bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 65: Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade
Authors: Gu Shengqing , Zhang Wubing , Wang Xiaoqing , Jiang Peng , Traugh Nicole , Li Ziyi , Meyer Clifford , Stewig Blair , Xie Yingtian , Bu Xia , Manos Michael , Font-Tello Alba , Gjini Evisa , Lako Ana , Lim Klothilda , Conway Jake , Tewari Alok , Zeng Zexian , Sahu Avinash Das , Tokheim Collin , Weirather Jason L. , Fu Jingxin , Zhang Yi , Kroger Benjamin , Liang Jin Hua , Cejas Paloma , Freeman Gordon J. , Rodig Scott J. , Long Henry , Gewurz Benjamin E. , Hodi F. Stephen , Brown Myles , Liu X. Shirley
Published: July 2021

Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a critical suppressor of the NF-κB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified SMAC mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T-cell-dependent killing, and synergizes with ICB. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.

Citation Format: Shengqing Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Nicole Traugh, Ziyi Li, Clifford Meyer, Blair Stewig, Yingtian Xie, Xia Bu, Michael Manos, Alba Font-Tello, Evisa Gjini, Ana Lako, Klothilda Lim, Jake Conway, Alok Tewari, Zexian Zeng, Avinash Das Sahu, Collin Tokheim, Jason L. Weirather, Jingxin Fu, Yi Zhang, Benjamin Kroger, Jin Hua Liang, Paloma Cejas, Gordon J. Freeman, Scott J. Rodig, Henry Long, Benjamin E. Gewurz, F. Stephen Hodi, Myles Brown, X. Shirley Liu. Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 65.
Abstract 659: Evaluation of homologous recombination repair related gene mutation on survival and drug response in Chinese epithelial ovarian cancer patients
Authors: Li Lei , Shao Kang , Zhang Jianwei , Liu Meng , Wu Kui , Wu Ming
Published: July 2021

Background: Target sequencing of epithelial ovarian cancer (EOC) has been widely used in clinical to detect the status of BRCA1/2 and genes in homologous recombination repair (HRR) pathway. But there still lacks of systematic evaluation of HRR related gene mutation effect on clinical outcome.

Methods: Totally 230 EOC patient is recruited and received OseqT panel sequencing including 12 HRR related genes, 5 mismatch repair related genes and 8 ovarian cancer related genes. All the patients received platinum-based chemotherapy. 25 of them received PARP inhibitor therapy. Their responses to the therapy, OS and PFS were collected for analysis.

Results: We found that BRCA2 and BRCA1/2 mutation carriers (somatic and germline) had longer OS (p value: 0.016 and 0.028) and PFS (p value: 0.002, 0.006) than non-carriers, PTEN and MSH2 germline mutation carriers had longer PFS (p value: 0.038, 0.049) than non-carries. When we compared germline pathogenic carriers and non-pathogenic carriers on OS and PFS, there is significant difference in PALB2 (p value: 0.036, 0.015) and STK11 (0.001, 0.018), BRCA1 mutation did not affect survival time in both OS and PFS. Then we observed the response to platinum-based chemotherapy. We found that the carriers of germline pathogenic variants in BRCA1, BRCA1/2 and HRR related genes were significant related with better response (p value: 0.16, 0.042 and 0.048), If we combined germline and somatic pathogenic variants together, the p value of BRCA1, BRCA1/2 and HRR related genes were changed to 0.001, 0.009 and 0.001. Somatic status of those gene alone had no relationship with chemotherapy response.In the patients received treatment of PARP inhibitor Niraparib, carriers of germline and somatic pathogenic variant in BRCA1 and BRCA1/2 were more sensitive to Niraparib (p value: 0.18, 0.008), There was only 1 BRCA2 pathogenic carrier and no other HRR related gene pathogenic carrier in 25 patients. So, the sensitivity of BRCA2 and HRR-related gene mutation carriers were not calculated.

Conclusions: In our cohort, BRCA2 and BRCA1/2 mutation carriers had longer OS and PFS than non-carriers. PTEN, MSH2, PALB2 and STK11 mutation status also had relationship with survival in some circumstances, BRCA1, BRCA1/2 and HRR-related genes could all be used to predict drug sensitivity, germline and somatic variant should be combined used to reach better performance.

Citation Format: Lei Li, Kang Shao, Jianwei Zhang, Meng Liu, Kui Wu, Ming Wu. Evaluation of homologous recombination repair related gene mutation on survival and drug response in Chinese epithelial ovarian cancer patients [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 659.
Abstract 672: Prognostic significance of urokinase plasminogen activator system in a naturally occurring model of osteosarcoma
Authors: Matsuyama Arata , Mutsaers Anthony J.
Published: July 2021

Introduction Human pediatric and canine osteosarcoma (OSA) are both highly metastatic primary bone cancers that share molecular and clinical similarities. Urokinase plasminogen activator (uPA) and its receptor uPAR promote invasion, metastasis and angiogenesis in multiple cancer types and have been shown to play critical roles in malignant characteristics of OSA in vitro, yet their clinical significance has not been investigated in OSA patients.

Methods Serum samples of dogs with naturally-occurring appendicular OSA (n=26) and clinically healthy dogs (n=6) were analyzed using commercially available canine-specific ELISA and uPA activity kits. Dogs with OSA that presented without metastatic disease at diagnosis and received treatment with amputation plus adjuvant carboplatin chemotherapy were included. Survival data and patient characteristics were obtained from medical records. Differences in serum uPA/uPAR results between the groups was tested by t test or Wilcoxan rank sum test. Kaplan Meier survival curve and log rank test were used for survival analysis in the OSA cohort after subgrouping by X-Tyle software. Well-established prognostic factors and serum uPA/uPAR results were tested for prognostic significance by cox regression analysis in both univariate and multivariate analyses.

Results Dogs with OSA had significantly higher serum uPA (p=0.008; 1905.4 vs 1439.5 pg/mL) but not uPAR (p=0.866) levels compared to healthy dogs. OSA-bearing dogs with high serum uPA had significantly shorter progression-free (p=0.003; 94 vs 266 days) and overall survival (p=0.01; 123 vs 338 days) than dogs with low uPA level. Similarly, dogs with high serum uPA activity had significantly shorter progression-free survival (p=0.043; 227 vs 266 days). Serum uPAR was not prognostic in this cohort. Multivariate analysis revealed increased serum uPA level (p=0.024) as a poor prognostic indicator in addition to other established prognostic factors in dogs such as humeral location (p=0.022) and increased monocyte count (p=0.015).

Conclusions Circulating uPA quantity and activity are increased in canine OSA patients with more aggressive disease, indicating importance of the uPA system in OSA disease progression. While an OSA-associated increase in circulating uPAR was not evident, this receptor likely contributes to OSA malignancy subsequent to the increased uPA ligand production. Serum uPA may be an attractive prognostic biomarker in OSA and the up-regulated uPA/uPAR axis should be further investigated as a potential therapeutic target for this disease.

Citation Format: Arata Matsuyama, Anthony J. Mutsaers. Prognostic significance of urokinase plasminogen activator system in a naturally occurring model of osteosarcoma [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 672.
Abstract 677: Immune biomarkers of response to Ra223 dichloride and stereotactic body radiation therapy in patients with oligometastatic prostate cancers
Authors: Alcantara Marice , Dorff Tanya , Liu Jessica , Frankel Paul , Twardowski Przemyslaw , Dandapani Savita , Kortylewski Marcin
Published: July 2021

Prostate cancer is the second leading cause of death in men in the developed countries. Androgen deprivation therapy (ADT) is commonly used to treat prostate tumors at earlier stages due to hormone-dependence of cancer cells. However, the onset of androgen-resistance with tumor progression and the negative impact of ADT on the quality of life are significant challenges. To address these issues, we have initiated a novel clinical trial combining radium Ra223 dichloride with stereotactic body radiation treatment (SBRT) and short course of ADT in patients with oligometastatic, castration-sensitive prostate cancer (NCT03351735). Patients with one to four oligometastatic prostate cancer lesions have been receiving ADT for nine months, together with SBRT to all metastatic sites and six cycles of Ra223 to target micrometastatic bone lesions. Eight out of the planned 24 patients have already completed the full treatment course, with five patients currently on surveillance (not requiring any further treatment) and three patients receiving next cycle of therapy. As part of this investigator-initiated study, we have performed a comprehensive immune characterization of peripheral immune cells and serum immune biomarkers in all treated patients. Based on flow cytometric analysis, we found a significant decrease in the percentage of CD4+ T cells befoe and after SBRT (cycle 1) but no changes in the elevated levels of programmed cell death-1 (PD-1), a marker of T-cell exhaustion, on the circulating CD4+ and CD8+ T cells. In addition, we observed high levels of the activated STAT3 (pSTAT3) in myeloid-derived suppressor cells (MDSCs), together with its downstream target Arginase-I. Finally, IL-8 stood out as a cytokine strongly elevated in plasma of patients who received the complete Ra223 treatment but not directly after SBRT. Overall, these preliminary results suggest that this combinatorial radiotherapy patients with oligometastatic prostate cancers impacts immune cell activity but rather than leading to T cell activation it may promote tolerogenic activity of MDSCs.

Citation Format: Marice Alcantara, Tanya Dorff, Jessica Liu, Paul Frankel, Przemyslaw Twardowski, Savita Dandapani, Marcin Kortylewski. Immune biomarkers of response to Ra223 dichloride and stereotactic body radiation therapy in patients with oligometastatic prostate cancers [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 677.
Abstract 69: A biological circuit involving Mef2c, Mef2d and Hdac9 controls the immunosuppressive functions of CD4+Foxp3+ T-regulatory cells and anti-cancer immunity
Authors: Giorgio Eros Di , Wang Liqing , Xiong Yan , Han Rongxiang , Samanta Arabinda , Trevisanut Matteo , Hancock Wayne W.
Published: July 2021

The Mads/Mef2 (Mef2a/b/c/d) transcription factors (TFs) regulate differentiation of myocytes, neurons and hematopoietic cells. Mef2 TFs are subject to regulation by negative feedback in that they promote transcription of their strong repressor Hdac9, providing temporal control of Mef2-driven differentiative responses. Disruption of this feedback occurs within various sarcomas and leukemias. In addition, Mef2 TFs indirectly control tumor progression by regulating antitumor immunity. We recently reported that in CD4+CD25+Foxp3+ T-regulatory (Treg) cells, Mef2d is required for the acquisition of an effector Treg phenotype and the activation of an epigenetic program that in turn represses the anti-cancer responses of CD4, CD8 and B-cells. We now report that similarly to Mef2d, deletion of Mef2c in Tregs switches off expression of Il10 and Ctla4 and leads to enhanced antitumor immunity in syngeneic models of lung cancer. Mechanistically, Mef2c does not directly bind to the regulatory elements of Ctla4 and Il10, but rather, its loss-of-function in Tregs induces the expression of the transcriptional repressor Hdac9. As a consequence, Mef2d, the more abundant member of the Mef2 family, is displaced from p300 and is converted by Hdac9 into a transcriptional repressor at these loci. This leads to the impairment of Treg suppressive properties and to enhanced anti-cancer immunity. These data further highlight the central role played by Mef2/Hdac9 axis in the regulation of CD4+Foxp3+ Treg function and provide a rationale for the development of small molecules targeting Mef2 and/or Mef2-containing complexes.

Citation Format: Eros Di Giorgio, Liqing Wang, Yan Xiong, Rongxiang Han, Arabinda Samanta, Matteo Trevisanut, Wayne W. Hancock. A biological circuit involving Mef2c, Mef2d and Hdac9 controls the immunosuppressive functions of CD4+Foxp3+ T-regulatory cells and anti-cancer immunity [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 69.
Abstract 691: Antibody conjugated to a bispecific RNA molecule targeting RIG-I and PLK1
Authors: Rady Tony , Erb Stéphane , Deddouche-Grass Safia , Morales Renaud , Bouchard Hervé , Chaubet Guilhem , Cianférani Sarah , Wiederschain Dmitri , Basse Nicolas , Wagner Alain
Published: July 2021

Simultaneous access to several targets has become the subject of intense studies in immuno-oncology. In order to benefit from the synergies provided by the activation of different signaling pathways in immunology and the knockdown of proteins involved in cancer cell survival, we established a bispecific approach. The activation of the innate immune response by delivering agonists of pattern-recognition receptors (PRR) such as RIG-I (retinoic acid-inducible I) represents a promising strategy. RIG-I detects short double-stranded RNA molecules ended by a 5'-di/triphosphate moiety (5'ppp-dsRNA). RIG-I activation promotes type I IFN secretion and cancer-cell selective apoptosis. To obtain a bifunctional molecule, the 5'ppp-dsRNA sequence was designed to silence PLK1 (polo-like kinase 1). Suppressing PLK1 expression with small interfering RNAs (siRNA) leads to cell cycle arrest and retards cancer cell growth. This concept of bifunctional RNAs has been validated by using non-targeted systems.1

To enhance this synergy, we conjugated this 5'ppp-siPLK1 to an antibody for a specific delivery to cancerous cells that overexpress erythropoietin-producing hepatocellular receptor A2 (EphA2) at their surface. Upon binding to EphA2 receptor, the antibody is well internalized, thus making it a good vehicle to deliver the bispecific 5'ppp-siPLK1. After EphA2-positive cells treatment, we observed RIG-I specific activation as well as PLK1 depletion. Both effects were correlated with cellular apoptosis and the mode of action was further confirmed with mechanistic and kinetic studies. Finally, while non-modified unconjugated siRNA has a very short half-life in plasma, we observed an increase in stability for the antibody-5'ppp-siPLK1 conjugates. These data suggest that anti-EphA2 receptor antibody could be used to deliver a bispecific RNA molecule.

References:1H. Poeck, R. Besch, C. Maihoefer, M. Renn, D. Tormo, S. S. Morskaya, S. Kirschnek, E. Gaffal, J. Landsberg, J. Hellmuth, A. Schmidt, D. Anz, M. Bscheider, T. Schwerd, C. Berking, C. Bourquin, U. Kalinke, E. Kremmer, H. Kato, S. Akira, R. Meyers, G. Häcker, M. Neuenhahn, D. Busch, J. Ruland, S. Rothenfusser, M. Prinz, V. Hornung, S. Endres, T. Tüting and G. Hartmann, 5′-triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma, Nat. Med., 2008, 14, 1256-1263.

Citation Format: Tony Rady, Stéphane Erb, Safia Deddouche-Grass, Renaud Morales, Hervé Bouchard, Guilhem Chaubet, Sarah Cianférani, Dmitri Wiederschain, Nicolas Basse, Alain Wagner. Antibody conjugated to a bispecific RNA molecule targeting RIG-I and PLK1 [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 691.
Abstract 694: Novel conditionally active bispecific EpCAM x CD3 T cell engagers targeting solid tumors
Authors: Cugnetti Ana Paula G. , Liu Haizhen , Wang Jing , Xing Charles , Wheeler Christina , Lucas Matthew , Chang Cathy , Frey Gerhard , Boyle William , Short Jay
Published: July 2021

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays many roles in cancer biology. EpCAM is an attractive therapeutic target due to its expression on most solid tumors. However, targeting of EpCAM protein has been limited since it is also expressed on normal epithelial tissues. In fact, initial attempts to develop EpCAM-specific T cell engagers were not successful due to severe cytokine release effects as well as serious on-target off-tumor drug related toxicities. Conditionally Active Biologic (CAB) technology is a proprietary platform that generates bispecific antibodies which have no or very little binding to CD3 or to the target antigen in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (Warburg effect). Using our CAB technology, we have developed CD3 mono-CAB (WT EpCAM x CAB CD3) and CD3/EpCAM dual-CAB (CAB EpCAM x CAB CD3) bispecific antibodies. In vitro and in vivo efficacy data as well as toxicology studies in non-human primates for mono- and dual-CAB EpCAM x CD3 bispecific antibodies targeting EpCAM will be presented. Our data demonstrate that both mono- and dual-CAB EpCAM x CD3 bispecific antibodies have potent anti-tumor activities in vivo and have much lower toxicity compared to non-CAB bispecific antibodies. The mono- and dual-CAB EpCAM x CD3 bispecific antibodies generated by the CAB technology represent a new class of potent, effective T-cell engagers with potential for increased safety margin and therapeutic index in the clinic.

Citation Format: Ana Paula G. Cugnetti, Haizhen Liu, Jing Wang, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William Boyle, Jay Short. Novel conditionally active bispecific EpCAM x CD3 T cell engagers targeting solid tumors [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 694.
Abstract 715: Flow cytometry analysis of immune response to COVID-19 vaccine candidates using an in vitro stimulation model
Authors: Shi Xiaoshan , Bornheimer Scott J. , Saksena Suraj , Widmann Stephanie , Tyznik Aaron
Published: July 2021

T cell immunity is vital for the control of viral infections. Cytotoxic CD8 T cells play a crucial role in eliminating virus-infected cells while CD4 helper T cells mediate host immune responses and promote B cells to secrete antibodies. For both, T cell recognition of viral antigens in the form of short peptides presented by HLA complexes is a prerequisite for T cell activation. Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has become a global pandemic that has disrupted economies and resulted in an enormous burden on health care systems. Despite the worldwide intensive efforts on development of COVID-19 therapeutics, a safe and effective COVID-19 treatment or vaccine is not yet available. In this study, we established an in vitro stimulation system in which peripheral blood mononuclear cells were treated with putative SARS-CoV-2 immunogenic peptides. T cell immune responses were measured using different quantitative flow cytometry panels that were designed for evaluating cytokine production or identifying T cell subsets. Evaluation of host immune responses with a suite of flow cytometric panels may prove to be useful in the study of COVID-19.

For Research Use Only. Not for use in diagnostic or therapeutic procedures. Class 1 Laser Product.BD-23276 (v1.0) 1120BD and the BD Logo are trademarks of Becton, Dickinson and Company. © 2020 BD. All rights reserved.

Citation Format: Xiaoshan Shi, Scott J. Bornheimer, Suraj Saksena, Stephanie Widmann, Aaron Tyznik. Flow cytometry analysis of immune response to COVID-19 vaccine candidates using an in vitro stimulation model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 715.
Abstract 722: The hallmark of COVID-19 cancer disparities: Cellular sequelae
Authors: McGhee Eva , LI Mengtao , Lin Yi-Ling , Carr Nefertari , Njubigbo Chinelo , Sadeghi Rohun , Su-Velez Brooke , Handler Julian , Handler Adin , Okoro Judith , Afework Sebhat , Vadgama Jay
Published: July 2021

Coronavirus disease-19 (COVID-19). Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus resulting in a severe threat to safety and public health. Genetic analyses suggest that SARS-COV-2 belongs to the Betacoronavirus group and Middle East respiratory syndrome coronavirus (MERS-CoV). Like most viruses, some are oncogenic, and genetic instability is involved in the initiating factor for tumor progression that is known to lead to malignancy, resulting in disease sequelae. Genomic instability is characterized by the increased rate of acquisition of alterations in the mammalian genome. These changes encompass a diverse set of biological end points including gene mutation and amplification, cellular transformation, clonal heterogeneity and delayed reproductive cell death. The loss of stability of the genome is becoming accepted as one of the most important aspects of viral induced carcinogenesis, and the numerous genetic changes associated with cancer cell implicate genomic stability as contributing to the neoplastic phenotype. The aim of this study is to analyze the influence of COVID-19 cancer related diseases and determine the epigenetic-genomic profiles in these diseases. In our experimental procedures, we will use oral epithelium cells as a model for this cancer study. We proposed a novel approach to study COVID-19-induced genetic changes with oral epithelium cells. We used these cells with COVID-19 co treatment to determine mechanisms that lead cells into crisis. Preliminary data using oral viral infected cells show that the viral infection can trigger certain gatekeeper proteins like p53 and pRB to be degraded and forcing cells to go into crises, and telomerase is turned on. In this study we will determine if COVID-19 transfected cells can follow the process using the Hayflick model, which show cells that are in crises, and some may progress to cancer. In summary, preliminary data show that viral infected cells that are none cancerous and are telomerase positive, may use a similar mechanism to send cells into crisis that turn telomerase on resulting in cellular malignancy.

Citation Format: Eva McGhee, Mengtao LI, Yi-Ling Lin, Nefertari Carr, Chinelo Njubigbo, Rohun Sadeghi, Brooke Su-Velez, Julian Handler, Adin Handler, Judith Okoro, Sebhat Afework, Jay Vadgama. The hallmark of COVID-19 cancer disparities: Cellular sequelae [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 722.
Abstract 738: Targeting metabolic vulnerabilities of endocrine resistant breast cancers using XPO1 and NAMPT inhibition
Authors: Zuo Qianying , Mogol Ayca , Imir Ozan , Landesman Yosef , Erdogan Zeynep Madak
Published: July 2021

Introduction: Approximately 70% of human breast cancers express estrogen receptor alpha (ERα), providing the potential for targeted endocrine therapy for patients. Unfortunately, 30-40% of ER+ patients still experience recurrence and metastasis with a 5-year relative overall survival rate of just 24%. Previously, we described metabolic changes in metastatic breast cancer cells that are driven by single therapies and the metastatic organ microenvironment. Combining selinexor (SEL), a small molecule inhibitor of exportin 1 (XPO1) approved by the FDA for treatment of some hematologic malignancies, with the current therapies used for advanced breast cancers (e.g. tamoxifen) decreased metabolic adaptations in response to individual drug treatments and prevented colony formation in hydrogels and tumor growth in xenograft models. Since we observed a reliance on NAD+ metabolism in cancer cells that are treated with single therapies, in the current study we investigated co-targeting metabolic alterations using SEL and the NAMPT inhibitor KPT-9274.

Methods: We established 3D cell culture systems in novel hydrogels derived from decellularized bone, lung, and liver tissues - the major sites of metastasis of ER+ breast cancers, and compared with standard Matrigel culture. Endocrine responsive (MCF7 and T47D) and resistant (MCF7 and T47D cells with ESR1 Y537S or D538G mutations) breast cancer cell lines were treated with SEL or KPT-9274. Tumorigenicity was assessed using in vitro cell viability and colony formation assays and in vivo breast cancer cell line xenografts in athymic mice. Metabolic changes were assessed using whole metabolite profiling by GC-MS and a Seahorse XF analyzer.

Results: Combining an FDA-approved XPO1 small molecule inhibitor, Selinexor (SEL) with the NAMPT inhibitors decreased metabolic adaptations in response to individual drug treatments, and prevented colony formation in hydrogels and tumor growth in xenograft models.

Conclusions: Targeting drug and metastatic-site induced adaptations to regenerate new vulnerabilities in endocrine-resistant breast tumors are novel. Given the need for better strategies for improving therapy response of metastatic ER+ tumors, our findings show uncovering the role XPO1-NAMPT crosstalk plays in metastatic breast cancer could lead to new combined therapies that reduce mortality.

Citation Format: Qianying Zuo, Ayca Mogol, Ozan Imir, Yosef Landesman, Zeynep Madak Erdogan. Targeting metabolic vulnerabilities of endocrine resistant breast cancers using XPO1 and NAMPT inhibition [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 738.
Abstract 743: Altered ER and PR transcription factor activity associated with endocrine therapy resistance in breast cancer
Authors: Huggins Rosemary J.
Published: July 2021

Half of estrogen receptor (ERα)-positive breast cancer patients treated with endocrine therapies display intrinsic or acquired therapy resistance. One-third of patients with acquired resistance present with metastatic tumors containing ERα-Y537S mutations. This mutation results in constitutive activity of ERα and altered ERα-associated gene expression. Previous research suggests that ERα and the progesterone receptor (PR) engage in complex interactions involving reciprocal regulation of ERα and PR transcription factor activity known as ERα/PR crosstalk. My central hypothesis is that ERα-Y537S alters the transcription factor activity of ERα and PR, causing dysregulation of gene expression in SERM-resistant breast cancer. While previous research has assessed the impact of the ERα-Y537S mutation on ERα-associated chromatin binding and gene expression, here I assess the effect of the resistance-associated ERα-Y537S mutation on ERα and PR activity and crosstalk. Simultaneous analysis of transcription factor binding activity (ChIP-seq), gene expression (RNA-seq), and proximity-based interaction (NanoBRET) indicates that active PR binding across the genome is increased in the context of ERα-Y537S, suggesting that ERα/PR crosstalk is significantly altered. Importantly, PR chromatin binding in the context of ERα-Y537S appears to be elevated regardless of the stimulation of PR activity with the agonist R5020. These findings, along with identification of candidate genes of potential therapeutic value, will be applied using patient-derived tumor organoids to determine the efficacy of simultaneously targeting ERα and PR to overcome endocrine therapy resistance in breast cancer.

Citation Format: Rosemary J. Huggins. Altered ER and PR transcription factor activity associated with endocrine therapy resistance in 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 743.
Abstract 748: Conjugated primary bile acids as a biomarker for hepatocellular carcinoma risk in two prospective cohorts
Authors: Thomas Claire Elizabeth , Luu Hung , Wang Renwei , Xie Guoxiang , Adams-Haduch Jennifer , Jin Aizhen , Koh Woon-Puay , Jia Wei , Behari Jaideep , Yuan Jian-Min
Published: July 2021

Background: Incidence rates of hepatocellular carcinoma (HCC) has been increasing for several decades in the U.S. Non-alcoholic liver disease (NAFLD) increasingly plays a role in the rising rate of HCC. Experimental data have shown that bile acids, which play key roles in the host-gut microbiota co-metabolism, contribute to the development of NAFLD and HCC. We propose to comprehensively examine the associations of bile acids with risk of HCC in two cohorts.

Methods: Thirty-five bile acids were quantified using the state-of-the-art ultraperformance liquid chromatography triple-quadrupole mass spectrometry assays in serum samples collected, on average, five years prior to diagnosis of 197 HCC and the same number of individually matched controls from the Singapore Chinese Health Study and the Shanghai Cohort Study. Conditional logistic regression was used to assess the associations for major bile acids and their conjugates, and bile acid ratios with the risk of HCC.

Results: Total primary bile acids were significantly elevated whereas the ratio of secondary bile acids over primary bile acids were significantly lower in HCC cases than controls in both cohorts (P's ≤ 0.001). Doubling of tauro- vs. glyco-conjugates of all bile acids, primary bile acids, and specifically chenodeoycholic acid resulted in an increase in HCC risk of 44, 48, and 34% (P = 0.004, <0.001, 0.001) respectively after adjustment for potential confounders.

Conclusion: Primary bile acids, especially tauro-conjugated bile acids were strongly associated with increased risk of HCC risk whereas the secondary vs. primary bile acids ratios were associated with decreased risk of HCC.

Citation Format: Claire Elizabeth Thomas, Hung Luu, Renwei Wang, Guoxiang Xie, Jennifer Adams-Haduch, Aizhen Jin, Woon-Puay Koh, Wei Jia, Jaideep Behari, Jian-Min Yuan. Conjugated primary bile acids as a biomarker for hepatocellular carcinoma risk in two prospective cohorts [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 748.
Abstract 768: Predictive role of circulating tumor cells in women with ovarian cancer
Authors: Singh Swarnima , Kumar Uday
Published: July 2021

Background: “Liquid biopsy”, where body fluids is screened for biomarkers is gathering substantial research. We aimed to examine women with suspected ovarian cancer for the presence of circulating tumor cells (CTCs) and study its role in prediction of chemoresistance and survival.

Methods: Magnetic powder labeled monoclonal antibodies for epithelial cell adhesion molecule (EpCAM), Mucin 1 cell surface associated ( MUC1) ,mucin 16, cell surface associated MUC16 or CA125 were prepared according to the manufacturer's protocol. Expression of three ovarian cancer related genes were detected in CTCs using multiplex reverse transcriptase-polymerase chain reaction (Multiplex RT-PCR). CTCs and serum CA125 were measured in 100 patients with suspected ovarian cancer. Correlations with clinicopathological parameters and treatment were analyzed.

Results: CTCs were detected in 18/70 (25.7%) of women with malignancy compared to 0/30 (0.0%) in those with benign gynecologic diseases (p=0.001). The sensitivity and specificity of the CTC test for predicting a malignant histology in pelvic masses was 27.7% (95% CI :16.3%,37.7%) and 100% (95% CI: 85.8%, 100%), respectively. The number of CTCs correlated with stage of ovarian cancer (p=0.030). The presence of EpCAM+CTC at primary diagnosis in ovarian cancer was found to be an independent predictor of a poor progression free survival (PFS) (HR,3.3; 95% CI, 1.3-8.4; p=0.010), overall survival (OS) (HR, 2.6; 95% CI,1.1-5.6; p=0.019) and resistance to chemotherapy (OR 8.6; 95% CI, 1.8-43.7; p=0.009).

Conclusion: Expression of EpCAM in CTC positive patients predicts chemotherapy resistance and prognosis, could aid clinicians in individualizing therapy, saving the patient from unnecessary side effects and systemic toxicity of platinum-based chemotherapy. Also, EpCAM expression can be a strong basis for further investigating anti-EpCAM targeted therapies in ovarian cancer.

Citation Format: Swarnima Singh, Uday Kumar. Predictive role of circulating tumor cells in women with ovarian 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 768.
Abstract 79: Crosstalk of PIM and LKB1 kinases in driving growth of prostate cancer cells
Authors: Mung Kwan Long , Eccleshall William , Santio Niina M. , Rivero-Müller Adolfo , Sahlgren Cecilia , Koskinen Päivi J.
Published: July 2021

The oncogenic PIM kinases and the tumor-suppressive LKB1 kinase have been linked to regulation of cell growth and proliferation. Here we have investigated their potential interactions as well as their relative impacts on tumorigenic growth of prostate cancer cells. The cellular functions of PIM and LKB1 kinases were evaluated using either pan-PIM inhibitors or CRISPR/Cas9-based genomic editing, with which all three PIM family members and/or LKB1 were knocked out from PC3 prostate cancer cells. In addition to cell-based 2D proliferation assays, we examined tumor growth using the chick embryo chorioallantoic membrane (CAM) xenograft model. In this report, we show that inhibition of PIM expression or activity results in increased phosphorylation of AMPK at Thr172 in an LKB1-dependent fashion. With in vitro kinase assays, we demonstrate that LKB1 is a novel direct substrate for PIM kinases and that Ser334 is one of the PIM target sites in LKB1. Accordingly, wild-type LKB1, but not the phosphodeficient S334A mutant can restore PIM inhibitor-induced AMPK phosphorylation in LKB1 knock-out cells. Whereas loss of LKB1 exaggerates formation of PC3-based tumors in the CAM xenograft model, co-deletion of PIM kinases attenuates it. The impairment of cell proliferation and tumor growth in cells lacking both PIM and LKB1 kinases not only underscores the potential crosstalk in signaling between these kinases, but also suggest that PIM inhibitors could be used to restrain growth of LKB1-deficient tumors.

Citation Format: Kwan Long Mung, William Eccleshall, Niina M. Santio, Adolfo Rivero-Müller, Cecilia Sahlgren, Päivi J. Koskinen. Crosstalk of PIM and LKB1 kinases in driving growth of prostate cancer cells [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 79.
Abstract 791: Incidence rates of digestive cancers among US military servicemen: Comparison with the rates in the general US population
Authors: Bytnar Julie A. , Shriver Craig D. , Zhu Kangmin
Published: July 2021

Background: Digestive cancers greatly contribute to the cancer burden in the United States. These cancers are more common among men and some are increasing among adults under age 50. Military population, which is dominantly male and young, and general populations differ in exposure to risk factors for these cancers. However, no studies have systematically investigated whether the incidence rates of these cancers differ between the two populations. This study aimed to compare incidence rates and trends of select digestive cancers between active-duty military and general populations.

Methods: Data were from the Department of Defenses' Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results 9 (SEER-9) registries. Age-adjusted incidence rates of colorectal, stomach, liver, and pancreatic cancers among men aged 20-59 years during 1990-2013 were compared between the two populations. Stratified analyses were done for colorectal and stomach cancers.

Results: The age-adjusted incidence rates of colorectal, stomach, liver, and pancreatic cancers were overall lower among active-duty than SEER (IRR=0.86, 95% CI=0.81-0.92; IRR=0.65, 95% CI=0.55-0.76; IRR=0.39, 95% CI=0.30-0.49; IRR=0.51, 95% CI=0.41-0.62, respectively). This was observed in the subgroups stratified by age for colorectal and stomach cancers except that among men aged 40-59 with colorectal cancer. The incidence rate of colorectal cancer was decreased the latest period (2010-2013) in ACTUR.

Conclusion: The incidence rates for selected digestive cancers overall were lower in the active-duty military population than the U.S. general population. This study highlights the need for more research enhancing our understanding of variations in these cancers between the two populations.

Citation Format: Julie A. Bytnar, Craig D. Shriver, Kangmin Zhu. Incidence rates of digestive cancers among US military servicemen: Comparison with the rates in the general US population [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 791.
Abstract 831: State of medical and surgical oncology training in India: An infrastructural challenge to delivering high-quality cancer care
Authors: Ozair Ahmad , Rahman Faique , Singh Kaushal K.
Published: July 2021

Introduction: Cancer care delivery in low- and middle-income countries (LMICs) is significantly influenced by the number and distribution of oncologists, which are products of the state of oncology training in those LMICs. In LMICs like India, where the number of trained oncologists is low, cancer care is often delivered by generalists, resulting in poorer outcomes. India, with a population of 1.38 billion people, was projected to have needed over 5000 oncologists in 2020. But, the Global Survey of Clinical Oncology Workforce reported only 1500 clinical oncologists here in 2018. Therefore, we sought to systematically determine and describe the current state of accredited oncology training in India.

Methods: We searched, in October 2020, the databases of two major accrediting bodies, the National Medical Council (NMC) and the National Board of Examinations (NBE) to determine the total number of programs and the positions therein for the fields of medical, surgical, and gynecological oncology. We correlated our search with the current regulations from NMC and NBE.

Results: Both the NMC and NBE currently offer training for 3-year specialty oncology training after 3-years of medical or surgical residency. We found India currently has a total of 166, 139, and 22 training positions for surgical, medical, and gynecological oncology respectively (Table 1). Significant variation in the number of positions exists, with a few institutions providing training to over 10 fellows, leading to concerns about the volume of training and exposure to cases. There is a clustering of training programs in major metropolitan cities.

Discussion: India is currently training a highly insufficient number of clinical oncologists for its increasing cancer burden. Clustering of training programs in metropolitan cities results in a greater likelihood of trained physicians practicing in the same location. Both of these may cause greater disparities in cancer care delivery.

Table 1.State of accredited oncology training programs and positions in India.SubspecialtyMCI-accredited trainingNBE-accredited trainingNumber of training programsTotal number of positionsMedian (IQR) number of positions per programNumber of training programsTotal number of positionsMean number of positions per programSurgical oncology23983 (2.5)36682Medical Oncology18762 (4)30632Gynecologic Oncology8152 (0.5)472

Citation Format: Ahmad Ozair, Faique Rahman, Kaushal K. Singh. State of medical and surgical oncology training in India: An infrastructural challenge to delivering high-quality cancer care [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 831.
Abstract 834: Association between ABO and Duffy blood types and circulating chemokines and cytokines
Authors: Van Alsten Sarah C. , Aversa John , Santo Loredana , Camargo M. Constanza , Huang Wen-Yi , Kemp Troy , Liu Jia , Samspon Joshua , Rabkin Charles S.
Published: July 2021

Background: Blood group antigens may play a role in immune and inflammatory processes. The aim of this analysis was to identify specific inflammatory pathways associated with blood group antigens.

Methods: We investigated associations between blood type and circulating inflammatory markers in data for 3,537 non-Hispanic white participants selected from previous case-control studies nested in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. Whole genome scans were used to infer blood types for twelve common antigen systems (ABO, Duffy, Lewis, RhE, Kidd, Kell, Secretor, Lutheran, Colton, Dombrock, Auberger, and Knops) based on well-characterized single nucleotide polymorphisms. Circulating levels of 96 immune- and inflammation-related biomarkers were measured on multiplex fluorescent bead-based panels. We estimated associations between blood type and markers using design-weighted linear or logistic regression adjusted for age, sex, smoking status, and principal components of population substructure, and using a Bonferroni correction to control for multiple comparisons.

Results: Among the 1,152 blood type-biomarker associations tested, we identified 10 which were significant after correction for multiple comparisons. ABO subtype was associated with levels of sVEGFR2, sVEGFR3, and sGP130, and Duffy subtype was associated with levels of CXCL6/GCP2, CXCL5/ENA78, CCL11/EOTAXIN, CXCL1/GRO, CCL2/MCP1, CCL13/MCP4, and CCL17/TARC. Post-hoc pairwise t-tests showed that individuals with type A blood had lower levels of all ABO-associated markers than individuals with type O or B blood, while individuals with type Fy(a+b-) had lower levels of all Duffy-associated markers than individuals with type Fy(a+b+) or Fy(a-b+).

Conclusion: ABO blood type is associated with levels of three circulating angiogenic markers, while Duffy blood type is associated with eight chemokines. Additional work to understand the clinical implications of these differences is needed.

Citation Format: Sarah C. Van Alsten, John Aversa, Loredana Santo, M. Constanza Camargo, Wen-Yi Huang, Troy Kemp, Jia Liu, Joshua Samspon, Charles S. Rabkin. Association between ABO and Duffy blood types and circulating chemokines and cytokines [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 834.
Abstract 835: T-cell abundance, clonality and disease specific survival in colorectal cancer
Authors: Bonner Joseph , Schmit Sephanie L. , Lindsey Sidney S. , Tsai Ya-Yu , Sanz-Pamplona Rebeca , Alonso M. Henar , Melas Marilena , Rennert Hedy S. , McDonnell Kevin J. , Idos Gregory , Walker Christopher P. , Kast W. Martin , Da Silva Diane , Robins Harlan S. , Greenson Joel K. , Moreno Victor , Rennert Gad , Gruber Stephen B.
Published: July 2021

Immune responses to colorectal cancer (CRC) are important prognostic factors as measured by either tumor infiltrating lymphocytes per high powered field or the presence of Crohn's like lymphoid reaction. New technologies to quantify specific features of immune responses include immunoSeq (Adaptive Biotechnologies), which accurately quantifies T-cell receptor (TCR) abundance and T-cell receptor clonality. Here we measured the independent contributions of TCR abundance and TCR clonality to 5-year CRC-specific survival in the Molecular Epidemiology of Colorectal Cancer (MECC) study. The MECC study consented, interviewed, and followed 6,006 incident cases of CRC diagnosed between March 31, 1998 and July 1, 2017 (median follow-up time = 6.9 years). Archived paraffin blocks were retrieved, and 2,750 cases had sufficient tissue and adequate DNA extraction to perform the immunoSeq assay. Analyses were restricted to 1,625 samples with more than 100 T-cells to permit accurate quantification of TCR abundance and TCR clonality as measured by Simpson Clonality Index. TCR abundance was log2 transformed for analyses, and Simpson Clonality Index was log2-transformed and z-scale normalized separately by assay version. In unadjusted models, dichotomized log2 transformed TCR abundance (Hazard Ratio (HR) = 0.57, 95% confidence interval (CI) 0.47-0.71, p=9.77E-08) and dichotomized TCR clonality (HR = 0.77, 95% CI 0.63-0.94, p=0.01) were each statistically significantly associated with 5-year CRC-specific survival. In a model with adjustment for age, sex, microsatellite instability, stage and assay version, both dichotomized log2 transformed TCR abundance (HR = 0.61, 95% CI, 0.49-0.75, p=3.03E-06), and dichotomized TCR clonality (HR = 0.81, 95% CI, 0.66-0.99, p=0.048) were associated with improved 5-year disease-specific survival.

Conclusion: TCR abundance and TCR clonality are independent prognostic indicators in CRC.

Citation Format: Joseph Bonner, Sephanie L. Schmit, Sidney S. Lindsey, Ya-Yu Tsai, Rebeca Sanz-Pamplona, M. Henar Alonso, Marilena Melas, Hedy S. Rennert, Kevin J. McDonnell, Gregory Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Harlan S. Robins, Joel K. Greenson, Victor Moreno, Gad Rennert, Stephen B. Gruber. T-cell abundance, clonality and disease specific survival in colorectal 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 835.