bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5366: Hotspot mutations of TP53 sensitize APC-mutated colorectal cancer cells to cetuximab in vitro
Authors: Yang Mingli , Wang Heiman , Davis Thomas B. , Pflieger Lance , Thota Ramya , Pledger W. Jack , Yeatman Timothy J. 
Published: June 2022

Abstract
EGFR inhibitor (EGFRi) therapies (cetuximab and panitumumab) have been approved for metastatic CRC patients who harbor wild-type KRAS/NRAS. Unfortunately, only ~50% of treated patients will respond to therapy. While FDA approved for first-line therapy, these agents are seldom used, significantly limiting their utility. Thus, there is an unmet need to develop additional biomarkers to identify EGFRi sensitive patients. Using an innovative hybrid approach fusing gene expression and DNA sequencing, we recently reported that combined mutations in APC and TP53, two major tumor suppressor genes, were strongly correlated with a validated gene expression signature measuring cetuximab sensitivity (CTX-S) in 468 CRC human tumors (Yang et al. Cancer Epidemiol Biomarkers Prev. 2019). Further analysis reported that APC and TP53 mutations predict cetuximab sensitivity across consensus molecular subtypes (CMS1-4) (Thota et al. Cancers. 2021). While APC truncated mutations are known to mediate WNT pathway activation, one of key features of CMS2 CRCs reported to be associated with cetuximab response, little is known about TP53 mutations with cetuximab sensitivity. To investigate a contributive role of mutant TP53 in vitro, we stably transfected expression plasmids of three hotspot mutations (R175H, R248W, R273H) of TP53 in APC-mutated CRC cells such as SW48 cells harboring WT KRAS/NRAS. Multiple stable clones for each of three TP53 mutations (empty vector as a control) were selected for biochemical and RNASeq analyses. We found that the three oncogenic mutations of TP53 enhanced cetuximab-mediated apoptosis under low serum culture conditions (2% FBS). Interestingly, the enhanced drug effect was associated with altered p53 pathway signatures as assessed by RNASeq. In support of the role of TP53 mutations, siRNA-knockdown of TP53 in SW48 cells also demonstrated an increased sensitivity to cetuximab treatments. Collectively, these in vitro analysis supports TP53 mutations, in combination with APC mutations, as predictive mutation biomarkers of cetuximab sensitivity in CRC.
Citation Format: Mingli Yang, Heiman Wang, Thomas B. Davis, Lance Pflieger, Ramya Thota, W. Jack Pledger, Timothy J. Yeatman. Hotspot mutations of TP53 sensitize APC-mutated colorectal cancer cells to cetuximab in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5366.
Abstract 5428: Evaluating cancer therapies combining radiotherapy with immunotherapy or inhibitors of the DNA damage response
Authors: Fan Feifei 
Published: June 2022

Abstract
Ionizing radiation has largely been recognized as a local targeted therapy by a variety of mechanisms, including inducing direct DNA damage of cancerous tissue or contributing to systemic antitumor immunity. The capacity of cancer cells to recognize DNA damages and initiate repair plays a major role in radio-resistance. Furthermore, the irradiated tumor cell death can enhance antitumor immunity by inducing antigen expression on tumor cells and activating lymphocytes. Recent evidence indicates that cancer cells can be made more sensitive to the effects of radiation (radio-sensitization) through inhibition of DNA repair pathways, and a growing body of evidence indicates that cancer immunotherapy may also have radio-sensitizing effects. The combination of radiation therapy and DDR inhibitors/immunotherapy presents a promising strategy for cancer therapy.In order to provide guidance on clinical therapeutic strategy selection, we established a beam-focused radiation platform (RadSource 2000 X-ray irradiator) to evaluate the anti-tumor efficacy of fractionated radiotherapy combination in a panel of cell lines and mouse models. We have tested the combination effect of DDR inhibitor in combination with radiotherapy in vitro and in vivo, both showing radio-sensitization effects and improvement in anti-tumor activity. We have also chosen several syngeneic models to test the combination strategy of radiotherapy and immune checkpoint inhibitors (PD-1 and PD-L1), and performed TIL analysis to explore the possible mechanisms of combination effect. In summary, our beam-focused radiation platform provides insights into the design of new therapeutic strategies and has become an effective tool in pre-clinical research of anti-cancer therapy.
Citation Format: Feifei Fan. Evaluating cancer therapies combining radiotherapy with immunotherapy or inhibitors of the DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5428.
Abstract 544: Role of an ankyrin domain protein in hepatocellular carcinoma progression
Authors: Lopez Samantha , Anilkumar Adithya , Doxtater Kyle , Kotnala Sudhir , Chauhan Neeraj , Yallapu Murali , Jaggi Meena , Chauhan Subhash , Tripathi Manish 
Published: June 2022

Abstract
Background: Liver cancer is the third leading cause of mortality attributed to cancer. Hepatocellular carcinoma (HCC) is the most prevalent form among various histological types accounting for 85% to 90% of primary liver cancers. As per Texas Cancer Registry, the Hispanic population had an incidence of 21.2 per 100,000 in Texas. The Rio Grande Valley, located in South Texas, is an underserved area composed highly of Hispanics. It faces multiple disparities that can attribute to increased risk factors of HCC and, thus, a higher liver cancer incidence and mortality. Due to this, there is a need to identify a new, inexpensive, and faster diagnostic biomarker in liver cancer. We have recently identified an extracellular secreted cancer antigen POTE-2, a member of the ankyrin domain-containing POTE gene family. Our preliminary data indicates high POTE-2 expression in HCC tumors. In this study, we will discuss the role of POTE-2 in HCC progression and its associated regulatory pathways.
Methods: The Cancer Genome Atlas (TCGA) database of HCC patients (n=371 tumor; n=50 normal) was analyzed. Liver cancer cell lines procured from ATCC were analyzed for POTE-2 mRNA and protein expression through RT-PCR and western blot, respectively. Lentiviral-based plasmids were used for overexpression and knockdown studies for oncogenic assays. Localization of POTE-2, YAP1, and PDL1 was identified with immunofluorescence.
Results: Comprehensive analysis of the TCGA database showed increased POTE-2 expression in tumors and is upregulated in all stages of HCC. Lentiviral transduction led to a change in phenotype in oncogenic assays. Modulation of POTE-2 expression led to changes in kinase activity and regulatory pathways. Immunofluorescence showed nuclear localization of YAP1 and PDL1 in the liver cancer cell lines.
Conclusion: These studies will help discover novel mechanisms of POTE-2 protein function, signaling pathways, and its role in liver cancer progression.
Citation Format: Samantha Lopez, Adithya Anilkumar, Kyle Doxtater, Sudhir Kotnala, Neeraj Chauhan, Murali Yallapu, Meena Jaggi, Subhash Chauhan, Manish Tripathi. Role of an ankyrin domain protein in hepatocellular carcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 544.
Abstract 5441: Discovery of a novel RAD51 inhibitor SCR-6992 targeting homologous recombination pathways in cancer
Authors: Gu Peng , Xue Liting , Chen Ping , Li Wenjing , Geng Ya , Zhou Feng , Yang Guimei , Hou Xiaohong , Zhao Chunyan , Yang Wenqing , Tang Renhong 
Published: June 2022

Abstract
Targeting DNA damage response (DDR) pathways has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR pathway, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibitors that can prevent RAD51 foci formation and particularly, a pre-clinical candidate molecule SCR-6992 with potent anti-tumor efficacies and desirable pre-clinical development drug properties. SCR-6992 exhibits remarkable anti-proliferative potency in human lymphoma Daudi cells in vitro (IC50 = 12 nM) while has no inhibitory effect in normal human cells. The combination of SCR-6992 with chemotherapeutic agents or DDR-targeting drugs produces synergistical anti-cancer response in lymphoma and solid tumor cell lines. Furthermore, SCR-6992 significantly inhibits tumor growth in Daudi xenograft tumor model with the tumor regression observed when dosed orally at 80 mg/kg/day. SCR-6992 also shows acceptable translational drug properties and pharmacokinetic profiles in both rodents and dogs. SCR-6992 was well tolerated in rats and dogs in 14-day dose range finding studies without noted hematological or gastrointestinal toxicities, when dosed up to 200 mg/kg and 40 mg/kg, respectively. Taken together, SCR-6992 demonstrates as an effective RAD51 inhibitor with encouraging anti-tumor activities and favorable development drug properties. The clinical development plans of SCR-6992 have been formulated for hematologic malignancies and solid tumors.
Citation Format: Peng Gu, Liting Xue, Ping Chen, Wenjing Li, Ya Geng, Feng Zhou, Guimei Yang, Xiaohong Hou, Chunyan Zhao, Wenqing Yang, Renhong Tang. Discovery of a novel RAD51 inhibitor SCR-6992 targeting homologous recombination pathways in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5441.
Abstract 5444: BPI-371153, an orally bioavailable small molecule PD-L1 inhibitor
Authors: Wang Yiqian , Jing Xiangyan , Chen Hong , Zhang Huijuan , Ma Tianyi , Zhang Yao , Zhang Chunhui , Zhang Guangzhi , Liu Xiangyong , Yan Dan , Guo Jing , Lan Hong , Wang Jiabing , Ding Lieming 
Published: June 2022

Abstract
PD-1/PD-L1 antibodies have entered mainstream of cancer treatment, but they came with limitations such as weak tumor penetration, immunogenicity, immune-related risks with a long half-life, and high cost. Small molecule inhibitors of PD-L1 are expected to overcome these limitations. We hereby present BPI-371153, an orally bioavailable small molecule that disrupts PD-1/PD-L1 interaction similar to PD-1/PD-L1 antibodies. BPI-371153 demonstrates high binding affinity to human PD-L1, induces PD-L1 dimeralization and disrupts PD-L1:PD-1 interaction (IC50 &lt;1 nM by HTRF assay). BPI-371153 induces PD-L1 internalization with an IC50 value of 4.2 nM as detected by flow cytometry, activates nuclear factor of activated T cell (NFAT) signaling in cell-based reporter assay, and effectively stimulates IFN-γ release in human peripheral blood monocyte-mediated tumor cell killing assay. In a syngeneic mouse model with murine MC38 colon tumor cells expressing human PD-L1 (MC38-hPD-L1 model), BPI-371153 suppressed tumor growth to an extent comparable to an anti-PD-L1 antibody. In immunocompromised mice grafted with the same cell line, no growth inhibition was observed, confirming that the pharmacologic effect of BPI-371153 indeed came from the immune system. In addition, this compound exhibits favorable ADME properties, with high oral exposure across multiple pre-clinical species. Phase I clinical trial of BPI-371153 is planned for early 2022.
Citation Format: Yiqian Wang, Xiangyan Jing, Hong Chen, Huijuan Zhang, Tianyi Ma, Yao Zhang, Chunhui Zhang, Guangzhi Zhang, Xiangyong Liu, Dan Yan, Jing Guo, Hong Lan, Jiabing Wang, Lieming Ding. BPI-371153, an orally bioavailable small molecule PD-L1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5444.
Abstract 5474: A new class of histone deacetylase inhibitors alleviate breast cancer cells growth and invasion capacity by targeting TIMP/MMP signaling
Authors: Bajbouj Khuloud , Sahnoon Lina , AL-Ali Abeer , Shafarin Jasmin , Binder Leonie , Rehman Reem Abdul , El-Awady Rafat , Al-Tel Taleb H. 
Published: June 2022

Abstract
Background: Mounting epidemiological and experimental evidences strongly suggest that epigenetic processes including histone modifications are involved in the development of drug resistance in breast cancer. Histone deacetylases (HDACs) selective inhibition is an important strategy of anticancer drug discovery field. However, lack of HDACs isozymes selective inhibitors associated with adverse side effects that limits their clinical applications. We have recently reported new and selective HDACs inhibitors displaying varying HDAC isozyme selectivity degrees that resulted in increased histones acetylation and apoptosis induction in cancer cells. In the present study, we investigated molecular mechanisms underlying anticancer potential of these molecules in breast cancer cells. Experimental methods: Proliferation ability, invasion capacity, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) major group’s gene expressions and protein levels, and the gelatinolytic activity of MMPs were analyzed after treatment of MCF-7 and MDA-MB-231 breast cancer cell lines with HDACs inhibitors compounds.
Results and Discussions: Two compounds, identified as MAL-4 and MAL-5, were selected based on the half-maximal inhibitory concentration (IC50) in both breast cancer cells. Treatment of MCF-7 and MDA-MB-231 breast cancer cells with 5 µM MAL-4 and MAL-5 significantly induces TIMP-2 mRNA and protein levels whereas MMP-2 and MMP-9 content and activities were reduced. Further analyses showed that MAL-4 and MAL-5 attenuated invasion capability of breast cancer cells.
Conclusion: We have demonstrated that the new compounds can be used as potential lead drug candidates for an effective anti-metastatic therapy mediated by HDAC inhibition in breast cancer.
Citation Format: Khuloud Bajbouj, Lina Sahnoon, Abeer AL-Ali, Jasmin Shafarin, Leonie Binder, Reem Abdul Rehman, Rafat El-Awady, Taleb H. Al-Tel. A new class of histone deacetylase inhibitors alleviate breast cancer cells growth and invasion capacity by targeting TIMP/MMP signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5474.
Abstract 5476: Novel azetidine-based STAT3 inhibitors induce misfolded protein response, endoplasmic reticulum stress and mitophagy, and inhibit breast tumor growth in vivo
Authors: Yue Peibin , Lopez-Tapia Francisco , Zhu Yinsong , Verma Nagendra , Alonso-Valenteen Felix , Mikhael Simoun , Medina-Kauwe Lali , Tius Marcus , Turkson James 
Published: June 2022

Abstract
Anticancer drugs that directly target Signal Transducer and Activator of Transcription (Stat)3 have remained elusive. We present azetidine-based small molecules as a new class of potent Stat3 inhibitors. Compounds H172 and H182 have potency (IC50) of 0.38-0.98 µM, H105 and H120 have IC50 of 1.75-2.07 µM against Stat3 DNA-binding activity in vitro, compared to the IC50 of &gt;17 µM against Stat1 or Stat5 activity. Treatment of the triple-negative breast cancer (TNBC), MDA-MB-231 and MDA-MB-468 cells with the new compounds inhibited constitutive Stat3 activation, promoted Stat3 ubiquitination, blocked anchorage-dependent and independent growth, with potency, EC50 of 1.0-1.9 μM, and induced apoptosis of these cells. By contrast, pYStat1, pYStat5, pS727Stat3, pSrc, pJanus kinase, or the induction of other signaling events are not inhibited in compound-treated cells, and normal or tumor cells that do not harbor aberrantly-active Stat3 are only weakly inhibited. In vivo delivery of H120 or H182 as a single agent inhibited growth of human TNBC xenografts, and of H278 (HCl salt of H182) combined with radiation abrogated tumor growth and improved survival in mouse TNBC syngeneic models. These studies provide novel mechanism of disruption of aberrantly-active Stat3 and its dynamics in showing that the azetidine-based Stat3 inhibitors trigger Stat3 ubiquitination, and tumor cell death. H182 and H172 are new entities for further therapeutic development against TNBC and other cancers that harbor aberrantly-active Stat3.
Citation Format: Peibin Yue, Francisco Lopez-Tapia, Yinsong Zhu, Nagendra Verma, Felix Alonso-Valenteen, Simoun Mikhael, Lali Medina-Kauwe, Marcus Tius, James Turkson. Novel azetidine-based STAT3 inhibitors induce misfolded protein response, endoplasmic reticulum stress and mitophagy, and inhibit breast tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5476.
Abstract 5499: Efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma: a multicenter, open-label, single-arm, phase II study (ICAPE)
Authors: Qian Kun , Hu Bin , He Ming , Wang Zi-Tong , Liu Yu , Liang Hua-Gang , Su Zhi-Yong , Cui Yu-Shang , Liu Li-Jun , Zhang Yi 
Published: June 2022

Abstract
Background: Currently, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have been proved to significantly improve the clinical outcome of patients with EGFR-mutant non-small-cell lung cancer (NSCLC). Icotinib is an oral, reversible and selective first-generation EGFR-TKI. The survival benefits of 1-year and 2-year adjuvant icotinib in patients with EGFR-mutant NSCLC have been confirmed in previous studies. However, the optimal duration of adjuvant icotinib remains unknown. This study (ICAPE) evaluated the efficacy of 1.5-year adjuvant therapy with icotinib for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma.
Methods: Patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma were enrolled in the multicenter, open-label, single-arm, phase II study. Eligible patients received oral icotinib 125 mg thrice daily for 1.5 years after complete surgical resection. Primary endpoint was disease-free survival (DFS). Secondary endpoints included 1-year, 3-year, as well as 5-year OS rates, and the DFS according to the BIM mutation status (mutant-type and wild-type) and EGFR mutation types (19 del and 21 L858R).
Results: Between March 2014 and January 2018, 79 patients were enrolled. The median follow-up time was 39.7 months with a median DFS and overall survival (OS) of 41.4 months (95% CI: 33.6-51.8) and 67.0 months (95% CI: 21.2-not reached [NR]), respectively. The 1-year, 3-year and 5-year OS rates were 100%, 83.3%, and 61.7%, respectively. No significant difference was found in the median DFS between patients with Bcl-2 interacting mediator of cell death (BIM) mutant-type and wild-type (NR vs. 41.7 months; p=0.75) and no significant difference was found in the median DFS according to EGFR mutation types (all p&gt;0.05).
Conclusions: The phase II ICAPE study demonstrated that 1.5-year adjuvant therapy with icotinib had a favorable survival benefit in patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma with a long median DFS and high 5-year OS rates which is consistent with other icotinib’s study. Icotinib is suggested to be used as an adjuvant therapy option in IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma.
Citation Format: Kun Qian, Bin Hu, Ming He, Zi-Tong Wang, Yu Liu, Hua-Gang Liang, Zhi-Yong Su, Yu-Shang Cui, Li-Jun Liu, Yi Zhang. Efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma: a multicenter, open-label, single-arm, phase II study (ICAPE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5499.
Abstract 5533: YIV-906 could modulate nuclear factor of activated T-cells (NFAT) activity of T cells for immune checkpoint blockade therapy and CAR T-cell therapy
Authors: Lam Wing , Liu Shwu-Huey , Cheng Peikwen , Cheng Yung-Chi 
Published: June 2022

Abstract
YIV-906 is a standardized botanical drug inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea, and vomiting. Results from seven Phase I/II to II clinical studies suggest that YIV-906 has potential to prolong survival and improve quality of life for patients who have liver, pancreatic, colorectal, and rectal cancer and received chemotherapy and/or radiation therapy. Currently, a phase II international clinical trial for using YIV-906 plus sorafenib to target HBV positive hepatocellular carcinoma as first line therapy (NCT04000737) had been initialized. Recently, we demonstrated that YIV-906 could enhance anti-tumor activity of anti-PD1 against hepatoma in mice by enhancing both adaptive immunity and innate immunity thought promoting T cell activation by modulating IDO activity and potentiating IFNg action to polarize macrophages into M1-like type. Here, by using Jurkat cells-staphylococcal superantigen E (SEE)-Raji cells cell culture model, we demonstrated that YIV-906 could promote T cell activation with up-regulation of CD69 by modulating nuclear factor of activated T-cells (NFAT) activity. This could be due to that YIV-906 could trigger protein phosphorylation of T cell receptor signaling cascades including, Lck, Fyn, Zap70, LAT and Pyk2. Importantly, YIV-906 could enhance Anti-PD1 action to recuse the depressed NFAT activity of Jurkat cells-PD1 cells when incubated with Raji-PD-L1 cells. In addition, YIV-906 could also enhance NFAT activity triggered by the interaction of chimeric antigen receptor (CAR-CD19-CD3z) on Jurkat cells and CD19 on Raji cells. Component S (Scutellaria baicalensis Georgi) of YIV-906 was found to play key roles of the above activities. Flavonoids of S, such as baicalein, chrysin and oroxylin A, were identified to have modulation effect on NFAT activity. In conclusion, YIV-906 could modulate both adaptive immunity and innate immunity to facilitate immune checkpoint blockade therapy or CAR T-cell therapy for treatment of cancer in patients. This is worthy of further investigation. (Supported by research fund from Yiviva, inc)
Citation Format: Wing Lam, Shwu-Huey Liu, Peikwen Cheng, Yung-Chi Cheng. YIV-906 could modulate nuclear factor of activated T-cells (NFAT) activity of T cells for immune checkpoint blockade therapy and CAR T-cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5533.