed and activated in human Merlin-deficient meningiomas and schwannomas. Infiltration of M2 macrophages may contribute to an overall increase in the expression of TAM receptors in these tumors. AXL and MERTK are important in schwannoma and meningioma pathogenesis and are potentially good therapeutic targets. MERTK inhibitor UNC2025 has the potential to be used as a common candidate for the treatment of NF2-related tumors.

Citation Format: Foram Dave, Sylwia Ammoun, C Oliver Hanemann. TAM receptors as potential therapeutic targets in NF2-related schwannomas and meningiomas [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 941.
Abstract 970: Gender-specific stratification of survival following immune checkpoint inhibitor therapy based on intratumoral expression of a B cell gene signature
Authors: Aragaki Adam K. , Hoffman-Censits Jean , Hahn Noah M. , McConkey David J. , Johnson Burles Avner
Published: July 2021

Despite intensive efforts there is still a great need to identify biomarkers that can accurately identify patients who will obtain the most clinical benefit from immune checkpoint inhibitor (ICI) therapy. High intratumoral CD8+ T cell gene signature (CD8TGS) expression, tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1) expression all enrich for response to ICI treatment across multiple cancer subtypes. Although high intratumoral B cell gene expression also correlated with ICI response in melanoma, whether it adds predictive value in other cancers is unknown. We analyzed tumor RNA sequencing data from the IMvigor 210 phase 2 clinical trial of atezolizumab in patients with advanced urothelial carcinoma to examine potential relationships between B cell gene expression and clinical outcomes. Tumors with high levels of both signatures (BCGS/CD8TS or B8T high/high) had the highest overall survival (OS) of all B8T groups. Surprisingly, the subset of tumors with B8T high/low expression patterns were associated with the worst OS. Moreover, the B8T cell signature stratified patients with high TMB, or high PD-L1, into subsets with differential OS outcomes. Whereas the B8T high/high tumors were associated with the best clinical outcomes in ICI treated men, they were not associated with better OS in ICI treated women. Conversely, women with B8T high/high tumors had the best clinical outcomes in non-ICI treated muscle invasive bladder cancer. Collectively, these data suggest that the B8T signature can enhance OS stratification in patients with advanced urothelial carcinoma who were treated with ICI therapy, and that sex-specific differences in the tumor immune microenvironment may drive disparate outcomes.

Citation Format: Adam K. Aragaki, Jean Hoffman-Censits, Noah M. Hahn, David J. McConkey, Burles Avner Johnson. Gender-specific stratification of survival following immune checkpoint inhibitor therapy based on intratumoral expression of a B cell gene signature [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 970.
Abstract 987: Ovarian carcinoma cells are susceptible to ferroptosis
Authors: Li Jing , Wong Oscar Gee , Cheung Annie Nga
Published: July 2021

Ovarian carcinoma (OC) is a malignancy with grave prognosis owing to its high recurrence rate and broad resistance to a variety of apoptosis-inducing chemotherapeutic agents. Induction of alternative, non-apoptotic cell death represents a novel strategy for anti-cancer therapies worldwide. Ferroptosis is a recently defined type of non-apoptotic cell death driven by the accumulation of iron-dependent lipid reactive oxygen species (ROS), resulting in membrane damage and cell rupture. Lines of evidence suggested that OC may be susceptible to ferroptosis. However, the exact effects mediated by ferroptosis and the underlying regulatory mechanisms in OC are not fully characterized. Herein, we sought to explore the susceptibility of a number of OC cell line models towards ferroptosis and investigate the possibility of enhancing conventional platinum-based chemotherapy with ferroptosis inducers. Ferroptosis inducers Erastin and RSL3 dose-dependently induced ferroptotic cell death in ovarian cancer cell lines OVCAR3 and TUOC1, hallmarked by a significant decrease of GSH level and increase of ROS and lipid peroxidation levels after treatment. Treatment by a lipid ROS scavenger ferrostatin-1 (Fer-1), but not by the apoptosis inhibitor Z-VAD-FMK, significantly rescued OVCAR3 and TUOC1 cells from Erastin- and RSL3- induced cell death. Additionally, Erastin and RSL3 could significantly promote cytotoxicity of cisplatin in a cisplatin-resistant ovarian cancer cells OVCA420. Collectively, our results indicate a crucial role of ferroptosis in susceptibility of ovarian carcinomas, suggesting a potential anticancer strategy.

Citation Format: Jing Li, Oscar Gee Wong, Annie Nga Cheung. Ovarian carcinoma cells are susceptible to ferroptosis [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 987.
Abstract 998: Mechanism of action of RXC004, a Wnt pathway inhibitor, in genetically-defined models of cancer
Authors: Phillips Caroline , Woodcock Simon , Eagle Catherine , Saunders Andrew , Tilston Craig , Bhamra Inder , Armer Richard
Published: July 2021

Background: RXC004 is a porcupine inhibitor, and thus a potent and selective inhibitor of Wnt ligand-dependent signalling. RXC004 is currently being investigated in a safety and tolerability study in cancer patients with solid tumours (NCT03447470). Certain Wnt pathway alterations, including loss-of-function RNF43 mutations and RSPO gene fusions, result in higher levels of the Wnt receptor Fzd on the cell surface increasing Wnt-ligand dependent signalling. These alterations are implicated in colorectal and pancreatic cancer. We present pre-clinical data on the effects of RXC004 in genetically defined models of cancer.

Methods: RXC004 in vitro effects on the metabolic activity of both sensitive (genetically selected RNF43 mutant or RSPO fusion models) and insensitive (beta-catenin mutant model) colorectal and pancreatic tumour cells lines were assessed. To test if these effects translated in vivo, RXC004 was also evaluated in an in vivo FDG-PET study in an RSPO fusion tumour cell line. In addition, as we had previously noted that RXC004 caused cell differentiation in an RSPO fusion model, we studied if pre-treatment with RXC004 would affect subsequent tumour growth post RXC004 induced cell differentiation in vivo.

Results: In tumour cell lines in vitro, RXC004 significantly reduced glucose uptake only in genetically selected tumour cell lines. In vivo FDG-PET studies also showed a reduction in FDG-PET signals post 7 days treatment of 5mg/kg QD RXC004. Imaging demonstrated that MaxSUV (maximum standardised uptake value) decreased by 31% in RXC004 treated versus vehicle treated tumours, furthermore biodistribution of PET ligand was significantly inhibited in tumours post 7 days RXC004 treatment. Pre-treatment of RXC004 in an in vivo mouse xenograft model for 7 days resulted in a significant reduction in tumour growth when tumour fragments from these pre-treated mice were re-implanted into naïve mice (P<0.05).

Conclusion: These data demonstrate that RXC004 monotherapy results in tumour cell differentiation accompanied by reduced metabolic activity in genetically selected tumours. RXC004-induced cell differentiation may therefore continue to provide patient benefit even post dosing. Moreover, FDG-PET imaging in clinical studies may allow early detection of the positive effects of RXC004 in a non-invasive manner, and prior to any changes in tumour volume by conventional RECIST measurements.

Citation Format: Caroline Phillips, Simon Woodcock, Catherine Eagle, Andrew Saunders, Craig Tilston, Inder Bhamra, Richard Armer. Mechanism of action of RXC004, a Wnt pathway inhibitor, in genetically-defined models of 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 998.
Abstract CT257: Phase 3 multicenter randomized trial of PSMA PET/CT prior to definitive radiation therapy for unfavorable intermediate-risk or high-risk prostate cancer [PSMA dRT]: Study Protocol
Authors: Calais Jeremie , Zhu Shaojun , Hrimas Nader , Eiber Matthias , Hadaschik Boris , Stuschke Martin , Herrmann Ken , Czernin Johannes , Kishan Amar U. , Nickols Nicholas G. , Elashoff David , Fendler Wolfgang
Published: July 2021

Background: Definitive radiation therapy (dRT) is an effective initial treatment of intermediate-risk (IR) and high-risk (HR) prostate cancer (PCa). PSMA PET/CT is superior to standard of care imaging (CT, MRI, bone scan) for detecting regional and distant metastatic PCa. PSMA PET/CT thus has the potential to guide patient selection and the planning for dRT and improve patient outcomes.

Methods: This is a multicenter randomized phase 3 trial (NCT04457245). We will randomize 312 patients to proceed with standard dRT (control Arm, n=150), or undergo a PSMA PET/CT scan at the study site (both 18F-DCFPyL and 68Ga-PSMA-11 can be used) prior to dRT planning (intervention arm, n = 162). dRT will be performed at the treating radiation oncologist facility. In the control arm, dRT will be performed as routinely planned. In the intervention arm, the treating radiation oncologist can incorporate PSMA PET/CT findings into the RT planning. Androgen deprivation therapy (ADT) is administered per discretion of the treating radiation oncologist and may be modified as a result of the PSMA PET/CT results. We assume that approximately 8% of subjects randomized to the PSMA PET arm will be found to have M1 disease and thus will be more appropriate candidates for long-term systemic or multimodal therapy, rather than curative intent dRT. PET M1 patients will thus not be included in the primary endpoint analysis. The primary endpoint is the success rate of patients with unfavorable IR and HR PCa after standard dRT versus PSMA PET-based dRT. Secondary Endpoints (whole cohort) include progression free survival (PFS), metastasis-free survival after initiation of RT, overall survival (OS), % of change in initial treatment intent and Safety.

Discussion: This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET/CT molecular imaging can improve outcomes in patients with PCa who receive dRT. In this trial the incorporation of PSMA PET/CT may improve the success rate of curative intent radiotherapy in two ways: to optimize patient selection as a biomarker and to personalizes the radiotherapy plan.

Citation Format: Jeremie Calais, Shaojun Zhu, Nader Hrimas, Matthias Eiber, Boris Hadaschik, Martin Stuschke, Ken Herrmann, Johannes Czernin, Amar U. Kishan, Nicholas G. Nickols, David Elashoff, Wolfgang Fendler. Phase 3 multicenter randomized trial of PSMA PET/CT prior to definitive radiation therapy for unfavorable intermediate-risk or high-risk prostate cancer [PSMA dRT]: Study Protocol [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 CT257.