bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B138: Biochemical and cell-based activities of ectonucleotidases CD39 and CD73 using a homogenous HTS formatted platform
Authors: Goueli Said , Hsiao kevin 
Published: March 2020

Abstract
The success of immunotherapy treatment in oncology ushered a new modality for treating a wide variety of cancers. However, lack of effect in some patients made it imperative to identify other pathways that are exploited by cancer cells to circumvent immune surveillance, and possibly synergize immune checkpoint treatment in those cases. It has been recently recognized that adenosine levels increased significantly in the tumor microenvironment and that adenosine/adenosine receptors play a powerful role as immunosuppressant and attenuating several effector T cell functions. The two main enzymes responsible for generating adenosine in the microenvironment are the ectonucleotidases CD39 and CD73, the former utilizes both ATP and ADP and producing AMP while the latter utilizes AMP and generates adenosine. Thus, these two enzymes combined are the major source for the bulk of adenosine produced in the microenvironment. They were shown to be validated targets in oncology leading to several clinical trials that include small molecules as well as antibodies, showing positive and encouraging results in the preclinical arena. Towards the development of novel drugs to target these enzymes, we have developed a platform that can be utilized to monitor the activities of both enzymes in vitro (biochemical) as well as in cells (cell based) assays. We have developed very sensitive and homogenous assays that enabled us to monitor the activity of both enzymes and demonstrate selectivity of known small molecule inhibitors as well as selective monoclonal antibodies. This should speed up screening for novel inhibitors leading to more effective cancer therapy
Citation Format: Said Goueli, kevin Hsiao. Biochemical and cell-based activities of ectonucleotidases CD39 and CD73 using a homogenous HTS formatted platform [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 B138. doi:10.1158/1535-7163.TARG-19-B138
Abstract C030: A new low potency DNA guanine monoalkylating ADC payload with enhanced i
n vivo tolerability
Authors: Veillard Nicolas , Andriollo Paolo , Cascio Francesco , Jackson Paul J. M. , Thurston David E. 
Published: March 2020

Abstract
Although five Antibody-Drug Conjugates (ADCs) have been approved and over eighty others are in development, the majority contain payloads belonging to two classes: tubulin inhibitors and DNA interactive agents. Most DNA-interactive payloads (e.g., the PBD dimers and IGNs) have potent cytotoxicity but ADCs containing them have high hydrophobicity and a narrow therapeutic window. Thus, there is interest in developing novel payloads which benefit from similar in vivo efficacy but possess lower hydrophobicity and a substantially wider Therapeutic Window (TW). The pyridinobenzodiazepines (PDDs) are a new class of sequence-selective, DNA guanine monoalkylating ADC payload which contain a polyheterocyclic chain with sufficient span to guide them to specific DNA sequences (e.g., transcription factor binding sites). The lead high potency PDD payload (FGX2-62) is active in vitro in the picomolar range in a wide panel of cell-lines, is easily conjugated and has in vivo potency at sub-mg/kg levels in ADC form. Within the PDD platform, we have now developed a lower potency DNA monoalkylator with substantially superior in vivo properties to other DNA alkylating agents. FGX20-75 is active in the low nanomolar range (e.g., 2.1 nM in the gastric cell-line SW48, 72 hour incubation), but is sufficiently hydrophilic to allow efficient conjugation at DARs &gt; 4. The increase in loading compared to other DNA-interactive payloads compensates for the drop in potency of FGX20-75, resulting in a potent ADC with substantially increased tolerability. ADCs have been generated by conjugating a maleimide-linked analogue of FGX20-75 to the EGFR-targeting antibody Cetuximab with DAR of 4.2. The ADCs exhibit significant in vivo efficacy compared to other DNA-interactive payloads, and a substantially increased tolerability profile. A maximum tolerated dose (MTD) has not yet been reached at 35 mg/kg (single dose, CD1 mice). The favourable hydrophobicity profile of the low potency alkylator (FGX20-75) and its ease of conjugation to antibodies, along with the significant in vivo efficacy and tolerability of the ADCs produced, suggest that this low potency DNA-alkylating payload represents a promising new approach in ADC development.
Citation Format: Nicolas Veillard, Paolo Andriollo, Francesco Cascio, Paul J. M. Jackson, David E. Thurston. A new low potency DNA guanine monoalkylating ADC payload with enhanced in vivo tolerability [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 C030. doi:10.1158/1535-7163.TARG-19-C030
Abstract C040: INTH-454, a p300/CBP interactome modulator, targets multiple pathogenesis factors in solid tumors and induces strong anti-proliferative effects in vitro and in vivo as single agent
Authors: Cattori Valentino , Hentsch Bernd , Kessler Ulrich 
Published: March 2020

Abstract
Background: INTH-454 is a novel rationally designed ligand of the CH1/TAZ1 domain of p300/CBP, two closely related paralog transcription co-activators crucially involved in cancer cell proliferation and tumor progression. Here, we report the in vitro and in vivo characterization of INTH-454 in preclinical models of castration-resistant prostate (CRPC) and gastrointestinal (GI) cancer. Methods: The anti-proliferative effects of INTH-454 were assessed in colon, gastric and prostate cancer cells harboring wild type, mutant or no p53 protein followed by cell cycle analysis, beta-galactosidase staining and caspase activation assays. Levels of p53, acetylated p53 and p21 were determined by Western blotting. The impact of INTH-454 on ubiquitination/degradation of p53 and p21 was investigated and pharmacodynamic and anti-tumoral effects of INTH-454 were illustrated in cell line and patient derived xenograft models of prostate and GI cancer. Results: INTH-454 exhibited anti-proliferative effects at low nanomolar concentrations in all cell lines inducing strong cell cycle arrest followed by senescence or cell death. Levels of p21 were stably increased independent of p53-status and the amount of both, total ubiquitinated protein and ubiquitinated p53, was significantly decreased in treated cells. Oral administration of INTH-454 triggered strong inhibition of tumor growth in xenograft mouse models of CRPC and GI cancer up to tumor eradication at well tolerated doses. Analysis of tumor tissue by immunohistochemistry and Western blotting confirmed the in vitro results and illustrated additional pharmacodynamic effects on disease specific markers such as reduction of VEGF and PSA. Conclusions: Blockage of the CH1/TAZ1 domain of p300/CBP has a profound effect on cell cycle regulation in cancer cells. INTH-454 causes cell cycle arrest through stabilization/overexpression of p21 in a p53-dependent and -independent manner followed by either cell death or senescence and sustained anti-tumoral effects in xenograft models of prostate and gastrointestinal carcinomas.
Citation Format: Valentino Cattori, Bernd Hentsch, Ulrich Kessler. INTH-454, a p300/CBP interactome modulator, targets multiple pathogenesis factors in solid tumors and induces strong anti-proliferative effects in vitro and in vivo as single agent [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 C040. doi:10.1158/1535-7163.TARG-19-C040
Abstract C055: Novel imipridone ONC206 inhibits cell proliferation and induces apoptosis in uterine serous cancer through altering MAPK/AKT/AMPK signaling network and metabolic reprogramming
Authors: Yeung Chi Lam Au , Hu Wen , Zhang Li , Ferri-Borgogno Sammy , Tarapore Rohinton , Lu Karen H , Mok Samuel C 
Published: March 2020

Abstract
Uterine serous carcinoma (USC) is the most aggressive subtype of endometrial cancer. Patients with advanced stage USC have poor survival rates and new treatment regimens are lacking. Recent clinical studies showed that imipridones constitute a novel class of agents with antitumor activities. Among them, ONC206, a novel orally bioavailable small molecule that has recently been shown to bind G protein-coupled receptor (GPCR)-dopamine receptor D2 (DRD2) by comprehensive GPCR screening, induces apoptosis in glioblastoma cells. However, the effects of ONC206 on USC progression and the mechanism of action have not been thoroughly explored. Using both in vitro and in vivo models, and multiple USC cell lines, the effects of ONC206 on cell proliferation, cell cycle progression, and apoptosis were determined. Reverse phase protein arrays (RPPAs) and Western blot analyses were used to determine the effect of ONC206 on the expression of key proteins in various signaling networks in ONC206 treated USC cells. The results showed that ONC206 suppressed USC cell proliferation and induces apoptosis in a does dependent manner. It increased the number of USC cells in the G1 phase of the cell cycle. Luciferase labeled USC cell ARK1-bearing mice treated with 100mg/kg ONC206 had significantly lower chemiluminescent signals than those treated with the control buffer. RPPA data showed that ONC206 treated USC cells had markedly lower expression signals in p38MAPK, p-AKT, p-S6, CDKs, and multiple mitochondrial proteins associated with mitochondrial ATP synthesis including MTCO1, SDHB, and HSPD1 than the control cells did. In addition, markedly higher expression levels of p-AMPK, Bim, and cleaved caspases were also observed in ONC206 treated cells than the control did. Significantly lower ATP levels and cytochrome c oxidase activities in ONC206 treated USC cells than in control cells were demonstrated by luminescent ATP detection assay kit and the cytochrome c oxidase assay kit. These data suggest that ONC206 suppresses USC progression through inhibiting MAPK/AKT network, which subsequently leads to cell cycle arrest, metabolic reprogramming and increased apoptosis. Further studies which demonstrate the optimal dosage and the efficacy of treatment of USC using ONC206 are warranted.
Citation Format: Chi Lam Au Yeung, Wen Hu, Li Zhang, Sammy Ferri-Borgogno, Rohinton Tarapore, Karen H Lu, Samuel C Mok. Novel imipridone ONC206 inhibits cell proliferation and induces apoptosis in uterine serous cancer through altering MAPK/AKT/AMPK signaling network and metabolic reprogramming [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 C055. doi:10.1158/1535-7163.TARG-19-C055
Abstract C098: Preclinical evaluation of eribulin in a veterinary clinical trial of metastatic spontaneous hemangiosarcoma in pet dogs
Authors: Lopes Christina Kelly , Post Gerald , Lambert Lindsay , Lewis Benjamin , Allen Thaddeus David , Patel Angel , Littlefield Bruce A 
Published: March 2020

Abstract
Eribulin is a microtubule dynamics inhibitor that is currently in clinical use for treatment of certain patients with advanced breast cancer or liposarcoma. FDA approval for both indications was based on extension of overall survival. Based on eribulin’s known vascular remodeling effects, its activity against at least one sarcoma type, and literature reports of taxane activity in angiosarcoma, we hypothesized that eribulin may show activity against angiosarcoma. Due to a paucity of preclinical cell-based, xenograft, and PDX models for human angiosarcoma, we sought other alternatives for preclinical testing in this disease. While rare in humans, angiosarcoma is common in some breeds of domestic dogs, where it is known in veterinary parlance as hemangiosarcoma (HSA). Accordingly, we undertook a small veterinary clinical trial to evaluate eribulin against spontaneous HSA in pet dogs. Canine HSA most frequently occurs in the spleen, so splenectomy is a common first-line treatment; however, non-splenic sites also occur and these are often unresectable. In keeping with eribulin’s clinical use in the metastatic setting, we selected metastatic canine HSA, which we defined as dogs with histologically confirmed HSA with either non-resectable or post-splenectomy residual disease confirmed by imaging (PET/CT, CT). Of 19 pets initially screened, 12 dogs were imaged; 6 of these had imageable disease and thus began eribulin treatment. Eribulin was administered using the human clinical schedule (d1,8Q21), with the first cycle at 0.3 mg/m2 followed by intra-patient dose escalation to 0.6 mg/m2 after determination of tolerability. Of the 6 dogs entering treatment, 5 completed cycle 1, 3 completed cycle 2, and 2 completed the full per-protocol 3 cycles of treatment. These 2 dogs survived 121 and 179 days after initial diagnosis, contrasting with the 0.9 month (~27 days) median survival time reported by Wendelburg et al. (JAVMA, 2015) for 52 post-splenectomy canine HSA patients with residual metastases. Although limited in scope, our results with spontaneous metastatic canine HSA in pet dogs provides a preclinical foundation for further exploration of eribulin in malignancies of vascular origin in both the veterinary and human settings.
Citation Format: Christina Kelly Lopes, Gerald Post, Lindsay Lambert, Benjamin Lewis, Thaddeus David Allen, Angel Patel, Bruce A Littlefield. Preclinical evaluation of eribulin in a veterinary clinical trial of metastatic spontaneous hemangiosarcoma in pet dogs [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 C098. doi:10.1158/1535-7163.TARG-19-C098
Abstract C101: Comprehensive identification of novel therapeutic targets for treatment of PD-1 resistant solid tumors via a genome-scale CRISPR/Cas9 in vivo T-cell screen
Authors: Mercier Isabelle Le , Merkin Jason J. , Keegan Sean , Calnan Conor , Hohmann Anja F. , Colletti Nick , Fagerberg Eric , Shenker Sol , Bullock Caroline , Wrocklage Chris , Tubo Noah , Xu Tianlei , Noyes Matt , Rahal Rami , Arlauckas Sean , Morales Aria Pearlman , Stegmeier Frank , Cadzow Louise , Schlabach Mike , Kryukov Gregory , Benson Micah J. 
Published: March 2020

Abstract
Although immunotherapy with PD-1/PD-L1 antagonists has significantly advanced patient care, the majority of cancer patients currently do not benefit from checkpoint inhibitor therapies. To identify novel targets for the treatment of PD-1 insensitive cancers, we developed a novel Immune-CRISPRomicsTM platform that enabled genome-wide CRISPR/Cas9 screens in primary T cells in an in vivo setting. Notably, the screen identified clinically active molecules, such as PD-1 and also predicted recent clinical failures. In addition, we identified multiple targets that enhanced anti-tumor T-cell function similar to or better than PD-1 as a monotherapy. The anti-tumor activity of targets was assessed across a collection of PD-1 sensitive and PD-1 refractory syngeneic tumor models. One of the targets identified, IO-7, was found to possess robust activity across multiple PD-1 refractory models. We found that inhibition of IO-7 leads to long-term T-cell memory and prevents tumor growth upon re-challenge. Moreover, mechanistic follow-up studies demonstrate that IO-7 inhibition leads to an expansion of central memory T-cell subsets, which have been implicated in driving the durable clinical response of checkpoint inhibitors. We describe the first genome-wide in vivo T-cell CRISPR/Cas9 screen, which identified multiple therapeutic targets that present promising therapeutic opportunities for the treatment of PD-1 resistant solid tumors.
Citation Format: Isabelle Le Mercier, Jason J. Merkin, Sean Keegan, Conor Calnan, Anja F. Hohmann, Nick Colletti, Eric Fagerberg, Sol Shenker, Caroline Bullock, Chris Wrocklage, Noah Tubo, Tianlei Xu, Matt Noyes, Rami Rahal, Sean Arlauckas, Aria Pearlman Morales, Frank Stegmeier, Louise Cadzow, Mike Schlabach, Gregory Kryukov, Micah J. Benson. Comprehensive identification of novel therapeutic targets for treatment of PD-1 resistant solid tumors via a genome-scale CRISPR/Cas9 in vivo T-cell screen [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 C101. doi:10.1158/1535-7163.TARG-19-C101
Abstract C121: Long Pentraxin-3 modulates bladder cancer progression
Authors: Matarazzo Sara , Melocchi Laura , Rezzola Sara , Grillo Elisabetta , Maccarinelli Federica , Giacomini Arianna , Taranto Sara , Zammataro Luca , Cerasuolo Marianna , Bugatti Mattia , Vermi William , Presta Marco , Ronca Roberto 
Published: March 2020

Abstract
Bladder tumors are a diffuse type of cancer with a relatively benign prognosis when treated at early stage/low-grade stages, but with poor outcome in the muscle invasive (MIBC) form or at recurrence. Long Pentraxin-3 (PTX3) is a component of the innate immunity with pleiotropic functions in the regulation of immune response, tissue remodeling and cancer progression. PTX3 may act as an oncosuppressor in different contexts, functioning as an antagonist of the FGF/FGFR system, rewiring the immune-microenvironment or acting through mechanisms not yet fully clarified. In this study, we report for the first time that PTX3 is differentially expressed in bladder cancer (BC) biopsies and tumor cell lines during the different stages of BC progression. Taking advantage of BC cell lines representative of different tumor grades, we demonstrate that PTX3 production by tumor cells decreases along the progression from low-grade to high grade/MIBC because of promoter methylation. In vitro and in vivo data reveal that PTX3 modulation in BC cells has a significant impact on different biological features of BC growth, including cell proliferation, motility, metabolism, stemness and drug resistance. In conclusion, PTX3 exerts an oncosuppressive effect on BC progression and may represent a potential functional biomarker in BC evolution.
Citation Format: Sara Matarazzo, Laura Melocchi, Sara Rezzola, Elisabetta Grillo, Federica Maccarinelli, Arianna Giacomini, Sara Taranto, Luca Zammataro, Marianna Cerasuolo, Mattia Bugatti, William Vermi, Marco Presta, Roberto Ronca. Long Pentraxin-3 modulates bladder cancer progression [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 C121. doi:10.1158/1535-7163.TARG-19-C121
Abstract CN05-02: Next generation strategies to overcome adaptive resistance to MAPK-directed therapies
Authors: Poulikakos Poulikos 
Published: March 2020

Abstract
Adaptive resistance remains a major challenge limiting the clinical effectiveness of inhibitors of oncogenic MAPK signaling (RAF and MEK inhibitors), there is thus a pressing need for compounds and combinatorial strategies that would potently and durably suppress MAPK signaling in the tumor, while retaining a broad therapeutic window. A common mechanism of adaptive resistance is mediated by feedback-induced RTKs and RAS activation by inhibitor that results in incomplete MAPK inhibition in the tumor. SHP2 (PTPN11) is a non-receptor tyrosine phosphatase and scaffold protein that mediates signal transduction downstream of multiple RTKs promoting RAS activation. Targeting SHP2 provides the opportunity to overcome adaptive resistance by co-targeting MAPK signaling and feedback-induced RTK-mediated RAS activation. Targeting SHP2 using a selective allosteric SHP2 inhibitor, in combination with inhibitors of components of MAPK signaling, prevents adaptive resistance and is broadly effective in Triple Negative Breast Cancer models and tumors with RAS mutations at G12, whereas tumors with RAS(G13D) or RAS(Q61X) mutations were resistant. This indicates that different RAS mutant proteins vary considerably in the dependence of their activity on upstream RTK/SHP2 signaling, suggesting hitherto unappreciated differences in their biochemical properties in cells. In each tumor that was sensitive to combined treatment, p(Y542)SHP2 induction was observed in response to MAPK signaling inhibition. In addition, a subset of BRAF(V600E) tumors was identified that were resistant to the combined treatment. In such tumors, FGFR signaling was found to drive feedback-induced RAS activation independently of SHP2, indicating additional combinatorial pharmacologic approaches for this subset of tumors. Thus, understanding mechanisms of adaptive resistance and response to pharmacologic perturbations of oncogenic signaling enables the rational design of more effective combinatorial strategies for the treatment of MAPK-driven cancers.
Citation Format: Poulikos Poulikakos. Next generation strategies to overcome adaptive resistance to MAPK-directed therapies [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 CN05-02. doi:10.1158/1535-7163.TARG-19-CN05-02
Abstract LB-A03: Molecular systems-guided imaging of multicellular in situ adaptation to targeted therapy in BRAF-mutant cancer
Authors: Wang Stephanie , Weissleder Ralph , Lauffenburger Douglas , Miller Miles 
Published: March 2020

Abstract
Adaptive signaling through receptor tyrosine kinases (RTKs) has been highly implicated in the resistance to drugs targeting constitutive RAS/RAF/MEK/ERK signaling, particularly in malignancies with constitutive V600 BRAF mutation. However, it has been difficult to systematically understand how such RTK-mediated bypass signaling is influenced by dynamic and localized interactions between tumor cells and neighboring stromal and immune populations. Here we present a pipeline that combines single-cell and bulk transcriptomic analysis from patients, with systems-level mapping of phosphosignaling pathways in co-cultures, to guide the longitudinal in vivo confocal (intravital) microscopy of adaptive bypass signaling in mouse models of BRAF-mutant cancer. This pipeline prioritizes key myeloid populations and phosphosignaling activities (including of ERK) to image in vivo. Intravital microscopy reveals how therapy-induced myeloid accumulation simultaneously shapes the local activity of multiple co-regulated signaling pathways in neighboring cancer cells, in a RTK-dependent manner. Overall, this work offers an integrative approach to quantitating multiple single-cell signaling pathway activities in the tumor microenvironment, and directly images the dynamics with which known cancer-cell autonomous mechanisms of targeted therapy resistance can be locally amplified by neighboring immune cell populations.
Citation Format: Stephanie Wang, Ralph Weissleder, Douglas Lauffenburger, Miles Miller. Molecular systems-guided imaging of multicellular in situ adaptation to targeted therapy in BRAF-mutant 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-A03. doi:10.1158/1535-7163.TARG-19-LB-A03