tbuckley/cabot-search huggingface dataset:
Abstract P4-04-13: S100a7/rage signaling promotes breast tumorigenesis through modulating tumor-associated macrophages
Authors: Ajeet K Verma, Tasha Wilkie, Sanjay Mishra, Manish Charan, Ramesh K Ganju
Journal: Cancer Research (2022)

Abstract S100A7 has been shown to be associated with breast cancer growth and metastasis. However, the molecular mechanism through which S100A7 promotes breast tumorigenesis is not completely understood. In this study, we revealed that S100A7 enhanced Stat3-mediated secretion of Serpin-E1 in triple negative breast cancer (TNBC) cell lines. Serpin-E1 has been shown to promote recruitment and polarization toward a pro-tumorigenic phenotype of tumor-associated macrophages through activating the Stat3 pathway. Importantly, we reported that the inhibition of Stat3 led to reduction of S100A7-mediated invasiness of TNBC cells and also significantly decreased the secretion of Serpin-E1 by cancer cells. We also revealed that Stat3 inhibition in TNBC cells or Serpin-E1 neutralization significantly reduced the migration of human monocytes/macrophages by transwell migration assay. We further demonstrate that murine ortholog of S100A7, mS100a7a15 enhanced mammary hyperplasia, tumor growth and metastasis through Stat3 activation. Previously, we reported that S100A7 mediated its tumorigenic effects through RAGE in breast cancer cells. Therefore, we also discovered that combinatorial treatment of Stat3 and RAGE inhibitors in mammary tumor bearing mS100a7a15 overexpression mouse model strongly decreased the tumor burden and enhanced the recruitment of tumor-suppressing M1-macrophages. We also found that combined inhibition of RAGE and Stat3 significantly increased the infiltration of CD4 T cells in the tumor microenvironment (TME). Collectively, these findings suggest S100A7/RAGE signaling pathway could be used as a novel therapeutic target to inhibit breast cancer growth and metastasis through modulating the TME. Citation Format: Ajeet K Verma, Tasha Wilkie, Sanjay Mishra, Manish Charan, Ramesh K Ganju. S100a7/rage signaling promotes breast tumorigenesis through modulating tumor-associated macrophages [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-13.
Identification of High-Risk Multiple Myeloma With a Plasma Cell Leukemia-Like Transcriptomic Profile
Authors: Davine Hofste op Bruinink, Rowan Kuiper, Mark van Duin, Tom Cupedo, Vincent H.J. van der Velden, Remco Hoogenboezem, Bronno van der Holt, H. Berna Beverloo, Erik T. Valent, Michael Vermeulen, Francesca Gay, Annemiek Broijl, Hervé Avet-Loiseau, Nikhil C. Munshi, Pellegrino Musto, Philippe Moreau, Sonja Zweegman, Niels W.C.J. van de Donk, Pieter Sonneveld
Journal: Journal of Clinical Oncology (2022)

Primary plasma cell leukemia (pPCL) is an aggressive subtype of multiple myeloma, which is distinguished from newly diagnosed multiple myeloma (NDMM) on the basis of the presence of ≥ 20% circulating tumor cells (CTCs). A molecular marker for pPCL is currently lacking, which could help identify NDMM patients with high-risk PCL-like disease, despite not having been recognized as such clinically.
Abstract P3-05-04: The histone demethylase hairless functions as a tumor suppressor gene in breast cancer development
Authors: Liang Liu, Yao Shen, Jasvinder Singh, Bindy Sah, Zhongming Chen, Christine Henzler, Wootae Ha, Tao Su, Hanina Hibshoosh
Journal: Cancer Research (2022)

Abstract The hairless (HR) gene encodes a transcription factor with histone demethylase activity that is essential for development and tissue homeostasis. Previous studies suggest that HR possesses antitumor activity in skin cancer models. Surveying human cancer genomics datasets identified frequent HR missense mutations or deletions in various human malignancies including breast cancers, suggesting that HR might function as a tumor suppressor in cancer development. By targeted sequencing, we identified HR mutations in approximately 29% of human breast cancer tissues (n=85), compared to 33% for BRCA2 and 17% for BRCA1 in the same sample cohort. Digital PCR assays also revealed frequent HR copy number loss across breast cancer subtypes. To further define HR’s putative tumor suppressor function in breast cancer and its mechanism of action, we reconstituted HR expression in HR-deficient human breast cancer cells. HR re-expression significantly suppressed tumor growth and metastasis in orthotopic xenograft mouse models. This antitumor activity of HR in breast cancer cells was partly associated with transcriptional activation of the CELF2 tumor suppressor gene, a new HR-regulated gene identified by RNA-seq studies. Consistent with HR’s H3K9 demethylase activity, pharmacological inhibition of H3K9 methylation inhibited HR-deficient breast cancer cell proliferation and migration. Taken together, these studies demonstrate that HR is a novel tumor suppressor, and pharmacological inhibition of H3K9 methylation may be explored to reduce HR-deficient breast cancer cell growth and survival. methylation inhibited HR-deficient breast cancer cell proliferation and migration in vitro, and tumor growth and metastasis in xenograft models. Taken together, these studies suggest that HR is a novel tumor suppressor, and pharmacological inhibition of H3K9 methylation may be explored to treat HR-deficient breast cancers. Citation Format: Liang Liu, Yao Shen, Jasvinder Singh, Bindy Sah, Zhongming Chen, Christine Henzler, Wootae Ha, Tao Su, Hanina Hibshoosh. The histone demethylase hairless functions as a tumor suppressor gene in breast cancer development [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-05-04.
Abstract P5-12-12: The role of a cancer testis-antigen in regulating tumor growth and oncogenic pathways in triple-negative breast cancer
Authors: Melina J Sedano, Alana L Harrison, Ine le, Shrikanth S Gadad
Journal: Cancer Research (2022)

Abstract Breast cancer is the second leading cause of cancer mortality in women after lung cancer; however, it is the primary cause of death among Hispanic women. About 10-20% of breast cancers are basal (triple-negative) subtype at the time of diagnosis, and they do not respond well to treatment regimens due to a lack of specific targets. Triple-negative breast cancer is a deadly and very aggressive tumor type associated with poor prognosis compared to other molecular subtypes of breast cancer, especially among Hispanic women. Thus, identifying novel molecules with prognostic and therapeutic value is critical to treat this ever-evolving disease. Numerous studies suggest that genes transcribed from chromosome X (X-linked genes) are implicated in cancers. The expression of these genes is tightly regulated and restricted to immune-privileged organs; however, many of them escape regulation and become aberrantly expressed in tumors.Interestingly, our genomic analysis suggests that several newly annotated X-linked genes are cancer testis-antigens (CT genes) that are highly antigenic and are located at regions previously considered to be gene deserts in the human genome. To date, very minimal is known about their expression and role in triple-negative breast cancer. In this regard, we used an integrated genomic approach to identify testis-tissue-specific genes that are differentially expressed in triple-negative breast cancer. Further, we identified a highly immunogenic cancer-testis gene by incorporating cutting-edge technology-driven (Global Run-On Sequencing) gene expression analysis. Mechanistically, by using cell-, mouse-based, and genomic approaches, we have found that candidate CT gene modulates gene expression, immune response, and tumor growth in triple-negative breast cancer. Hence, it has the potential to change the way triple-negative breast cancer is diagnosed and treated. S.S.G. is supported by a First-time Faculty Recruitment Award from the Cancer Prevention and Research Institute of Texas (CPRIT; RR170020). S.S.G. is also supported by a grant from Lizanell and Colbert Coldwell foundation. Citation Format: Melina J Sedano, Alana L Harrison, Ine le, Shrikanth S Gadad. The role of a cancer testis-antigen in regulating tumor growth and oncogenic pathways in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-12-12.
Harnessing radiotherapy-induced NK-cell activity by combining DNA damage–response inhibition and immune checkpoint blockade
Authors: Emmanuel C Patin, Magnus T Dillon, Pablo Nenclares, Lorna Grove, Heba Soliman, Isla Leslie, Davina Northcote, Galabina Bozhanova, Eva Crespo-Rodriguez, Holly Baldock, Harriet Whittock, Gabriella Baker, Joan Kyula, Jeane Guevara, Alan A Melcher, James Harper, Hormas Ghadially, Simon Smith, Malin Pedersen, Martin McLaughlin, Kevin J Harrington
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Despite therapeutic gains from immune checkpoint inhibitors (ICI) in many tumor types, new strategies are needed to extend treatment benefits, especially in patients failing to mount effective antitumor T-cell responses. Radiation and drug therapies can profoundly affect the tumor immune microenvironment. Here, we aimed to identify immunotherapies to increase the antitumor response conferred by combined ataxia telangiectasia and Rad3-related kinase inhibition and radiotherapy. Methods Using the human papillomavirus (HPV)-negative murine oral squamous cell carcinoma model, MOC2, we assessed the nature of the antitumor response following ataxia telangiectasia and Rad3-related inhibitor (ATRi)/radiotherapy (RT) by performing RNA sequencing and detailed flow cytometry analyses in tumors. The benefit of immunotherapies based on T cell immunoreceptor with Ig and ITIM domains (TIGIT) and Programmed cell death protein 1 (PD-1) immune checkpoint blockade following ATRi/RT treatment was assessed in the MOC2 model and confirmed in another HPV-negative murine oral squamous cell carcinoma model called SCC7. Finally, immune profiling was performed by flow cytometry on blood samples in patients with head and neck squamous cell carcinoma enrolled in the PATRIOT clinical trial of combined ATRi/RT. Results ATRi enhances radiotherapy-induced inflammation in the tumor microenvironment, with natural killer (NK) cells playing a central role in maximizing treatment efficacy. We demonstrated that antitumor activity of NK cells can be further boosted with ICI targeting TIGIT and PD-1. Analyses of clinical samples from patients receiving ATRi (ceralasertib) confirm the translational potential of our preclinical studies. Conclusion This work delineates a previously unrecognized role for NK cells in the antitumor immune response to radiotherapy that can be augmented by small-molecule DNA damage–response inhibitors and immune checkpoint blockade.
Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials
Authors: Josep M. Llovet, Amit G. Singal, Augusto Villanueva, Richard S. Finn, Masatoshi Kudo, Peter R. Galle, Masafumi Ikeda, Sophie Callies, Louise M. McGrath, Chunxiao Wang, Paolo Abada, Ryan C. Widau, Elena Gonzalez-Gugel, Andrew X. Zhu
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Ramucirumab is an effective treatment for patients with advanced hepatocellular carcinoma (aHCC) and baseline alpha-fetoprotein (AFP) ≥400 ng/mL. We aimed to identify prognostic and predictive factors of response to ramucirumab in patients with aHCC with AFP ≥400 ng/mL from the phase III REACH and REACH-2 randomized trials. Patients and Methods: Patients with aHCC, Child-Pugh class A with prior sorafenib treatment were randomized in REACH and REACH-2 (ramucirumab 8 mg/kg or placebo, biweekly). Meta-analysis of individual patient-level data (pooled population) from REACH (AFP ≥400 ng/mL) and REACH-2 was performed. A drug exposure analysis was conducted for those with evaluable pharmacokinetic data. To identify potential prognostic factors for overall survival (OS), multivariate analyses were performed using a Cox proportional hazards regression model. To define predictors of ramucirumab benefit, subgroup-by-treatment interaction terms were evaluated. Results: Of 542 patients (316 ramucirumab, 226 placebo) analyzed, eight variables had independent prognostic value associated with poor outcome (geographical region, Eastern Cooperative Oncology Group performance score ≥1, AFP &amp;gt;1,000 ng/mL, Child-Pugh &amp;gt;A5, extrahepatic spread, high neutrophil-to-lymphocyte ratio, high alkaline phosphatase and aspartate aminotransferase). Ramucirumab survival benefit was present across all subgroups, including patients with very aggressive HCC [above median AFP; HR: 0.64; 95% confidence interval (CI): 0.49–0.84] and nonviral aHCC (HR: 0.56; 95% CI: 0.40–0.79). While no baseline factor was predictive of a differential OS benefit with ramucirumab, analyses demonstrated an association between high drug exposure, treatment-emergent hypertension (grade ≥3), and increased ramucirumab benefit. Conclusions: Ramucirumab provided a survival benefit irrespective of baseline prognostic covariates, and this benefit was greatest in patients with high ramucirumab drug exposure and/or those with treatment-related hypertension.
ACUTE INCREASE IN VASCULAR LOAD AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT MAY IMPROVE WITH TIME AND RESULT IN LONG TERM IMPROVED CARDIAC EFFICIENCY
Authors: Ning Song, Audrey Adji, Sara Hungerford, Mayooran Namasivayam, Christopher Hayward, Andrew Jabbour, David W.M. Muller
Journal: Journal of the American College of Cardiology (2022)
Safety and Efficacy of Combination Maintenance Therapy with Ixazomib and Lenalidomide in Patients with Posttransplant Myeloma
Authors: Krina K. Patel, Jatin J. Shah, Lei Feng, Hans C. Lee, Elisabet M. Manasanch, Jasper Olsem, Ashley Morphey, Xiao Jiao Huo, Sheeba K. Thomas, Qaiser Bashir, Muzaffar H. Qazilbash, Donna M. Weber, Robert Z. Orlowski
Journal: Clinical Cancer Research (2022)

Abstract Purpose: In this study, the addition of ixazomib to lenalidomide maintenance post-autologous stem cell transplant (ASCT) in 64 patients with newly diagnosed multiple myeloma was evaluated on the basis of the observed benefit of lenalidomide-only maintenance in prior studies. Patients and Methods: Patients were started on maintenance therapy with lenalidomide and ixazomib within 60–180 days of stem cell infusion. Results: Response rates deepened over time from baseline post-ASCT for 39 patients. The complete response (CR)/stringent CR rate was 43% and median overall survival was not reached with a median follow-up of 62 months (range, 25–82 months). Median PFS (mPFS) for all patients was 73 months and has not been reached for those with International Staging System (ISS) stage 1 disease. mPFS in 9 patients who had ISS stage 3 disease and 14 patients who had high-risk cytogenetics was 34 and 25 months, respectively. Twenty-two patients had progressive disease, while 19 patients continue to receive dual maintenance. The most common grade 3/4 adverse events included neutropenia, leukopenia, thrombocytopenia, lung infections, diarrhea, and maculopapular rash. Second primary malignancies occurred in 9 patients. Toxicity led to dose reductions in ixazomib and lenalidomide in 20 and 31 patients, respectively. Discontinuation of ixazomib due to toxicity occurred in 4 patients. Grade 1/2 neuropathy occurred in 22 patients and led to reduction or discontinuation of ixazomib in 2 patients. Conclusions: The addition of ixazomib to lenalidomide maintenance demonstrated a better than expected PFS compared with historical data using lenalidomide alone and was safe and tolerable.
Abstract P4-02-07: Lasofoxifene as a potential treatment for aromatase inhibitor resistant ER positive breast cancer
Authors: Muriel Laine, Marianne E Greene, Tiffany Leng, Justyna D Kurleto, Sophia Li, Barry Komm, Geoffrey L Greene
Journal: Cancer Research (2022)

Abstract Postmenopausal patients with estrogen receptor positive (ERα+) primary invasive breast cancer are typically treated with aromatase inhibitors (AIs) as first line adjuvant therapy. Patients who become resistant to AIs are treated with fulvestrant and/or CDK4/6 inhibitors, such as palbociclib, as second line therapy. Lasofoxifene, a selective estrogen receptor modulator (SERM), was developed for the treatment of vaginal atrophy and osteoporosis. Our previous studies, performed in an MCF-7 xenograph metastatic breast cancer mouse model with activating ERα mutations, showed that lasofoxifene, both alone and in combination with palbociclib, was more effective than fulvestrant at inhibiting tumor growth and metastasis to the liver, lung, bone and brain. In the current study, we compared the efficacy of lasofoxifene +/- palbociclib to fulvestrant +/- palbociclib combinations in a letrozole-induced, AI-resistant breast tumor model (MCF-7 LTLT cells) that does not express ERα activating mutations. Luciferase-GFP tagged LTLT cells were injected into the mammary ducts of NSG mice (MIND model) and tumor progression was monitored by live luminescence imaging of primary tumors, as well as ex vivo imaging and histochemical analysis of metastatic sites at study endpoint. Primary tumor area was also measured at study endpoint. Lasofoxifene +/- palbociclib was significantly more effective than fulvestrant +/- palbociclib at inhibiting primary tumor growth. In addition, all treatments, except fulvestrant, inhibited bone metastasis versus vehicle. These data show that lasofoxifene is more effective than fulvestrant in this tumor model and suggest that lasofoxifene has potential as an effective therapy for AI resistant breast cancers that do not express ERα activating mutations. Citation Format: Muriel Laine, Marianne E Greene, Tiffany Leng, Justyna D Kurleto, Sophia Li, Barry Komm, Geoffrey L Greene. Lasofoxifene as a potential treatment for aromatase inhibitor resistant ER positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-07.
Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels
Authors: Jose A. Mazzitelli, Leon C. D. Smyth, Kevin A. Cross, Taitea Dykstra, Jerry Sun, Siling Du, Tornike Mamuladze, Igor Smirnov, Justin Rustenhoven, Jonathan Kipnis
Journal: Nature Neuroscience (2022)
MACHINE LEARNING FOR HYPERTROPHIC CARDIOMYOPATHY COHORT IDENTIFICATION FROM ECHOCARDIOGRAMS
Authors: Mateo Alzate Aguirre, Nasibeh Zanjirani Farahani, Moein Enayati, Johan Martijn Bos, Kaylan S. Pasupathy, Jeffrey Benjamin Geske, Patricia A. Pellikka, Garvan C. Kane, Jae K. Oh, Michael John Ackerman, Adelaide Maria Arruda-Olson
Journal: Journal of the American College of Cardiology (2022)
Reply to Kamal Kant Sahu’s Letter to the Editor re: Veerle H. Groen, Karin Haustermans, Floris J. Pos, et al. Patterns of Failure Following External Beam Radiotherapy With or Without an Additional Focal Boost in the Randomized Controlled FLAME Trial for Localized Prostate Cancer. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2021.12.012
Authors: Linda G.W. Kerkmeijer, Floris J. Pos, Uulke A. van der Heide, Bas Israël, Cédric Draulans, Karin Haustermans
Journal: European Urology (2022)
ATP11B inhibits breast cancer metastasis in a mouse model by suppressing externalization of nonapoptotic phosphatidylserine
Authors: Jun Xu, Sek Man Su, Xin Zhang, Un In Chan, Ragini Adhav, Xiaodong Shu, Jianlin Liu, Jianjie Li, Lihua Mo, Yuqing Wang, Tingting An, Josh Haipeng Lei, Kai Miao, Chu-Xia Deng, Xiaoling Xu
Journal: Journal of Clinical Investigation (2022)

Cancer metastasis is the cause of the majority of cancer-related deaths. In this study, we demonstrated that no expression or low expression of ATP11B in conjunction with high expression of PTDSS2, which was negatively regulated by BRCA1, markedly accelerates tumor metastasis. Further analysis revealed that cells with low ATP11B expression and high PTDSS2 expression (ATP11BloPTDSS2hi cells) were associated with poor prognosis and enhanced metastasis in breast cancer patients in general. Mechanistically, an ATP11BloPTDSS2hi phenotype was associated with increased levels of nonapoptotic phosphatidylserine (PS) on the outer leaflet of the cell membrane. This PS increase serves as a global immunosuppressive signal to promote breast cancer metastasis through an enriched tumor microenvironment with the accumulation of myeloid-derived suppressor cells and reduced activity of cytotoxic T cells. The metastatic processes associated with ATP11BloPTDSS2hi cancer cells can be effectively overcome by changing the expression phenotype to ATP11BhiPTDSS2lo through a combination of anti-PS antibody with either paclitaxel or docetaxel. Thus, blocking the ATP11BloPTDSS2hi axis provides a new selective therapeutic strategy to prevent metastasis in breast cancer patients.
Abstract P4-07-12: An evaluation of lymphovascular invasion in relation to biology and prognosis according to subtypes in invasive breast cancer
Authors: Reiki Nishimura, Tomofumi Osako, Yasuhiro Okumura, Masahiro Nakano, Hiroko Otsuka, Mamiko Fujisue, Nobuyuki Arima
Journal: Cancer Research (2022)

Abstract Background: Lymphovascular invasion (LVI) is associated with a poor outcome in breast cancer. The purpose of this study was to evaluate the clinical significance of LVI in primary breast cancer and to investigate disease-free survival (DFS) as a prognostic marker according to the breast cancer subtypes. The clinical significance of LVI was analyzed to investigate the biology and prognosis. Patients and Methods: This study examined 4,652 consecutive invasive breast cancer cases excluding the patients with non-invasive cancer, Stage IV and neo-adjuvant therapy from February 2002 to February 2021. Clinicopathological characteristics and prognosis of LVI positive and negative tumors were compared. LVI was evaluated in hematoxylin and eosin staining specimen from surgically resected samples. The ER, PgR, Ki-67, p53, HER2 status were evaluated using immunohistochemistry (IHC). Breast cancer subtypes were categorized based on the IHC data derived from ER/PgR, HER2 and Ki-67 (cutoff point: 20%) in invasive tumors. The median follow-up period was 95 months. Results: The LVI expression rates were 29.2%(low: 19.7% and high: 9.5%)in all primary cases. The LVI positive rate significantly correlated with ER/PgR negative, HER2 positive, p53 overexpression, higher Ki-67 index values, higher nuclear grade, positive nodes, and larger tumor. Moreover, the subtypes significantly correlated with LVI positivity; 20% in Luminal A, 34.6% in Luminal B, 40.9% in Lumina/HER2, 38.1% in HER2 enriched, and 29.8% in Triple Negative (TN). There were significant differences in DFS between LVI status in Luminal A, Luminal B, and TN subtypes, but there were no difference in the Luminal/HER2 and HER2 enriched subtypes. A multivariate analysis revealed that LVI was a significant factor in Luminal B and TN subtypes. Conclusion: LVI significantly correlated with the advanced and aggressive characteristics in breast cancer. Luminal A type had a lower LVI rate and HER2 type had a higher rate. Moreover, LVI was a significant prognostic factor in Luminal B and TN subtypes. These data suggest that the LVI status was useful in predicting the prognosis in HER2 negative breast cancer. Citation Format: Reiki Nishimura, Tomofumi Osako, Yasuhiro Okumura, Masahiro Nakano, Hiroko Otsuka, Mamiko Fujisue, Nobuyuki Arima. An evaluation of lymphovascular invasion in relation to biology and prognosis according to subtypes in invasive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-12.