bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5569: Discovery of tumor-specific T cell receptors (TCRs) by reverse genetic engineering platform
Authors: Han Yanyan , Liang Xiaoling , Ou Shudan , Chen Xihe , Ma Minjun , Li Jun , Ma Yifan , Zhou Xiangjun 
Published: September 2020

Abstract
TCR-T therapy is an ideal cell therapeutic strategy against solid tumors. However, the traditional method of TCR cloning has two major problems. First, we could only develop TCRs against previously discovered tumor antigen epitopes. Second, the affinity maturation of TCR sometimes leads to mortal toxicities due to the unexpected cross-reactivities. Therefore we hereby present a reverse genetic engineering platform to clone tumor specific TCRs from immunotherapies benefit cancer patients. Multi-antigen stimulating cell therapy (MASCT) is a cell-based immunotherapy combining therapeutic DC vaccine and adoptive T cell transfer, the IND application of which was approved in China. We observed dynamic T cell responses against multiple tumor-associated antigens used in MASCT-treated HCC patients, which showed a significant correlation with clinical outcome. Based on this observation, we propose that expanded tumor-specific T cells in MASCT-benefit cancer patients could be good sources to isolate clinical relevant TCRs. A HPV positive metastatic cervical cancer patient has shown partially response after MASCT treatment alone, and survived over 5 years. Moreover, a metastatic lung cancer patient has also shown partially response and survived for longer than 2 years after combination treatment of MASCT and anti-PD1 antibody. Enhanced and persist T cell responses against several TAAs as well as HPV antigens were detected in PBMCs of both patients. We successfully expended and isolated tumor antigen-specific T cells by IFNγ-secreting cell enrichment, and obtained alpha/beta chains paired TCR sequences using single T cell NGS technology. We selected 14 pairs of TCRs isolated from cervical cancer patient for further validation. TCRs from lung cancer patient were currently under synthesis or sequencing. Among 14 TCRs, a TAA-specific TCR and a HPV18E7-specific TCR showed superior antigen specificity and optimum avidity, and would be applied for TCR-T development. Of notes, our reverse genetic engineering of TCR-T (ReGET) platform.can not only identify both HLA class I and II-restricted TCRs, but also identify novel epitopes of tumor antigens, which may provide new targets for TCR-T therapy against solid tumors.
Citation Format: Yanyan Han, Xiaoling Liang, Shudan Ou, Xihe Chen, Minjun Ma, Jun Li, Yifan Ma, Xiangjun Zhou. Discovery of tumor-specific T cell receptors (TCRs) by reverse genetic engineering platform [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5569.
Abstract 5674: Discovery of AZD9833, an oral small molecule selective degrader of the estrogen receptor (SERD)
Authors: Scott James S. , Moss Thomas , Stokes Steve , Nissink Willem M. , Morrow Christopher J. , Lawson Mandy , Cureton Natalie , Gangl Eric , Gutierrez Pablo Morentin , Mather Richard , Lindemann Justin P. , Sykes Andrew , Fisher David , Polanski Radoslaw , Carroll Danielle , Twomey Aisling Barton , Klinowska Teresa 
Published: September 2020

Abstract
The estrogen receptor alpha (ERα) is expressed in &gt;70% of breast cancers and is a clinically validated target in oncology. Anti-hormonal therapies that block ER function directly (e.g. tamoxifen) or therapies that block the production of estrogen itself (e.g., aromatase inhibitors) have proven to be effective treatments of the disease. Further advances in disease control have been made with the development of the Selective Estrogen Receptor Degrader (SERD) fulvestrant, which both antagonizes ERα-driven tumor cell growth and causes degradation of the ERα receptor. The first-generation oral SERDs, including AZD9496, showed full ER degradation in MCF-7 cells but incomplete ER degradation in other cell lines, and partial agonism. Building on that learning, extensive structure-enabled chemical optimization has resulted in the identification of a next generation oral SERD AZD9833, a potent degrader and antagonist of the ERα receptor (both EC50 &lt;1 nM in MCF7 cells) with favorable physicochemical properties (logD7.4 &lt;3). AZD9833 delivers maximal ERα degradation equivalent to fulvestrant in all ER+ cell lines tested, including MCF7, CAMA1, T47D and BT474. In addition, and in contrast to AZD9496, AZD9833 does not cause ER agonism in the endometrial carcinoma cell line Ishikawa in vitro and does not cause an increase in the thickness of the endometrium in juvenile rats. In several patient-derived and cell line xenograft models, including models with clinically relevant ESR1 mutations, AZD9833 completely suppresses tumor growth and gives equivalent pharmacodynamic activity to supra-clinical levels of fulvestrant. Furthermore, in an ESR1 wild-type and an ESR1 D538G PDX model, AZD9833 demonstrated combinatorial benefit with palbociclib. Based on this preclinical data AZD9833 has progressed into a multi-stage monotherapy and palbociclib combination First Time in Patient clinical trial, SERENA-1 (NCT03616587).
Citation Format: James S. Scott, Thomas Moss, Steve Stokes, Willem M. Nissink, Christopher J. Morrow, Mandy Lawson, Natalie Cureton, Eric Gangl, Pablo Morentin Gutierrez, Richard Mather, Justin P. Lindemann, Andrew Sykes, David Fisher, Radoslaw Polanski, Danielle Carroll, Aisling Barton Twomey, Teresa Klinowska. Discovery of AZD9833, an oral small molecule selective degrader of the estrogen receptor (SERD) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5674.
Abstract 5681: Design, synthesis and study of small molecules with both AR degradation and AKR1C3 inhibitory activities
Authors: Xing Enming , Kong Xiaotian , Lou Wei , Shi Ruihua , Cheng Xiaolin , Gao Allen C. , Li Pui Kai 
Published: September 2020

Abstract
Prostate cancer is the most common cancer in men and it is estimated that 32,000 men in the US alone will die of this cancer in 2019. Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer therapy. However, most of the patients will progress to castration resistance prostate cancer (CRPC) after several years of treatment. The current treatment of CRPC includes chemotherapeutic agents (docetaxel) and agents that target androgen signaling (abiraterone, enzalutamide and apalutamide). Ultimately, however, most patients develop resistance to the treatments. Two of the mechanisms of resistance involve the expression of constitutively active androgen receptor variant (AR-V7) and the increase in intra-tumoral biosynthesis of androgens. Several treatment strategies targeting AR-V7 have been reported. For the intra-tumoral biosynthesis of androgens, one of the enzymes, AKR1C3, plays a critical role in the development of CRPC and has been reported to be consistently elevated in CRPC patients who are resistant to abiraterone and enzalutamide.
We have been involved in the development of agents to treat CRPC and overcome drug resistance of CRPC patients. We reported that niclosamide, an FDA-approved anthelminthic agent, could degrade AR-V7. We also reported that niclosamide, as well as an AKR1C3 inhibitor, indomethacin, were able to overcome enzalutamide and abiraterone resistance in several prostate cancer cell lines, suggesting that niclosamide is also an AKR1C3 inhibitor. By examining the reported structures of AKR1C3 inhibitors, niclosamide was found to contain the core scaffold of 4-Hydroxy-1-(4-methoxybenzyl)-N-(3-(trifluoromethyl) phenyl)-1H-1,2,3-triazole-5-carboxamide. Using this knowledge, we designed a series compounds with dual AR degrading and AKR1C3 inhibitory activities. Preliminary studies showed the compounds caused AR-V7 degradation and to a lesser extent AR full length degradation. The compounds also inhibited AKR1C3 and caused a dose dependent growth inhibition of several prostate cancer cell lines.
Citation Format: Enming Xing, Xiaotian Kong, Wei Lou, Ruihua Shi, Xiaolin Cheng, Allen C. Gao, Pui Kai Li. Design, synthesis and study of small molecules with both AR degradation and AKR1C3 inhibitory activities [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5681.
Abstract 5751: Patient-reported toxicities in head and neck cancer patients treated with immunotherapy
Authors: James Brian W. , Hoogland Aasha I. , Irizarry-Arroyo Nathaly , Muzaffar Jameel , Kirtane Kedar , Kish Julie A. , Jim Heather S. , Chung Christine H. 
Published: September 2020

Abstract
Background: Immune checkpoint inhibitors (ICIs) (i.e. nivolumab, pembrolizumab) are FDA-approved agents used in the treatment of various head and neck malignancies. While much is known about clinician-rated adverse clinical events of these immunotherapies from clinical trials, less is known about patient-reported toxicities. The goal of the current study was to describe patient-reported toxicities in patients receiving ICIs for head and neck cancer.
Methods: Patients with head and neck cancer were recruited as part of a larger study on quality of life on ICIs. Prior to initiation of ICIs, participants completed a sociodemographic questionnaire and a measure of symptomatic toxicities of ICIs developed based on input form providers, patients, and caregivers. Patients completed follow-up symptom assessments every 6-8 weeks until cancer progression. Severity of each symptom over the past 7 days was rated on a 5-point scale (i.e., 0 = “not at all,” 4 = “very much”). A score of 3 or 4 was considered moderate to severe symptomatology.
Results: There were 45 patients (22% female; M age = 62), who completed a least 2 symptom assessments before cancer progression. The five most common moderate to severe symptoms at baseline were fatigue (27%), changes in taste (18%), insomnia (16%), coughing (11%), and muscle aches (9%). At the assessment before cancer progression, the five most common moderate to severe symptoms were fatigue (38%), insomnia (24%), rash (13%), cough (13%), and numbness in hands and feet (13%). From the baseline assessment to the last symptom assessment preceding progression, most patients reported worsening skin dryness (49%), skin sensitivity (46%), weakness in arms of legs (46%), and itching (42%). Most patients also reported worsening fatigue (49%), although a large subset reported improvements in fatigue (36%).
Conclusion: Results indicate that fatigue and insomnia are the most common and severe patient-reported toxicities of ICIs for head and neck cancer. These preliminary findings warrant larger future studies with longer follow-up to better understand changes in patient-reported toxicities in this population.
Citation Format: Brian W. James, Aasha I. Hoogland, Nathaly Irizarry-Arroyo, Jameel Muzaffar, Kedar Kirtane, Julie A. Kish, Heather S. Jim, Christine H. Chung. Patient-reported toxicities in head and neck cancer patients treated with immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5751.
Abstract 5817: Anti-tropomyosin drugs prevent the rescue of vincristine-induced mitotic spindle defects
Authors: Gunning Peter , Wang Yao , Stear Jeff H. , Swain Ashleigh , Xu Xing , Bryce Nicole , Alieva Irina B. , Dugina Vera B. , Cripe Timothy , Stehn Justine , Hardeman Edna C. 
Published: September 2020

Abstract
Drugs targeting a major component of the actin filaments of cancer cells, tropomyosin Tpm3.1, synergize with anti-microtubule drugs in neuroblastoma and lung cancer models both in vitro and in vivo and a wide range of other cancer types in vitro. We have determined the mechanism of synergy in HeLa cells to gain insight into the potential interaction of actin filaments and microtubules in the survival and proliferation of cancer cells. HeLa cells exhibit a strong synergistic response to the combined treatment of vincristine (VCR) and anti-Tpm3.1 compounds, marked by an enhanced reduction in cell viability, apoptosis induction and mitotic cell cycle arrest. Tpm3.1 localizes to the cell cortex during mitosis, potentially associating with the microtubule network, particularly the dynein/dynactin complexes responsible for mediating cortical pulling forces during spindle assembly. VCR alone causes supernumerary NuMA organized acentrosomal microtubule organizing centers upon nuclear envelope breakdown, which can be resolved via a clustering mechanism to achieve bipolar cell division. The addition of anti-Tpm3.1 compounds inhibits NuMA-associated clustering in VCR-treated cells, leading to irreparable defects during spindle assembly and thus a largely increased number of cells with multi-polar spindles undergoing mitotic delay and catastrophe. We conclude that actin/Tpm3.1 filaments contribute to the formation of the bipolar spindle and play a critical role in the clustering of acentrosomal microtubule asters.
Citation Format: Peter Gunning, Yao Wang, Jeff H. Stear, Ashleigh Swain, Xing Xu, Nicole Bryce, Irina B. Alieva, Vera B. Dugina, Timothy Cripe, Justine Stehn, Edna C. Hardeman. Anti-tropomyosin drugs prevent the rescue of vincristine-induced mitotic spindle defects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5817.
Abstract 5822: Targeting an immortalization mutation to control glioblastoma
Authors: Iyer Jayashree S. , Tang Nanyun , Ferdosi Shayesteh R. , Gokhale Vijay , Hurley Laurence H. , Dhruv Harshil D. , Berens Michael E. 
Published: September 2020

Abstract
Glioblastoma multiforme (GBM), the most aggressive primary brain cancer, is a heterogeneous disease. Standard treatment of temozolomide and radiation therapy has remained unchanged for the past thirty years. However, over 80% of GBM tumors have a telomerase reverse transcriptase (TERT) promoter mutation, or TPM. Telomerase is an enzyme containing the catalytic subunit, telomerase reverse transcriptase (TERT), that mediates telomere elongation in the nucleus. In the absence of any effective molecular targeting therapy for GBM, the elucidation of oncogenic signaling of TERT could open new avenues in GBM treatment. Canonically, mutations of TERT, which result in TERT upregulation, maintain telomere length in the nucleus and promote indefinite proliferation of cancer cells. However, a non-canonical function of TERT in the mitochondria has recently been suggested. We screened GBM cell models against a novel small molecule inhibitor (RG1534, Reglagene Inc.) that interferes with the functionality of a mutated TERT promoter. RG1534 selectively suppresses glioma cell viability without affecting non-transformed normal human astrocytes. A dose dependent response was observed in glioma cell lines, resulting in a decrease in TERT mRNA expression. To validate this, TERT protein levels in glioma cells treated with RG1534 were measured and results showed a reduction in expression post treatment. More interestingly, RG1534 treatment leads to rapid induction of apoptosis in glioma cell line which does not correlate with the time course of the telomere shortening effect. Based on prior findings that mitochondrial TERT is involved in DNA damage, we conducted the fractionation of various glioma cell lines to measure the protein expression of TERT in subcellular compartments. We observed a higher expression of TERT in the mitochondria compared to the nucleus. This suggests that TERT may have non-canonical functions outside of telomeric elongation. In summary, our results demonstrate that non-canonical functions of TERT may play a critical role in glioma pathobiology and warrants further study.
Citation Format: Jayashree S. Iyer, Nanyun Tang, Shayesteh R. Ferdosi, Vijay Gokhale, Laurence H. Hurley, Harshil D. Dhruv, Michael E. Berens. Targeting an immortalization mutation to control glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5822.
Abstract 5831: Clearance of therapy-induced senescent cancer cells by the senolytic ABT-263 in a model of non-small cell lung cancer
Authors: Carpenter Valerie , Saleh Tareq , Gewirtz David 
Published: September 2020

Abstract
While most chemotherapies will initially lead to tumor reduction in patients, residual tumor cells that enter a state of dormancy can re-emerge as aggressive, recurrent disease after treatment is terminated. One mechanism by which cancer cells may escape chemotherapy-induced death is senescence. Senescence is a specialized form of cell cycle arrest that is primarily characterized as a durable, prolonged loss of proliferative capacity. While senescence was traditionally considered to be irreversible, evidence has accumulated in recent years supporting the premise that senescence is instead a durable form of growth arrest from which a subpopulation of cells can ultimately escape. Moreover, the accumulation of senescent cells post cancer therapy has been linked with a plethora of unfavorable outcomes. A sequential approach in which chemotherapy is followed by a senolytic, an emerging class of drugs that selectively kill senescent cells, may therefore delay or circumvent recurrent disease by eliminating residual senescent cells. To this end, we tested whether etoposide- or radiation-treated non-small cell lung cancer (NSCL) cells become susceptible to the BH-3 mimetic ABT-263– an established senolytic– following senescence induction. Treatment with etoposide or radiation induced a robust senescent state, as evidenced by the development of multiple senescent phenotypes. Senescent tumor cells demonstrated increased sensitivity to ABT-263 compared to non-senescent cells, undergoing rapid apoptosis subsequent to ABT-263 exposure. We further determined that ABT-263's mechanism of action appears to depend upon the disruption of the BCL-XL/Bax interaction. ABT-263's capacity to eliminate senescent cells is conserved in vivo, as tumor-bearing animals treated with etoposide followed by ABT-263 undergo rapid tumor reduction followed by tumor maintenance, while etoposide-only treated animals develop progressive disease subsequent to treatment completion. These data support the use of senolytics as complementary therapy to eliminate residual tumor cells following chemotherapy or radiation, and thereby potentially delay or reduce recurrent disease.
Citation Format: Valerie Carpenter, Tareq Saleh, David Gewirtz. Clearance of therapy-induced senescent cancer cells by the senolytic ABT-263 in a model of non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5831.
Abstract 5855: The genomic landscape of Mongolian hepatocellular carcinoma
Authors: Candia Julián , Bayarsaikhan Enkhjargal , Tandon Mayank , Budhu Anuradha , Forgues Marshonna , Lack Justin , Chao Ann , Chinburen Jigjidsuren , Wang Xin W. 
Published: September 2020

Abstract
Mongolia has the highest incidence of-and mortality from- hepatocellular carcinoma (HCC) in the world, which is between three and seven times higher than that observed in other high-incidence populations, such as South Korea, Thailand, and China. In Mongolia, where cancer is the second most common cause of death accounting for nearly a fifth of deaths, HCC is the most prevalent cancer type at about 40% of all cancers. Despite the daunting proportion of this longstanding health crisis, the molecular landscape of Mongolian HCC has not been studied yet. Filling this gap, we aim to identify robust molecular subclasses and driver features informative of the etiology and progression of the disease. Here, we describe molecular characteristics of 76 Mongolian HCC patients by whole-exome and whole-transcriptome sequencing. We present a comprehensive comparison of mutational signatures, driver genes and molecular subtypes of Mongolian HCC versus 373 HCC patients of different ethnicities and diverse etiologies. Mongolian HCC consists of several similar prognostic molecular subtypes in patients from other areas of Asia, Europe and North America as well as several unique types, suggesting potentially the presence of unique etiologies linked to Mongolian patients. Consistently, Mongolian HCC exhibits several common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analyses but also a unique driver (SPTA1) that may be linked to hepatitis D viral infection. Furthermore, unique hotspot missense mutations were identified in driver genes GTF2IRD2B and PNRC2. These results indicate the existence of novel molecular mechanisms at play in Mongolian hepatocarcinogenesis.
Citation Format: Julián Candia, Enkhjargal Bayarsaikhan, Mayank Tandon, Anuradha Budhu, Marshonna Forgues, Justin Lack, Ann Chao, Jigjidsuren Chinburen, Xin W. Wang. The genomic landscape of Mongolian hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5855.
Abstract 5868: Cell barcoding, genetic screens and expression profiling at a single-cell level
Authors: Chenchik Alex , Makhanov Mikhail , Darst Russell , Deng Debbie , Tedesco Donato , Diehl Paul , Kobzik Lester 
Published: September 2020

Abstract
Novel single-cell methods for profiling clonal composition and phenotypes of genetically modified cancer cells may improve understanding of tumorigenesis and guide the development of new anti-cancer drugs. To facilitate these studies, we developed a panel of lentiviral barcoded sgRNA libraries to label and monitor cancer cells in time-course experiments in vitro and in mouse xenograft models. The sgRNA effectors and cellular barcodes are transcribed from lentiviral constructs and can be detected by NGS in a single-cell RNA expression profiling assay, allowing characterization of the subpopulation of cells descended from a single, barcoded knockout progenitor cell. To scale up genetic analysis, cell barcodes were incorporated in conjunction with sgRNA effector libraries to identify clonal phenotypic changes induced by specific genetic disruptions in progeny cells derived from a single progenitor cell. However, effective single-cell genetic screening designed for even only a few hundred genes requires expression profiling of one hundred thousand cells (or more) and is not practical using currently available instrumentation. Data will be presented showing how genetic screen technology combined with targeted RNA expression profiling of barcoded knockout cells can be applied for large-scale genetic screens and significantly improve phenotyping of distinct cell populations in several cancer model systems. Preliminary studies demonstrate the assay to have unparalleled throughput, sensitivity, and improved cost-effectiveness for high-throughput drug target discovery applications.
Citation Format: Alex Chenchik, Mikhail Makhanov, Russell Darst, Debbie Deng, Donato Tedesco, Paul Diehl, Lester Kobzik. Cell barcoding, genetic screens and expression profiling at a single-cell level [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5868.