bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 995: Alpelisib and vorinostat modulate critical genes in basal-2 triple negative breast cancer cells and inhibit cell growth and invasion
Authors: Lyn-Cook Beverly D. , Word Beverly , Hammons George , Emamzadeh Fatemeh Nouri 
Published: July 2021

Abstract
Triple negative breast cancer (TNBC) is a heterogeneous disease that continues to be an unmet medicine need. It has a high mortality rate in younger women, especially African Americans. African American women are not sufficiently involved in clinical trials in which novel drugs are being tested. The aggressive and biology of subtypes of this cancer are being researched; however, no targeted therapy has been successful to date. Alpelisib is a selective inhibitor of PIK3 in the PIK3/ATK pathway and has been approved for treatment of advanced metastatic breast cancer. This study was conducted to investigate the effects of Alpelisib and vorinostat (an HDAC inhibitor), either alone or in combination, in the basal-2, a subtype of TNBC, cell line, HCC1806 from a African American woman. Alpelisib alone decreased protein expression of GSKβ, crk and DDX5. Alpelisib significantly upregulated the expression of AKT1 protein. In combination with vorinostat, a synergistic effect was noted with AKT1 protein expression. Different isoforms of AKT has been shown to exert anti-cancer effects. Also, the combination significantly decreased GSKβ protein expression. GSKβ regulates epithelial-mesenchymal transition and cancer stem cell properties. Decreased expression of DDX5 has been shown to result in decreased cell growth. These drugs also decreased invasion. Results from this study suggest that Alpelisib should be further investigated in basal-2 TNBC, alone or in combination with vorinostat.
Citation Format: Beverly D. Lyn-Cook, Beverly Word, George Hammons, Fatemeh Nouri Emamzadeh. Alpelisib and vorinostat modulate critical genes in basal-2 triple negative breast cancer cells and inhibit cell growth and invasion [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 995.
Abstract CT210: Trial in Process: Phase 1 studies of BI 1701963, a SOS1::KRAS Inhibitor, in combination with MEK inhibitors, irreversible KRASG12C inhibitors or irinotecan.
Authors: Hofmann Marco H. , Lu Hengyu , Duenzinger Ulrich , Gerlach Daniel , Trapani Francesca , Machado Annette A. , Daniele Joseph R. , Waizenegger Irene , Gmachl Michael , Rudolph Dorothea , Vellano Christopher P. , Marotti Marcelo , Vucenovic Vitomir , Heffernan Timothy P. , Marszalek Joseph R. , Petronczki Mark P. , Kraut Norbert 
Published: July 2021

Abstract
The SOS1i::KRAS inhibitor BI 1701963 is the first direct RAS signaling modifier to enter phase I clinical trials both as a monotherapy as well as in combination. SOS1::KRAS inhibitors exhibit activity against a broad spectrum of KRAS alleles, including the major G12D/V/C and G13D oncoproteins, while sparing the interaction of KRAS with SOS2. Here, we present pre-clinical data showing enhanced pathway modulation and synergistic anti-tumor effects following vertical pathway inhibition of BI 1701963 in combination with mitogen-activated protein kinase inhibitors (MEKi; trametinib and BI 3011441) or KRAS G12C inhibitors (MRTX849 and BI 1823911). Furthermore, SOS1::KRAS inhibitor treatment sensitizes tumor cells to increased DNA damage in combination with irinotecan. Our results highlight the suitability of SOS1::KRAS inhibitors as a backbone in combination therapies targeting KRAS-dependent tumors. Pre-clinical combination data supported the start of multiple phase I trials investigating the safety, tolerability, recommended dose and preliminary efficacy of BI 1701963 alone and in combination with other anti-cancer agents. Combination trials of BI 1701963 with MEKi include cohorts of patients with KRAS mutant solid tumors, such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), cholangiocarcinoma and pancreatic adenocarcinoma. Trials exploring the combination of BI 1701963 with irreversible KRAS G12C inhibitors (MRTX849 and BI 1823911) will include cohorts of patients with KRAS G12C mutant NSCLC and CRC. In a further study, the combination of BI 1701963 with irinotecan is being evaluated in patients with KRAS mutant CRC. Primary endpoints include dose-limiting toxicities, treatment-emergent or -related adverse events. Secondary endpoints include pharmacokinetic and pharmacodynamic properties of combination regimens and preliminary efficacy.
Citation Format: Marco H. Hofmann, Hengyu Lu, Ulrich Duenzinger, Daniel Gerlach, Francesca Trapani, Annette A. Machado, Joseph R. Daniele, Irene Waizenegger, Michael Gmachl, Dorothea Rudolph, Christopher P. Vellano, Marcelo Marotti, Vitomir Vucenovic, Timothy P. Heffernan, Joseph R. Marszalek, Mark P. Petronczki, Norbert Kraut. Trial in Process: Phase 1 studies of BI 1701963, a SOS1::KRAS Inhibitor, in combination with MEK inhibitors, irreversible KRASG12C inhibitors or irinotecan. [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 CT210.
Abstract CT232: A phase II study of toripalimab plus anlotinib as maintenance therapy in extensive-stage small cell lung cancer
Authors: Lv Dongqing , Wu Guixian , Lin Xiaomai , Lin Ling , Pan Weijia 
Published: July 2021

Abstract
A phase II study of toripalimab plus anlotinib as maintenance therapy in extensive-stage small cell lung cancer
Background: Maintenance therapy is a promising therapeutic approach for extensive-stage small cell lung cancer (ES-SCLC), especially in light of the IMpower 133 trial (Horn NEJM 2018). The results of the E3501, SALUTE, and CALGB 30306 trials showed that in first-line treatment of ES-SCLC, bevacizumab combined with chemotherapy improved only progression-free survival (PFS) but not overall survival (OS). However, in the ALTER 1202 study, anlotinib used as a third- or further-line treatment in patients with ES-SCLC improved PFS and OS (Cheng WCLC 2018). Toripalimab is a novel PD-1 inhibitor that, when combined with anlotinib as maintenance therapy for ES-SCLC, may improve disease control.Methods: This is a phase 2, single-arm study of toripalimab plus anlotinib, a vascular endothelial growth factor receptor inhibitor, as maintenance therapy in adult patients with ES-SCLC following their completion of platinum-based first-line chemotherapy. Eligible patients must have measurable (RECIST v1.1) ES-SCLC, an ECOG performance status of 0 or 1, and are required to have shown complete response, partial response, or stable disease as per RECIST 1.1 following 4–6 cycles of platinum-based chemotherapy. Twenty participants will be enrolled to receive toripalimab (240 mg, IV, Q3W) + anlotinib (12 mg, oral, Q3W). Patients will be treated until the disease progresses, unacceptable toxicity occurs, or for up to 2 years. Prophylactic cranial irradiation will be permitted at the investigator's discretion. The primary endpoints are PFS and OS. Secondary endpoints include safety, objective response rate, disease control rate, and time to response. Exploratory endpoints include Tumor Mutational Burden (TMB) and PD-L1 protein expression, immune gene transcript expression (PD-1, PD-L1, CTLA-4, and others) ,and correlation of these endpoints with clinical responses and drug resistance. This study is currently open and accruing patients. Clinical trial information: NCT04363255. Research Sponsor: Shanghai Junshi Biosciences Co.
Citation Format: Dongqing Lv, Guixian Wu, Xiaomai Lin, Ling Lin, Weijia Pan. A phase II study of toripalimab plus anlotinib as maintenance therapy in extensive-stage 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 CT232.
Abstract LB005: High quality neoantigens are immunoedited in long term survivors of pancreatic cancer
Authors: Luksza Marta , Sethna Zachary , Rojas Luis , Soares Kevin , Elhanati Yuval , Lihm Jayon , Hoyos David , Kappagantula Rajya , Moore Alvin M. , Patterson Erin , Iacobuzio-Donahue Christine , Greenbaum Benjamin , Balachandran Vinod P. 
Published: July 2021

Abstract
Cancer immunoediting, a hallmark of cancer, predicts that lymphocytes recognize tumor-specific mutations (neoantigens) to kill immunogenic tumor cells and select less immunogenic clones to survive in immunocompetent hosts. Yet, though proven in mice, whether immunoediting governs how human tumors evolve naturally, and the principles of how the immune system edits tumors remain unclear. Here, we report that T cell rich tumors of rare long-term survivors of human pancreatic ductal adenocarcinoma longitudinally lose immunogenic features predicted by a fitness model based on immune recognition of high quality neoantigens. We find that compared to T cell poor tumors in short-term survivors, long-term survivors evolve less immunogenic recurrent tumors over 10 years with fewer clones, fewer neoantigens, and new neoantigens of markedly lower quality, to indicate that the immune system edits lower fitness clones with high-quality neoantigens. To explore if the immune system more broadly selects against non-self-like changes in host genomes, we define a minimal amino acid substitution distance sufficient for T cell receptors to discriminate self from non-self mutations. We find that both primary and recurrent tumors in long but not short-term survivors are enriched in self-like mutations, to suggest that the immune system depletes non-self-like mutations. Thus, we submit longitudinal evidence that the immune system edits neoantigens to sculpt recurrent human pancreatic ductal adenocarcinomas, a lethal tumor largely considered resistant to endogenous immune attack. Furthermore, we demonstrate that the neoantigen quality fitness model predicts how immune pressure changes tumor cell populations over time, with significant implications for cancer biology and immunotherapy. More broadly, our results argue that cancer immunoediting is a fundamental principle of how human cancers evolve in immunocompetent hosts.
Citation Format: Marta Luksza, Zachary Sethna, Luis Rojas, Kevin Soares, Yuval Elhanati, Jayon Lihm, David Hoyos, Rajya Kappagantula, Alvin M. Moore, Erin Patterson, Christine Iacobuzio-Donahue, Benjamin Greenbaum, Vinod P. Balachandran. High quality neoantigens are immunoedited in long term survivors of pancreatic 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 LB005.
Abstract LB073: The growth inhibitory effect of paclitaxel on gefitinib-resistant non-small cell lung cancer (NSCLC) cells during the COVID-19 pandemic
Authors: Mohiuddin Md , Kimura Hideharu , Sone Takashi , Watanabe Satoshi , Matsuoka Hiroki , Saeki Keigo , Terada Nanao , Abo Miki , Kasahara Kazuo 
Published: July 2021

Abstract
Background: Coronavirus disease 2019 (COVID-19) has posed a great challenge for the treatment of cancer patients. COVID-19 presents as a severe respiratory infection in aging individuals, including lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. Conversely, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence could worsen COVID-19. Considering the above-mentioned facts, our present work aimed to investigate the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant NSCLC cells (PC9-MET) and to reveal the underlying mechanisms. Methods: PC9-MET cells were treated with paclitaxel for 72 h and were then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, ROS assay, SA-β-Gal staining, TUNEL assay and Western blotting.Results: Our results revealed that paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3, cleaved caspase-9 and cleaved PARP. Additionally, paclitaxel increased ROS production, leading to DNA damage. Importantly, paclitaxel eliminated cellular senescence, which was observed by SA-β-Gal staining.Conclusion: In light of these findings, paclitaxel could be a promising anticancer drug and could offer a new therapeutic strategy for gefitinib-resistant NSCLC during the COVID-19 pandemic.
Citation Format: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara. The growth inhibitory effect of paclitaxel on gefitinib-resistant non-small cell lung cancer (NSCLC) cells during the COVID-19 pandemic [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 LB073.
Abstract LB075: Development of SARS-CoV-2 neutralizing protein by ACE2 receptor engineering for severe infection and patients with underlying diseases
Authors: Kwon Byoung S. , Lee Seunghyun , Choi Jin-Kyung , Hwang Bora , Im Sun-Woo , Lim Yun-Sook , Kim Bumseok , Hwang Soon B. , Jeh HoonSung 
Published: July 2021

Abstract
Since the Spike protein on the surface of SARS coronavirus 2 (SARS-CoV-2) binds to the ACE2 receptor in human cells, the development of neutralizing proteins or antibodies targeting the receptor binding domain (RBD) of the spike protein is an important strategy for SARS-COV-2 therapy. We chose to develop molecularly-evolved soluble ACE2 protein on three grounds; 1) it can trap and neutralize the SARS-CoV-2 as neutralizing antibodies do, 2) it can supplement angiotensin II-converting enzyme activities that protect lung, heart, and kidneys of severe cases of infections and patients with underlying diseases, and 3) it may trap effectively SARS-CoV-2 mutants even though the mutations compromise the protection by neutralizing antibodies or vaccine. For the enhancement of ACE2 binding affinity to RBD, we used the 3D complex structure between ACE2 and RBD to select the major contributing ACE2 amino acids, a library targeting selected amino acids and random mutations were constructed and screened using yeast surface display. The engineered ACE2, EU129, was fused with the human IgG1 Fc for long half-life and viral clearance. The binding affinity of EU129 to RBD was increased by about 500-folds compared to ACE2 wild-type in SPR analysis, and the neutralizing activity was also increased by about 130-folds compared to ACE2 wild-type in surrogate virus neutralization test (sVNT). In addition, it was confirmed that the enzymatic activity of ACE2, which prevents organ damage due to SARS-CoV-2 infection in the human, is maintained at a level similar to that of ACE2 wild-type. In vitro assays using live SARS-CoV-2 virus and Vero E6 cells, EU129 was shown to be more effective in inhibiting viral infection and amplification than ACE2 wild-type, which was confirmed through protein and RNA level and cell morphology change of the live virus. In vivo stability assays using BALB/c mice, EU129 showed enhanced binding to the RBD and maintained enzymatic activity similar to ACE2 wild-type. We generated EU129 with the improved binding affinity and neutralizing activity through ACE2 receptor engineering. It has angiotensin II-converting enzymatic activity for organ protection, thus EU129 is a better therapeutic candidate for severe cases of SARS-CoV-2 infection and patients with underlying diseases such as cancers.
Citation Format: Byoung S. Kwon, Seunghyun Lee, Jin-Kyung Choi, Bora Hwang, Sun-Woo Im, Yun-Sook Lim, Bumseok Kim, Soon B. Hwang, HoonSung Jeh. Development of SARS-CoV-2 neutralizing protein by ACE2 receptor engineering for severe infection and patients with underlying diseases [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 LB075.
Abstract LB099: The inhibitory effect of pemetrexed disodium heptahydrate on the growth of A549 cells
Authors: Mohiuddin Md , Kimura Hideharu , Sone Takashi , Watanabe Satoshi , Matsuoka Hiroki , Saeki Keigo , Terada Nanao , Abo Miki , Kasahara Kazuo 
Published: July 2021

Abstract
Background: Pemetrexed disodium heptahydrate (pemetrexed) is currently used for the treatment of patients with advanced non-small cell lung cancer (NSCLC). More than 30% of lung cancer cases involve KRAS mutations. In this study, we examined the anticancer ability of pemetrexed in KRAS-dependent A549 lung cancer cells. Methods: A549 cells were treated with pemetrexed for 72 h and then evaluated by a TUNEL assay, ROS assay and Western blotting. Results: The apoptotic effect of pemetrexed was observed through increased levels of cleaved caspase-9 (Asp 315), cleaved caspase-3 (Asp 175) and cleaved PARP. Furthermore, pemetrexed increased ROS-mediated DNA damage and enhanced the proapoptotic Bax protein expression, leading to the loss of mitochondrial membrane potential (MMP). The increased expression of the β-galactosidase protein was correlated with the induction of cellular senescence. Significantly, pemetrexed induced cytotoxicity without inhibiting the RAS/RAF/MEK/ERK signaling pathway, while pemetrexed induced autophagy, which activated the AMPK/mTOR signaling pathway. Conclusion: Taken together, these findings indicate that, in addition to apoptosis, pemetrexed-induced autophagy and cellular senescence, providing a promising direction for the development of KRAS-targeted therapy.
Citation Format: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara. The inhibitory effect of pemetrexed disodium heptahydrate on the growth of A549 cells [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 LB099.
Abstract LB100: Pemetrexed disodium heptahydrate and cisplatin have distinctive growth inhibitory effects in monotherapy and combination therapy on A549 cells
Authors: Mohiuddin Md , Kimura Hideharu , Sone Takashi , Watanabe Satoshi , Matsuoka Hiroki , Saeki Keigo , Terada Nanao , Abo Miki , Kasahara Kazuo 
Published: July 2021

Abstract
Background: Cisplatin combined with pemetrexed disodium heptahydrate (pemetrexed) is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung cancer (NSCLC). However, its individual growth inhibitory effects on KRAS-dependent A549 human lung cancer cells as monotherapy and combination therapy are not well understood. The aim of this study was to compare the effects of cisplatin (CDDP) and pemetrexed (PEM) on A549 cells as monotherapy and combination therapy.Methods: For in vitro studies, A549 cells were exposed to cisplatin and pemetrexed as monotherapy and combination therapy for 72 h. The results were then evaluated by a cell viability assay, apoptosis assay, ROS assay, TUNEL assay and Western blotting.Results: Our results revealed that cisplatin monotherapy was the most potent growth inhibitor; cisplatin plus pemetrexed combination therapy had an intermediate effect; and pemetrexed monotherapy induced a minimal growth inhibitory effect in the A549 cell line, which was observed by the inhibition of the RAS/RAF/MEK/ERK signaling pathway. Furthermore, apoptotic effects were examined according to ROS-mediated DNA damage and increased levels of cleaved caspase-3, cleaved caspase-9 and cleaved PARP. Interestingly, cisplatin monotherapy was the primary eliminator of cellular senescence; combination therapy with cisplatin plus pemetrexed had an intermediate eliminator effect, while pemetrexed monotherapy increased cellular senescence in A549 cells, which was assessed by the expression of the β-galactosidase protein. The results of Western blotting of proteins in the AMPK/mTOR signaling pathway indicated that the highest inducer of autophagy was pemetrexed monotherapy, while combination therapy with cisplatin plus pemetrexed had an intermediate inhibitory effect on autophagy. Cisplatin monotherapy showed the strongest autophagy inhibitory activity.Conclusion: In light of these findings, cisplatin monotherapy showed the most potent anticancer effects, suggesting that cisplatin monotherapy may be more effective than pemetrexed monotherapy or cisplatin plus pemetrexed combination therapy in A549 cells.
Citation Format: Md Mohiuddin, Hideharu Kimura, Takashi Sone, Satoshi Watanabe, Hiroki Matsuoka, Keigo Saeki, Nanao Terada, Miki Abo, Kazuo Kasahara. Pemetrexed disodium heptahydrate and cisplatin have distinctive growth inhibitory effects in monotherapy and combination therapy on A549 cells [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 LB100.
Abstract LB102: Effect of mistletoe extract on growth and proliferation of prostate cancer cells
Authors: Boyapati Kavya , Kumar Rajendra , Wilson Lillian , Yang Yuhan , Topiwala Deven , Soundappan Keerti , Panagopoulos Eleni , Page Ivelisse , Durham Jennifer , Carducci Michael , Paller Channing , Kachhap Sushant 
Published: July 2021

Abstract
Complementary and alternative medicines are explored for their role in improving the quality of life of patients with cancer. Many anti-cancer drugs have been derived from natural sources. Mistletoe extract, composed of lectins, viscotoxins, flavonoids, and other biologically active substances, has two mechanisms of action: tumor cytotoxicity and immunomodulation. The cytotoxic effects of mistletoe extract are a result of protein synthesis interference, cell cycle inhibition, and apoptosis induction. Further, mistletoe extract has been shown to have anti-angiogenic properties. In Europe, Helixor M, mistletoe extract from Viscum album mali, is used as an anthroposophic medicine in the treatment of malignant and non-malignant tumors, malignant disorders with accompanying impairment of the hematopoietic organs, stimulation of bone marrow activity, reducing the risk of tumor recurrence, and diagnosed pre-cancerous disorders. However, only limited evaluation of mistletoe extract has been conducted in the United States. We studied the effects of Helixor M in prostate cancer. To evaluate its effect on cell proliferation and survival, we treated androgen receptor (AR) positive (LNCaP, LAPC4 and VCaP) and AR negative (PC3 and DU-145) cell lines with Helixor M. Our data indicates that LNCaP and LAPC4 cells were most sensitive to Helixor M while PC3, DU-145, and VCaP cells were relatively resistant to treatment. While AR protein levels and NF-kappaB subunits remained unaffected by treatment, there was an induction of apoptosis along with a concomitant decrease in LC3B, an autophagy marker, in all the sensitive prostate cancer cell lines. In search of pathways that may synergize with growth inhibition by Helixor M, we utilized CRISPR knockouts of TBK1, a kinase involved in autophagy induction, in LNCaP cells and tested whether TBK1 knockouts are synthetically lethal with Helixor M. Helixor M induced increased apoptosis in TBK1 knockouts as compared to parental LNCaP cells, indicating that TBK1 loss might be synthetically lethal with Helixor M.
Citation Format: Kavya Boyapati, Rajendra Kumar, Lillian Wilson, Yuhan Yang, Deven Topiwala, Keerti Soundappan, Eleni Panagopoulos, Ivelisse Page, Jennifer Durham, Michael Carducci, Channing Paller, Sushant Kachhap. Effect of mistletoe extract on growth and proliferation of prostate cancer cells [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 LB102.