bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Enhanced Radiosensitivity in Solid Tumors using a Tumor-selective Alkyl Phospholipid Ether Analog
Authors: Elsaid Mohamed Y. , Shahi Ankita , Wang Albert R. , Baiu Dana C. , Li Chunrong , Werner Lauryn R. , Singhal Sorabh , Hall Lance T. , Weichert Jamey P. , Armstrong Eric A. , Bednarz Bryan P. , Harari Paul M. , Iyer Gopal , Otto Mario
Published: April 2023

Abstract
Antitumor alkyl phospholipid (APL) analogs comprise a group of structurally related molecules with remarkable tumor selectivity. Some of these compounds have shown radiosensitizing capabilities. CLR127 is a novel, clinical-grade antitumor APL ether analog, a subtype of synthetic APL broadly targeting cancer cells with limited uptake in normal tissues. The purpose of this study was to investigate the effect of CLR127 to modulate radiation response across several adult and pediatric cancer types in vitro as well as in murine xenograft models of human prostate adenocarcinoma, neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma. In vitro, CLR127 demonstrated selective uptake in cancer cells compared to normal cells. In cancer cells, CLR127 treatment prior to radiation significantly decreased clonogenic survival in vitro, and led to increased radiation-induced double-stranded DNA (dsDNA) breakage compared with radiation alone, which was not observed in normal controls. In animal models, CLR127 effectively increased the antitumor response to fractionated radiotherapy and led to delayed tumor regrowth at potentially clinically achievable doses. In conclusion, our study highlights the ability of CLR127 to increase radiation response in several cancer types. Given almost universal uptake of CLR127 in malignant cells, future research should test whether the observed effects can be extended to other tumor types. Our data provide a strong rationale for clinical testing of CLR127 as a tumor-targeted radiosensitizing agent. Mol Cancer Ther; 17(11); 2320–8. ©2018 AACR.
Data from Inhibition of the Histone H3K27 Demethylase UTX Enhances Tumor Cell Radiosensitivity
Authors: Rath Barbara H. , Waung Isabella , Camphausen Kevin , Tofilon Philip J.
Published: April 2023

Abstract
The processes mediating the repair of DNA double-strand breaks (DSB) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications, including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines. Irradiation of tumor cells resulted in a rapid loss of H3K27me3, which was prevented by the siRNA-mediated knockdown of the H3K27 demethylase UTX. Knockdown of UTX also enhanced the radiosensitivity of each tumor cell line. Treatment of tumor cells with the H3K27 demethylase inhibitor GSKJ4 immediately before irradiation prevented the radiation-induced decrease in H3K27me3 and enhanced radiosensitivity. As determined by neutral comet analysis and γH2AX expression, this GSKJ4 treatment protocol inhibited the repair of radiation-induced DSBs. Consistent with in vitro results, treatment of mice bearing leg tumor xenografts with GSKJ4 significantly enhance radiation-induce tumor growth delay. In contrast with results generated from tumor cell lines, radiation had no effect on H3K27me3 levels in normal fibroblast cell lines and GSKJ4 did not enhance their radiosensitivity. These data suggest that H3K27me3 demethylation contributes to DSB repair in tumor cells and that UTX, the demethylase responsible, provides a target for selective tumor cell radiosensitization. Mol Cancer Ther; 17(5); 1070–8. ©2018 AACR.
Data from CAT-02-106, a Site-Specifically Conjugated Anti-CD22 Antibody Bearing an MDR1-Resistant Maytansine Payload Yields Excellent Efficacy and Safety in Preclinical Models
Authors: Drake Penelope M. , Carlson Adam , McFarland Jesse M. , Bañas Stefanie , Barfield Robyn M. , Zmolek Wesley , Kim Yun Cheol , Huang Betty C.B. , Kudirka Romas , Rabuka David
Published: April 2023

Abstract
Hematologically derived tumors make up ∼10% of all newly diagnosed cancer cases in the United States. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1. CD22 is a clinically validated target for the treatment of NHL, but no anti-CD22 agents have yet been approved for this indication. Recent approval of an anti-CD22 antibody–drug conjugate (ADC) for the treatment of relapsed/refractory ALL supports the rationale for targeting this protein. An opportunity exists for a next-generation anti-CD22 antibody–drug conjugate (ADC) to address unmet medical needs in the relapsed/refractory NHL population. We describe a site-specifically conjugated antibody–drug conjugate, made using aldehyde tag technology, targeted against CD22 and bearing a noncleavable maytansine payload that is resistant to MDR1-mediated efflux. The construct was efficacious against CD22+ NHL xenografts and could be repeatedly dosed in cynomolgus monkeys at 60 mg/kg with no observed significantly adverse effects. Exposure to total ADC at these doses (as assessed by AUC0-inf) indicated that the exposure needed to achieve efficacy was below tolerable limits. Together, the data suggest that this drug has the potential to be used effectively in patients with CD22+ tumors that have developed MDR1-related resistance to prior therapies. Mol Cancer Ther; 17(1); 161–8. ©2017 AACR.
Data from Targeting the BRD4-HOXB13 Coregulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress Metastatic Castration-Resistant Prostate Cancer
Authors: Nerlakanti Niveditha , Yao Jiqiang , Nguyen Duy T. , Patel Ami K. , Eroshkin Alexey M. , Lawrence Harshani R. , Ayaz Muhammad , Kuenzi Brent M. , Agarwal Neha , Chen Yunyun , Gunawan Steven , Karim Rezaul M. , Berndt Norbert , Puskas John , Magliocco Anthony M. , Coppola Domenico , Dhillon Jasreman , Zhang Jingsong , Shymalagovindarajan Subramaniam , Rix Uwe , Kim Youngchul , Perera Ranjan , Lawrence Nicholas J. , Schonbrunn Ernst , Mahajan Kiran
Published: April 2023

Abstract
Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification of the mechanisms by which CRPCs evade androgen deprivation therapies (ADT) is critical to develop novel therapeutics. We uncovered that CRPCs rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, a member of the BET bromodomain family, epigenetically promotes HOXB13 expression. Consistently, genetic disruption of HOXB13 or pharmacological suppression of its mRNA and protein expression by the novel dual-activity BET bromodomain-kinase inhibitors directly correlates with rapid induction of apoptosis, potent inhibition of tumor cell proliferation and cell migration, and suppression of CRPC growth. Integrative analysis revealed that the BRD4-HOXB13 transcriptome comprises a proliferative gene network implicated in cell-cycle progression, nucleotide metabolism, and chromatin assembly. Notably, although the core HOXB13 target genes responsive to BET inhibitors (HOTBIN10) are overexpressed in metastatic cases, in ADT-treated CRPC cell lines and patient-derived circulating tumor cells (CTC) they are insensitive to AR depletion or blockade. Among the HOTBIN10 genes, AURKB and MELK expression correlates with HOXB13 expression in CTCs of mCRPC patients who did not respond to abiraterone (ABR), suggesting that AURKB inhibitors could be used additionally against high-risk HOXB13-positive metastatic prostate cancers. Combined, our study demonstrates that BRD4-HOXB13-HOTBIN10 regulatory circuit maintains the malignant state of CRPCs and identifies a core proproliferative network driving ADT resistance that is targetable with potent dual-activity bromodomain-kinase inhibitors.
Data from NEO212 Inhibits Migration and Invasion of Glioma Stem Cells
Authors: Marín-Ramos Nagore I. , Thein Thu Zan , Cho Hee-Yeon , Swenson Stephen D. , Wang Weijun , Schönthal Axel H. , Chen Thomas C. , Hofman Florence M.
Published: April 2023

Abstract
Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10-fold more cytotoxic to glioma stem cells (GSC) than TMZ, and is active against TMZ-resistant tumor cells. In this study, we show that NEO212 decreases migration and invasion of primary cultures of patient-derived GSCs, in both mesenchymal USC02 and proneural USC04 populations. The mechanism by which NEO212 reduces migration and invasion appears to be independent of its DNA alkylating effects, which cause cytotoxicity during the first hours of treatment, and is associated with a decrease in the FAK/Src signaling pathway, an effect not exhibited by TMZ. NEO212 also decreases the production of matrix metalloproteinases MMP2 and MMP9, crucial for GSC invasion. Gene expression analysis of epithelial and mesenchymal markers suggests that NEO212 increases the expression of epithelial-like characteristics, suggesting a reversion of the epithelial-to-mesenchymal transition process. Furthermore, in an in vivo orthotopic glioma model, NEO212 decreases tumor progression by reducing invasion of GSCs, thereby increasing survival time of mice. These studies indicate that NEO212, in addition to cytotoxicity, can effectively reduce migration and invasion in GSCs, thus exhibiting significant clinical value in the reduction of invasion and malignant glioma progression. Mol Cancer Ther; 17(3); 625–37. ©2018 AACR.
Data from Role of EphB3 Receptor in Mediating Head and Neck Tumor Growth, Cell Migration, and Response to PI3K Inhibitor
Authors: Bhatia Shilpa , Griego Anastacia , Lennon Shelby , Oweida Ayman , Sharma Jaspreet , Rohmer Christina , Uyanga Nomin , Bukkapatnam Sanjana , Van Court Benjamin , Raben David , Young Christian , Heasley Lynn , Karam Sana D.
Published: April 2023

Abstract
Eph proteins have emerged as critical drivers affecting tumor growth and progression in human malignancies. Our The Cancer Genome Atlas (TCGA) data analysis showed that EphB3, a receptor tyrosine kinase, is frequently coamplified with PIK3CA in head and neck squamous cell carcinoma (HNSCC). We therefore hypothesized that EphB3 amplification plays a protumorigenic role in HNSCC and that EphB3 and PIK3CA are cooperating oncogenes that contribute toward its pathogenesis. This hypothesis was not experimentally supported, because EphB3 knockdown failed to alter HNSCC tumor cell growth in vitro or in vivo with an orthotopic model. However, responsiveness of EphB3 knockdown tumors to the PI3K inhibitor, BKM120, was significantly decreased in terms of both tumor growth delay and survival. This is correlated with an increase in prosurvival proteins, S6 and BcL-XL, in the EphB3 shRNA tumors treated with BKM120 compared with controls. We further observed that EphB3 knockdown resulted in increased migration in vitro and increased EMT gene signature in vivo. To explain these results, we examined EphB3 phosphorylation levels in HNSCC at baseline. Although total EphB3 levels were high, we found low phospho-EphB3 levels in HNSCCs. Forced EphB3 phosphorylation with an ephrin-B2–Fc fusion protein resulted in decreased HNSCC migration and cell growth, and enhanced response to BKM120 in vitro. These data collectively indicate that progression of HNSCC selects for low/inhibited EphB3 activity to enhance their survival and migratory abilities and decrease response to PI3K signaling. Therefore, strategies focused on activating EphB3 might be helpful to inhibit tumor growth and enhance sensitivity to PI3K inhibitors in HNSCC. Mol Cancer Ther; 17(9); 2049–59. ©2018 AACR.
Data from Analysis of HSP27 and the Autophagy Marker LC3B+ Puncta Following Preoperative Chemotherapy Identifies High-Risk Osteosarcoma Patients
Authors: Livingston J. Andrew , Wang Wei-Lien , Tsai Jen-Wei , Lazar Alexander J. , Leung Cheuk Hong , Lin Heather , Advani Shailesh , Daw Najat , Santiago-O'Farrill Janice , Hollomon Mario , Gordon Nancy B. , Kleinerman Eugenie S.
Published: April 2023

Abstract
Chemotherapy-induced autophagy is a proposed mechanism of chemoresistance and potential therapeutic target in osteosarcoma. We evaluated heat shock protein 27 (HSP27) and autophagy-related proteins as predictors of pathologic treatment response and prognostic markers among osteosarcoma patients who received standard chemotherapy. We analyzed 394 tumor specimens (pre-treatment, post-treatment, and metastases) from 260 osteosarcoma patients by immunohistochemistry for cytoplasmic light chain 3B (LC3B)-positive puncta, sequestosome 1 (SQSTM1), high mobility group box 1 (HMGB1), and HSP27 expression. The staining percentage and intensity for each marker were scored and the extent to which marker expression was correlated with pathologic response, relapse-free survival (RFS), and overall survival (OS) was assessed. LCB3+ puncta in post-treatment primary tumors (50%) and metastases (67%) was significantly higher than in pre-treatment biopsy specimens (30%; P = 0.023 and <0.001). Among 215 patients with localized osteosarcoma, both pre-treatment [multivariate hazard ratio (HR), 26.7; 95% confidence interval (CI), 1.47–484; P = 0.026] and post-treatment HSP27 expression (multivariate HR, 1.85; 95% CI, 1.03–3.33; P = 0.039) were associated with worse OS. Lack of LC3B+ puncta at resection was an independent poor prognostic marker in both univariate (HR, 1.78; 95% CI, 1.05–3.03; P = 0.034) and multivariate models (HR, 1.75; 95% CI, 1.01–3.04; P = 0.045). Patients with LC3B+/HSP27− tumors at resection had the best 10-year OS (75%) whereas patients with LC3B−/HSP27+ tumors had the worst 10-year survival (25%). Neither HSP27 expression nor the presence of LCB3+ puncta was correlated with pathologic treatment response. Our findings establish HSP27 expression and LC3B+ puncta as independent prognostic markers in osteosarcoma patients receiving standard chemotherapy and support further investigation into strategies targeting HSP27 or modulating autophagy in osteosarcoma treatment. Mol Cancer Ther; 17(6); 1315–23. ©2018 AACR.
Data from ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment
Authors: Patel Hetal , Periyasamy Manikandan , Sava Georgina P. , Bondke Alexander , Slafer Brian W. , Kroll Sebastian H. B. , Barbazanges Marion , Starkey Richard , Ottaviani Silvia , Harrod Alison , Aboagye Eric O. , Buluwela Laki , Fuchter Matthew J. , Barrett Anthony G. M. , Coombes R. Charles , Ali Simak
Published: April 2023

Abstract
Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including estrogen receptor (ER)-α. Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40 nmol/L; IC50 values for CDK1, CDK2, CDK5, and CDK9 were 45-, 15-, 230-, and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2 and 0.3 μmol/L. In xenografts of both breast and colorectal cancers, the drug has substantial antitumor effects. In addition, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia and small-cell lung cancer. Mol Cancer Ther; 17(6); 1156–66. ©2018 AACR.
Data from Tumor Sidedness and Enriched Gene Groups for Efficacy of First-line Cetuximab Treatment in Metastatic Colorectal Cancer
Authors: Sunakawa Yu , Mogushi Kaoru , Lenz Heinz-Josef , Zhang Wu , Tsuji Akihito , Takahashi Takehiro , Denda Tadamichi , Shimada Ken , Kochi Mitsugu , Nakamura Masato , Kotaka Masahito , Segawa Yoshihiko , Tanioka Hiroaki , Negoro Yuji , Moran Miriana , Astrow Stephanie H. , Hsiang Jack , Stephens Craig , Fujii Masashi , Ichikawa Wataru
Published: April 2023

Abstract
Molecular differences in tumor locations may contribute to the sidedness-specific response to cetuximab in metastatic colorectal cancer (mCRC). We investigated genes associated with the response to cetuximab treatment depending on tumor sidedness. Our study included 77 patients with mCRC (13/63, right/left) with KRAS exon 2 wild-type tumors from phase II trials of first-line therapy with cetuximab. Expression levels of 2,551 genes were measured in tissue samples by HTG EdgeSeq Oncology Biomarker Panel. Univariate Cox regression analysis using log2 values of counts per million (CPM) was conducted in each sidedness to assess associations with clinical outcomes, and to define the optimal cut-off point for clinically significant genes. In addition, a gene set enrichment analysis (GSEA) was performed to identify significant gene pathways in each sidedness. Sixty-nine patients were assessable for gene expression data. Overexpression of BECN1 [log2(CPM) ≥ 6.8] was associated with favorable survival, regardless of tumor sidedness. High expression of NOTCH1 [log2(CPM) ≥ 7.5] predicted significantly longer progression-free survival (PFS; median 14.7 vs. 11.1 months, HR 0.43, P = 0.01) and overall survival (OS; median 42.8 vs. 26.5 months, HR 0.35, P = 0.01) in left side but not in right side. The GSEA showed that regulation of DNA replication gene set correlated with favorable survival in the left, whereas the subcellular component and leukocyte migration gene sets were associated with good survival in the right. In conclusion, genes contributing to the efficacy of cetuximab treatment may differ according to the sidedness in mCRC. NOTCH1 may potentially discriminate favorable responders to cetuximab in patients with left-sided tumors.
Data from Combined Inhibition of PI3Kβ and mTOR Inhibits Growth of PTEN-null Tumors
Authors: Lynch James T. , Polanska Urszula M. , Hancox Ursula , Delpuech Oona , Maynard Juliana , Trigwell Catherine , Eberlein Catherine , Lenaghan Carol , Polanski Radoslaw , Avivar-Valderas Alvaro , Cumberbatch Marie , Klinowska Teresa , Critchlow Susan E. , Cruzalegui Francisco , Barry Simon T.
Published: April 2023

Abstract
Loss of the tumor suppressor PTEN confers a tumor cell dependency on the PI3Kβ isoform. Achieving maximal inhibition of tumor growth through PI3K pathway inhibition requires sustained inhibition of PI3K signaling; however, efficacy is often limited by suboptimal inhibition or reactivation of the pathway. To select combinations that deliver comprehensive suppression of PI3K signaling in PTEN-null tumors, the PI3Kβ inhibitor AZD8186 was combined with inhibitors of kinases implicated in pathway reactivation in an extended cell proliferation assay. Inhibiting PI3Kβ and mTOR gave the most effective antiproliferative effects across a panel of PTEN-null tumor cell lines. The combination of AZD8186 and the mTOR inhibitor vistusertib was also effective in vivo controlling growth of PTEN-null tumor models of TNBC, prostate, and renal cancers. In vitro, the combination resulted in increased suppression of pNDRG1, p4EBP1, as well as HMGCS1 with reduced pNDRG1 and p4EBP1 more closely associated with effective suppression of proliferation. In vivo biomarker analysis revealed that the monotherapy and combination treatment consistently reduced similar biomarkers, while combination increased nuclear translocation of the transcription factor FOXO3 and reduction in glucose uptake. These data suggest that combining the PI3Kβ inhibitor AZD8186 and vistusertib has potential to be an effective combination treatment for PTEN-null tumors. Mol Cancer Ther; 17(11); 2309–19. ©2018 AACR.
Data from Next-Generation Sequencing of Tissue and Circulating Tumor DNA: The UC San Diego Moores Center for Personalized Cancer Therapy Experience with Breast Malignancies
Authors: Shatsky Rebecca , Parker Barbara A. , Bui Nam Q. , Helsten Teresa , Schwab Richard B. , Boles Sarah G , Kurzrock Razelle
Published: April 2023

Abstract
Clinical-grade next-generation sequencing (NGS) of tissue- and blood-derived circulating tumor DNA (ctDNA) allows assessment of multiple genomic alterations in patients with cancer. We analyzed ctDNA (54–70 genes) in 62 patients with advanced breast cancer (median = five prior therapies); 38 also had tissue NGS (236–315 genes). Overall, 42 of 62 patients (68%) had detectable (characterized) ctDNA alterations (variants of unknown significance excluded), and 37 of 38 (97%) had tissue alterations. The median (range) number of characterized alterations in ctDNA was 1 (0–7), and in tissue, 4 (0–17). The most common alterations in ctDNA were in TP53 (37% of patients) and PIK3CA (23%), and for tissue, TP53 (37%) and PIK3CA (24%); EGFR amplification was seen in ctDNA (11%), but not in tissue. Concordance between ctDNA and tissue appeared higher if <6 months separated the sample acquisition, although small sample size precluded statistical validation. Overall, 32 of 67 tissue alterations (48%) were also detected in ctDNA; 35 of 72 ctDNA alterations (48%) were also in tissue. Excluding estrogen receptor and ERBB2, 41 of 62 patients (66%) had potentially actionable alterations in ctDNA, and 36 of 38 (95%), in tissue (with potential actionability based on either preclinical or clinical evidence). If ≥1 genomic alteration had ctDNA ≥5%, survival was shorter than if ctDNA was <5% (median, 6.7 vs. 17.9 months; P = 0.01). In conclusion, tissue and ctDNA NGS reveal potentially actionable alterations in most patients. The genomic results of ctDNA and tissue NGS overlap, but there are differences, perhaps reflecting temporal spacing and tumor heterogeneity. ctDNA quantification also provides prognostic information.
Data from MicroRNA-203 Inhibits Long Noncoding RNA HOTAIR and Regulates Tumorigenesis through Epithelial-to-mesenchymal Transition Pathway in Renal Cell Carcinoma
Authors: Dasgupta Pritha , Kulkarni Priyanka , Majid Shahana , Shahryari Varahram , Hashimoto Yutaka , Bhat Nadeem S. , Shiina Marisa , Deng Guoren , Saini Sharanjot , Tabatabai Z. Laura , Yamamura Soichiro , Tanaka Yuichiro , Dahiya Rajvir
Published: April 2023

Abstract
This study aims to investigate the role of miR-203–HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, invasion, migration, and colony formation along with in vivo tumor xenograft model. Profiling of miR-203 and HOTAIR expression revealed that miR-203 was significantly underexpressed, whereas HOTAIR was overexpressed in RCC cell lines and clinical specimens compared with normal cell line and tissue. Both miR-203 and HOTAIR expression significantly distinguished malignant from normal tissues and significantly correlated with clinicopathologic characteristics of patients. Overexpression of miR-203 significantly inhibited proliferation, migration, and invasion with an induction of apoptosis and cell-cycle arrest. However, HOTAIR suppression resulted in the similar functional effects in the same RCC cell lines. In silico, RNA-22 algorithm showed a binding site for miR-203 in HOTAIR. We observed a direct interaction between miR-203 and HOTAIR by RNA-immunoprecipitation (RIP) and luciferase reporter assays. We show that miR-203–HOTAIR interaction resulted in the inhibition of epithelial-to-mesenchymal transition (EMT) and metastatic genes as indicated by induction of key metastasis-suppressing proteins E-cadherin, claudin (epithelial markers), and PTEN along with induction of tumor suppressor genes p21 and p27. A significant decrease in vimentin (mesenchymal marker), KLF4, and Nanog (stemness markers) was also observed. This is the first report demonstrating miR-203–mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis. Mol Cancer Ther; 17(5); 1061–9. ©2018 AACR.
Data from Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor
Authors: Langdon Casey G. , Platt James T. , Means Robert E. , Iyidogan Pinar , Mamillapalli Ramanaiah , Klein Michael , Held Matthew A. , Lee Jong Woo , Koo Ja Seok , Hatzis Christos , Hochster Howard S. , Stern David F.
Published: April 2023

Abstract
Pancreatic adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death in the United States. PDAC is difficult to manage effectively, with a five-year survival rate of only 5%. PDAC is largely driven by activating KRAS mutations, and as such, cannot be directly targeted with therapeutic agents that affect the activated protein. Instead, inhibition of downstream signaling and other targets will be necessary to effectively manage PDAC. Here, we describe a tiered single-agent and combination compound screen to identify targeted agents that impair growth of a panel of PDAC cell lines. Several of the combinations identified from the screen were further validated for efficacy and mechanism. Combination of the bromodomain inhibitor JQ1 and the neddylation inhibitor MLN4294 altered the production of reactive oxygen species in PDAC cells, ultimately leading to defects in the DNA damage response. Dual bromodomain/neddylation blockade inhibited in vivo growth of PDAC cell line xenografts. Overall, this work revealed novel combinatorial regimens, including JQ1 plus MLN4294, which show promise for the treatment of RAS-driven PDAC. Mol Cancer Ther; 16(6); 1041–53. ©2017 AACR.
Data from Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth
Authors: Tauro Marilena , Shay Gemma , Sansil Samer S. , Laghezza Antonio , Tortorella Paolo , Neuger Anthony M. , Soliman Hatem , Lynch Conor C.
Published: April 2023

Abstract
Bone metastasis is common during breast cancer progression. Matrix metalloproteinase-2 (MMP-2) is significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor- or host-derived MMP-2 contributes to breast cancer growth and does so by processing substrates, including type I collagen and TGFβ latency proteins. These data provide strong rationale for the application of MMP-2 inhibitors to treat the disease. However, in vivo, MMP-2 is systemically expressed. Therefore, to overcome potential toxicities noted with previous broad-spectrum MMP inhibitors (MMPIs), we used highly selective bisphosphonic-based MMP-2 inhibitors (BMMPIs) that allowed for specific bone targeting. In vitro, BMMPIs affected the viability of breast cancer cell lines and osteoclast precursors, but not osteoblasts. In vivo, we demonstrated using two bone metastatic models (PyMT-R221A and 4T1) that BMMPI treatment significantly reduced tumor growth and tumor-associated bone destruction. In addition, BMMPIs are superior in promoting tumor apoptosis compared with the standard-of-care bisphosphonate, zoledronate. We demonstrated MMP-2–selective inhibition in the bone microenvironment using specific and broad-spectrum MMP probes. Furthermore, compared with zoledronate, BMMPI-treated mice had significantly lower levels of TGFβ signaling and MMP-generated type I collagen carboxy-terminal fragments. Taken together, our data show the feasibility of selective inhibition of MMPs in the bone metastatic breast cancer microenvironment. We posit that BMMPIs could be easily translated to the clinical setting for the treatment of bone metastases given the well-tolerated nature of bisphosphonates. Mol Cancer Ther; 16(3); 494–505. ©2017 AACR.
Data from Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer
Authors: Wang Ruizhong , Bhat-Nakshatri Poornima , Padua Maria B. , Prasad Mayuri S , Anjanappa Manjushree , Jacobson Max , Finnearty Courtney , Sefcsik Victoria , McElyea Kyle , Redmond Rachael , Sandusky George , Penthala Narsimha , Crooks Peter A , Liu Jianguo , Zimmers Teresa , Nakshatri Harikrishna
Published: April 2023

Abstract
Breast cancer progression is associated with systemic effects, including functional limitations and sarcopenia without the appearance of overt cachexia. Autocrine/paracrine actions of cytokines/chemokines produced by cancer cells mediate cancer progression and functional limitations. The cytokine-inducible transcription factor NF-κB could be central to this process, as it displays oncogenic functions and is integral to the Pax7:MyoD:Pgc-1β:miR-486 myogenesis axis. We tested this possibility using the MMTV-PyMT transgenic mammary tumor model and the NF-κB inhibitor dimethylaminoparthenolide (DMAPT). We observed deteriorating physical and functional conditions in PyMT+ mice with disease progression. Compared with wild-type mice, tumor-bearing PyMT+ mice showed decreased fat mass, impaired rotarod performance, and reduced grip strength as well as increased extracellular matrix (ECM) deposition in muscle. Contrary to acute cachexia models described in the literature, mammary tumor progression was associated with reduction in skeletal muscle stem/satellite-specific transcription factor Pax7. Additionally, we observed tumor-induced reduction in Pgc-1β in muscle, which controls mitochondrial biogenesis. DMAPT treatment starting at 6 to 8 weeks age prior to mammary tumor occurrence delayed mammary tumor onset and tumor growth rates without affecting metastasis. DMAPT overcame cancer-induced functional limitations and improved survival, which was accompanied with restoration of Pax7, Pgc-1β, and mitochondria levels and reduced ECM levels in skeletal muscles. In addition, DMAPT restored circulating levels of 6 out of 13 cancer-associated cytokines/chemokines changes to levels seen in healthy animals. These results reveal a pharmacological approach for overcoming cancer-induced functional limitations, and the above-noted cancer/drug-induced changes in muscle gene expression could be utilized as biomarkers of functional limitations. Mol Cancer Ther; 16(12); 2747–58. ©2017 AACR.
Abstract 101: Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma
Authors: Nakano Yusuke , Kitagawa Akihiro , Hashimoto Masahiro , Abe Tadashi , Hisamatsu Yuichi , Toshima Takeo , Yonemura Yusuke , Masuda Takaaki , Inoue Akira , Eguchi Hidetoshi , Doki Yuichiro , Mimori Koshi
Published: April 2023

Background & Aim: Intrahepatic cholangiocarcinoma(ICC) accounts for about 5% of all primary liver cancer and is reported to be common in Southeast Asia and parts of Chile, but in recent years it has been increasing in other areas including Europe and the United States. ICC leads to a dismal outcome as the commonly used chemotherapy exhibit purely palliative effects on ICC, enabling only a limited improvement in survival until today. As ICC harbors few actionable target genes with inter-tumor genomic heterogeneity, ICC is considered to be one of the most intractable malignancies of all. Therefore, we implemented the multi-omics analysis especially with comprehension of the oncogenic metabolic changes to confer new treatment strategies. This study aims to unravel the evolution of ICC and identify ICC-specific metabolic pathways and essential targets for eradicating ICC.

Approach: We collected 12 primary ICC cases and 77 specimens and conducted a multi-omics approach, including genomics, transcriptomics, proteomics, and metabolomics for each material.

Results: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case indicates a “neutral evolution manner”, regardless of their tumor stage. Upregulation of BCAT1 and BCAT2 might enrich the ‘branched-chain amino acids (BCAA), such as Val, Leu, and Ile degradation pathway’. ICCs cases with the accumulated ubiquitous metabolites, BCAA exhibited poorer prognosis than those cases without BCAA accumulation significantly.

Conclusions: Regardless of the inter-tumor heterogeneity in genomic aberrations among ICC cases, we discovered the ubiquitous enrichment of the BCAA metabolic pathway in each tumor. We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.

Citation Format: Yusuke Nakano, Akihiro Kitagawa, Masahiro Hashimoto, Tadashi Abe, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda, Akira Inoue, Hidetoshi Eguchi, Yuichiro Doki, Koshi Mimori. Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma [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 101.
Abstract 1041: Circulating tumor (ct)DNA molecular response rate (MRR) as a potential surrogate for radiologic objective response rate (ORR): A meta-analysis of immunotherapy studies
Authors: Zhang Qu , Houseman Andy , Yuan Sammy , Harding Joe , Zhou Helen , Feng Bin , Washburn Michael L.
Published: April 2023

Background: Previous studies have shown that ctDNA MR defined by 50% reduction of ctDNA levels after immune checkpoint inhibitor (ICI) treatment is significantly associated with improved survival. However, discordance between MR and radiologic response was observed, hindering the potential use of MR as a surrogate endpoint. We report a meta-analysis of MR rate (MRR) and radiologic objective response rate (ORR) with ICI intervention. The relationship between MRR difference and hazard ratio of survival has also been assessed using two independent approaches.

Methods: MRR, ORR and overall survival (OS) data were compiled from 9 study arms where metastatic solid tumors were treated by ICI. Weighted least squares linear regression method was used to study the relationship between MRR and ORR. Patient level MR and OS data were downloaded from the original report (Set 1) or by digitizing Kaplan-Meier plot using Guyot algorithm (Set 2). The correlation of MRR difference between two arms and hazard ratio for OS was assessed using samples generated by bootstrapping with replacement. Similarly, a parametric simulation by fitting a piecewise exponential curve was also performed to confirm the above finding.

Results: A total of 958 patients were eligible for this analysis. A significant correlation between MRR and ORR was identified across 9 study arms after adjusting sample size (Adjusted R2=0.91, P<0.0001). Under a hypothetical scenario of two randomized study arms, an inverse correlation between MRR difference and hazard ratio was observed using both bootstrapping and parametric simulation approaches across different conditions. A stronger negative trend was found in Set 1 compared with Set 2, where MR showed a better association with OS in the former (HR=0.27 versus HR=0.41)

Conclusions: This meta-analysis showed for the first time that ctDNA molecular response rate may be a surrogate for radiologic objective response rate in ICI and could enable early decision making. Since most of the data analyzed here is from patients with non-small cell lung cancer, the extrapolation of these findings to other tumor types needs further validation.

Citation Format: Qu Zhang, Andy Houseman, Sammy Yuan, Joe Harding, Helen Zhou, Bin Feng, Michael L. Washburn. Circulating tumor (ct)DNA molecular response rate (MRR) as a potential surrogate for radiologic objective response rate (ORR): A meta-analysis of immunotherapy studies [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 1041.
Abstract 1050: Non-invasive detection of circulating mRNA markers in diseases of the colon and rectum
Authors: Vymetalkova Veronika , Siskova Anna , Vodicka Pavel , Jungwirth Jiri , Bruha Jan
Published: April 2023

Colorectal cancer (CRC) is a worldwide health burden with nearly 1.2 million new cases expected each year globally. When CRC is identified early, there is a five-year survival rate of about 90% but it drops to near 12% once there are distant metastases. Early detection of colorectal adenoma is warranted as it represents the precancerous lesion of CRC. The removal of colorectal adenoma can effectively prevent the subsequent development of CRC. The only preventive strategy is to undergo appropriate endoscopic surveillance and early detection of adenoma or CRC In this study, we focused on the transcriptome profile in patients with colon adenomas, incident colorectal cancer (CRC) and in the healthy population. MRNA transcripts were, in addition to tissues, isolated from the plasma and stool. Plasma and stool analyses should reveal potential mRNA signatures capable of non-invasive determination of the average individual risk of predisposition to adenomas or CRCs. Relevant plasma/stool mRNA will be further validated in another group of individuals with similar clinical characteristics and analyzed in relation to diet and lifestyle factors. For patients with CRC, plasma and stool specimens are collected repeatedly to reveal whether the transcripts identified by us will decrease or diminish in CRC patients after successful surgery. We hypothesize that altered mRNA signatures in plasma and stool may serve as a robust, powerful non-invasive and sufficiently sensitive tool in the early detection of adenomas or CRCs. The bioinformatic analysis is currently running and the results will be presented during the meeting. The long-term significance of the project lays on improvement of the therapy efficacy in colon cancer patients. Supported by grant GACR 22-05942S and by the Ministry of Health of the Czech Republic, grant nr. NU22J-03-00033.

Citation Format: Veronika Vymetalkova, Anna Siskova, Pavel Vodicka, Jiri Jungwirth, Jan Bruha. Non-invasive detection of circulating mRNA markers in diseases of the colon and rectum [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 1050.
Abstract 1077: Porcupine inhibition enhances enzalutamide efficacy in drug resistant prostate cancer
Authors: Jones Katelyn Makayla , Liu Xiaoqi
Published: April 2023

Androgen receptor (AR) signaling continues to participate as a vital component of castration-resistant prostate cancer (CRPC). Subsequently, this has led to the development of Androgen Signaling Inhibitors (ASI), specifically Enzalutamide (ENZ), which is a direct inhibitor of AR, to clinically manage CRPC. Inevitably, ENZ treatment only provides improvement for approximately two months before advancing to an incurable form, ENZ-resistant CRPC. With PCa ranking as the second leading cause of cancer-related deaths in USA males, there is an urgency and necessity for the discovery and development of novel therapeutic approaches for CRPC. Wnt signaling has been extensively documented in its involvement in PCa and the tumor microenvironment (TME), however the mechanism of how the Wnt signaling cascades contribute to ENZ resistance is still ambiguous. Recently we have published that the activation of the canonical Wnt pathway contributes to the progression of ENZ resistance in CRPC and using a combination of β-catenin inhibitor with ENZ resulted in the synergistic inhibition of patient derived xenograft (PDX) tumor growth. Regarding the non-canonical Wnt pathway, we confirmed its contribution to invasion and migration which leads to metastasis in ENZ-resistant CRPC, and when the downstream effector ROCK is depleted or depleted ROCK cells are treated with ENZ, there is a significant hindering of cell migration and invasion. Also, utilizing a combination therapy of ROCK inhibitor with ENZ synergistically inhibited the growth of PDX tumors. Hence the reasoning that by simultaneously inhibiting both the canonical and non-canonical Wnt signaling cascade will result in the inhibition of cell proliferation, migration, and invasion. The goal of this study was to define the mechanism of PORCN in ENZ-resistant CRPC and develop a therapeutic approach to combat this disease. My research has determined that Porcupine (PORCN) is associated with CRPC progression to ENZ-resistance, and that an inhibition or loss of PORCN has resulted in the regain of ENZ sensitivity in ENZ-resistant models. This model has also demonstrated that PORCN and Wnt signaling engage in a paramount role contributing to AR activation, promoting CRPC progression, and the development of ENZ resistance.

Citation Format: Katelyn Makayla Jones, Xiaoqi Liu. Porcupine inhibition enhances enzalutamide efficacy in drug resistant prostate 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 1077.
Abstract 108: Spatio-temporal view of malignant histogenesis and cancer evolution via formation of polyploid giant cancer cell
Authors: Li Xiaoran , Zhong Yanping , Zhang Xudong , Sood Anil , Liu Jinsong
Published: April 2023

To understand how malignant tumors develop from single cells, we used long-term, time-lapse, live-cell imaging to track the dynamics of the cell membrane, nucleus, spindle, and cell cycle regulators during the development of high-grade, serous, carcinoma-derived organoids. Organoids are highly heterogeneous and include 2 major subtypes. Type-1 organoids are relatively homogeneous and develop via traditional mitosis, whereas type-2 organoids are highly heterogenous and are composed of differently sized polyploid giant cancer cells (PGCCs). Tracking the origin of PGCCs in type-2 organoids shows single cells first undergo asymmetric mitosis and nuclear fusion, followed by endoreplication, multipolar restitution mitosis, multipolar endomitosis, and karyokinesis. At the cellular level, the formation of PGCCs was associated with the formation of transient intracellular cells, termed fecundity cells. The fecundity cells underwent decellularization via the dissolution of the cell membrane, which allowed a giant nucleus to form via nuclear fusion. Different PGCCs underwent nuclear budding, decellularization, or entosis to form Russian doll-like tissue structures that facilitated rapid tumor growth and evolution. The uncoupling of nuclear augmentation from cytokinesis led to a rapid increase in the nuclear-to-cytoplasmic ratio and increased the genomic content of PGCCs, which facilitated macro-genomic evolution during tumor development. Our live-cell imaging evidence allows us to link nuclear replication and cancer evolution to the nuclear morphologies observed by pathologists under the microscope. PGCCs may be the central regulators of malignant histogenesis, cancer evolution, and physical barriers conferring resistance to immune therapy.

Citation Format: Xiaoran Li, Yanping Zhong, Xudong Zhang, Anil Sood, Jinsong Liu. Spatio-temporal view of malignant histogenesis and cancer evolution via formation of polyploid giant cancer cell [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 108.
Abstract 1092: Targeting one-carbon metabolism radiosensitizes pancreatic ductal adenocarcinoma cells (PDAC)
Authors: Nenwani Minal , Achreja Abhinav , Animasahun Olamide , Sarangi Itisam , Roy Jyotirmoy , Choppara Srinadh , Wuchu Fulei , Paserba Miya , Mittal Anjali , Quispe Sergio , Mohan Aradhana , Morgan Meredith , Lawrence Theodore S. , Nagrath Deepak
Published: April 2023

One of the most challenging aspects of PDAC is intense therapeutic resistance towards radiotherapy. Cellular signaling pathways are tightly regulated to protect and withstand constant DNA-damaging insults. Similarly, pancreatic cancer cells are known to activate important metabolic events in the advent of cellular stress. Fuel sources obtained via the high metabolic flexibility of PDAC cells confer on them enhanced survival and the ability to escape therapy-induced cell death. To this end, we aim to dissect the role of altered metabolic reprogramming in radioresistant PDAC cells. Investigation of systemic metabolic changes post-radiation of 8Gy in in vitro systems revealed reduced total NAD/NADH ratio and hinted at the increased dependency of PDAC cells on the one-carbon metabolic pathway. Using combinatorial stable-isotope tracing techniques, we confirmed the role of methylene tetrahydrofolate dehydrogenase (MTHFD1/2) enzymes as key regulators in maintaining total NAD/NADH ratio in irradiated cells. Moreover, inhibition of the one-carbon metabolic pathway hindered the ability of PDAC cells to resolve radiation-induced DNA damage. In summary, we propose that PDAC cells modulate the flux of MTHFD1/2 enzymes to reprogram their metabolic state and generate intermediates for DNA repair and cell survival, thus establishing MTHFD1/2 enzymes as potential therapeutic targets to tackle radioresistance.

Citation Format: Minal Nenwani, Abhinav Achreja, Olamide Animasahun, Itisam Sarangi, Jyotirmoy Roy, Srinadh Choppara, Fulei Wuchu, Miya Paserba, Anjali Mittal, Sergio Quispe, Aradhana Mohan, Meredith Morgan, Theodore S. Lawrence, Deepak Nagrath. Targeting one-carbon metabolism radiosensitizes pancreatic ductal adenocarcinoma cells (PDAC) [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 1092.