bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract KN01: Dissecting antitumor immune response in ovarian cancer
Authors: Coukos George 
Published: March 2020

Abstract
In epithelial ovarian cancer (EOC), intratumoral or intraepithelial tumor infiltrating lymphocytes (TILs), i.e. T cells specifically infiltrating tumor islets, occur in approximately half of the patients and correlate with longer survival. As with many other solid tumors, despite promising results in mouse models, response of EOC to PD-1 blockade has been quite limited in the clinic, but the mechanisms underlying therapeutic failures in immunoreactive human tumors harboring TILs are not well understood. Our work has sought to answer the following key questions: a) whether ovarian TILs are tumor-specific; b) if so, what are the relevant antigens recognized by TILs; c) whether the PD-1/PD-L1 pathway is relevant; d) if so, what are the mechanisms underlying response to PD-1 blockade; and finally e) what mechanisms govern TIL recruitment and engraftment. The data presented will show that there is indeed a spontaneous and tumor-specific T-cell response in a proportion of EOC, accurately heralded by intraepithelial CD8+ TILs. Tumor-specific antigens will be discussed. Our work also shows that the PD-1/PD-L1 is a central immune checkpoint pathway in these tumors. However, only a fraction of such tumors with ieTILs respond to PD-1. We dissected the mechanisms underlying response to PD-1 blockade and therapeutic approaches to enhance response to PD-1 in human and mouse preclinical models. Therapeutic approaches to achieve effective immunotherapy in ovarian cancer will be discussed, including combination checkpoint blockade, adoptive T cell therapy and new rational combinations. Finally, successful T-cell engraftment in ovarian cancer requires tumor cell-derived CCL5 and is amplified by myeloid cell-secreted IFNg-inducible CXCL9, dependent on activation of tumor-infiltrating lymphocytes (TILs). Spontaneous, epigenetically-mediated loss or stable knockdown of ccl5 leads to CD8+ T-cell loss and immune desertification in the mouse, while forced ccl5 expression prevents loss of cxcl9 and TILs, and leads to attenuated tumor growth. Accordingly, CCL5-CXCL9 co-expression reveals immunoreactive tumors with prolonged survival and response to PD-1 blockade. The impact of homologous recombination and BRCA loss on the establishment of immunoreactive tumors will be also discussed.
Citation Format: George Coukos. Dissecting antitumor immune response in ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr KN01. doi:10.1158/1535-7163.TARG-19-KN01
Abstract LB-A04: Rapid non-uniform adaptation to conformation-specific KRAS G12C inhibition
Authors: Xue Jenny , Zhao Yulei , Aronowitz Jordan , Mai Trang T , Vides Alberto , Qeriqi Besnik , Kim Dongsung , Li Chuanchuan , Stanchina Elisa de , Mazutis Linas , Risso Davide , Lito Piro 
Published: March 2020

Abstract
KRAS GTPases are activated in one-third of cancers and KRAS G12C is the most common activating alteration in lung adenocarcinoma. KRAS G12C inhibitors are in Phase-I clinical trials and early data show only partial responses in lung cancer patients. How cancer cells bypass inhibition, to prevent maximal responses to therapy, is not understood. Because KRAS G12C cycles between an active and inactive conformation, and the inhibitors only bind to the latter, we hypothesized that isogenic cell populations respond non-uniformly. Here we studied the effect of treatment at the single cell level and showed that shortly after treatment, some cancer cells were sequestered in a quiescent state with low KRAS activity, while others reactivated KRAS to resume proliferation. By combining cell fate-specific gene expressions and results from a CRISPR-Cas9 screen, we identified that this rapid divergent response is due to new KRAS G12C produced in response to suppressed MAPK output. Upstream-acting adaptive signals, such as epidermal growth-factor receptor and aurora kinase signaling, maintain new KRAS G12C protein in its active/drug-insensitive state to restore KRAS output. Cells without these adaptive changes (or cells where they are pharmacologically inhibited) remain sensitive to drug treatment, because new KRAS G12C is either not available, or it exists in its inactive/drug-sensitive state. Combined inhibition of these adaptive signals along with KRAS G12C produced more potent antitumor effects in vivo. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome to maximize the therapeutic potential of conformation-specific KRAS G12C inhibitors in the clinic.
Citation Format: Jenny Xue, Yulei Zhao, Jordan Aronowitz, Trang T Mai, Alberto Vides, Besnik Qeriqi, Dongsung Kim, Chuanchuan Li, Elisa de Stanchina, Linas Mazutis, Davide Risso, Piro Lito. Rapid non-uniform adaptation to conformation-specific KRAS G12C inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A04. doi:10.1158/1535-7163.TARG-19-LB-A04
Abstract LB-A07: Targeting nucleotide excision repair defects in cancer
Authors: Topka Sabine , Steinsnyder Zoe , Tkachuk Kaitlyn , Ravichandran Vignesh , Madsen Mogens Winkel , Furberg-Barnes Helena , Iyer Gopakumar , Stanchina Elisa De , Joseph Vijai , Offit Kenneth 
Published: March 2020

Abstract
A proportion of cancer patients carry inherited pathogenic variants or somatic alterations in the DNA helicase genes ERCC2 and ERCC3, important components of the nucleotide excision repair (NER) pathway. Cancer risk associated with mutations in nucleotide excision repair is not very well understood and there are no targeted therapies available for patients with NER gene mutations. We have recently shown that functionally significant cancer-associated mutations in ERCC3 exhibit remarkable sensitivity against the fungal sesquiterpene IlludinS. Irofulven, a derivative of IlludinS, has previously been evaluated as an antitumor agent in multiple clinical trials and has shown antitumor activity in a subset of patients. Based on the observation that ERCC3 mutant cell lines are highly sensitive to IlludinS we explored the role of Irofulven as a potential therapeutic agent to treat patients with hypomorphic mutations in nucleotide excision repair genes. We used CRISPR/Cas9 to create isogenic pairs of wildtype and mutant ERCC2 or ERCC3 cell lines and assessed in vitro and in vivo response to Irofulven. In vitro studies showed significantly increased sensitivity of the ERCC3 mutant cells towards Irofulven, when compared to commonly used drugs such as PARP inhibitors or alkylating agents. ERCC2 mutant cells showed elevated in vitro sensitivity to Irofulven even surpassing response to the current standard of care agent Cisplatin. Additionally, in vitro experiments show impaired ability of ERCC2/3 mutant cells to repair Irofulven induced DNA damage. The enhanced Irofulven sensitivity of ERCC3 mutants was replicated in vivo by xenograft experiments. Transcriptome analyses of the tumor tissues gave insights into pathways deregulated in the mutant background and revealed novel biology mediating Irofulven sensitivity suggesting potential for the development of combinatorial therapies. Similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC2 and ERCC3 could constitute potential biomarkers of therapeutic response. The present study provides pre-clinical evidence that a subset of tumors with mutations in nucleotide excision repair pathway genes exhibits exceptional sensitivity to Irofulven.
Citation Format: Sabine Topka, Zoe Steinsnyder, Kaitlyn Tkachuk, Vignesh Ravichandran, Mogens Winkel Madsen, Helena Furberg-Barnes, Gopakumar Iyer, Elisa De Stanchina, Vijai Joseph, Kenneth Offit. Targeting nucleotide excision repair defects in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A07. doi:10.1158/1535-7163.TARG-19-LB-A07
Abstract LB-A08: Novel strategy for treatment of triple-negative breast cancer by highly potent caspase-cleavable docetaxel prodrug
Authors: Cho Youngseok , Kim Harin , Chung Seung Woo , Byun Youngro 
Published: March 2020

Abstract
Despite the emergence of advanced therapeutics such as targeted therapy and immunotherapy in the modern oncology, cytotoxic chemotherapy still remains as the first-line treatment option in a wide range of cancers attributing to its potency. Many endeavors have been made to overcome the toxicity issues of cytotoxic chemotherapy by improving the specific delivery to the tumor, with active tumor targeting being one of the most popular approaches. However, such an approach has been challenged by the intratumor heterogeneity and the lack of valid molecular target in many types of cancer. Here, we introduce a novel albumin-binding prodrug MPD03 that could specifically deliver highly potent cytotoxin docetaxel to the tumor as an important component of chemotherapy for the treatment of triple-negative breast cancer (TNBC). MPD03 was synthesized by conjugating docetaxel to the C-terminus of the KGDEVD peptide via self-eliminating linker and introducing a maleimide group to the Lys sid chain of the peptide. MPD03 was able to bind albumin after administration via maleimide group for an extended circulation time and metabolized into docetaxel in tumor specific manner by reacting with the caspase-3 upregulated in tumor by apoptosis inducing agent, exerting a highly potent anticancer effect with good safety profile in TNBC xenograft model. PARP inhibitor olaparib was used in combination therapy with MPD03 in our strategy in terms of apoptosis inducer. Using our treatment regimen, we seek to expand our strategy to eradicate metastatic tumors.
Citation Format: Youngseok Cho, Harin Kim, Seung Woo Chung, Youngro Byun. Novel strategy for treatment of triple-negative breast cancer by highly potent caspase-cleavable docetaxel prodrug [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A08. doi:10.1158/1535-7163.TARG-19-LB-A08
Abstract LB-A09: EED targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex
Authors: Hsu Jessie Hao-Ru , Rasmusson Timothy , Robinson James , Pachl Fiona , Read Jon , Kawatkar Sameer , O'Donovan Daniel H , Bagal Sharan , Code Erin , Rawlins Philip , Argyrou Argyrides , Tomlinson Ronald , Gao Ning , Zhu Xiahui , Chiarparin Elisabetta , Jacques Kelly , Shen Minhui , Woods Haley , Bednarski Emma , Wilson David M. , Drew Lisa , Castaldi M. Paola , Fawell Stephen , Bloecher Andrew 
Published: March 2020

Abstract
Deregulation of the PRC2 components EZH2, SUZ12, and EED plays critical roles in driving aberrant hypermethylation of H3K27 and tumorigenicity of many solid and hematological malignancies. Although SAM competitive small molecule inhibitors of EZH2 show promising clinical activity in PRC2-dependent cancers, preclinical data suggests that resistance can be acquired through secondary mutations in EZH2 that abrogate drug target engagement. To address these limitations, we have designed several hetero-bifunctional PROTACs (Proteolysis Targeting Chimera) to efficiently target EED for elimination. Our EED-targeting PROTACs bind to EED (pKD= 9.02-9.27) and promote stable ternary complex formation with the E3 ubiquitin ligase. The PROTACs potently inhibit PRC2 enzyme activity (pIC50= 8.11-8.17) that results in a decrease in H3K27me3 levels in cells. Interestingly, EED-targeting PROTACs induce rapid degradation of EED, as well as its associated proteins, including EZH2 and SUZ12 in the PRC2 complex. Inhibition of the ubiquitin proteasome pathway abrogates PROTAC-mediated degradation of EED and its associated proteins. Furthermore, the EED targeting PROTACs selectively inhibit proliferation and survival of PRC2-dependent cancer cells (GI50= 49-58 nM). In summary, our data demonstrate a novel therapeutic modality in treating PRC2 dependent cancer through PROTAC mediated platform.
Citation Format: Jessie Hao-Ru Hsu, Timothy Rasmusson, James Robinson, Fiona Pachl, Jon Read, Sameer Kawatkar, Daniel H O'Donovan, Sharan Bagal, Erin Code, Philip Rawlins, Argyrides Argyrou, Ronald Tomlinson, Ning Gao, Xiahui Zhu, Elisabetta Chiarparin, Kelly Jacques, Minhui Shen, Haley Woods, Emma Bednarski, David M. Wilson, Lisa Drew, M. Paola Castaldi, Stephen Fawell, Andrew Bloecher. EED targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A09. doi:10.1158/1535-7163.TARG-19-LB-A09
Abstract LB-B02: Orthogonal pathogen challenges in tumor burdened mice reveal systemic impairment of de novo immune responses
Authors: Hiam Kamir , Allen Breanna , Spitzer Matthew 
Published: March 2020

Abstract
Harnessing immune defense mechanisms has revolutionized cancer therapy. However, the limited efficacy of these approaches across patients and cancer types reflects our incomplete understanding of the factors governing immune responses in cancer. Here, we use orthogonal viral and bacterial challenges in mice with preexisting malignancy to assess functionality of the immune system in cancer. The tumor burdened immune system mounted dampened peripheral T cell responses characterized by reduced proliferation and effector differentiation. Disruptions in T cell activity in vivo were not cell intrinsic but rather due to reduced responses in antigen-presenting cells (APCs). Promoting APC activation was sufficient to restore T cell responses to orthogonal infection. These results demonstrate that tumor development dynamically reshapes the function of the immune macroenvironment, arguing for a deeper understanding of the tumor-experienced systemic context for rational immunotherapeutic design.
Citation Format: Kamir Hiam, Breanna Allen, Matthew Spitzer. Orthogonal pathogen challenges in tumor burdened mice reveal systemic impairment of de novo immune responses [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B02. doi:10.1158/1535-7163.TARG-19-LB-B02
Abstract LB-C01: The kinase polypharmacology landscape of clinical PARP inhibitors
Authors: Antolin Albert A , Ameratunga Malaka , Banerji Udai , Clarke Paul , Workman Paul , Al-Lazikani Bissan 
Published: March 2020

Abstract
Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although often this is done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. The most potently inhibited off-targets are CDK16 for rucaparib (IC50 = 381 nM) and DYRK1B for niraparib (IC50 = 254 nM). These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic.
Citation Format: Albert A Antolin, Malaka Ameratunga, Udai Banerji, Paul Clarke, Paul Workman, Bissan Al-Lazikani. The kinase polypharmacology landscape of clinical PARP inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-C01. doi:10.1158/1535-7163.TARG-19-LB-C01
Abstract LB-C11: Targeting metastatic prostate cancer with a multi-functional therapy approach
Authors: Gordon Ryan , Zhang Limin , Pattanayak Abhinandan , Li Wenqi , Bergan Raymond 
Published: March 2020

Abstract
Prostate cancer (PCa) cells move throughout the body, hone to and destroy the bone microenvironment, grow and thereby cause death. Our historical inability to target cell movement has precluded our realization of multifunctional therapy wherein each of these processes is targeted. Our group has recently shown that inhibition of intracellular activation of Raf1 with the small molecule therapeutic, KBU2046, permits for the first time selective inhibition of cell motility. Here we demonstrate that simultaneous disruption of multiple distinct functions that drive progression of PCa to induce death results in advanced disease control. Using an orthotopic murine model of human PCa metastasis, KBU2046 combined with docetaxel achieves sustained anti-tumor action and improved inhibition of metastasis, compared to monotherapy. KBU2046 does not interfere with androgen deprivation or androgen receptor antagonist mediated hormone therapy in either in vitro or in vivo models. Cell movement is necessary for osteoclast-mediated bone degradation. KBU2046 inhibits Raf1 and its downstream activation of MEK1/2 and ERK1/2 in osteoclasts, inhibiting cytoskeleton rearrangement, resorptive cavity formation and bone destruction in vitro, with improved effects observed when the bone microenvironment is chemically modified by pretreatment with zoledronic acid. Using a murine cardiac injection model of human PCa bone destruction quantified by computed tomography, KBU2046 plus zoledronic acid exhibited improved inhibitory efficacy, compared to monotherapy. The combined disruption of pathways that drive cell movement, honing to the bone and growth constitutes a multi-functional targeting strategy that provides advanced disease control.
Citation Format: Ryan Gordon, Limin Zhang, Abhinandan Pattanayak, Wenqi Li, Raymond Bergan. Targeting metastatic prostate cancer with a multi-functional therapy approach [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-C11. doi:10.1158/1535-7163.TARG-19-LB-C11
Abstract LB-C15: EpCAM-high liver cancer stem cells resist natural killer cell-mediated cytotoxicity by upregulating CEACAM1
Authors: Sung Pil Soo , Yoon Seung Kew 
Published: March 2020

Abstract
Natural killer (NK) cells are innate lymphoid cells with potent cytolytic functions that defend the host against microbial infections and tumours. Here, we investigated the cytotoxic effects of NK cells on epithelial cell adhesion molecule (EpCAM)-expressing liver cancer stem cells (CSCs). The frequency of recurrence after curative resection was higher in patients with peritumoural EpCAM expression than patients with pantumoural or negative EpCAM expression. Co-culture experiments demonstrated that EpCAMhigh Huh-7 cells resisted NK cell-mediated cytotoxicity. Silencing carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), which is overexpressed on the surface of EpCAMhigh Huh-7 cells and other hepatoma cells or primary hepatocytes, restored cytotoxicity of NK cells against EpCAMhigh Huh-7 cells. Neutralization of CEACAM1 on the NK cells also enhanced the killing of Huh-7 cells, suggesting CEACAM1 expressed on the NK cells transmits inhibitory signals into the NK cells. EpCAMhigh Hepa1-6 cells formed larger tumours with higher CEACAM1 expression levels in vivo. Neutralization of CEACAM1 in Hepa1-6 xenograft mouse model resulted in more activated phenotype of tumour-infiltrating NK cells and delayed growth of the tumour. Finally, CEACAM1 expression positively correlated with EpCAM expression in human HCC tissues and the serum CEACAM1 levels were also significantly higher in patients with EpCAM+ HCC. Moreover, analyses with TCGA dataset revealed that EpCAM expression shows positive correlation with CEACAM1 expression in various types of cancers. In conclusion, our data demonstrated that EpCAMhigh liver CSCs resist NK cell-mediated cytotoxicity by upregulating CEACAM1 expression.
Citation Format: Pil Soo Sung, Seung Kew Yoon. EpCAM-high liver cancer stem cells resist natural killer cell-mediated cytotoxicity by upregulating CEACAM1 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-C15. doi:10.1158/1535-7163.TARG-19-LB-C15
Abstract PL03-01: Targeting DNA Repair and Defective DNA repair
Authors: Bono Johann de 
Published: March 2020

Abstract
Genomic instability and defective DNA repair (DDR) are key hallmarks of many currently incurable malignancies, with these often associating with poorer outcomes and more aggressive disease. DDR supports tumor evolution but can generate genomic alterations leading to neoantigen generation from single nucleotide alterations and genomic rearrangements/fusions, which may lead to tumor sculpting by immune responses and tumor cell adaptations to abrogate anticancer immune responses through not only immune checkpoint expression but also the secretion of cytokines and chemokines that impact immune cell migration and function. Multiple studies have now shown that DDR can be a vulnerability, both through synthetic lethal strategies with drugs like PARP and ATR inhibition and DNA damaging agents, as well as through strategies targeting the immune response as best exemplified by mismatch repair defects and PD-1 targeting and more recently emerging evidence on CDK12 alterations. This presentation will focus on the therapeutic targeting of tumors with DNA repair defects, synthetic lethal strategies, and the challenges of developing anticancer drugs targeting DNA repair.
Citation Format: Johann de Bono. Targeting DNA Repair and Defective DNA repair [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PL03-01. doi:10.1158/1535-7163.TARG-19-PL03-01