bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1221: The landscape of 2,706 RET alterations from 89,754 adult patients with cancer: Clinical implications
Authors: Adashek Jacob J. , Andreev-Drakhlin Alexander , Roszik Jason , Desai Aakash P. , Subbiah Vivek 
Published: July 2021

Abstract
Background: Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions have been recognized as potent drivers of oncogenesis in multiple malignancies. Recently, highly potent and selective RET inhibitors, selpercatinib and pralsetinib have been FDA approved for RET fusion+ NSCLC and selpercatinib for RET+ thyroid cancers. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies.
Patients and methods: 96,324 samples from 89,754 patients available from AACR Project Genie database version 8 were analyzed for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types accessed July 21, 2020. The races of the samples within the cohort were 69,962 (72.6%) white, 5,388 (5.6%) Black, 4,909 (5.1%) Asian, 163 (0.17%) Native American, 48 (0.05%) Pacific Islander, and 15,854 (16.5%) were unknown.
Results: There were 56,382 (58.5%) samples from primary tumors, 24,204 (25.1%) samples from unspecified metastasis sites, 4,798 (5.0%) from distant organ metastasis, 1,379 (1.4%) from lymph node metastasis, 1,279 (1.3%) from local recurrence, and 8,282 (8.6%) unknown. In 96,324 tumor samples there were 2,706 (2.81%) RET alterations. This included 223 (0.23%) fusions, 1,689 RET mutations found (1.75%) in 21 tumor histologies, and 794 (0.82%) RET amplifications identified; where the most abundant tissues harboring RET fusions were NSCLC (n = 121), papillary thyroid cancer (n = 53), breast cancer (n = 8) and colorectal cancer (n = 7) and the most abundant tissues harboring RET missense mutations were NSCLC (n = 355), colorectal cancer (n = 292), melanoma (n = 236), and thyroid cancer (n = 127). NSCLC samples with RET fusions had significantly co-altered KRAS, SETD2, PVRL4, EZH1, and RRAGC.
Conclusions: RET fusions represent extremely rate events in multiple cancers. RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted because RET is highly targetable with therapeutics.
Citation Format: Jacob J. Adashek, Alexander Andreev-Drakhlin, Jason Roszik, Aakash P. Desai, Vivek Subbiah. The landscape of 2,706 RET alterations from 89,754 adult patients with cancer: Clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1221.
Abstract 1227: Oncofusion driven de novo enhancer assembly promotes malignancy in Ewing sarcomavia aberrant expression of the stereociliary protein LOXHD1
Authors: Deng Qu , Natesan Ramakrishnan , Cidre-Aranz Florencia , Arif Shehbeel , Liu Ying , Rasool Reyaz , Wang Pei , Crammer Zvi , Chou Margaret , Kumar Chandan , Weber Kristy , Eisinger Karin , Grillet Nicolas , Grünewald Thomas , Asangani Irfan 
Published: July 2021

Abstract
Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1-ETS (EWS-FLI1/EWS-ERG) transcription factors drive EwS by orchestrating an oncogenic transcription program through de novo enhancers. Pharmacological targeting of these oncofusions has been challenged by unstructured prion-like domains and common DNA binding motifs in the EWSR1 and ETS, respectively. Alternatively, identification and characterization of mediators and downstream targets of EWS-FLI1 dependent or independent function could offer novel therapeutic options. By integrative analysis of thousands of transcriptomic datasets representing pan-cancer cell lines, primary cancer, metastasis, and normal tissues, we have identified a 32 gene signature (ESS32) in EwS that could stratify EwS from pan-cancer. Of the ESS32, LOXHD1 - coding for a stereociliary protein was the most exquisite gene expressed in EwS. CRISPR-Cas9 mediated deletion or silencing of EWS-FLI1 bound upstream de novo enhancer elements in EwS cells led to the loss of LOXHD1 expression and altered the EWS-FLI1, MYC, and HIF1a pathway genes, resulting in decreased proliferation and invasion in vitro and in vivo. These observations open up new avenues for developing LOXHD1-targeted small molecules or cellular therapies for this deadly disease.
Citation Format: Qu Deng, Ramakrishnan Natesan, Florencia Cidre-Aranz, Shehbeel Arif, Ying Liu, Reyaz Rasool, Pei Wang, Zvi Crammer, Margaret Chou, Chandan Kumar, Kristy Weber, Karin Eisinger, Nicolas Grillet, Thomas Grünewald, Irfan Asangani. Oncofusion driven de novo enhancer assembly promotes malignancy in Ewing sarcomavia aberrant expression of the stereociliary protein LOXHD1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1227.
Abstract 1240: RRM2 and mutant p53 as therapeutic targets in TNBC
Authors: Sultana Nahid , Wilson Elizabeth A. , Elford Howard L. , Faridi Jesika S. 
Published: July 2021

Abstract
Triple negative breast cancer (TNBC) is a highly aggressive type of cancer associated with poor prognosis and characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2). TNBC accounts for 10 - 15% of all new cases of breast cancer. TNBC is heterogenous in nature (70% basal-like) and currently doesn't have effective targeted therapy. As such, dose-dense chemotherapeutic agents used in combination, such as doxorubicin (DOXO) with cyclophosphamide, is the regimen of choice for TNBC. However, DOXO has limited efficacy as a therapeutic agent owing to acquired drug resistance and its cardiotoxic effects. Ribonucleotide reductase (RR) is the rate limiting enzyme required for the conversion of ribonucleotide to deoxyribonucleotide in DNA synthesis during cell proliferation. Didox (3,4 dihydroxybenzohydroxamic acid) is a unique RR inhibitor with iron chelating and free radical scavenging properties. We have previously identified that ribonucleotide reductase M2 (RRM2) is upregulated in TNBC cells and is a key contributor to acquired drug resistance. We found that Didox not only inhibits RRM2, but it also reduces mutant p53 protein levels and inhibits the activation of the NF-κB pathway. Through this inhibition, we found that Didox works synergistically with DOXO to inhibit TNBC tumor growth while also minimizing DOXO-induced cardiac damage in mice. In our present study, we have observed that RRM2 expression is upregulated in TNBC patients from three independent data sets and that high RRM2 levels are associated with lower recurrence free survival (RFS) and overall survival (OS). Interestingly, high levels of RRM2 were only predictive of lower RFS and OS in patients with wild-type p53 but not mutant p53. Additionally, we have found that Didox downregulates mutant p53 protein levels in TNBC cell lines but does not alter total p53 in cells with functioning p53. Our data confirms that Didox induced downregulation of mutant p53 is not a transcriptional effect. Finally, we have identified that RRM2 protein levels increase in TNBC with progression of stage as measured in patient tissue microarray analysis. Our data presents a novel and promising approach for the treatment of TNBC that involves inhibition of RRM2, NF-kB activation, and mutant p53 that merits further clinical investigation in human models.
Citation Format: Nahid Sultana, Elizabeth A. Wilson, Howard L. Elford, Jesika S. Faridi. RRM2 and mutant p53 as therapeutic targets in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1240.
Abstract 1246: Anticancer activitiy of indolo[2,3-c]quinoline stabilization of the KRAS promoter G4mid structure
Authors: Psaras Alexandra Maria , Miller Jared , Tumey L. Nathan , Brooks Tracy A. 
Published: July 2021

Abstract
KRAS is a well validated anti-cancer therapeutic target; many active drug discovery programs are ongoing with foci on individual mutant isoforms, necessitating a wide array of drugs to be developed and missing cancers with dysregulation of non-mutant KRAS. Transcriptional down-regulation has been demonstrated to be lethal to tumor cells with aberrant KRAS signaling, irrespective of mutational status, and to potentially have a wide therapeutic window. G-quadruplex (G4) formation within KRAS's core promoter offers a molecular target to decrease the gene expression. Targeted G4-stabilization within the KRAS promoter targets cancer cells' acquired addiction to the transforming event of aberrant KRAS signaling through an activating mutation or protein overexpression, and thus is applicable to both of these deviant states. Small molecules that specifically inhibit transcriptional expression of KRAS genes have great potential for patients whose tumors have disregulated KRAS function. In the current works, compounds clarify the physiologically relevant G4 within the KRAS promoter (G4mid) through a combination of ex vivo screening, luciferase, cytotoxicity, and transcriptional regulation assays. A small set of novel indolo[2,3-c]quinoline compounds were synthesized and a newly optimized FRET Melt2 assay with a Z' score of &gt;0.5 was used to determine KRAS G4mid stabilization efficacy and selectivity. Compounds were then examined for KRAS promoter stabilization using a luciferase assay, pancreatic and ovarian cancer cytotoxicity by an MTS assay, and correlative changes in KRAS transcription as measured by multiplexed qPCR. JM-222 is the lead indolo[2,3-c]quinoline compound that demonstrates KRAS G4mid selective stabilization and promoter regulation, cancer cell cytotoxicity and altered KRAS transcription. These works highlight the function of G4mid in regulating KRAS transcription, novel synthetic methods for indolo[2,3-c]quinoline synthesis, the improved utility of the FRET Melt2 assay, and the overall potential for small compound-mediated KRAS promoter G4 stabilization for patients harboring tumors with aberrant KRAS signaling.
Citation Format: Alexandra Maria Psaras, Jared Miller, L. Nathan Tumey, Tracy A. Brooks. Anticancer activitiy of indolo[2,3-c]quinoline stabilization of the KRAS promoter G4mid structure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1246.
Abstract 1268: A novel treatment approach for melanoma by dually targeting MCT1 and MCT4 lactate transporters
Authors: Sharma Sambad , Goreczny Gregory , Noonepalle Satish Kumar , Palmer Erica , Garcia-Hernandez Maria , Banerjee Daliya , Escobedo Jaime , Villagra Alejandro , Sandanayaka Vincent 
Published: July 2021

Abstract
Cancer cells are metabolically rewired to activate glycolysis, which results in the generation and excretion of lactate as a byproduct. Although lactate was previously thought to be a waste product of anaerobic respiration, increasing evidence has revealed that distinct cell populations within tumors use lactate as a source of energy through TCA cycle. This metabolic symbiosis between distinct cell populations, hypoxic lactate consumers, and oxidative glycolytic lactate exporters within the tumor is regulated by differential expression of lactate transporters, mainly MCT1 and MCT4. Therefore, dual targeting of MCT1 and MCT4 is a novel approach to treat cancer. We have developed a compound, NGY-B, which binds and inhibits both MCT1 and MCT4 transporters. This compound has shown to significantly increase intracellular lactate levels in melanoma models and thereby decreasing in vitro cell proliferation. When cultured in the media with exogenous lactate to mimic the tumor microenvironment, NGY-B greatly reduced lactate uptake by cancer cells. Mechanistically, NGY-B deactivated glycolytic pathway by reducing hexokinase 2 (HK2), phosphoglycerate dehydrogenase (PHGDH), and pyruvate dehydrogenase kinase 1 (PDK1) expression. Additionally, NGY-B treatment strongly decreased STAT3 and mTOR signaling pathways. Furthermore, the in vivo therapeutic efficacy of NGY-B was validated in xenograft and syngeneic mouse models of melanoma. While a significant reduction in tumor size was observed in A375 xenograft model treated with NGY-B, a robust tumor growth reduction was evident in SM1 immunocompetent syngeneic melanoma mouse model, suggesting the involvement of immune cells for higher response in this model. Supporting this premise, we also found that NGY-B treated cells showed a decrease in PD-L1, B7-H3, and B7-H4 expression. Overall, our results indicate that NGY-B inhibits melanoma by targeting metabolic symbiosis and activating antitumor immune response mechanisms.
Citation Format: Sambad Sharma, Gregory Goreczny, Satish Kumar Noonepalle, Erica Palmer, Maria Garcia-Hernandez, Daliya Banerjee, Jaime Escobedo, Alejandro Villagra, Vincent Sandanayaka. A novel treatment approach for melanoma by dually targeting MCT1 and MCT4 lactate transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1268.
Abstract 1284: P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation
Authors: Tian Xiaobing , Ahsan Nagib , El-Deiry Wafik S. 
Published: July 2021

Abstract
A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53-/-). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression.
Citation Format: Xiaobing Tian, Nagib Ahsan, Wafik S. El-Deiry. P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1284.
Abstract 1287: Novel NSAID derivatives containing selenium as potent cytotoxic agents against cancer
Authors: Ramos-Inza Sandra , Encío Ignacio , Sharma Arun K. , Sanmartín Carmen , Plano Daniel 
Published: July 2021

Abstract
Cancer is currently one of the major health problems of the human population and a prominent cause of death worldwide. The introduction of a selenium atom (Se) in the structure of organic molecules has demonstrated to be a valid approximation in the design of novel chemotherapeutic agents with several biological effects, including antitumoral activity. On the other hand, non-steroidal anti-inflamatory drugs (NSAIDs) have gained interest in recent years in terms of their chemopreventive and chemotherapeutic activities, whether when they are evaluated alone, as a combination therapy, or in the form of structurally modified analogs.On the basis of these findings, and taking into account the results of previous studies by our research group, we have developed a new series of twenty-five NSAID analogs bearing Se in their structure with several variations. The new compounds were tested in four cancer cell lines (HTB-54, DU-145, HT-29 and MCF-7) and two non-malignant cells (184B5 and BEAS-2B), showing promising results with IC50 values below 10 μM. The cytotoxicity of the five most potent and selective molecules was further studied in other cancer cell lines as well. Taken together, this work supports the design of new derivatives containing Se as potential antitumoral agents.
Citation Format: Sandra Ramos-Inza, Ignacio Encío, Arun K. Sharma, Carmen Sanmartín, Daniel Plano. Novel NSAID derivatives containing selenium as potent cytotoxic agents against cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1287.
Abstract 1307: Assessment of long IVT mRNA fragments with the Fragment Analyzer system
Authors: Luttgeharm Kyle D. , Borg Solange , Pocernich Chava 
Published: July 2021

Abstract
Quality control analysis of long in vitro transcribed (IVT) RNAs is challenging due to the lack of commercially available kits for sizing RNA over 6,000 nt, thus, to analyze long IVT RNAs, an extended separation method was developed for the Agilent 5200 Fragment Analyzer using a commercially available RNA ladder. IVT mRNA was produced using the RiboMAX Large Scale RNA Production System (Promega). RNA transcripts 9,000 and 10,000 nt in length were diluted in nuclease-free water and separated on the Agilent 5200 Fragment Analyzer system with the Agilent RNA kit (15 nt) (p/n DNF-471) with the following modifications. The Lonza RNA marker (Lonza) (long RNA Ladder) replaced the Agilent RNA Ladder and was diluted in nuclease-free water to 96 ng/μL. The long RNA Ladder was added to the Agilent RNA Diluent Marker (15 nt) (p/n DNF-369-0004) according to the RNA kit protocol. The standard separation method (8 kV for 45 minutes) for the RNA kit (15 nt) was manually altered to the extended RNA method (4 kV for 90 minutes) in the Agilent 5200 Fragment Analyzer software for fragments greater than 6,000 nt. The extended RNA method with the long RNA Ladder was employed for all subsequent runs. The long RNA Ladder separated with the extended method displayed enhanced resolution compared to separation with the standard method as seen by the increased spacing between the ladder peaks and the increased sharpness of the 9,000 nt peak. The extended RNA method reported a lower average sizing percent error (-0.7 %) over the entire concentration range of the kit compared to the standard RNA method (8.4 %) for the 9,000 nt sample. The 10,000 nt IVT mRNA average percent sizing error was similar between the two separation methods throughout the dilution series. Using the extended method, the 9,000 and 10,000 nt IVT mRNA samples were successfully analyzed with good sizing precision and accuracy, demonstrating that a commercially available RNA ladder can be used with the Fragment Analyzer system to provide accurate sizing of large IVT mRNA samples. The extended RNA method is recommended when extremely accurate sizing or high resolution is needed for determining the presence of degradation or sizing differences from incomplete transcription in IVT mRNA samples longer than 6,000 nt. For Research Use Only. Not for use in diagnostic procedures.
Citation Format: Kyle D. Luttgeharm, Solange Borg, Chava Pocernich. Assessment of long IVT mRNA fragments with the Fragment Analyzer system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1307.
Abstract 1312: Anticancer activity of CA102N in breast cancer cells in vitro and in vivo
Authors: Tchaparian Eskouhie , Lin Louis , Wang Ann 
Published: July 2021

Abstract
CA102N is a novel anticancer product designed to deliver its payload (Nim) to cells via the CD44 receptor. CA102N is currently in Phase 1 clinical trial for the treatment of metastatic colorectal cancer (mCRC). The major target of CA102N is the PI3K/Akt/mTOR cell signaling pathway, one of the most significantly deregulated pathway in several human cancers, including breast cancer. In the present study, the anticancer activity of CA102N was assessed on cell signaling, cell proliferation, and apoptosis in vitro in MDA-MB-231 human breast cancer cells. The antitumor efficacy was also tested in vivo in xenograft mice. We demonstrated that CA102N selectively inhibited MDA-MB-231 breast cancer cell growth and proliferation in vitro Administration of CA102N at 4.6mg/kg in xenograft mice resulted in effective tumor growth inhibition (TGI, 80%) with no apparent treatment-related toxicity. Suppression of PI3K/Akt downstream signaling was also detected in vitro. These results suggest that CA102N may represent a new potential treatment option for breast cancer. Combinations therapies and schedules are currently being explored in mice. to maximize the basis for its advancement therapy into the clinic.
Citation Format: Eskouhie Tchaparian, Louis Lin, Ann Wang. Anticancer activity of CA102N in breast cancer cells in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1312.