bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1413: Targeting the RNA-binding protein HuR to overcome chemoresistance in triple-negative breast cancer
Authors: Wei Lanjing , Zhang Qi , Zhong Cuncong , Aubé Jeffrey , Welch Danny R. , Wu Xiaoqing , Xu Liang 
Published: July 2021

Abstract
Patients with triple-negative breast cancer (TNBC) have a lower 5-year relative survival rate (77%) than overall for breast cancer (91%). Chemotherapy remains the primary choice for the systemic treatment of TNBC. However, patients frequently develop resistance to conventional chemotherapy, resulting in poorer prognosis and higher recurrence than other subtypes of breast cancer. Therefore, overcoming chemotherapy resistance is critical for the successful treatment of TNBC. The RNA-binding protein Hu antigen R (HuR) plays an important role in chemotherapy resistance. HuR is a posttranscriptional regulator, which can stabilize target mRNAs by binding to U- or AU-rich elements (ARE) mainly in 3' untranslated region (UTR) of mRNA and upregulate their translation. The encoded proteins are implicated in multiple cancer hallmarks, including chemoresistance. The overexpression of HuR, especially accumulated cytoplasmic expression, is related to chemoresistance in many types of cancer. We hypothesize that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of mRNA and thus reduce the translation of proteins responsible for chemoresistance.Recently, our lab reported a small molecule HuR inhibitor, KH-3, which potently inhibits HuR function by disrupting the HuR-mRNA interactions. KH-3 effectively suppresses growth and invasion of TNBC cells in vitro and in vivo. In this study, we assessed whether HuR is a target for overcoming chemoresistance and evaluated whether KH-3, as a small molecule HuR functional inhibitor, could enhance the efficacy of chemotherapy for TNBC cells. To determine whether HuR inhibition overcomes acquired chemoresistance of TNBC, we generated cell sublines derived from human MDA-MB-231 with acquired resistance against docetaxel or doxorubicin. KH-3 could synergize TNBC cells to chemotherapy in vitro and in vivo. Interestingly, KH-3 treatment could re-sensitize chemoresistant TNBC cells to drugs, indicating that HuR inhibition can overcome acquired chemoresistance. Regarding mechanisms of action, several pathways and HuR direct target mRNA are implicated in docetaxel and doxorubicin resistance, but detailed molecular mechanisms are still under investigation. This study provides a new strategy to overcome chemotherapy resistance and improve the survival of TNBC.
Citation Format: Lanjing Wei, Qi Zhang, Cuncong Zhong, Jeffrey Aubé, Danny R. Welch, Xiaoqing Wu, Liang Xu. Targeting the RNA-binding protein HuR to overcome chemoresistance in triple-negative breast 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 1413.
Abstract 1423: Shikonin impairs the growth of docetaxel-resistant prostate cancer cells by necroptosis
Authors: Markowitsch Sascha D. , Juetter Kira M. , Schupp Patricia , Hausschulte Kristine , Vakhrusheva Olesya , Cinatl Jindrich , Michaelis Martin , Efferth Thomas , Haferkamp Axel , Juengel Eva 
Published: July 2021

Abstract
Introduction: Prostate carcinoma (PCa) is the most common malignancy in men. Androgen-targeted therapy and chemotherapy are currently the treatment of choice for advanced stages. Due to resistance towards these therapies, prognosis remains poor and new treatment options are urgently required. Shikonin (SHI) from Traditional Chinese Medicine (TCM) might be promising, since it induces anti-tumor effects in different tumor entities. However, data on PCa are few, and data on resistant PCa are not existent.
Material and Methods: Parental (=sensitive) and docetaxel-resistant PCa cell lines, PC3, DU145, LNCaP, and 22Rv1 were exposed to SHI [0.1 - 1.5 μM] for 24, 48, or 72 hours. Untreated cells served as controls. Tumor cell growth, proliferation, cell cycle, and the expression of cell cycle regulating proteins were assessed. Several cell deaths, like apoptosis, necrosis and necroptosis as well as the metabolic activity were evaluated.
Results: Time- and dose-dependent exposure to SHI significantly reduced tumor cell growth and proliferation in parental and docetaxel-resistant PCa cells, compared to the untreated controls. This was accompanied by cell cycle arrest in the G2/M phase in parental PC3 and docetaxel-resistant DU145 and S phase arrest in resistant 22Rv1, associated with modulated expression of cell cycle regulating proteins. Significant apoptotic effects were observed in parental and docetaxel-resistant PC3, DU145, 22Rv1, and resistant LNCaP. Moreover, SHI induced necroptosis in all parental and resistant PCa cells, as shown by additional application to the necroptosis inhibitor necrostatin-1. In line with this, RIP-1 expression enhanced under SHI exposure. In contrast, SHI did not alter the metabolic activity of the PCa cells.
Conclusion: Significant anti-tumor effects are apparent in parental but also in docetaxel-resistant PCa cells after SHI application. Thus, adding SHI to standard therapies might be a promising treatment strategy for patients with advanced prostate cancer. Further investigations are necessary to verify our findings.
Funding: Friedrich-Spicker-Stiftung (2017).
Acknowledgments: The main portion of the results presented here are part of the MD thesis of Kira M. Juetter at the Department of Urology and Pediatric Urology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.
Citation Format: Sascha D. Markowitsch, Kira M. Juetter, Patricia Schupp, Kristine Hausschulte, Olesya Vakhrusheva, Jindrich Cinatl, Martin Michaelis, Thomas Efferth, Axel Haferkamp, Eva Juengel. Shikonin impairs the growth of docetaxel-resistant prostate cancer cells by necroptosis [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 1423.
Abstract 1440: Novel imipridone ONC206 suppresses ovarian cancer progression through modulating immune cell response
Authors: Yeung Chi Lam Au , Hu Wen , Ferri-Borgogno Sammy , Tarapore Rohinton S. , Allen Joshua E. , Lu Karen H. , Mok Samuel C. 
Published: July 2021

Abstract
Advanced ovarian cancer (stages III and IV) is the most lethal gynecologic malignancy in the United States. Survival of this cancer has not improved to a major extent over the past decade. High-grade serous ovarian cancer (HGSC), in particular, is notable for its initial sensitivity to chemotherapy using platinum and taxane combination following debulking surgery. However, the vast majority of these cancers (&gt;75-80%) recur within 12-24 months after diagnosis, and patients die of progressively chemotherapy-resistant disease. The identification of prognostic or predictive markers, for ovarian cancer is crucial to the development of therapeutic targets and thus improvement of survival. ONC201 is the first clinical bitopic antagonist of dopamine receptor D2 (DRD2), that is well tolerated and currently being investigated in several clinical trials for oncology. ONC206 is a chemical derivative of ONC201 with the same impridone core structure, which is also a DRD2 antagonist that exhibits distinct receptor pharmacology and nanomolar potency in various preclinical cancer models. However, the effects of ONC206 on HGSC progression and the mechanism of action have not been thoroughly explored. Preliminary data demonstrated that overexpression of DRD2 is associated with poor overall survival rates in patients with advanced stage HGSC. ONC206-treated HGSC cells demonstrated significantly lower growth rates and higher percentage of apoptotic cells than ONC201-treated cells did in vitro. Besides, intraperitoneal injection of ONC206 (100 mg/kg) twice a week into HGSC-bearing immunocompetent mice demonstrated decreased tumor volume in vivo. In addition, by using suspension mass cytometry with a panel of 28 antibodies, fresh tumor tissues from ONC206-treated mice showed markedly increase in intratumoral NK cells and activated CD8+ T cells densities. These data suggest that ONC206 is more potent than ONC201 in suppressing HGSC growth directly. In addition, ONC206 may also suppresses HGSC growth through activating immune cell response in tumor tissues. Further studies that define the molecular mechanism by which DRD2 modulates the tumor suppressive effect of ONC206 on HGSC cells by suppressing HGSC directly or enhancing anti-tumor immune cell activity will be perform to establish ONC206 as a novel therapeutic agent in treatment of HGSC patients.
Citation Format: Chi Lam Au Yeung, Wen Hu, Sammy Ferri-Borgogno, Rohinton S. Tarapore, Joshua E. Allen, Karen H. Lu, Samuel C. Mok. Novel imipridone ONC206 suppresses ovarian cancer progression through modulating immune cell 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 1440.
Abstract 1445: A nuclear localizing peptide that targets glioblastoma
Authors: Lewis Calvin D. , Singh Abhay , Kapoor Vaishali , Hallahan Dennis E. 
Published: July 2021

Abstract
Glioblastoma (GBM) is one of the most aggressive and fatal primary brain neoplasms with a median survival of less than 15 months even after current standard of cares including surgical resection, radiotherapy and systemic therapy. Although systemic anticancer agents, such as temozolomide, are used as the standard of care for GBM, therapeutic efficacy is limited due to the off-target systemic toxicity of traditional chemotherapeutics. Targeted systemic therapy is emerging as an important treatment strategy for cancer therapy. Phage display peptide library was used to discover peptides that undergo endocytosis in GBM. We have identified a novel peptide that accumulates intracellularly in multiple GBM cell lines. Intracellular localization was quantified by FACS analysis of the FITC-labeled peptide. As compared to untreated GBM cells, D54, U251 and SF295 human GBM cell lines treated with 5.55 µM of peptide-FITC conjugate showed a significant FITC-positive shift on FACS analysis with 83%, 85% and 71% of cells internalizing the peptide, respectively. Confocal laser scanning microscopy experiments further confirm the intracellular targeting of the FITC-peptide in D54, U251 and SF295 GBM cell lines with associated peptide nuclear localization. Further studies are underway to elucidate the microscopic biodistribution of the nuclear homing peptide (NHP) in GBM mouse models. This work is significant as a novel cell surface, intracellular or nuclear binding partner may be identified for peptide-targeted cancer drug therapy. Furthermore, the NHP has potential to be translated to the clinic as targeted therapy for GBM patients in the form of a peptide-drug conjugate.
Citation Format: Calvin D. Lewis, Abhay Singh, Vaishali Kapoor, Dennis E. Hallahan. A nuclear localizing peptide that targets glioblastoma [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 1445.
Abstract 1462: KF1601, a novel orally bioavailable inhibitor of Bcr-Abl T315I, without inducing thrombotic microangiopathy
Authors: Kwon HyunJin , Ahn Sung-Min , Chang Kiho , Kim WooSik , Khan Amir , LEE Doohyun , Lee Seungyeon , Han Ye Ri , Im Chun Young 
Published: July 2021

Abstract
Targeting Bcr-Abl with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML) by significantly improving patients' survival. However, the gatekeeper mutation T315I confers resistance to TKIs targeting Bcr-Abl, presenting a formidable task in CML's clinical management. Ponatinib is the only approved drug for Bcr-AblT315I, but often accompanies severe, life-threatening side effects. Herein, we report KF1601, a novel orally bioavailable TKI: 1) KF1601 inhibited kinase functions of both Bcr-AblWT and Bcr-AblT315I with nanomolar IC50 values; 2) In xenograft models using Ba/F3 Bcr-AblT315I cell line, it showed promising in vivo antitumor efficacy, comparable to that of ponatinib; 3) In animal models, it did not cause thrombotic microangiopathy, a major mechanism of ponatinib's toxicity. In summary, KF1601 is a promising drug candidate for safely treating CML patients with drug-resistant Bcr-AblT315I mutation.
Citation Format: HyunJin Kwon, Sung-Min Ahn, Kiho Chang, WooSik Kim, Amir Khan, Doohyun LEE, Seungyeon Lee, Ye Ri Han, Chun Young Im. KF1601, a novel orally bioavailable inhibitor of Bcr-Abl T315I, without inducing thrombotic microangiopathy [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 1462.
Abstract 1482: M4645 is a potent and highly selective inhibitor of disease relevant cKIT mutations for the treatment of metastatic or recurrent GIST
Authors: Linde Nina , Blum Andreas , Dorsch Dieter , Graedler Ulrich , Busch Michael , Glaser Nina , Petersson Carl , Ruff Aaron , Sherbetjian Eva , Esdar Christina 
Published: July 2021

Abstract
Oncogenic mutations in cKIT in exons 9 and 11 are the main driver of gastrointestinal stromal tumors (GIST). Imatinib is standard of care in 1L in unresectable metastatic or recurrent GIST, yet secondary resistance mutations in exons 13/14 and 17/18 of the cKIT kinase domain frequently arise limiting efficacy. Currently approved 2L and 3L therapies sunitinib and regorafenib target these mutations only to some extent and show limited clinical benefit. Even with the recent approval of ripretinib as 4L treatment, a high unmet medical need remains for patients with imatinib resistance mutations in exon13/14. M4645 was designed to particularly inhibit the frequent V654A resistance mutation in exon 13 of cKIT. Based on cKIT inhibitor scaffolds identified within the Merck compound collection, a 3,5,6-substituted indazole-lead was discovered. Substituent optimization in the 5- and 6-positions of the core scaffold resulted in highly selective kinase inhibitors. Through variation at the 3-position, potency and physicochemical properties were optimized, resulting in the candidate molecule M4645 which combined potency, kinase selectivity, and solubility with a good safety profile. The excellent kinase selectivity could be rationalized by the crystal structure of cKIT V654A mutant kinase domain in complex with M4645. M4645 showed potent inhibition of cKIT autophosphorylation and of downstream P-ERK1/2 and P-AKT signaling in cell lines bearing activating and resistance mutations of cKIT. Dose-dependent inhibition of cKIT activation was demonstrated in a GIST xenograft model expressing the cKIT resistance mutation V654A in exon 13. Strong antitumor activity was observed in cell line and patient-derived GIST xenograft models with this imatinib resistance mutation. Compared to imatinib, M4645 induced prolonged anti-tumor response in a GIST model with a primary activating mutation of cKIT. In summary, the favorable profile and strong antitumor activity, particularly in GIST models expressing the V654A resistance mutation, suggests superiority of M4645 compared to currently available &gt; 2L treatment options for unresectable metastatic or recurrent GIST patients.
Citation Format: Nina Linde, Andreas Blum, Dieter Dorsch, Ulrich Graedler, Michael Busch, Nina Glaser, Carl Petersson, Aaron Ruff, Eva Sherbetjian, Christina Esdar. M4645 is a potent and highly selective inhibitor of disease relevant cKIT mutations for the treatment of metastatic or recurrent GIST [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 1482.
Abstract 1487: Cytotoxic CD4+ T cells contribute to anti-tumor immune responses in NSCLC
Authors: Lau Denise , Khare Sonal , Reiman Derek , Rand Tim , Salahudeen Ameen A. , Khan Aly 
Published: July 2021

Abstract
Immune checkpoint blockade (ICB) is widely used to treat non-small cell lung cancer (NSCLC) patients and works by inhibiting the PD-1/PDL1 axis to reinvigorate exhausted T cells. In the prevailing model, the primary mechanism for direct tumor cell killing occurs through cytotoxic CD8+ T cells. Here, we use single-cell multi-omic profiling (a combination of single-cell RNA sequencing, TCR sequencing, and surface protein profiling) in 10 NSCLC patients to identify a population of CD4+ T cells that are tumor-infiltrating, clonally expanded, and express a cytotoxic gene program. Concordantly, we found in the same patients a subpopulation of tumor cells with elevated HLA class II expression, suggesting a mechanism for tumor-mediated antigen presentation to CD4+ T cells. Finally, we show that a cytotoxic CD4 gene signature is associated with improved progression-free survival in a cohort of 180 NSCLC patients treated with ICB regimens, including those with loss of heterozygosity at the HLA class I locus. Overall, these results suggest a model where cytotoxic CD4+ T cells can perform direct tumor cell killing in a class II restricted manner and that their presence is associated with favorable ICB outcomes in NSCLC.
Citation Format: Denise Lau, Sonal Khare, Derek Reiman, Tim Rand, Ameen A. Salahudeen, Aly Khan. Cytotoxic CD4+ T cells contribute to anti-tumor immune responses in NSCLC [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 1487.
Abstract 1534: Mesothelin isoform 2 is a novel target for allogenic CARγδT cell therapy in solid tumors
Authors: Wang Xiaohong , Chen Yibin , Gopisetty Anupama , Mirandola Leonardo , Piccotti Lucia , Nguyen Quynh , Chiriva-Internati Maurizio 
Published: July 2021

Abstract
Mesothelin (MSLN) is a tumor-associated antigen over-expressed on the cell surface of various malignant tumor cells, including majority of mesothelioma and ovarian cancer. MSLN-directed therapy has been intensively studied in preclinical and clinical settings. However, the clinical efficacy and safety of mesothelin-targeted therapy remains to be demonstrated. To identify a safe and effective target for CAR-T cell therapy in solid tumors, we used artificial intelligent platform developed with public and private RNA transcription database to identify cancer-associated antigens caused by alternative spicing. One of interesting targets is an alternative spicing isoform from MSLN. Human MSLN transcript has at least three isoforms. The isoform 1 is the predominant transcript detected in normal and tumor tissues and has been a promising target for cancer immunotherapy. The isoform 2 is the minor transcript using alternatively spliced exons producing 8 additional amino acids insertion compared to isoform 1. The isoform 3 produces a truncated and soluble MSLN. Our data demonstrated that MSLN isoform 2 is specifically expressed in ovarian cancers but not normal tissues, confirmed by Q-PCR studies. Furthermore, we generated mouse hybridoma antibodies specifically targeting MSLN isoform 2. The antibody specificity was screened and confirmed by ELISA-based reaction to MSLN isoform 2-specific peptide and flow cytometry-based binding to 293T cells overexpressing MSLN isoform 2 but not isoform 1 proteins. We further detected the endogenous MSLN isoform 2 expression in human mesothelioma cell line NCI H226 and further confirmed MSLN isoform 2 expression on human primary mesothelioma and ovarian cancer tissue but not normal tissues by immunohistochemistry staining. To study if targeting MSLN isoform 2 with chimeric antigen receptor (CAR) can control the tumor growth, we made CAR retrovirus construct and showed that genetically modified allogenic gamma-delta T cells expressing CAR for MSLN isoform 2 can kill human mesothelioma cells in vitro and in vivo. In summary, we have demonstrated that MSLN isoform 2 is a tumor-specific antigen, which can be targeted for CAR-T cell therapy.
Citation Format: Xiaohong Wang, Yibin Chen, Anupama Gopisetty, Leonardo Mirandola, Lucia Piccotti, Quynh Nguyen, Maurizio Chiriva-Internati. Mesothelin isoform 2 is a novel target for allogenic CARγδT cell therapy in solid tumors [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 1534.
Abstract 1549: ACLX-001, a novel BCMA-targeted CAR-T cell therapy that can be activated, silenced, and reprogrammed in vivo with soluble protein adapters in a dose dependent manner
Authors: Edwards Justin P. , Buonato Janine , LaFleur David , Swers Jeffrey , Mu Jenny , Zaritskaya Liubov , Ng Sinnie , Gupta Ankit , Wang Hui , McCullough Samantha , Hilbert David , Tice David 
Published: July 2021

Abstract
Genetically engineered T cells have demonstrated great promise in the treatment of hematologic malignancies including Acute Lymphocytic Leukemia, Non-Hodgkin's lymphoma, and Multiple Myeloma. However, those achievements are often associated with uncontrolled toxicities, compromised T cell persistence, and frequent tumor relapse. Herein, we report a novel T cell therapy comprising a soluble tumor targeting protein (SPRX001) that specifically binds BCMA-expressing multiple myeloma cells and “TAGS” those cells for destruction by TAG-specific, ex vivo transduced T cells known as Antigen Receptor Complex (ARC) T cells. Functional in vitro studies of ARC-T cells produced from healthy subjects in combination with SPRX001 after co-culture with multiple BCMA-expressing cancer cell lines demonstrated dose-dependent cytokine production, T cell proliferation, degranulation and cytotoxic activity. The cytolytic machinery of the ARC-T cells is only activated when the tri-complex of the ARC-T cell, SPRX001, and BCMA-expressing cell is fully formed. In the absence of any one component, ARC-T cells are not activated thereby preventing kill of the intended target cells. ACLX-001 demonstrated dose- and schedule-dependent in vivo efficacy in disseminated BCMA-expressing tumor models in NSG immunocompromised mice. SPRX001 doses of 0.3 mg/kg daily or 3 mg/kg twice a week were able to eliminate measurable tumor burden as early as 7 days post dosing that lasted for the duration of the study. ARC-T cell expansion and contraction tracked tumor burden in vivo and displayed a diverse memory phenotype. The data support the paradigm that ARC-T cells can be activated and silenced by controlling the dose and schedule of administered SPRX001, which may improve the safety and effectiveness of T cell therapy.
Citation Format: Justin P. Edwards, Janine Buonato, David LaFleur, Jeffrey Swers, Jenny Mu, Liubov Zaritskaya, Sinnie Ng, Ankit Gupta, Hui Wang, Samantha McCullough, David Hilbert, David Tice. ACLX-001, a novel BCMA-targeted CAR-T cell therapy that can be activated, silenced, and reprogrammed in vivo with soluble protein adapters in a dose dependent manner [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 1549.