bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2820: The effect of Pten haploinsufficiency on genomic and transcriptomic profiles in combined genetically-engineered mouse models for colonic neoplasia based on Apc inactivation
Authors: Sada Haruki , Niitsu Hiroaki , Nakahara Hikaru , Sakamoto Naoya , Tashiro Hirotaka , Ohdan Hideki , Hinoi Takao 
Published: March 2024

Abstract
Background and Aim: We have reported genetically-engineered mouse models for colonic neoplasia by using our novel CDX2P-Cre mice, in which Cre is restrictedly expressed in colonic epithelial cells. Although colonic tumors are generated in CDX2P-Cre;Apcflox/+ (CPC;Apc) mice with highly penetrant rate, greater number and deeper invasion of colonic tumors were observed in CDX2P-Cre;Apcflox/+;Ptenflox/+ (CPC;Apc+Pten), possibly resulting from haploinsufficiency of Pten gene. We have also confirmed shorter lifespan in CPC;Apc+Pten than that in CPC;Apc (AACR Annual Meeting 2018). Here, we test if these phenotypes come from one copy loss of Pten itself or secondary genetic and/or transcriptomic alterations induced by Pten loss by using whole genome sequence (WGS) and RNA sequence from macroscopically-dissected colonic tumors (bulk RNA-seq).
Methods: WGS for five tumors and five livers as counterpart controls in each mouse model was performed by DNBSEQ platforms. Bulk RNA-seq was performed for three tumors in each model.
Results: In the analysis using B-allele frequency, copy-neutral LOH occurred in chromosome 18 including Apc loci specifically in colonic neoplasia in both CPC;Apc and CPC;Apc+Pten mice. In contrast, LOH was not observed in chromosome 19 including Pten loci in CPC;Apc+Pten mice. We also confirmed remarkably decreased coverage of reads in reference mapping in Apc locus, and there was a slight decrease of coverage in Pten locus. There were no additional driver gene mutations in CPC;Apc or CPC;Apc+Pten in WGS. All these results suggested just one copy loss of Pten resulting in aggressive tumor phenotype in CPC;Apc+Pten mice. In RNA-seq and subsequent GSEA comparing colonic tumors in CPC;Apc+Pten with those in CPC;Apc revealed upregulation of some signal pathways including mTORC1. Supporting this observation, number of colon tumors, especially adenocarcinomas, were decreased by rapamycin administration to CPC;Apc+Pten. Similarly, rapamycin was more effective in tumorids from CPC;Apc+Pten those from CPC;Apc.
Conclusion: WGS reveals one copy loss of Pten locus is the only genetic alteration in CPC;Apc+Pten when compared with CPC;Apc. One copy loss of Pten is sufficient to upregulate mTORC1 pathway in a CPC;Apc+Pten mouse model, resulting in promotion of tumor formation and invasion.
Citation Format: Haruki Sada, Hiroaki Niitsu, Hikaru Nakahara, Naoya Sakamoto, Hirotaka Tashiro, Hideki Ohdan, Takao Hinoi. The effect of Pten haploinsufficiency on genomic and transcriptomic profiles in combined genetically-engineered mouse models for colonic neoplasia based on Apc inactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2820.
Abstract 2824: Establishing prostate cancer models for orthotopic and bone metastatic growth using the 22Rv1cell line
Authors: Zdrojewska Justyna , Fagerlund Katja , Mäki-Jouppila Jenni H. , Suominen Mari I. 
Published: March 2024

Abstract
Prostate cancer is the second most common cancer in men with new cases diagnosed in 1.4 million men each year. Luckily the 5-year survival rates in developed countries are high reaching over 90%. However, approximately one third will develop a metastatic disease. In metastatic patients, prostate cancer almost always progresses despite the androgen deprivation therapy and is then referred to as “castration-resistant (mCRPC)”. Bone is involved in 80% of patients with metastasis, and the bone lesions are typically osteoblastic. The 22Rv1 human prostate carcinoma cell line is androgen sensitive and shown to express androgen receptor (AR). They also express low levels of prostate-specific membrane antigen (PSMA). The aim of this study was to establish orthotopic and intratibial preclinical in vivo prostate cancer models that can be used in drug development when targeting cancer cells and their local environment. Male athymic nude mice (5-6 weeks old) and NOG mice (over 20 weeks old) were used in the study. 2.5 × 105 22Rv1 cells (ATCC) were inoculated orthotopically into the prostate of NOG mice, and 5 × 105 cells were inoculated intratibially into the bone marrow cavity of athymic nude mice. Tumor growth was followed by PSA measurements every second week using Human PSA ELISA assay. In addition, in the intratibial model, tumor-induced bone changes were monitored by X-ray imaging of the hind limbs. Prostates and hind limbs were collected at sacrifice, fixed in 10% NBF, and processed to paraffin blocks for further histological analysis. Sections of prostate were stained with hematoxylin-eosin (HE) and AR. Tumor-bearing and contralateral (healthy) tibias were stained with HE - OrangeG, MGT, TRAP, and AR. The observed tumor take rate was 92% in the orthotopic and 100% in the intratibial models. Confirmed by IHC, tumors formed in both the orthotopic and intratibial models expressed AR. 22Rv1 cells formed osteoblastic - lytic mixed bone lesions in the intratibial model. Based on lesion areas, randomization of the tumor bearing mice in the intratibial model can be done after 2 weeks from cancer cell inoculation. Taken together, the 22Rv1 prostate cancer models are relatively fast growing, express AR and present good take rates. Furthermore, the intratibial model represents robust tumor-induced changes in bone with strong osteoblastic component. Thus, these models have several advantages in efficacy studies of novel drug candidates for prostate cancer.
Citation Format: Justyna Zdrojewska, Katja Fagerlund, Jenni H. Mäki-Jouppila, Mari I. Suominen. Establishing prostate cancer models for orthotopic and bone metastatic growth using the 22Rv1cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2824.
Abstract 2877: Enhancing diagnostic precision in peritoneal cancer metastasis: Photodynamic diagnosis-guided laparoscopy in a rabbit model
Authors: Kim Hyoung-Il , Rivera-Piza Adriana , Lee Sunghwan 
Published: March 2024

Abstract
Introduction: Precise diagnostic workup is crucial for developing effective treatment strategies in cancer patients. Peritoneal carcinomatosis, often missed in preoperative CT scans and conventional laparoscopy, poses diagnostic challenges. This study aimed to assess the diagnostic accuracy of staging laparoscopy using photodynamic diagnosis (PDD) with the photosensitizer phonozen activated at 405 nm in a rabbit model of peritoneal carcinomatosis.
Methods: Female New Zealand white rabbits (16-20 weeks old) were utilized to establish the model through peritoneal inoculation of VX2 sarcoma cells, resulting in distinct solid-tumor nodules for laparoscopic evaluation. A customized dual-emission laparoscope, capable of both white-light and 405 nm blue-light, was employed for PDD. To minimize blue-light background interference, a 550 nm long-pass filter was placed between the laparoscope and the video camera, optimizing the process. The PDD-enhanced diagnostic laparoscopy comprised a tripartite approach: 1) initial peritoneal cavity exploration under white-light and labeling of suspect nodules, followed by 2) utilization of blue light with the long-pass filter to identify red-light emissions from distinctly labeled tumor cells, and 3) open laparotomy served to palpate the peritoneal surface and identify additional or missed tumor nodules.
Results: Analysis of data from 12 rabbits with 267 tumor nodules revealed that sensitivity and specificity of diagnostic laparoscopy for detecting tumor nodules increased from 84.9% and 18.8% with white light alone to 90.8% and 25.0% when aided by PDD, respectively. These findings underscore the substantial improvement in diagnostic accuracy achievable by combining the rabbit model of peritoneal carcinomatosis with PDD in laparoscopic procedures.
Conclusion: The heightened sensitivity and specificity observed in this study hold significant promise for positively impacting clinical practice, providing a more accurate and effective approach to the diagnosis and management of peritoneal carcinomatosis.
Citation Format: Hyoung-Il Kim, Adriana Rivera-Piza, Sunghwan Lee. Enhancing diagnostic precision in peritoneal cancer metastasis: Photodynamic diagnosis-guided laparoscopy in a rabbit model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2877.
Abstract 2884: Resistance to pan-FGFR inhibition is determined by the EMT phenotype associating with clinical outcome in HNSCC
Authors: Broghammer Felix , Gouda Mahesh , Korovina Irina , Brunner Cornelia , Coppes Robert P. , Gires Olivier , Seifert Michael , Cordes Nils 
Published: March 2024

Abstract
Receptor tyrosine kinases (RTK) and integrins coalesce at focal adhesions. These cell membrane areas serve as huge signaling hubs critically contributing to central aspects of cancer cell survival and therapy resistance. Despite the fact that these receptors mutually interact, co-dependencies between these receptors and associated therapeutically exploitable vulnerabilities remain largely unclear in HPV-negative head and neck squamous cell carcinoma (HNSCC). Here, we evaluated the cytotoxic and radiochemosensitizing potential of targeting 10 RTK and β1 integrin in up to 20 different 3D matrix grown HNSCC cell models. RNA sequencing and protein-based biochemical assays were performed for molecular and pathway characterization. Bioinformatically identified transcriptomic signatures were applied to patient cohorts to show clinical relevance. Our observations demonstrate that fibroblast growth factor receptors (FGFR 1-4) present with the strongest cytotoxic and radiosensitizing potential, both as monotherapy and in combination with β1 integrin inhibition, surpassing the efficacy of the other investigated RTK. Pharmacological pan-FGFR inhibition elicited a variable response spectrum ranging from cytotoxicity/radiochemosensitization to resistance/radioprotection. Transcriptomic characterization revealed an association of these contrasting responses to FGFR inhibition with a mesenchymal-to-epithelial transition (MET) for sensitive cell models and a partial epithelial-to-mesenchymal transition (EMT) for resistant cell models. Accordingly, deactivation of EMT associated kinases like EGFR, PKC and PAK proved effective in diminishing the adaptive FGFR-driven resistance. Importantly, the translation of the adaptive resistance profiles to HNSCC patient cohorts showed its prognostic value and provided conclusive validation of the presence of EMT-related vulnerabilities that can be strategically used for therapeutic intervention. In conclusion, our study demonstrates that pan-FGFR inhibition induces both a highly beneficial radiochemosensitizing and a detrimental radioprotective effect in HNSCC cell models. Adaptive EMT-associated resistance appears to be of clinical importance, and we provide effective molecular approaches to exploit this therapeutically.
Citation Format: Felix Broghammer, Mahesh Gouda, Irina Korovina, Cornelia Brunner, Robert P. Coppes, Olivier Gires, Michael Seifert, Nils Cordes. Resistance to pan-FGFR inhibition is determined by the EMT phenotype associating with clinical outcome in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2884.
Abstract 2888: Sensitization of radiation resistant colon cancer - The oxygenated microbubble hydrogel approach
Authors: Jose Ashok David , Chong Celine Hui-Ning , Jaiswal Jagdish , Wu Zimei , Thakur Sachin Sunil 
Published: March 2024

Abstract
Background: Hypoxia, a state of reduced oxygen that develops within the tumor due to its irregular vasculature, could result in treatment resistance. Mounting evidence suggests that reoxygenation of the tumor could improve outcomes of conventional cancer therapies. Our approach combats hypoxia using oxygenated lipid microbubbles (OMB) loaded in a temperature sensitive gel. The OMB would carry the oxygen while the gel would sustain its release into the tumor microenvironment.
Objectives: To formulate an oxygen loaded MB dispersed in a temperature sensitive poloxamer hydrogel for intratumoral administration.
Methods: OMB were generated by first preparing a liposomal mixture DSPC:DSPE-PEG2000, which was dispersed in a thermosensitive poloxamer hydrogel (P407:P188). This was pressurized with oxygen and vortexed in a gas-tight vial. Characterizations included OMB size distribution, injectability, thermosensitivity, oxygen loading and release, and the impact of the formulation on efficacy of radiotherapy against a colon cancer cell line (HCT116) was evaluated.
Results: DSPC:DSPE-PEG2000 liposomes at a molar ratio of 94:6 dispersed in P407:P188 (21:6.5 %w/w) generated OMB with a size distribution in the acceptable range of 0.8-8 µm. Formulations were within the established limits of injectability (F&lt;38N) at room temperature, and gelled near physiological temperatures enabling a sustained release of oxygen.. The formulation co-treatment enhanced radiotherapy significantly as evidenced by the remarkable reductions of clonogenic survival rates in both hypoxic and normoxic HCT116 cells (reduction by 78% vs 68% compared to just their respective radiated controls; p&lt;0.0001 for both cases).
Conclusion: Reoxygenation with a newly developed OMB hydrogel formulation effectively sensitized HCT116 to radiotherapy in vitro. Studies are underway to explore the importance of reoxygenation rate and extent for optimal tumor sensitization.
Citation Format: Ashok David Jose, Celine Hui-Ning Chong, Jagdish Jaiswal, Zimei Wu, Sachin Sunil Thakur. Sensitization of radiation resistant colon cancer - The oxygenated microbubble hydrogel approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2888.
Abstract 29: A genetically modified tumor-infiltrating lymphocytes product (GT216) enhanced anti-tumor efficacy against solid tumor by fine-tuning multiple negative immune regulators
Authors: Sun Jingwei , Tan Yiyang , Jin Jiahui , Wang Jingman , Chen Lingyun , Guo Fengbiao , Tan Yongchao , Xu Zhao , Liu Yarong 
Published: March 2024

Abstract
Adoptive cell therapy by tumor-infiltrating lymphocytes (TILs) has demonstrated promising clinical benefits for patients with solid tumors. However, the large-scale expansion during manufacture may drive hypofunction or exhaustion status of the final TIL product, leading to impaired anti-tumor efficacy and persistence post infusion. Grit Biotechnology designed a genetically engineered TIL product (GT216) to overexpress an intracellular protein that is induced by antigen-specific T cell response and mediates the degradation of multiple immunoregulatory molecules, which releases the therapeutic potential of TIL with enhanced cytotoxicity as well as persistence in vitro and in vivo. Multiple vector construct designs of GT216 were compared and the best design was selected based on stable and efficient expression of surrogate marker in TILs. GT216 could be successfully manufactured by Grit’s StemTexp® and StaViral® platforms with good memory phenotype and no signs of overactivation or exhaustion. In vitro functional analysis showed that GT216 demonstrated significantly increased cytotoxicity and cytokine production when cocultured with tumor cells and better tumor control ability during a serial killing assay than conventional TILs. Notably, GT216 TILs eradicated tumor growth with low IL-2 support in NOG mice inoculated with HLA-matched tumor cells while conventional TILs showed limited tumor control with high IL-2, corelated with their better infiltration and persistence in tumor and periphery. In summary, GT216 demonstrated enhanced anti-tumor efficacy and persistence as well as reduced IL-2 dependency in vitro and in vivo, supporting the clinical evaluation of GT216 as a next-generation TIL therapy in treatment of refractory solid tumors.
Citation Format: Jingwei Sun, Yiyang Tan, Jiahui Jin, Jingman Wang, Lingyun Chen, Fengbiao Guo, Yongchao Tan, Zhao Xu, Yarong Liu. A genetically modified tumor-infiltrating lymphocytes product (GT216) enhanced anti-tumor efficacy against solid tumor by fine-tuning multiple negative immune regulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 29.
Abstract 2922: Sensory innervation as a novel driver of ovarian cancer progression
Authors: Knarr Matthew , Cummins Katherine , Racordon Dusan , Reavis Hunter , Lippert Timothy , Hausler Ryan , Rawat Priyanka , Ryu Suyeon , Moon Jamie , Hoon Dave , Greenberg Roger , Vermeer Paola , Drapkin Ronny 
Published: March 2024

Abstract
One of the main challenges currently faced in ovarian cancer treatment is that the primary platinum/taxane therapy used to treat patients does not meaningfully extend survival. The overall survival for ovarian cancer patients with advanced disease is less than 30% with most patients recurring within 5 years of initial therapy. Once resistant disease develops there are few second line therapy options, which inevitably leads to disease progression. Thus, there is a critical need to identify new therapies that can overcome ovarian cancer chemoresistance and produce meaningful increases in patient survival. In recent years, new efforts have focused on targeting the tumor microenvironment (TME), the complex mixture of non-cancer cells that surround and support the cancer cells within the tumor. Different strategies have evolved to target the TME, such as immune checkpoint inhibitors or angiogenesis inhibitors. However, these TME targeting therapies have limited effect when used to treat ovarian cancer patients. Most ovarian tumors have a microenvironment that is highly immunosuppressive and do not respond or are resistant to angiogenesis inhibitors. Thus, new TME targeting therapies must be developed that can induce a therapeutic effect in ovarian tumors and can be used to treat most ovarian cancer patients. A novel TME component ripe for therapeutic targeting are the nerve fibers that infiltrate tumors in a process termed tumor innervation. Recent studies in several cancers have shown that tumor innervation can promote tumor growth/metastasis. However, in ovarian cancer the role of innervation in promoting cancer progression remains undefined. Here we show that Transient Receptor Potential cation channel subfamily V member 1 (TRPV1)+ sensory innervation plays a significant role in driving ovarian cancer growth and metastasis. Analysis of patient samples shows that sensory nerve fiber innervation is much higher in ovarian tumors vs benign reproductive tissue. In addition, ablation of TRPV1 sensory nerve fibers in vivo causes reduced tumor burden and prolongs survival in a syngeneic mouse model of ovarian cancer metastasis. Taken together, our results establish TRPV1+ sensory innervation as a novel driver of ovarian cancer growth/metastasis and a potential therapeutic target for ovarian cancer treatment.
Citation Format: Matthew Knarr, Katherine Cummins, Dusan Racordon, Hunter Reavis, Timothy Lippert, Ryan Hausler, Priyanka Rawat, Suyeon Ryu, Jamie Moon, Dave Hoon, Roger Greenberg, Paola Vermeer, Ronny Drapkin. Sensory innervation as a novel driver of ovarian cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2922.
Abstract 2965: GADD45B as a mechanism for enhanced treatment response with the combination of copanlisib and romidepsin in colorectal cancer
Authors: Maduscha Kennedy , Schmitz Alexa , DeStefanis Rebecca , Pasch Cheri , Deming Dustin 
Published: March 2024

Abstract
Background: Treatment options for molecular subtypes of colorectal cancer (CRC) are urgently needed, including for PIK3CA mutant CRC. Previous work in our lab demonstrated enhanced activity of copanlisib in combination with romidepsin in PIK3CA mutant CRC models. Here we investigate the induction of GADD45B as a mechanism of the enhanced induction of apoptosis seen with this treatment strategy.
Methods: RNA sequencing was done on the CRC 2D cell line, SW48PK (Horizon Discovery, SW48 PIK3CAH1047R/+ mutation) as well as PIK3CA mutant and wild-type patient derived cancer organoids (PDCOs) through the UW Biotechnology Center. All lines were treated with copanlisib, romidepsin, or combination and were compared with untreated controls. GADD45B gene expression was also confirmed on SW48PK, PIK3CA mutant, wild type, and PIK3CA and KRAS mutant PDCOs using RT-qPCR.
Results: RNA sequencing determined that there was an increase of GADD45B expression in the SW48PK 2D cell line as well as in PIK3CA mutant and wild-type PDCOs treated with the combination compared to untreated controls (average log2 fold change= 1.83). A significant increase in GADD45B expression was seen in the SW48PK combination treatment group compared to the control group at 6 hours (combination median fold change= 2.7, p= 0.045) and 24 hours (4.1, p&lt; 0.001). For PIK3CA mutant PDCOs treated with the combination, there was significant increase in GADD45B expression at 6 hours (9.45, p= 0.005) and 24 hours (14.7, p= 0.002) compared to untreated control. In wild type PDCOs, there was a significant increase in GADD45B expression in the combination compared to untreated control at 6 hours (32.95, p=0.004) but not after 24 hours (2.6, p= 0.42). For KRAS mutant PDCOs, there was a significant increase in GADD45B expression in combination treated cells at 6 (9.9, p= 0.001) and 24 hours (3.3, p= 0.047), however, this increase was less than PIK3CA mutant PDCOs at 24 hours (3.3 vs 14.7).
Conclusions: Copanlisib in combination with romidepsin increases GADD45B expression in PDCOs and SW48PK. Further studies will determine if GADD45B is required for this treatment response.
Citation Format: Kennedy Maduscha, Alexa Schmitz, Rebecca DeStefanis, Cheri Pasch, Dustin Deming. GADD45B as a mechanism for enhanced treatment response with the combination of copanlisib and romidepsin in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2965.