bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 126: Extreme selection constrains ability of EGFR-driven lung adenocarcinoma to diversify in response to erlotinib therapy
Authors: Fisk J Nicholas , Gaffney Stephen , Politi Katerina , Gettinger Scott , de Miguel Fernando , Townsend Jeffrey 
Published: April 2023

Abstract
The acquisition of resistance by tumors to targeted molecular therapies remains one of the greatest challenges in precision medicine. Evolutionary techniques, such as phylogenetic analysis and the thoughtful calculation of selection intensities, are well suited to offer guiding insights in describing and, ultimately, overcoming therapeutic resistance.
Here, we quantify the relative importance of mutations occurring during EGFR targeted therapy on a cohort of Lung Adenocarcinoma (LUAD) patients using clinical records to calibrate phylogenetic chronograms to identify variants occurring on branches of the tumor phylogeny coinciding with targeted EGFR therapy and calculate the evolutionarily-derived cancer effect size for those variants. We then compare these results to other cancer contexts to reveal the strikingly high effect size of the EGFR T790M mutation. To probe and quantify the constraints therapeutically driven selection pressure places on the cohort, we predict the neoantigen composition for each patient for both extant and ancestral tumor states, using a general allele frequency selection model to calculate selection on cancer variants constituting putative neoantigens. We then compare the proportion of negatively and positively selected neoantigens to non-neoantigen variants within the tumor to deduce if neoantigens are subject to additional immune scrutiny in a background of therapeutics. Lastly, we perform ancestral state reconstruction and mutational signature analysis to provide further insight on mutational processes on both individual patient and cohort levels, detailing how these endogenous and exogenous processes shift between etiologically pertinent time-points. Taken together, our results detail the degree of selection on cancer undergoing targeted therapy and highlights unique shifts in mutational processes in response to such therapies, ultimately offering quantitative insights that can inform clinical decision making regarding therapeutic strategies in Lung Adenocarcinoma and provide a framework for analyzing similar cancer systems.
Citation Format: J Nicholas Fisk, Stephen Gaffney, Katerina Politi, Scott Gettinger, Fernando de Miguel, Jeffrey Townsend. Extreme selection constrains ability of EGFR-driven lung adenocarcinoma to diversify in response to erlotinib therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 126.
Abstract 1293: GPRC5A drives an implantation-like phenotype in early-stage lung disseminated cancer cells of esophageal squamous carcinoma
Authors: Zhou Hongyu , Liu Beilei , Wong Ching Ngar , Guan Xinyuan 
Published: April 2023

Abstract
Esophageal squamous carcinoma (ESCC) is one of the leading malignancies worldwide, especially in Asian countries, largely threatening human life. The 5-year survival rate of ESCC is less than 20%, and patients with distant metastases have dismal survival with &lt;5% of five-year survival rate. Traditional therapies e.g., surgery, chemotherapy, radiotherapy demonstrate poor clinical outcomes for ESCC patients. Metastases are commonly seen in ESCC patients, and lung metastases approximately account for 5% of all ESCC metastases. The underlying mechanism of ESCC lung metastasis remains unsettled. In our study, we established ESCC lung metastasis mice model via intravenous injection of ESCC cells in multiple timepoints. Lung disseminated cancer cell (DCCs) of different timepoints were isolated and thrown into single cell RNA sequencing (scRNA-seq). Via bioinformatic analysis, we found the upregulated genes in early-stage lung DCCs were highly enriched in embryo development, placenta development, pre-implantation embryos processes, neither in late-stage lung DCCs. It highly suggested that ESCC lung metastasis process might be similar to embryo implantation. Based on above findings, 5 intersected genes (GPRC5A, FSTL3, WNT7A, TM4SF1, NT5E) of early-stage lung DCCs and embryo implantation were figured out to construct an implantation-like signature. Enrichment analysis results implied that ESCCs subgroups with implantation-like phenotype showed higher ability to migration, focal adhesion and response to stress. Preliminary data indicated that the representative gene GPRC5A was upregulated in ESCC tumors compared with normal esophageal epithelium in clinical samples and public databases. GPRC5A overexpression promoted tumor growth, invasion, migration and sphere formation both in vivo and in vitro, as the same as other two signature genes, WNT7A and FSTL3. Moreover, GPRC5A-overexpresssing ESCC cells displayed high ability to develop resistance to stress and generated less reactive oxygen species (ROS) in vitro. In vivo, GPRC5A overexpression increased the quantalities of early-stage lung DCCs in ESCC lung metastasis mice model and disruption of GPRC5A expression abolished its pro-metastatic effect. Together, our preliminary findings identify an implantation-like signature in early-stage ESCC lung metastasis and disrupting this phenotype helps to prevent ESCC tumorigenesis and metastasis.
Citation Format: Hongyu Zhou, Beilei Liu, Ching Ngar Wong, Xinyuan Guan. GPRC5A drives an implantation-like phenotype in early-stage lung disseminated cancer cells of esophageal squamous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1293.
Abstract 1319: Saffron (Crocus sativus) extract inhibits migration and invasion of cancer cells through modulation of MMP-3 and MMP-9 expression
Authors: King Tyler , Moscardini Stefana , Martin McKenzie , Rehman Fatima K. 
Published: April 2023

Abstract
Saffron is a spice that has been used throughout history for various therapeutic properties. Recently, it has also been documented to have a significant anticancer effect on primary tumors. However, limited studies are found studying its effect on the metastatic potential of cancers. The goal of our study was to explore the effect of saffron on the migration and metastatic potential of breast cancer cells.
Methods: MDA468 breast carcinoma cells were treated with varying concentrations of Saffron (100-1000 ug/mL) and examined using Q-phase holographic time-lapse microscopy to measure the movement of cells over time. The anticancer activity of Saffron was confirmed using cell viability assays. Invasion and metastatic potential were studied using Boyden-chamber and scratch wound assays. Finally, the tumorigenicity of the cell line was examined through colony formation assays in the presence and absence of Saffron.
Results: Q-phase microscopy revealed a reduction in projections and significantly reduced movements in cells after Saffron treatment. The inhibition of migration, cell mobility and invasion by Saffron was confirmed through scratch wound and Boyden chamber assays (p&lt;.01). Saffron extract also resulted in inhibition of viability in a dose-dependent manner and colony formation assays found markedly reduced size and number of colonies in the presence of the extract. Western blot results showed marked reduction of MMP-3 and MMP-9 expression in Saffron-treated cells.
Conclusions: Our results found saffron to be effective in decreasing breast cancer carcinoma cells MDA468’s viability, migration, and tumorigenicity. Initial results indicate that Saffron may reduce migratory ability of cancer cells through the modulation of metalloproteinases.
Citation Format: Tyler King, Stefana Moscardini, McKenzie Martin, Fatima K. Rehman. Saffron (Crocus sativus) extract inhibits migration and invasion of cancer cells through modulation of MMP-3 and MMP-9 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1319.
Abstract 1352: SOX17 plays a critical role in immune evasion of colorectal cancer
Authors: Goto Norihiro , Goto Saori , Westcott Peter , Imada Shinya , Agudo Judith , Yilmaz Omer 
Published: April 2023

Abstract
Colorectal cancers (CRCs) are a leading cause of cancer-related death. Most CRCs are immune cold, and do not respond to checkpoint blockade therapy except for microsatellite-high CRCs harboring high mutational burdens. Deciphering the mechanism by which CRC cells evade immune surveillance has the potential to dramatically improve the prognosis of CRC patients. During tumor evolution of CRCs, epigenetic changes play critical roles in addition to accumulation of genetic mutations. However, distinct mutational patterns and patient backgrounds render it challenging to distinguish the driver epigenetic alterations from passenger epigenetic alterations induced by gene mutations or other environmental factors. Identification of the driver epigenetic alterations may provide novel mechanistic insights into colon cancer biology including how they evade immune surveillance. Here, we utilized the colon cancer organoid orthotopic transplantation approach to establish colon cancer organoids from different stages of the tumors, and performed comprehensive epigenomic and transcriptomic analyses to understand the epigenetic alterations during tumor evolution. We found that in vivo environment induces epigenetic alterations that converge on SOX17, a transcription factor that is required for endoderm development. SOX17 is re-expressed in colon cancers in vivo, but not in the in vitro organoid culture, and reprograms tumor cell fate with fetal intestinal gene expressions. Importantly, SOX17 knockout leads to tumor rejection in immunocompetent mice, but not in immunodeficient mice, by turning immune cold tumors into hot tumors with robust intratumoral infiltration of activated CD8+ T cells. Mechanistically, SOX17 directly downregulates Ifngr1 expression and mitigates MHC-I expression to evade CD8+ T cell-mediated tumor cell killing. Together, our result reveals that SOX17 is a master transcription factor that induces the in vivo epigenetic reprograming of tumors, which contributes to the immune evasion of colon cancers.
Citation Format: Norihiro Goto, Saori Goto, Peter Westcott, Shinya Imada, Judith Agudo, Omer Yilmaz. SOX17 plays a critical role in immune evasion of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1352.
Abstract 1499: HOXC6 gene functions as an oncogenic driver in HPV+ head and neck squamous cell carcinoma (HNSCC)
Authors: Choudhury Subhendu Roy , Mukhina Vera , Vyshkvorkina Iuliia , Gore Jessica , Anderson Alexa , Gaykalova Daria A. 
Published: April 2023

Abstract
Homeobox C6 (HOXC6) belongs to the member of the homeobox family, a highly conserved transcription factor that plays an essential role in morphogenesis and cellular differentiation during embryonic development. Previous studies reported that the dysregulation of HOXC6 gene expression plays a crucial role in carcinogenesis. HOXC6 is reportedly over-expressed in several types of human cancer, including breast, leukemia, and lung cancers. Moreover, higher expression of HOXC6 leads to lymph node metastasis. In addition, it has been also demonstrated that in prostate cancer cells, HOXC6 downregulation reduced cell proliferation by inducing apoptosis. Although the precise mechanisms of HOXC6 in carcinogenesis still need to be investigated. In a secondary data analysis from our previous study, we identified HOXC6 is upregulated and enriched with tumor type-specific enhancer region in HPV+HNSCC samples. Moreover, we used publicly available TCGA data consisting of 520 HNSCC samples and a JHU cohort with 47 HPV+ HNSCC samples to illustrate that HOXC6 is more highly expressed in HPV+ HNSCC than in adjacent normal samples. We further validated the HOXC6 overexpression through an in vitro study using HPV+HNSCC cell lines and patient tissue samples. Clinicopathological data from TCGA indicated that higher HOXC6 expression correlated with poor overall survival. To explore the function of HOXC6 in HNSCC, we knocked down HOXC6 in HPV+ HNSCC cells via siRNA and performed the cell proliferation assay. We observed that HOXC6 downregulation decreased the cell proliferation rate compared to control samples. In conclusion, our results suggest HOXC6 acts as an oncogenic driver in HPV+ HNSCC progression, which is potentially regulated by tumor type-specific enhancers and may serve as a potential biomarker.
Citation Format: Subhendu Roy Choudhury, Vera Mukhina, Iuliia Vyshkvorkina, Jessica Gore, Alexa Anderson, Daria A. Gaykalova. HOXC6 gene functions as an oncogenic driver in HPV+ head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1499.
Abstract 1548: CO-1008, an ADC program targeting leukemic progenitor and blast AML cells, but not normal hematopoetic progenitor cells
Authors: Kaushik Garima , Vishwakarma Bandana , Bell Marina , Komurov Kakajan 
Published: April 2023

Abstract
The overall survival of patients diagnosed with Acute Myeloid Leukemia (AML) remains low. While initial responses to therapy are favorable, the duration of response is short, and overcoming therapeutic resistance has proven difficult. The presence of chemoresistant leukemic stem cells (LSCs), among other mechanisms, has been implicated as a driver in the observed relapse. Antibody-drug conjugates (ADC) are targeted cancer therapeutics that leverage antigen specificity to deliver a potent cytotoxic payload. Recently, ADCs have shown promise in the clinic, but can also present safety and efficacy concerns. Mylotarg, an FDA approved CD33-directed ADC used to treat Acute Myeloid Leukemia, was the first ADC to be approved. The therapeutic is active against most AML tumors but can lead to severe myelotoxicity given the expression of CD33 on normal myeloid progenitor cells. We leveraged a pharmaco-pheno-multiomic analysis of primary AML tumors to uncover a previously unexplored target expressed on both LSCs and AML blasts, but not normal hematopoetic progenitor cells or other normal tissue. The target also showed capacity to rapidly internalize and has activity of well-established oncogenic kinases associated with expression. A novel monoclonal antibody (IgG1) with favorable binding and biophysical characteristics was established against this novel target and conjugated to a highly potent cytotoxic agent, creating a novel ADC. This ADC shows strong binding across AML tumors with effective internalization and highly potent killing of AML tumors.
Citation Format: Garima Kaushik, Bandana Vishwakarma, Marina Bell, Kakajan Komurov. CO-1008, an ADC program targeting leukemic progenitor and blast AML cells, but not normal hematopoetic progenitor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1548.
Abstract 1563: Concomitant inhibition of Aurora kinase A and WEE1 kinases results in synergistic tumor control and heightens DNA replication stress in head and neck and lung carcinomas
Authors: Lee Jong Woo , Kim Sundong , Cruz-Gomez Sebastian , Shi Jackie , Yang Cindy , Burtness Barbara 
Published: April 2023

Abstract
Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) and lung cancer mainly harbor disruptive mutations in TP53 and/or CDKN2A tumor suppressor genes, which are associated with refractoriness to treatment as well as poor prognosis and survival. Mutational loss of TP53 function fosters elevated expression of Aurora kinase A (AURKA) that plays a crucial role in mitotic progression at G2/M and stabilizes DNA replication forks at S phase. We have previously demonstrated that combined inhibition of AURKA and WEE1, a G2/M checkpoint kinase induced by replication stress, results in synergistic anti-tumor effects in HNSCC in vitro and in vivo. We have now further confirmed synergy using the highly selective AURKA inhibitor VIC1911 in HNSCC and lung cancers harboring TP53 mutations and explored mechanisms of cell death. VIC1911 and adavosertib combination synergistically suppressed cell growth and survival in both 2D- and 3D-culture systems relative to vehicle or single-agent treatment in TP53-mutated HNSCC FaDu and CAL27, and lung cancer A549 and NCI-H358 cells, with no observable toxicity in normal cells, predicting a favorable therapeutic index. Furthermore, combination treatment accelerated mitotic entry and resulted in accumulation of mitotic catastrophe, as demonstrated by time-lapse imaging, and apoptotic cell death as evidenced by cleaved PARP assays. Notably, we found that combination VIC1911 and adavosertib in HNSCC cells drastically slowed and stalled progression of replication forks in DNA fiber analysis (Mean: DMSO=3.117; adavosertib=1.495; VIC1911=0.9757; combination=0.5548 kb/min; P &lt;0.0001) and amplified DNA damage as measured by γH2AX, indicating induction of severe replication stress. In vivo, this combination resulted in significant tumor regression in both HNSCC and lung adenocarcinoma patient-derived and cancer cell-derived xenografted mice compared with either vehicle or single-agent treatment. Taken together, these results suggest that AURKA inhibition increases dependency on WEE1 by enhancing replication stress and mitotic catastrophe, and support clinical evaluation of combined AURKA and WEE1 inhibition as a novel and effective treatment for HNSCC and lung cancer patients with elevated AURKA expression.
Citation Format: Jong Woo Lee, Sundong Kim, Sebastian Cruz-Gomez, Jackie Shi, Cindy Yang, Barbara Burtness. Concomitant inhibition of Aurora kinase A and WEE1 kinases results in synergistic tumor control and heightens DNA replication stress in head and neck and lung carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1563.
Abstract 1648: Discovery of a potent and selective PARP1 inhibitor and trapper with anti-tumor activities in HRD tumors
Authors: Gao Mingming , Li Zhentian , Fan Qipeng , Pan Jun , Bai Yu , Zhang Hewen , Li Yu , Wu Yongzhong , Liu Phillip C.C. , Wu Liangxing , Yao Wenqing , Wang Hui 
Published: April 2023

Abstract
PARP1/2 inhibitors are FDA approved for treatment of cancers such as ovarian, prostate, pancreas and breast with greatest activity against tumors harboring BRCA1 or 2 mutation or homologous recombination deficiency (HRD). A shared adverse event that contributes to a narrow therapeutic index and limits combination potential is hematologic toxicity. First generation PARP inhibitors are not selective against PARP2, which has been shown to play a role in the survival of hematopoietic progenitor cells in animal models. However genetic studies suggest that the synthetic lethality from PARP trapping with HRD is primarily dependent on PARP1. We hypothesized that a potent and selective PARP1 inhibitor and trapper would achieve equivalent anti-tumor activity as non-selective PARP inhibitors while alleviating toxicities caused by PARP2 inhibition.
SNV-001 is a novel, proprietary, potent, and selective PARP1 inhibitor and trapper. In PARylation assays, SNV-001 inhibited PARP1 activity with low nanomolar potency and displayed greater than 500-fold selectivity against PARP2. In cellular PARP trapping assays, SNV-001 potently trapped PARP1 on DNA in a dose-dependent manner but did not trap PARP2 up to 25 µM. Functionally, SNV-001 exhibited selective growth inhibitory activity against cancer cell lines with impaired HR function. In anti-proliferation and colony formation assays of BRCA-mutant cell lines including MDA-MB-436 (BRCA1 deficient) and DLD1 (BRCA2 knockout), SNV-001 inhibited cell growth and colony formation with single-digit nM IC50 values while having minimal effects against BRCA-WT cells. In a subcutaneous MDA-MB-436 xenograft tumor model, SNV-001 administered orally once daily achieved dose-dependent inhibition of PARylation in vivo. Furthermore, SNV-001 showed dose-dependent tumor growth inhibition using low daily doses with greater efficacy compared to olaparib dosed at 100 mg/kg once daily. In the cohort receiving a higher dose of SNV-001, all animals showed complete regression after 35 days of treatment without any clinical signs of toxicity.
In summary, we have discovered SNV-001, a potent and selective PARP1 inhibitor and trapper that shows excellent activity against cancer models with HRD in vitro and in vivo. These data support advancement of SNV-001 into clinical development for patients with tumors characterized by HRD.
Citation Format: Mingming Gao, Zhentian Li, Qipeng Fan, Jun Pan, Yu Bai, Hewen Zhang, Yu Li, Yongzhong Wu, Phillip C.C. Liu, Liangxing Wu, Wenqing Yao, Hui Wang. Discovery of a potent and selective PARP1 inhibitor and trapper with anti-tumor activities in HRD tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1648.