bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B022: The NEDD8 pathway as a therapeutic target in HER2-amplified colorectal cancer
Authors: Invrea Federica , Carugo Alessandro , Petti Consalvo , Draetta Giulio , Medico Enzo 
Published: December 2022

Abstract
Colorectal cancer (CRC) is a heterogeneous disease with a wide spectrum of clinical outcomes, from indolent resectable disease to aggressive-metastatic cases. Primary and acquired resistance limits the efficacy of available treatments, and the identification of effective drug combinations is needed to further improve patients' outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induces tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a drop-out loss-of-function synthetic lethality screening with a shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at various levels could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. Our results suggested possible therapeutic opportunities in specific CRC clinical settings. We further focused on HER2-amplified CRC and found marked sensitivity to pevonedistat in a CRC cell line carrying HER2 amplification. In these cells, long-term in vitro treatment with a combination of lapatinib and trastuzumab induces the emergence of colonies of long-term persisters (i.e., cells surviving to several weeks of HER2/EGFR blockade). These persisters display extremely slow growth and senescence features, however they fully recover upon removal of the blockade, mimicking disease relapse in patients after treatment suspension. Interestingly, persister colonies maintained sensitivity to pevonedistat, displaying a marked decrease when pevonedistat was added after six weeks of HER2/EGFR blockade, independently of the continuation of the blockade. These results unveil the possibility of employing pevonedistat in HER2-amplified CRC patients subsequently to tumor stabilization or regression by HER-2/EGFR blockade.
Citation Format: Federica Invrea, Alessandro Carugo, Consalvo Petti, Giulio Draetta, Enzo Medico. The NEDD8 pathway as a therapeutic target in HER2-amplified colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B022.
Abstract B030: Dipeptidase-1 is a highly upregulated protein in CRC exosomes: Potential clinical relevance
Authors: Bechard Matthew E. , Glass Sarah E. , Coffey Robert J. 
Published: December 2022

Abstract
Bert Vogelstein and co-workers identified DPEP1 in 2001 as one of the top six upregulated genes encoding a membrane or secreted protein in colorectal adenomas and cancers (CRCs). DPEP1 is a GPI-linked, zinc-dependent dipeptidase whose enzymatic activity includes processing extracellular glutathione and converting LTD4 to LTE4. Recently, it was reported to act nonenzymatically as a receptor for neutrophils on liver and lung endothelial cells and to influence monocyte migration. DPEP1 has been reported to have roles in cancer proliferation, invasion and metastasis. We recently showed that DPEP1 is the most abundant protein in small extracellular vesicles (sEVs) released from CRC cell lines by mass spectrometry and is present in a subset of EGFR+/CD81+ exosomes along with other clinically relevant biomarkers by fluorescence-activated vesicle sorting (FAVS) (Q Zhang et al., Nature Cell Biology 23:1240-1254, 2021). We also found that DPEP1/CEACAM5 double-positive exosomes are increased in the plasma from three CRC patients compared to normal controls. Immunohistochemical staining for DPEP1 in clinically well-annotated adenoma and CRC tissue microarrays has revealed staining in 27% of adenomas and 71% of CRCs, whereas no staining was observed in normal colonic tissue. Moreover, diffuse cytoplasmic staining in CRCs was associated with a worse progression-free and overall survival. We have now generated adenoma organoids, some of which express endogenous DPEP1 that localizes to the apical plasma membrane in 3D organoids and when cultured as polarized monolayers on Transwell filters. We plan to examine the bi-directional effects of cellular DPEP1 and DPEP1-containing EVs and freshly isolated neutrophils and/or their EVs in a co-culture system that is part of our recently funded Translational and Biological Science in Early Lesions (TBEL) NCI U54 grant.
Citation Format: Matthew E. Bechard, Sarah E. Glass, Robert J. Coffey. Dipeptidase-1 is a highly upregulated protein in CRC exosomes: Potential clinical relevance [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B030.
Abstract IA003: ctDNA Guiding adjuvant treatment in early stage colon cancer: Are we moving the needle?
Authors: Tie Jeanne 
Published: December 2022

Abstract
My presentation will summarize the accumulating evidence on the ability of circulating tumor DNA to detect minimal residual disease and track adjuvant treatment efficacy in colorectal cancer and the potential for ctDNA to reshape the adjuvant treatment paradigm. I will also discuss the rationale and results of the DYNAMIC trial (ctDNA-guiding adjuvant therapy study in stage II colon cancer) and other ongoing ctDNA-based trials.
Citation Format: Jeanne Tie. ctDNA Guiding adjuvant treatment in early stage colon cancer: Are we moving the needle? [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA003.
Abstract IA004: Moving the needle: It is time for universal germline and somatic genetic testing in all colorectal cancer patients
Authors: Goldberg Richard M. 
Published: December 2022

Abstract
The rapid evolution and commercialization of new techniques for analyzing DNA have extended our knowledge of inherited genetic abnormalities that can predispose a person to develop colorectal and other cancers. Concomitantly, the genetic fingerprinting of individual tumors has fueled the development of targeted therapies and informed their appropriate deployment for the management of individual patients. Recently, Cercek and colleagues at Memorial Sloan Kettering Cancer Center reported that all 14 patients with MSI-H rectal cancers treated in a clinical trial in the neoadjuvant setting with the PD-L1 inhibitor dostarlimab had complete remissions of their disease without chemotherapy, radiation, or surgery and those individuals are being followed to determine if, as hoped and expected, those remissions are durable (PMID:35660797). These insights have led and will continue to lead us to develop specific strategies to manage and minimize risk for affected individuals and their family members with inherited cancer susceptibility syndromes. They are also enabling us to decipher the practical value of the heterogeneity of colorectal cancers based upon the identification of inherited or acquired genetic abnormalities that drive the development and progression of an individual patient’s cancer. Now it is time to deploy germline and somatic genetic testing as a standard of care in the clinic, universally and equitably, for individualizing the assessment of inherited colorectal cancer susceptibility and for individualizing care in patients with colorectal cancer. Implementing this strategy will require resource allocation to ensure that health care teams and the patients that they care for both understand and derive the maximum possible benefit from implementing this new approach.
Citation Format: Richard M. Goldberg. Moving the needle: It is time for universal germline and somatic genetic testing in all colorectal cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA004.
Abstract IA005: Risk prediction in colorectal cancer screening: Reflections on the current status
Authors: Schoen Robert E. 
Published: December 2022

Abstract
Colorectal cancer screening is an effective means of reducing colorectal cancer incidence and mortality. However, the testing we have, though effective, is costly and inefficient, with the majority of people undergoing an expensive, negative screening examination such as colonoscopy. Risk prediction is a potential means to tailor screening and personalize care to risk. Individuals could be directed to a less invasive test (FIT or blood testing) as opposed to a more invasive test (colonoscopy), or to other adjustments such as modifying the starting age for screening. The polygenic risk score is an objective, reproducible risk assessment tool, that has promise, but its utility and possible application in clinical practice will require considerably more investigation. Other challenges include determining the “threshold“ for assignment to a low risk as opposed to a high risk screening strategy, and ensuring that risk assessment does not deter subsequent screening behavior.
Citation Format: Robert E. Schoen. Risk prediction in colorectal cancer screening: Reflections on the current status [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA005.
Abstract IA006: The effect of ancestry and the genomics of colorectal cancer: Implications on incidence and outcomes
Authors: Myer Parvathi A. 
Published: December 2022

Abstract
Blacks have a higher incidence of colorectal cancer (CRC) and worse survival rates when compared to Whites. Comprehensive genomic profiling was performed in 46,140 colorectal adenocarcinoma cases. Ancestry-informative markers identified 5,301 patients of African descent (AFR) and 33,770 patients of European descent (EUR). AFR were younger, had fewer MSI-H tumors, and had significantly more frequent alterations in KRAS, APC, and PIK3CA. AFR had increased frequency of KRAS mutations specifically KRAS G12D and KRAS G13. There were no differences in rates of actionable kinase driver alterations (HER2, MET, NTRK, ALK, ROS1, RET). In patients with young onset CRC (&lt;50 years), AFR and EUR had similar frequency of MSI-H and TMB-H tumors, and strikingly different trends in APC mutations by age, as well as differences in MAPK pathway alterations. These findings inform treatment decisions, impact prognosis, and underscore the need for model systems representative of our diverse US population. Further studies are needed to investigate the role of colon polyps and the effect of genomics, ancestry and social determinants of health on CRC incidence and outcomes.
Citation Format: Parvathi A. Myer. The effect of ancestry and the genomics of colorectal cancer: Implications on incidence and outcomes [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA006.
Abstract IA008: Modeling immune-epithelial interactions in health and disease using human intestinal enteroid co-cultures
Authors: Zachos Nicholas C. 
Published: December 2022

Abstract
Human intestinal enteroids derived from Lgr5+ actively dividing adult stem cells offer a relevant ex vivo system to study biological processes of the human small intestine and colon. While these primary cultures recreate cellular and functional features of the intestinal epithelium of the small intestine (enteroids) or colon (colonoids), they are limited by the lack of associated cell types, including immunological cells, nerves, stromal cells that help maintain tissue homeostasis and respond to external challenges. In the gut, innate immune cells interact with the epithelium by conducting lumial surveillance, support barrier function, and deploy effector functions in response to injury/damage. We have established a co-culture system of enteroid/colonoid monolayers and underlying macrophages and polymorphonuclear neutrophils to recapitulate the cellular framework of the human intestinal epithelial niche. Human intestinal enteroids can generated from biopsies or resected tissue from any segment of the human intestine/colon and maintained in long-term cultures in a basement membrane-rich matrix supplemented with growth factor-conditioned media necessary to maintain intestinal stem cell homeostasis. Immune cells are isolated from fresh human whole blood or frozen peripheral blood mononuclear cells (PBMC) and co-cultured with human intestinal enteroids/colonoids grown as confluent monolayers on permeable supports (e.g., Transwells). This configuration allows for controlled access to the apical side of the epithelium to mimic the gut luminal environment as well as the basolateral side occupied by immune cells to mimic the mucosal environment. Enteroid-immune co-cultures enable multiple outcome measures, including transepithelial resistance, production of cytokines/chemokines, phenotypic analysis of immune cells, tissue immunofluorescence imaging, protein or mRNA expression, antigen or microbe uptake, and other cellular functions.
Citation Format: Nicholas C. Zachos. Modeling immune-epithelial interactions in health and disease using human intestinal enteroid co-cultures [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA008.
Abstract IA016: Stem cells, therapy resistance and metastasis in colorectal cancer
Authors: Batlle Eduard 
Published: December 2022

Abstract
The Cancer Stem Cell (CSC) concept states that tumor growth, analogous to the renewal of healthy tissues, is fueled by small numbers of dedicated stem cells. It provides attractive explanations for the clinical behavior of cancers and inspires treatment strategies that specifically target CSCs, the 'beating heart' of the tumor. Over the past years, an avalanche of studies has identified CSCs by expression of individual marker genes but the nature and features of these cells remain largely uncharacterized. As a case of example, LGR5 has been established as a bonafide marker of CSCs in gastrointestinal tumors. Many CRCs contain abundant LGR5+ cells yet clonal analysis suggests that only a small proportion of these cells function as CSCs. It is also known that many CRCs contain few or no LGR5+ cells, yet these tumors may still exhibit a hierarchical organization. Here, I will discuss our recent work on the functional states adopted by LGR5+ cells during CRC progression and the role of this cell population in chemotherapy resistance and metastatic dissemination.
Citation Format: Eduard Batlle. Stem cells, therapy resistance and metastasis in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA016.
Abstract IA017: Microbiota drivers of colorectal cancer and their translation to prevention
Authors: Sears Cynthia L. 
Published: December 2022

Abstract
Abundant data support that the microbiota, both communities and individual pathogenic bacteria, promote the development of colorectal cancer (CRC). More limited data support that CRC is initiated by specific bacteria or communities. This talk will focus on bacterial contributors to CRC pathogenesis, potential mechanisms, gaps in knowledge and potential approaches to enabling use of the colon microbiota and its members to advance CRC prevention. Improved approaches to prevention are particularly key to identify those at risk for early onset CRC that represents a global change in CRC epidemiology.
Citation Format: Cynthia L. Sears. Microbiota drivers of colorectal cancer and their translation to prevention [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA017.
Abstract IA019: Molecular pathological epidemiology of tumor microbiota and immunity can give etiologic insights
Authors: Ogino Shuji 
Published: December 2022

Abstract
This lecture discusses the integration of tumor microbiology and immunology into evolving/expanding molecular pathological epidemiology (MPE) research framework (Ogino et al. Gut 2011; Ogino et al. Annu Rev Pathol 2019; Inamura et al. Gut 2022; etc.), which will open new opportunities. Neoplasms represent heterogeneous pathological processes due to interactive influences of the exposome (including the microbiome), the immune system, and neoplastic cells. Hence cancers should be regarded as not only microenvironmental diseases but also environmental and systemic diseases (Inamura et al. Gut 2022). To address this complexity, we investigate influences of exposures on microbial-tumor-immune interactions in tumor microenvironment. Colorectal cancer (CRC) provides an ideal model, as the colorectum is the most microbial rich organ and there are many established or putative risk factors for CRC. In our proof-of-principle studies that used the Nurses’ Health Study and Health Professionals Follow-up Study along with tumor tissue biobanks having 1700 CRC cases, we can provide evidence for influences of prudent diets (Mehta et al. JAMA Oncol 2017), inflammatory diets (Liu et al. Clin Gastroenterol Hepatol 2018), and western diets (Arima et al. Gastroenterology 2022) on developments of cancer subtypes with intratumor bacteria such as Fusobacterium nucleatum and pks+ Escherichia coli. We have also gain insights into interactions between microbes and immune cells. We have discovered an inverse relationship between F. nucleatum and T cell infiltrates (Mima et al. JAMA Oncol 2015), especially CD3+CD4+CD45RO+ memory helper T cells (Borowsky et al. Clin Cancer Res 2021). In situ spatial single cell analyses using multispectral fluorescence imaging and machine learning can shed light on the roles of microbes as well as various immune cell infiltrates in CRC (Vayrynen et al. Cancer Immunol Res 2021; Vayrynen et al. J. ImmunoTher Cancer 2021; Vayrynen et al. Cancer Immunol Res 2022; Akimoto et al. Front Immunol 2022). The integrative MPE approach is also expected to advance research on early-onset cancers (Akimoto et al. Nat Rev Clin Oncol 2021; Ugai et al. Nat Rev Clin Oncol, in press). Our new research paradigm to integrate microbial and immune assays on archival tumor tissue in large-scale population studies can provide not only etiological insights but also possible paths for precision medicine and prevention.
Citation Format: Shuji Ogino. Molecular pathological epidemiology of tumor microbiota and immunity can give etiologic insights [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA019.
Abstract IA020: The gut microbiome in colorectal cancer
Authors: Atreya Chloe E. 
Published: December 2022

Abstract
The gut microbiome plays important roles in colorectal cancer (CRC) initiation, treatment, and survivorship. This talk will highlight preliminary results from two pilot studies: Gut microbiome & Oral fluoropyrimidines (GO) and Lifestyle and Outcome in Gastrointestinal Cancer (LOGIC). GO investigated the impact of oral fluoropyrimidines (e.g., capecitabine) on gut microbes via longitudinal stool sampling. Despite marked inter- and intra-individual differences in diversity and community structure, we detected multiple consistent taxonomic differences. LOGIC asked: how do diet and lifestyle, measured by the American Cancer Society (ACS) score, correlate with gut microbiota characteristics in CRC survivors? We found that components of the ACS score related to fruit and vegetable consumption, but not the overall ACS score, significantly associated with variations in microbial community structures, diversity, and differences in abundance of microorganisms at various taxonomic levels. Practical considerations influencing the design of follow-up studies in progress will be discussed.
Citation Format: Chloe E. Atreya. The gut microbiome in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA020.
Abstract PR010: Inhibition of HGF maturation overcomes cetuximab resistance in colorectal cancer
Authors: Graves-Deal Ramona , Jones Vivian T. , Bogatcheva Galina T. , Cao Zheng , Harmych Sarah J. , Damalanka Vishnu , Klampfer Lidija , Coffey Robert J. , Janetka James W. , Singh Bhuminder 
Published: December 2022

Abstract
We have previously identified that activation of receptor tyrosine kinases (RTKs), MET and RON contributed to resistance to the EGF receptor (EGFR)-directed therapeutic antibody, cetuximab. These findings originated from our in vitro 3D type I collagen cultures of human colorectal cancer (CRC) cell line HCA-7 derivatives CC, SC, and CC-CR. CC are sensitive to cetuximab, while SC and CC-CR are resistant. Both de novo and acquired modes of cetuximab resistance in SC and CC-CR, respectively, could be overcome by crizotinib, a multi-RTK inhibitor that also targets MET and RON. Conversely, exogenous administration of MET ligand, HGF could transiently induce cetuximab resistance which could be further overcome by crizotinib addition. HGF/HGFL are synthesized as inactive precursors and require cleavage by proteases (HGFA, Matriptase, and Hepsin) to be biologically active. To inhibit HGF/HGFL cleavage in cetuximab-resistant cells, we employed inhibitors of HGF/HGFL proteases (ZFH7116 and VD2173) and were able to overcome both de novo and acquired cetuximab resistance. A survey of TCGA datasets indicated that HGF/HGFL were overexpressed in several CRC CMS subtypes. We next expressed human HGF in cetuximab-sensitive CC cells and observed that HGF overexpression imparts cetuximab resistance. Moreover, cetuximab resistance induced by HGF overexpression could be overcome by the downstream MET inhibition (with crizotinib), and we are now testing if the upstream inhibition of HGF proteases (with ZFH7116/VD2173) also overcomes cetuximab resistance. Combined these results indicate that inhibition of HGF cleavage and maturation may be a novel way to overcome resistance to EGFR-targeted therapies in CRC.
Citation Format: Ramona Graves-Deal, Vivian T. Jones, Galina T. Bogatcheva, Zheng Cao, Sarah J. Harmych, Vishnu Damalanka, Lidija Klampfer, Robert J. Coffey, James W. Janetka, Bhuminder Singh. Inhibition of HGF maturation overcomes cetuximab resistance in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR010.