bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1375: Activity of pemetrexed in patients with driver oncogene positive non-small cell lung cancer and squamous histology
Authors: Nie Yunan , Patil Tejas , Camidge David Ross 
Published: July 2021

Abstract
Pemetrexed, a multi-targeted antifolate chemotherapy agent, has been used both as a single agent chemotherapy as well as in combination given its favorable side effect profile, and has been the only effective continuation maintenance chemotherapy regimen after initial doublet use associated with increased overall survival (OS) among non-squamous non-small cell lung cancers. The current labelled indications for pemetrexed in NSCLC are restricted to those with non-squamous histology due to previous studies that showed worse outcomes in patients with squamous histology when compared to non-squamous histology. More recently, however, in the era of increased molecular profiling of NSCLC, it has been observed that patients with ALK, ROS1, and RET gene fusions have demonstrated marked sensitivity to pemetrexed. This retrospective case series, therefore, evaluated the response to pemetrexed among a cohort of 9 oncogene-driven patients with squamous (or adenosquamous) histologies who did receive pemetrexed based chemotherapy. Response rates, progression free survival (PFS), and OS for these patients were compared to a historical group of patients published in previous studies that examined pemetrexed response. The results indicated a positive response to pemetrexed in patients with an actionable driver oncogene occurring in the context of squamous or adenosquamous histology. Patients in the oncogene-driven adenosquamous/squamous group had significantly higher response rates as compared to the historical squamous cell group and no significant difference in response rates as compared to the historical adenocarcinoma comparison group. In summary, contrary to prior studies, this case series does suggest that pemetrexed may be a viable treatment option in patients with squamous cell histology who also have a targetable mutation.
Citation Format: Yunan Nie, Tejas Patil, David Ross Camidge. Activity of pemetrexed in patients with driver oncogene positive non-small cell lung cancer and squamous histology [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 1375.
Abstract 1387: MET inhibition radiosensitizes KRAS-mutant rectal cancer
Authors: D'Ambrosio Antonio , Verginelli Federica , Orzan Francesca , Albano Raffaella , Casanova Elena , Luraghi Paolo , De Bacco Francesca , Bertotti Andrea , Trusolino Livio , Senetta Rebecca , Sapino Anna , Mastro Elena Del , Gatti Marco , Comoglio Paolo M. , Boccaccio Carla 
Published: July 2021

Abstract
Rectal carcinoma, representing about a third of all newly diagnosed colorectal cancers, is one of the most common malignant tumors. The standard of care for locally advanced rectal cancer (LARC), consisting of neoadjuvant chemo/radiotherapy prior to surgical resection, is poorly effective, leading to complete tumor regression only in 10-30% of the cases. Approximately 40% of LARC harbor activating KRAS mutations, which have been extensively associated with primary resistance to targeted EGFR therapy and with radioresistance as well. Previous work showed that the MET receptor tyrosine kinase supports radioresistance and can be inhibited to radiosensitize tumor cell subpopulations retaining stem-like properties. Here, we show that LARC often express high levels of MET and can be successfully radiosensitized by MET inhibition. This was assessed in rectal stem-like cells isolated from human tumors (rectospheres), and transplanted in the mouse to regenerate tumors that faithfully reproduce the phenotype, the genotype and the therapeutic response of the original tumor. Mechanistically, we found that radioresistant KRAS-mutant rectospheres display significantly higher basal levels of RAD51, a master regulator of DNA homologous recombination repair, and increased RAD51 recruitment to irradiation-induced DNA double-strand breaks, as compared with KRAS-wild type rectospheres. Importantly, we showed that MET pharmacological inhibition by small-molecule kinase inhibitors, combined with radiotherapy, impairs RAD51 expression and function. This leads to DNA damage accumulation and results in effective radiosensitization of K-RAS-mutant rectal stem-like cells in vitro and in vivo, and significant inhibition of experimental tumors. Therefore, preclinical evidence is provided that MET can be exploited as a therapeutic target to radiosensitize KRAS-mutant rectal cancer at stem-like cell level.
Citation Format: Antonio D'Ambrosio, Federica Verginelli, Francesca Orzan, Raffaella Albano, Elena Casanova, Paolo Luraghi, Francesca De Bacco, Andrea Bertotti, Livio Trusolino, Rebecca Senetta, Anna Sapino, Elena Del Mastro, Marco Gatti, Paolo M. Comoglio, Carla Boccaccio. MET inhibition radiosensitizes KRAS-mutant rectal 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 1387.
Abstract 1430: In vivo PoC study and design for Phase I clinical study of SJP1604, a nucleolin-targeted therapeutic agent to treat entire population of relapsed/refractory acute myeloid leukemia patients
Authors: Um Jihyun , Lee Dohyeong , Kim So Hee , Huh Eun-Hye , Park Yongbin , Moon Sung Hwan , Lee Soo Jin , Lee Je-Hwan , Ki Min-Hyo 
Published: July 2021

Abstract
SJP1604 (APTA-16) is an aptamer-drug conjugate (APTA-DC) specifically targeting nucleolin, which is highly expressed only on the cell membrane of acute myeloid leukemia (AML) cells including relapsed/refractory aute myeloid leukemia (R/R AML). We previously presented the outstanding anti-leukemic activity of SJP1604 on AML cells including drug-resistant AML cells while standard chemotherapies showed no efficacy in vitro and in vivo. Therefore, we were able to conclude that only SJP1604 exhibits excellent resistance overcoming efficacy regardless of genetic defects of AML cells. Additionally, we recently identified that SJP1604 markedly eradicated AML cell engraftment with decreasing expression level of nucleolin protein in the bone marrow cells of MOLM-13 xenograft mouse model. These findings demonstrate that SJP1604 contributes to anti-leukemic effects through the regulation of nucleolin protein. We also figured out that nucleolin as a clinical biomarker was significantly highly expressed on AML and R/R AML patient-derived bone marrow cells. In particular, nucleolin expression is highly overexpressed in the bone marrow cells of entire population of R/R AML patients. Upto recent, considered as one of the major targeted therapeutics for AML, FLT3 inhibitors can target 25-30% of AML patients only. Therefore, our results mentioned above are very noteworthy finding showing the high potential of SJP1604 to be further developed as the first innovative targeted therapy to treat entire population of R/R AML patients. Herein, we show a phase I clinical trial design of SJP1604 to perform an open-label, first-in-human, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity in patients with R/R AML.
Citation Format: Jihyun Um, Dohyeong Lee, So Hee Kim, Eun-Hye Huh, Yongbin Park, Sung Hwan Moon, Soo Jin Lee, Je-Hwan Lee, Min-Hyo Ki. In vivo PoC study and design for Phase I clinical study of SJP1604, a nucleolin-targeted therapeutic agent to treat entire population of relapsed/refractory acute myeloid leukemia patients [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 1430.
Abstract 1431: Role of emt biomarkers in mediating osimertinib resistance in non-small cell lung cancer
Authors: Racherla Kavya Sri , Dovalovsky Katrina , Puri Neelu 
Published: July 2021

Abstract
Osimeritinib (OR), a Tyrosine Kinase Inhibitor is a first-line therapy in EGFR-mutant NSCLC patients. Resistance to OR treatment may occur due to acquired C797S mutations, MET amplifications and ALK rearrangements and other mechanisms not clearly defined. EMT may be one of the reasons for TKI resistance. EMT is a process by which epithelial cells acquire mesenchymal characteristics that increase invasiveness. We hypothesize that loss of E-cadherin during EMT, results in abnormal localization of p120 catenin, an E-cadherin regulating protein, and Kaiso factor, a repressor of Wnt signaling, promoting oncogenesis. Protein arginine methyl transferase 1 (PRMT1) an EMT regulator catalyzes methylation of Twist1, which represses E-cadherin. However, their role in OR resistance is still unknown. We have made parental (P) NSCLC cells, H2170, H358, H1975 and H3255 resistant to OR. MTT assays were performed on the parental cells and OR resistant cells which showed that the H2170OR, H3255OR, H358OR, H1975OR cells had IC50 for OR, 2.8-14 fold higher in comparison to parental cells, respectively. We further performed qPCR to study the modulation of EMT biomarkers in OR cells as compared to parental cells and found upregulation of PRMT1, p120 catenin and Kaiso factor by 1.5-3.67 fold respectively in H1975 cells and 1.5-5.73 fold in H3255 cells. Immunofluorescence studies in H1975OR cells for expression of PRMT1 showed that there was 3.18 fold increase as compared to 2.21 fold increase in Erlotinib resistant H1975 (H1975ER) and 4.77 fold increase in H3255OR as compared to 2.27 fold increase in H3255ER. After transfection with p120 siRNA we found that OR efficacy was increased by 33% in comparison to mock siRNA and OR treated cells. The percentage wound closure after 24 hours was found to be 26.2% in the p120-catenin siRNA transfected cells as compared to 7.4%.in mock siRNA transfected cells (p&lt;0.05) indicating its role in EMT and cell migration. Furthermore, our results showed increased expression of p120 catenin in smokers with 50% of smokers showing high expression compared to 0% and 5.8% of quit smokers and nonsmokers indicating that high p-120 expression was associated with smoking (P=0.002). In conclusion, biomarkers like PRMT1 may mediate the process of EMT by methylation of Twist1 and upregulation of p120 that prevents transcriptional repression of Kaiso factor target genes, promoting EMT in OR and ER resistant cells. p-120 expression was found to be higher in smokers compared to quit/nonsmokers indicating that it may have a potential role in lung cancer.
Citation Format: Kavya Sri Racherla, Katrina Dovalovsky, Neelu Puri. Role of emt biomarkers in mediating osimertinib resistance in non-small cell lung 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 1431.
Abstract 1443: CHKing melanoma: CHK1 inhibitor +low dose hydroxyurea triggers immunogenic cell death and immunostimulatory cytokine expression to drive an anti-tumor immune response
Authors: Gabrielli Brian G. , Proctor Martina , Cruz Jazmina Gonzalez , Zeng Bijun , Dolcetti Riccardo , Keane Colm , Haass Nikolas , Wells James 
Published: July 2021

Abstract
About half of melanomas respond to immunotherapy, but we currently lack reliable markers to identify likely responders. Therefore, a large number of patients receive this expensive therapy for no benefit. We have previously shown that inhibition of the cell cycle regulator, Checkpoint kinase 1 (CHK1), with subclinical dose of the replication stress inducer hydroxyurea is cytotoxic in a high proportion of melanomas tested. We now report that CHK1 inhibitor + low dose hydroxyurea (LDHU) treatment triggers immunostimulatory cytokine and chemokine expression, and an immunogenic form of cell death. In xenograft models, the drug combination blocks tumor growth for extended periods after the completion of treatment. In syngeneic mouse melanoma models, the drug combination also effectively controls tumor growth and induces regression in a proportion of cases. It also increases immune cell infiltration and activation of a tumor directed cytotoxic T cell response. We also demonstrate that the drug combination does not adversely affect an adaptive immune response or rapidly proliferating human T cells. The mechanism by which drug treatment promotes cytokine expression is unlikely to involve the cGAS-STING signalling pathway which is commonly defective in melanomas. Using two engineered mouse melanoma models we have found that CHK1 inhibitor + LDHU increases cytotoxic CD8+ T cells and NK cell infiltration and activation, but we have also found increased CD4+ Treg tumor infiltration and increased CD8+ T cell PD-1 expression. We have also found increased expression of other immune checkpoint regulators. This indicates a strong anti-tumor immune response is initiated but immune suppression and T cell exhaustion have limited the extent of the response of the tumor infiltrating T cells. However, circulating T cells retained strong anti-tumor activity. The harvested tumors from the drug combination treated mice that do increase in size after treatment show strong evidence of cytotoxic activity. These data provide evidence that CHK1 inhibitors + LDHU is well tolerated and triggers a strong anti-cancer immune response that should combine with immune therapy, although the selection of the target of the immunotherapy will be critical for successfully overcoming the immune suppression triggered.
Citation Format: Brian G. Gabrielli, Martina Proctor, Jazmina Gonzalez Cruz, Bijun Zeng, Riccardo Dolcetti, Colm Keane, Nikolas Haass, James Wells. CHKing melanoma: CHK1 inhibitor +low dose hydroxyurea triggers immunogenic cell death and immunostimulatory cytokine expression to drive an anti-tumor immune response [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 1443.
Abstract 1457: Discovery of biomarkers assocaited with treatment responses to sorafenib and transarterial chemoembolisation (TACE) in Chinese hepatocellular carcinoma patients
Authors: Wu Zhiqiang , Zhou Xiaoyu , Wang Shengzhou , Li Jinhuai , Liu Jun , Guo Wenbo 
Published: July 2021

Abstract
Background: Liver cancer is one of the most deadly tumors. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers. Sorafenib, a multi-target kinase inhibitor, is one the main systemic therapy drug of HCC. It increased the median overall survival time from 7.9 mo to 10.7 mo for patients with advanced stage HCC. However, about 60% of HCC patients done't respond well to sorafenib, and most of them develop progression in below 6 mo. Similarly, TACE is also an effective treatment of HCC but only with partial response rate. Therefore, finding new strategies to screen the best matched patients is key to improve the efficacy of sorafenib and TACE treatment.
Methods: We evaluated the efficacy of sorafenib starting with 98 HCC patients but only 73 patients completed the study because 24 dropped out due to death (n=2), drug violation (n=4), adverse reactions (n=3), and failure of outcome evaluation (n=15). Forty-five patients were treated by TACE. We divided the patients to a progressive disease (PD) group (46.6%, 34 patients) and a Non-PD group (53.4%, including 2 with partial response and 37 with stable disease) based on their CT and MRI evaluations. At the same time, we performed Whole-exome sequencing (WES) on the tumor samples and patient-matched blood samples.
Results: We found the PD group, comparing with the Non-PD group, had a higher proportion of patients with MSI (P = 0.028) and mutations in WNT/ß-catenin signaling and chromatin modification pathways, as well as cytoband deletions at 21q11, 1p21.1, 8q24.3, 11p11.12, 5p15.33, and 17q25.3. On contrast, cytoband amplifications at 12p13, 21q22.3, and 8q21 only appeared in the Non-PD group. We also observed a prominent decrease in the PD group COSMIC mutational signature 10 which is believed to associate with POLE mutation. We found MUC16 and FLG2 genes were related to a better survival time. Mutation of NANOGNB, and cytoband deletions at 3q11.2, 4q13.2,11q11,11q22.2 and 17q25.3 were related to a shorter survival time. (p&lt;0.05 for all above except otherwise specified).
Conclusions: We found several genes and chromosome variation were associated with sorafenib efficacy and overall survival in HCC patients. These findings indicated that mutations and chromosomal fragment deletions can lead to sorafenib resistance. Mutations of MUC16 and FLG2 may be potential drug targets in HCC.
Citation Format: Zhiqiang Wu, Xiaoyu Zhou, Shengzhou Wang, Jinhuai Li, Jun Liu, Wenbo Guo. Discovery of biomarkers assocaited with treatment responses to sorafenib and transarterial chemoembolisation (TACE) in Chinese hepatocellular carcinoma patients [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 1457.
Abstract 1459: PTP4A3 phosphatase is a novel drug target for epithelial ovarian cancer
Authors: Cornelison John Robert , Rastelli Ettore J. , Hart Duncan J. , Mendelson Anna J. , Sharlow Elizabeth R. , Wipf Peter , Lazo John S. 
Published: July 2021

Abstract
High grade serous ovarian cancer (HGSOC) is the deadliest epithelial ovarian cancer (EOC) variant, with a bleak outcome that kills &gt;14,000 women annually in the US. In past four decades, first line therapies have changed only modestly. While dramatic advances in targeted- and immune-based therapies have been seen in some solid tumors, they have not been reported in patients with HGSOC. Recurrent and chemoresistant HGSOC is common. Therefore, it is imperative that new HGSOC drug targets be interrogated. The Protein Tyrosine Phosphatases of Regenerating Liver (PRL or PTP4A) family is significantly upregulated in a variety of tumors, including HGSOC. A bioinformatic analysis of the ovarian cancer using the KMplot Survival Database revealed that high PTP4A3 expression was associated with poor survival in EOC (p&lt;0.0001, hazard ratio (HR)=1.35). In HGSOC early stage disease, PTP4A3 expression levels were also correlated with survival (stage I/II- p=0.0013, HR=3.2), with low expressing patients surviving twice as long as high expressing patients (upper quartile survival in low expression cohort = 81.2 months compared to high expression cohort = 44.3 months). This survival difference appeared independent of myc amplification and was more pronounced in advanced disease (stage III/IV). qPCR profiling of established HGSOC cell lines, including Kuramochi, COV362 and OVCAR4, showed 5-20 fold increases in PTP4A3 gene expression versus nonmalignant control cells. A potent, specific, allosteric small molecule inhibitor of PTP4A3, KVX-053, markedly reduced the growth and survival of chemoresistant and chemosensitive EOC cell lines independent of their BRCA or p53 status. Moreover, treatment of the HGSOC OVCAR4 cell line with KVX-053 (1 μM) inhibited the oncogenic Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway through loss of phosphorylation of STAT3. Evaluation of a series of next-generation KVX-053-based analogs including chemodegraders yielded chemotypes with enhanced cytotoxic effects. These results demonstrate a clear path for the development of the PTP4A family of tyrosine phosphatases as a novel therapeutic target in a HGSOC.
Citation Format: John Robert Cornelison, Ettore J. Rastelli, Duncan J. Hart, Anna J. Mendelson, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. PTP4A3 phosphatase is a novel drug target for epithelial ovarian 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 1459.
Abstract 1479: Pan-cancer efficacy of BRAF and/or MEK inhibitors in BRAF V600-mutant multiple non-melanoma cancers: A clinico-genomic study
Authors: Adashek Jacob J. , Desai Aakash P. , Menta Arjun K. , Roszik Jason , Subbiah Vivek 
Published: July 2021

Abstract
Background: BRAF and MEK inhibitors are currently FDA approved for melanoma, non-small cell lung cancer, and anaplastic thyroid cancer. The lack of clinical benefit with BRAF inhibition in BRAF V600+ colorectal cancer (CRC) has prevented its tissue-agnostic drug development. However, updated results from Vemurafenib-Basket study (Cancer Discov. 2020 May;10(5):657-663 ) and the NCI-match trial ( J Clin Oncol. 2020 Nov 20;38(33):3895-3904) reveal that BRAF pathway inhibition is active in &gt; 20 unique cancer types.
Objective: We aimed to describe the characteristics of BRAF V600 and study real-world outcomes using a clinico-genomic analysis using the AACR Genie database and the current medical literature.
Methods: We reviewed the AACR GENIE database for the prevalence of BRAF V600 mutations across tumor types. We conducted a literature search (using PubMed from 2012-2019) for case reports of clinical response and outcomes in patients with BRAF V600 mutation-positive non-melanoma cancers who received BRAF inhibitor therapy.
Results: Among 96,324 samples, BRAF V600 mutations were seen in 43 different tumor types across 2,963 samples (3.07 %) in the AACR GENIE database. BRAF V600 was most commonly present in thyroid cancer (40.9%), parathyroid cancer (31.8%), melanoma (26.1%), histiocytosis (25.7%), and head and neck NOS (14.3%). Literature review revealed total of 178 cases across 69 tumor types. The most common cases included Erdheim-Chester disease (n = 30, 16.9%), papillary thyroid carcinoma (n=16, 8.9%), anaplastic thyroid carcinoma (n = 13, 7.3%), and hairy cell leukemia (n = 13, 7.3%). Furthermore, dabrafenib (BRAF), dabrafenib/trametinib (BRAF+MEK), trametinib(MEK), vemurafenib (BRAF), vemurafenib/trametinib (BRAF+MEK), vemurafenib/cobimetinib (BRAF+MEK) were used in 34% (n =56), 16% (n = 27), 4% (n = 6), 44% (n = 72), 1% (n = 1), 2% (n =3), respectively. Overall, median PFS was 6.5 months, and median OS was 28.5 months with a median duration of response (DOR) of 8 months.
Conclusion: BRAF V600 mutations are prevalent across multiple non-melanoma cancers, lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers. Continued drug development is warranted beyond the current BRAF+/- MEK approved cancers.
Citation Format: Jacob J. Adashek, Aakash P. Desai, Arjun K. Menta, Jason Roszik, Vivek Subbiah. Pan-cancer efficacy of BRAF and/or MEK inhibitors in BRAF V600-mutant multiple non-melanoma cancers: A clinico-genomic study [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 1479.