bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB037: Chromatin modifications guide Pax5 dependent gene expression in NE like prostate cancer
Authors: Bhattacharya Sreyashi , Islam Ridwan , Bodas Sanika , Mishra Juhi , Das Dipanwita , Datta Kaustubh , Dutta Samikshan 
Published: June 2022

Abstract
Background: Prolonged ablation of androgen receptor pathway in prostate cancer leads to the emergence of therapy resistant neuroendocrine-like (NE-like) aggressive lineage. This NE development is associated with chromatin reprogramming underlying epigenetic alterations and changes in transcriptional network. Clinically, NE development follows a poorer progression with multifaceted therapeutic challenges. Current lack of effective understanding of this NE trans-differentiation process limits the stratification of therapeutic window with further worsened patient management. The following study aims to identify the sequential molecular players responsible for therapy resistant NE like development.
Objective: The primary objective of this study is to understand how chromatin modifications along with epigenetic regulation dictates the establishment of NE trans-differentiation process in Prostate Cancer in response to Androgen Receptor blockade therapy.
Methods: We generated various NE-like cell lines either by genetic modification or therapeutic selection. We performed RNA Seq, ATAC Seq and acetylated Histone (H3K18 and H3K27) ChIP Seq in our developed NE and adenocarcinoma cell lines. We next compared ATAC Seq and Acetylated histone ChIP Seq with RNA Seq in C4-2B and C4-2BER.
Results: Our ATAC Seq and acetylated histone footprints (Ac H3K18 and Ac H3K27 ChIP Seq) analyses revealed an enhanced chromatin accessibility during adenocarcinoma to NE transformation. Overlapping RNA seq results further suggested newly transcribed neuronal genes with higher degrees of promoter accessibility. Transcription Factor scanning analysis among newly active gene promoters revealed preferential binding of Pax5, whose expression has been validated to be selectively occurring in NE lineage unlike adenocarcinoma. Further analysis of Pax5 promoter site suggested that changes in 5-hydroxymethylation pattern during adenocarcinoma to NE transformation guided the recruitment of PBX1 at Pax5 promoter. Validating NE patient expression in silico supported that PBX1/Pax5 expressions are selective in NE lineage development.
Conclusions: Our study concludes that specific chromatin alterations guide the recruitment of PBX1 to upregulate Pax5 to maintain a therapy resistant neuronal surrounding in NE-like prostate cancer development.
Citation Format: Sreyashi Bhattacharya, Ridwan Islam, Sanika Bodas, Juhi Mishra, Dipanwita Das, Kaustubh Datta, Samikshan Dutta. Chromatin modifications guide Pax5 dependent gene expression in NE like prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB037.
Abstract LB043: Identification and characterization of cancer-associated fibroblast subpopulations in lung adenocarcinoma
Authors: Kim Daeseung , Kim Jeong Seon , Kim Seoree , Chun Sang Hoon , Kim Jae Jun , Cheon Inyoung , Lee Sieun , Yoon Jung Sook , Hong Soon Auck , Won Hye Sung , Kang Keunsoo , Ahn Young-Ho , Ko Yoon Ho 
Published: June 2022

Abstract
Background: Cancer-associated fibroblasts (CAFs) reside within the tumor microenvironment, facilitating cancer progression and metastasis via direct and indirect interactions with cancer cells as well as other stromal cell types. CAFs are comprised of heterogeneous subpopulations of activated fibroblasts, including myofibroblastic, inflammatory, or immunosuppressive CAFs. In this study, we sought to identify subpopulations of CAFs isolated from human lung adenocarcinomas and describe their transcriptomic as well as functional characteristics through single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatics analyses.
Methods: We isolated and cultured two types of CAFs. Total CAFs were isolated after negative selection using cell-type-specific antibodies against lymphocytes (CD45), macrophages (CD68), endothelial cells (CD31), and epithelial cells (Ep-CAM). THY1+ CAFs were isolated after additional selection based on CAF-specific marker THY1. Total CAFs (n=5,139 cells) and THY1+ CAFs (n=4,038 cells) were subjected to 10X Genomics scRNA-seq. scRNA-seq data were then integrated and analyzed using the Seurat method.
Results: Cell trajectory analysis of combined total and THY1+ CAFs revealed two branching points with five distinct branches. Based on Gene Ontology analysis, we denoted Branch 1 as “immunosuppressive”, Branch 2 as “neoantigen-presenting”, Branch 4 as “myofibroblastic”, and Branch 5 as “proliferative” CAFs. We selected representative branch-specific markers and measured their expression levels in total and THY1+ CAFs. We also investigated the effects of these markers on CAF activity under co-culture with lung cancer cells.
Conclusions: This study describes novel subpopulations of CAFs in lung adenocarcinoma, highlighting their potential value as therapeutic targets.
Citation Format: Daeseung Kim, Jeong Seon Kim, Seoree Kim, Sang Hoon Chun, Jae Jun Kim, Inyoung Cheon, Sieun Lee, Jung Sook Yoon, Soon Auck Hong, Hye Sung Won, Keunsoo Kang, Young-Ho Ahn, Yoon Ho Ko. Identification and characterization of cancer-associated fibroblast subpopulations in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB043.
Abstract LB049: Spatial immune determinants of ICB response in STK11-mutated non-small cell lung cancer
Authors: Uhlitz Florian , Linn Douglas , Krall Elsa Beyer , Egger Jacklynn , Rizvi Hira , Chang Jason , Nicholson Benjamin , Vanguri Rami , Chow Andrew , Hellmann Matthew , Shah Sohrab 
Published: June 2022

Abstract
Response to immune checkpoint blockade (ICB) in non-small cell lung cancers (NSCLC) is associated with recurring mutations in tumor suppressor genes STK11 and TP53. Whereas STK11-mutated patients are mostly insensitive, TP53-mutated patients commonly respond to ICB. Previous studies have linked mutational status in these genes to differences in cell type composition of the tumor microenvironment (TME). However, it remains unclear if differences in cell type compositions as well as cell-cell interactions in turn could account for the observed differences in treatment response and overall survival in NSCLC. Here, we perform spatial profiling of immune and stromal phenotypes in the TME of 119 NSCLC patients using imaging mass cytometry (IMC) on tissue microarrays (TMA). Matching data from MSK IMPACT (clinical sequencing) was used to establish mutation profiles and therapeutic response was included in the analysis. We find that STK11-mutated NSCLC is characterized by decreased CD4 T cell and increased neutrophil abundance, while TP53-mutated NSCLC is associated with increased CD8 T cell and decreased endothelial cell abundance. Accordingly, we stratified the patient population into TME classes by cell type composition. We found that while mutational status does not inform overall survival in our cohort, stratification by cell type abundance strongly associates with patient outcome (p-value: 0.000146, logRank test). Patients with neutrophil-rich TMEs show worse overall survival (25% 5-year survival), while patients with increased endothelial cell and macrophage abundance have a tendency to live longer (80% and 75% 5-year survival respectively). Furthermore, we interrogate pairwise proximity of immune cell types and states to construct cellular networks in NSCLC. Together, our findings suggest that TME cell type composition and cellular networks are potential molecular determinants for ICB therapeutic response in NSCLC patients.
Citation Format: Florian Uhlitz, Douglas Linn, Elsa Beyer Krall, Jacklynn Egger, Hira Rizvi, Jason Chang, Benjamin Nicholson, Rami Vanguri, Andrew Chow, Matthew Hellmann, Sohrab Shah. Spatial immune determinants of ICB response in STK11-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB049.
Abstract LB066: Targeting low density lipoprotein receptors in the pancreatic adenocarcinoma
Authors: Flores Leo , Qu Xuewei , Malicet Cedric , Lecorche Pascaline , Delpassand Ebrahim , Temsamani Jamal , Tworowska Izabela 
Published: June 2022

Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor 5-year overall survival rate at all stages of disease (7-10%). The immunohistochemistry of pancreatic cancer tissue has shown a significantly higher level of positive LDLR (low-density lipoprotein receptor) staining in primary tumors compared to the normal adjacent pancreas. LDLR is overexpressed in the epithelial pancreatic adenocarcinoma, irrespectively of tumor size, stage, and aggressiveness. The objective of this study was to determine the LDLR-targeting properties of 68Ga-labeled peptide conjugate, 68Ga-RMX-VH, in pancreatic adenocarcinoma cell lines.
Methods: RMX-VH peptide conjugate (25-50μg) was labeled with 68Ga (50-100mCi, ITM Germany) in mild conditions in the presence of scavenger, sodium ascorbate (8mg/ml). The cellular uptake and competition studies of the radiotracer (15μCi/well) were completed in multiple pancreatic adenocarcinoma cell lines and in vivo in PDAC xenografts generated in athymic nude mice. The PET/CT images were acquired using a G4 PET/X-ray camera (Sofie Biosciences; 10min/scan) at 1h, 2h post-injection. This study determined in vivo and in vitro time-dependent accumulation of this agent in LDLR-overexpressing pancreatic adenocarcinoma cells.
Results: 68Ga-RMX-VH was synthesized with higher than 95% radiochemical purity. The radiotracer was incubated in pancreatic adenocarcinoma cell lines for 1h and has shown the highest uptake in HPAF-II (6.7%ID/mg) and BxPC-3 (5.3 %ID/mg) and MiaPaCa2 (4.75 %ID/mg), respectively. Western blot showed a variable level of LDLR overexpression in human pancreatic cancer cells. The microPET imaging studies confirmed rapid accumulation and retention of radiotracer in the tumor (1.18 %ID/g) and elimination through kidneys (4.5 %ID/g) and bladder (SUV ratio of tumor to kidneys: 0.21). These results correlate with previously reported retention of the agent in Pk4a pancreatic adenocarcinoma.
Conclusions: RMX-VH has the potential to evaluate the role of LDL receptors in pancreatic adenocarcinoma. We have initiated the exploratory clinical study of this agent in LDLR-overexpressing solid tumors, including pancreatic adenocarcinoma.
Citation Format: Leo Flores, Xuewei Qu, Cedric Malicet, Pascaline Lecorche, Ebrahim Delpassand, Jamal Temsamani, Izabela Tworowska. Targeting low density lipoprotein receptors in the pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB066.
Abstract LB150: Clinical outcome prediction of prostate cancer using machine learning based on fusion gene detection
Authors: Luo Jian-Hua , Liu Silvia , Yu Yan-Ping 
Published: June 2022

Abstract
Prediction of the clinical outcomes of prostate cancer remains a challenge. Recently, we discovered a panel of 8 fusion genes that occurred in aggressive prostate cancer. In order to make the fusion gene test clinically ready as a predictor, we have modified to test into a semi-quantitative Taqman QRT-PCR. In the funding period, Two hundred seventy-one prostate cancer samples with clinical follow-up were collected from University of Pittsburgh Medical Center. In addition, 194 prostate cancer samples from University of Wisconsin, Madison and 108 prostate cancer samples from Stanford University were collected. Taqman QRT-PCRs were performed on these samples. Significant numbers of samples were found positive for some of these fusion genes. The expression of MAN2A1-FER, SLC45A2-AMACR, MTOR-TP53BP1 fusions are associated with prostate cancer recurrence in the UPMC cohort. Cross-validation showed that fusion gene model predicts up to 91% clinical outcomes of prostate cancer accurately. When cohorts of UPMC, Stanford and Wisconsin were combined, the accuracy is 74%. The combination of fusion with Gleason appeared to improve the overall accuracy from 77% (Gleason) to 92% (Gleason+fusion) in the UPMC cohort, and from 71% (Gleason) to 82% (Gleason+fusion) when all three cohorts are combined. When fusion combined with both pathology stage and Gleason, the accuracy was improved a little further: 93% accuracy in the UPMC cohort and 83% when all three cohorts are combined. In summary, fusion transcript prediction model may have a role in prostate cancer prognosis prediction and guiding the management of prostate cancer patients.
Citation Format: Jian-Hua Luo, Silvia Liu, Yan-Ping Yu. Clinical outcome prediction of prostate cancer using machine learning based on fusion gene detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB150.
Abstract LB505: Design and discovery of MRTX0902, a potent, selective, and orally bioavailable SOS1 inhibitor
Authors: Ketcham John M. , Briere David M. , Burns Aaron C. , Christensen James G. , Gunn Robin J. , Haling Jacob , Ivetac Anthony , Khare Shilpi , Kuehler Jon , Kulyk Svitlana , Laguer Jade , Lawson John D. , Moya Krystal , Nguyen Natalie , Olson Peter , Rahbaek Lisa , Smith Christopher R. , Sudhakar Niranjan , Thomas Nicole C. , Vanderpool Darin , Wang Xiaolun , Marx Matthew A. 
Published: June 2022

Abstract
KRAS mutations are the most common activating mutations in human cancer that ultimately lead to hyperactivation of the MAPK pathway and uncontrolled growth. KRAS functions as a small GTPase that cycles through its GTP-loaded “on” state and its GDP-loaded “off” state, a highly regulated process that is crucial for normal cell proliferation and survival. The guanine nucleotide exchange factor (GEF) SOS1 plays a critical role in this process by regulating the “on/off” state of KRAS. The protein-protein interaction between SOS1 and KRAS facilitates turnover of KRAS from the GDP-loaded inactive state to its activated and GTP-loaded state, a critical step to enable productive KRAS effector binding and activation of downstream signaling. The KRASG12C inhibitor, adagrasib (MRTX849), irreversibly binds to the GDP-loaded inactive conformation of KRASG12C and has recently shown encouraging clinical activity across several cancer types. As adagrasib binds preferentially to the inactive state of KRAS, blockade of SOS1 is anticipated to shift KRASG12C into the adagrasib-susceptible GDP-loaded state. Furthermore, this combination strategy could be used to target other mutant-driven cancers within the MAPK pathway using the appropriate KRASmut inhibitors and/or inhibitors of other targets within the MAPK pathway including MEK or EGFR. MRTX0902 was identified using iterative structure-based design as a selective inhibitor of SOS1 that demonstrates an IC50 value of 2 nM in a SOS1 HTRF binding assay and 30 nM in an MKN1 cellular assay. In pharmacokinetic evaluation across species, MRTX0902 demonstrated low extraction ratios and moderate to high bioavailability in mice, rats, and dogs. In preclinical models, MRTX0902 augmented the antitumor activity of adagrasib and other selected therapies. The design, discovery, and preclinical characterization of the potential best-in-class candidate MRTX0902 will be described.
Citation Format: John M. Ketcham, David M. Briere, Aaron C. Burns, James G. Christensen, Robin J. Gunn, Jacob Haling, Anthony Ivetac, Shilpi Khare, Jon Kuehler, Svitlana Kulyk, Jade Laguer, John D. Lawson, Krystal Moya, Natalie Nguyen, Peter Olson, Lisa Rahbaek, Christopher R. Smith, Niranjan Sudhakar, Nicole C. Thomas, Darin Vanderpool, Xiaolun Wang, Matthew A. Marx. Design and discovery of MRTX0902, a potent, selective, and orally bioavailable SOS1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB505.
Abstract LB516: MDM2/MDM4 amplification and CDKN2A deletion in melanoma brain metastases and GBM may have implications for targeted therapeutics and immunotherapy
Authors: Arnoff Taylor E. , El-Deiry Wafik S. 
Published: June 2022

Abstract
Melanoma has a five-year survival rate of 27% for distant metastatic disease, and there remains a paucity of targeted therapies for metastatic disease and biomarkers that predict metastasis to specific sites. We analyzed 1081 primary melanoma samples and 358 metastatic melanoma samples and found that metastatic disease is enriched for amplifications in both MDM2 and MDM4 compared to primary disease, and these amplifications are associated with a lower probability of overall survival. Two additional negative regulators of TP53, namely USP7 and PPM1D, are enriched for alterations in metastatic melanoma compared to primary melanoma. MDM4 amplifications are associated with a higher rate of metastasis to the brain, liver, and lungs, while MDM2 amplifications are associated with a higher rate of metastasis to the brain, liver, and adrenal glands. These findings suggest that patients with metastatic melanoma show an enhanced dysregulation of the TP53 pathway compared to primary disease; though still under ongoing preclinical evaluation to assess therapeutic implications, we propose that patients with metastatic melanoma and TP53 wild-type status may be more likely to benefit from MDM2, MDM4, USP7, and PPM1D inhibitors, both alone and in combination, compared to those with primary disease. Additionally, we found that patients with MDM2 alterations were more likely to have a deep deletion in CDKN2A, alterations that are also associated with a higher rate of metastasis to the brain. We found that patients with a CDKN2A deep deletion had a statistically significant higher rate of alterations in TTN, MUC16, LRP1B, NF1, and SERPINB4, alterations that have all been previously associated with a favorable response to immune checkpoint inhibitors in melanoma. We therefore propose that CDKN2A deletion may serve as a biomarker to predict response to immunotherapy in melanoma. Moreover, given prior documented cases of patients diagnosed with both melanoma and glioblastoma multiforme (GBM), we found that GBM displays the highest rate of deep deletions in CDKN2A (54.39%) across all cancer types screened. We analyzed 619 GBM samples and found that 9.16% display an MDM2 amplification and 9.52% display an MDM4 amplification. Given the genomic similarities between melanoma and glioblastoma, we suggest that patients with melanoma or GBM and amplifications in MDM2/4 and CDKN2A deletions may need the development of combinations of targeted inhibitors of MDM2/4, CDK’s and immunotherapy. We are currently pursuing these translational directions.
Citation Format: Taylor E. Arnoff, Wafik S. El-Deiry. MDM2/MDM4 amplification and CDKN2A deletion in melanoma brain metastases and GBM may have implications for targeted therapeutics and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB516.
Abstract LB520: A pharmacodynamic platform using liquid biopsy to support dose selection for the ATR inhibitor ART0380 (IACS-030380)
Authors: Patel Manish , Moore Kathleen N. , Piscitello Desiree , Majithiya Jayesh , Luzarraga Marina Roy , Millward Helen , Holt Sarah V. , Johnson Melissa 
Published: June 2022

Abstract
Inhibition of ataxia telangiectasia and Rad-3 related (ATR) kinase offers therapeutic promise for DNA damage response deficient tumors. In addition, ATR inhibitors may offer even broader clinical utility when combined with PARPi’s, chemo, immune or radiation therapy. Flat-fixed dosing of ATR inhibitors alone or in combination has provided clinical benefit but is associated with on target, dose limiting haematological toxicity. Strategies to refine dose selection of this class of medicine may further optimize clinical benefit. The aim of our ongoing investigation is to determine if the dose selection for clinical development of the novel ATR inhibitor ART0380 (IACS-030380) may be optimized based on the degree of PD engagement in both tumor and normal tissue from patients. To do this, we have utilized in vitro and in vivo cancer models to help us understand the dynamic and temporal response to several biomarkers of ATR inhibition and DNA damage. Once established in vitro, we selected key markers, such as γH2AX and pKAP1, to explore in vivo using doses predicted to be biologically effective in man and have shown that these are modulated following exposure to ART0380. To enable the serial assessment of PD engagement in both tumor and normal tissue, we have developed an assay in the phase 1 study of ART0380 (NCT04657068) to measure γH2AX levels in circulating tumor cells (CTC’s) and normal cells (PBMC’s). A significant advantage of this approach is that samples are taken from the same blood draw and at several timepoints following exposure to ART0380. So far, our studies have shown that in patients, who have experienced drug exposures predicted to be biologically effective, γH2AX levels in CTC’s increase by up to 20% respectively from baseline while γH2AX in PBMC’s remains unaffected. This observation may highlight that target engagement has taken place for ART0380 in the tumor without an effect in normal tissue, a phenomena perhaps explained by the pharmacokinetic profile of ART0380. The clinical study is ongoing and we continue to monitor individual patient responses, toxicity, and correlate with PD engagement in tumor and normal tissue circulating biopsies. In addition, we are now expanding our analysis into a multiplexed assay where we will measure pKAP1 as well as γH2AX to build a more detailed assessment of PD activity in patients. Updated data will be presented.
Citation Format: Manish Patel, Kathleen N. Moore, Desiree Piscitello, Jayesh Majithiya, Marina Roy Luzarraga, Helen Millward, Sarah V. Holt, Melissa Johnson. A pharmacodynamic platform using liquid biopsy to support dose selection for the ATR inhibitor ART0380 (IACS-030380) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB520.