bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2557: Slit2 inhibits small cell lung cancer by targeting tumor microenvironment
Authors: Ahirwar Dinesh K. , Charan Manish , Misri Swati , Shilo Konstantin , Ganju Ramesh 
Published: June 2022

Abstract
Small cell lung cancer (SCLC) is the deadliest subtype of lung cancer with a 5-year survival rate of &lt;5% in extensive-state disease and is designated by US Congress as a “recalcitrant cancer”. Recently approved by FDA, immune checkpoint blockade (ICB) immunotherapy showed marginally improved survival and only in a few patients, suggesting an inert immune tumor microenvironment (TME) and the existence of SCLC subtypes. Therefore, there is a significant need to develop more effective therapies for SCLC. In addition to the nearly universal biallelic inactivation of Rb and Tp53 genes in human SCLC tumors, comprehensive genome-wide screening studies have identified major co-occurring mutations in PTEN, CREBBP, EP300, SLIT2, MLL, COBL, and EPHA7 genes. Among them, SLIT2 showed the highest level of genomic abnormalities defined by a pronounced clustering of mutations and frequent genomic loss. However, the role of Slit2 in SCLC has not been defined yet. By using genetically engineered human SCLC cells overexpressing Slit2 or recombinant Slit2 (rSlit2) protein, we show that Slit2 inhibits SCLC cells proliferation, migration, and invasion properties and tumor sphere formation ability of drug-resistant SCLC cells in vitro. The mechanistic studies have identified inhibition of AKT and β-catenin mediated signaling pathways by Slit2 overexpression. Next, we implanted human SCLC cell lines into the immunocompromised NSG mice subcutaneously followed by treatment with rSlit2 or sterile saline. Analysis of tumor volume over the 4 weeks showed that rSlit2 treatment significantly reduced the growth of SCLC tumors. Further analysis of tumors showed that rSlit2 treated tumors harbor less M2-like CD206+ macrophages. Overall, these results suggest that Slit2 possesses tumor suppressive properties and could be developed as a novel therapeutic agent against SCLC.
Citation Format: Dinesh K. Ahirwar, Manish Charan, Swati Misri, Konstantin Shilo, Ramesh Ganju. Slit2 inhibits small cell lung cancer by targeting tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2557.
Abstract 2559: Tumor lipogenesis influences macrophage polarization in advanced prostate cancer
Authors: Martinez Shannalee R. , Risso Carla Barrientos , Vergne Ralphdy , Wall Nathan R. , Dutil Julie , Casiano Carlos A. , Ruiz-Deya Gilberto , Osterman Carlos Joel Diaz 
Published: June 2022

Abstract
Aberrant lipid metabolism in prostate tumors is linked to aggressive disease and poor outcomes. The purpose of this study was to identify mechanisms by which lipid metabolism in prostate cancer cells influences the tumor immune microenvironment, with emphasis on the activation of macrophages. Our hypothesis that fatty acid synthase-driven de novo lipogenesis promotes immune evasion via alternative M2-like macrophage activation was tested using human monocyte (U937)-derived macrophages co-cultured with prostate cancer cells in the presence of fatty acid synthase inhibitors. Monocytes were differentiated to macrophages in vitro using phorbol-12-myristate-13-acetate for 48 hours prior to co-culture with prostate cancer cells. Macrophage polarization following co-culture with prostate cancer cells was evaluated using multi-parameter flow cytometry to detect established M1 (CD80, CD86) and M2 (CD163, CD206) markers. Furthermore, the expression of fatty acid synthase and pan-macrophage marker CD68 in human prostate tumor tissue microarrays was evaluated using multiplex immunohistochemistry. The lipogenic enzyme and macrophage staining correlated with disease progression, reaching peak levels in metastatic tissues. These findings indicate that tumoral fatty acid synthase is an important mediator of tumor-immune crosstalk, particularly in the context of aggressive and metastatic prostate cancer. These data further suggest that fatty acid synthesis represents a targetable complement to immune-enhancing therapies by modulating tumor cell metabolism, underscoring the need for further evaluation of agents targeting lipid metabolism in prostate cancer.
Citation Format: Shannalee R. Martinez, Carla Barrientos Risso, Ralphdy Vergne, Nathan R. Wall, Julie Dutil, Carlos A. Casiano, Gilberto Ruiz-Deya, Carlos Joel Diaz Osterman. Tumor lipogenesis influences macrophage polarization in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2559.
Abstract 2563: FAK inhibitor APG-2449 and CDK4/6 inhibitor palbociclib synergistically suppress mesothelioma tumor growth via autophagy induction
Authors: Tao Ran , Fang Douglas D. , Li Yuanbao , Zhai Guoqin , Zhou Feng , Wang Qixin , Deng Jing , Yang Dajun , Zhai Yifan 
Published: June 2022

Abstract
Malignant mesothelioma is a rare but highly lethal malignancy, with a 5-year survival rate of less than 10%. Current treatment, which combines surgery, chemotherapy, radiation, and immunotherapy, yields marginal benefit and ultimately results in drug resistance or recurrence. Therefore, developing more effective treatments is an urgent unmet need. Among the most common genomic abnormalities in mesothelioma are alterations of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) and neurofibromin 2 (NF2). Combined CDKN2A deletions and NF2 loss is a negative prognostic factor for both progression-free and overall survival. Mesothelioma cells lacking expression of CDKN2A/B or NF2 are reported to be sensitive to CDK4/6 or focal adhesion kinase (FAK) inhibition, respectively. This study explored the potential utility of combining CDK4/6 inhibitor palbociclib and APG-2449, an investigational, clinical-stage ALK/ROS1/FAK inhibitor, in preclinical models of mesothelioma. Compared to controls and either single agent, the combination of palbociclib and APG-2449 enhanced inhibition of growth of cultured mesothelioma cells. This binary combination also synergistically induced durable antitumor activity in multiple murine mesothelioma models, including both cell line- and patient-derived xenografts. Mechanistically, treatment of mesothelioma cells with this combination likely downregulated FAK phosphorylation and enhanced cellular senescence and autophagy, as evidenced by an increase in the percentage of β-galactosidase-positive cells and upregulation in protein expression levels of autophagy markers P62 and LC3B. The combination also downregulated DNA damage-relevant proteins high mobility group box protein 1 (HMGB1) and γ-H2A histone family member X (ϒ-H2AX). Taken together, the data implicate that an interplay between autophagy and DNA damage repair contributes to the synergistic antitumor effects. In summary, our results unveil a novel potential therapeutic strategy of targeting both FAK and CDK4/6 in order to synergistically inhibit tumor growth in mesothelioma. The synergistic effects are evidently mediated by induced autophagy and enhanced cellular senescence. This preclinical study lays a foundation for future clinical development of APG-2449 combined with CDK4/6 inhibitors for mesothelioma.
Citation Format: Ran Tao, Douglas D. Fang, Yuanbao Li, Guoqin Zhai, Feng Zhou, Qixin Wang, Jing Deng, Dajun Yang, Yifan Zhai. FAK inhibitor APG-2449 and CDK4/6 inhibitor palbociclib synergistically suppress mesothelioma tumor growth via autophagy induction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2563.
Abstract 2574: Q901; a highly selective covalent cdk7 inhibitor inducing substantial anti-tumor effect in a broad spectrum of solid tumor lineages
Authors: Yu Donghoon , Jeon Yeejin , Lee Seung-Joo , Kim Jaeseung , Nam Kiyean 
Published: June 2022

Abstract
As a key regulator of its dual role in transcription and cell cycle progression, CDK7 has been determined to be an attractive therapeutic target in a variety of tumor types driven by cell cycle dysregulation and aberrant control of the transcriptional processes. Q901 is an irreversible small molecule inhibitor with extreme selectivity and potent inhibition activity for CDK7, which forms a covalent bond with C312 of the CDK7 C-terminal domain. Q901 demonstrated selective cytotoxic activities in a broad spectrum of solid tumor lineages. TP53 mutation could be a potential predictive marker for the Q901 response as TP53 wild-type cancer cells demonstrates a significantly increased cytotoxic response compared to TP53 mutant cells in the bioinformatic analysis. In addition, gene expression profiling analysis showed a dose-response increase of POLR2A expression upon Q901 treatment and a correlation with tumor growth inhibition rate, indicating that POLR2A might be a potential PD marker for the Q901-induced response. Taken together, these data support the clinical development of Q901 for solid tumor indications. Q901 is progressing to IND-enabling studies to support the start of Phase 1 oncology clinical trials in early 2022.
Citation Format: Donghoon Yu, Yeejin Jeon, Seung-Joo Lee, Jaeseung Kim, Kiyean Nam. Q901; a highly selective covalent cdk7 inhibitor inducing substantial anti-tumor effect in a broad spectrum of solid tumor lineages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2574.
Abstract 2584: Development of an Fc gamma receptor fully-humanized mouse model to support the accurate preclinical study of therapeutic antibodies
Authors: Zhang Mingkun , Ju Cunxiang , Li Ying , Jiang Yunlong , Yu Weiwei , Li Shuai , Sun Hongyan , Li Zhiying , Zhao Jing , Gao Xiang 
Published: June 2022

Abstract
The Fc gamma receptor (FcγR), a member of the immunoglobulin superfamily, binds the IgG Fc segment of antibodies and is mainly expressed on the surface of immune cell. The FcγR binds to the Fc region of an antibody that is attached to target cells, transmitting an activation or inhibition signal to the FcγR expressing cells, resulting in various biological responses and functions. Many therapeutic antibodies are developed based on the engineering of the Fc region to fine-tune the FcγR mediated effects.
There are four subtypes of mouse FcγRs, including Fcgr1, Fcgr2b, Fcgr3, and Fcgr4. In contrast, human FcγRs consist of at least seven members, including FCGR1A, FCGR1B, FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B. Additionally, the expression pattern of even the orthologous FcγR genes varies between humans and mice. e.g., the distribution of mouse FCGR3 and FCGR2. Therefore, animals harboring the murine FcγRs are not ideal models for the accurate preclinical evaluation of human therapeutic antibodies. To address this problem, we established an FcγRs fully humanized mouse model by injecting an engineered human bacterial artificial chromosome construct carrying all seven human FcγR genes into mouse zygotes. The transgene carriers were mated with another strain in which all mouse FcγR genes were knocked out to establish the colony.
Unlike the endogenous mouse FcγR genes expression profiles, the transgenic human FcγR genes regulated under the control of the human control elements retain the human expression pattern. For example, the transgenic human FCGR3A was observed on mouse NK cells and macrophages, whereas the FCGR3B was detected on mouse neutrophils only, which were consistent with their expression patterns in humans. Antibody-dependent cellular cytotoxicity (ADCC) experiment indicated that a human therapeutic antibody could direct NK cells derived from the FcγRs fully-humanized mice to kill target tumor cells. Moreover, a significant anti-tumor effect could also be achieved by an ADCC based human antibody in tumor-bearing FcγRs humanized mice.
Taken together, the FcγR gene fully-humanized model established in this study demonstrates a human FcγR expression pattern and functionality, thus providing a valuable tool for accurate preclinical evaluation of human therapeutic antibodies.
Citation Format: Mingkun Zhang, Cunxiang Ju, Ying Li, Yunlong Jiang, Weiwei Yu, Shuai Li, Hongyan Sun, Zhiying Li, Jing Zhao, Xiang Gao. Development of an Fc gamma receptor fully-humanized mouse model to support the accurate preclinical study of therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2584.
Abstract 2593: Combined ATR+PARP inhibition exhibits potent synergy in colorectal and pancreatic cancer cytotoxicity
Authors: Ochsner Anna M. , Huntington Kelsey E. , Zhou Lanlan , Carneiro Benedito , El-Deiry Wafik 
Published: June 2022

Abstract
Precision medicine continues to expand treatment options for patients tailored to tumor phenotype. In homologous recombination (HR) deficient cancers like those with BRCA1/2-mutations, inhibition of poly (ADP-ribose) polymerase (PARP) has shown improved mortality compared to older gold standard therapies like DNA damaging agents. Unfortunately estimates upward of 40% of patients develop resistance to PARP inhibitor monotherapy during the course of their treatment. We explored potential synergistic drug combinations to re-sensitize tumors with acquired PARP inhibitor resistance in pancreatic and colorectal cancer. We hypothesized that dual inhibition of the DDR pathway through PARP and Ataxia telangiectasia and Rad3 related (ATR) inhibition would combine synergistically especially in cell lines with existing HR deficiencies through a synthetic lethality-mediated response. The ATR inhibitor Ceralasertib was selected for its potent antagonism of the DDR pathway, a key pathway associated with cell survival through DNA repair. Pancreatic and colorectal cell lines were carefully selected based on their varying mutational profiles to study differences in response to dual treatment. CellTiter-Glo® (CTG) was used after drug treatment to quantify IC-50. CTG synergy and combination indices were used to study drug combinations, and western blotting identified changes in protein expression among key mediators of cell survival and apoptosis. Colony forming assays and cytokine profiling using Luminex technology (and single cell cytokine profiling) were performed to study changes within the tumor microenvironment. We observed strong synergy and cytotoxicity in addition to increased apoptosis and cellular disassembly following treatment with dual ATR+PARP inhibition compared to monotherapy alone. Western Blot showed upregulation of cleaved PARP and cleaved Caspase 8 with combination therapy, and cytokine profiles provided insights into immune-suppressive versus stimulatory TME after drug treatment. There is potent synergy when ATR inhibitors are added to PARPi therapy in the context of pancreatic and colorectal cancers. Ongoing research efforts are further characterizing the mechanisms underlying these observed synergies in the same and additional tumor types such as prostate and ovarian cancer.
Citation Format: Anna M. Ochsner, Kelsey E. Huntington, Lanlan Zhou, Benedito Carneiro, Wafik El-Deiry. Combined ATR+PARP inhibition exhibits potent synergy in colorectal and pancreatic cancer cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2593.
Abstract 2607: Inhibition of HDAC3 induces BRCAness and potent synergy with PARP inhibition in neuroendocrine prostate and small cell lung cancers
Authors: Nagl Stephanie , Devore Kendra , Hirschfeld Gregg , Kotlarczyk Kari , Diaz Damaris , Wang Tong , Murray Maggie , Gonzales Paul , Gately Stephen Thomas 
Published: June 2022

Abstract
HDAC3 is essential for transcriptional repression and is required for the activity of NCOR1 & SMRT co-repressors complexes. Inhibition of HDAC3 results in the suppression of genes responsible for DNA damage repair and maintenance of genomic stability. HDAC3/NCOR1 also play critical roles in tumor metabolism and immune cell biology. GB-3103 is a novel and potent inhibitor of HDAC3 with an IC50 of 0.56nM that was tested for activity against human neuroendocrine prostate (NEPC) and small cell lung cancers (SCLC). RNA-seq analysis of GB-3103 treated human tumor cells revealed induction of BRCAness, inhibition of genes from DNA repair pathways and inhibition of PI3K-AKT1, MYC and p53 signaling. GB-3103 showed potent in vitro anticancer activity against the human H660 NEPC line, with an IC50 of 28nM, and 21nM against the murine PNEC30 line and potent IC50 of 16nM against NCI-H209 human lung neuroendocrine cancer. Because of the potent induction of BRCAness we used zero interaction potency (ZIP) model to test the activity of the combination of GB-3103 with a PARP inhibitor against human H660 and murine PNEC30 cell lines. These experiments revealed synergy for the combination of PARPi with GB-3103 in NEPC. GB-3103 was subsequently tested alone and in combination with olaparib in a xenograft model of H660. GB3103 (TGI=3%) showed minimal activity at the selected dose against H660 compared to single agent olaparib (TGI=67%). However, when combined with olaparib, GB-3103 revealed potent synergy (TGI=96%, p&lt;0.01). In the NCI-H209 human lung neuroendocrine xenograft model, GB-3103 showed robust activity as a single agent (TGI=83%) compared to single agent olaparib (TGI=33%) and single agent talazoparib (TGI=69%). When combined with olaparib, GB-3103 induced synergistic antitumor effect (TGI=99%, p&lt;t0.001) when compared to olaparib treatment alone. When combined with talazoparib, GB-3103 induced synergistic antitumor effect (TGI &gt;100%, p&lt;0.001) when compared to talazoparib treatment alone. Taken together, these data confirm the important role of HDAC3 in neuroendocrine prostate and small cell lung cancers and suggest HDAC3 inhibition by GB-3103 could be an effective approach for patients with neuroendocrine cancers particularly when combined with inhibitors of PARP.
Citation Format: Stephanie Nagl, Kendra Devore, Gregg Hirschfeld, Kari Kotlarczyk, Damaris Diaz, Tong Wang, Maggie Murray, Paul Gonzales, Stephen Thomas Gately. Inhibition of HDAC3 induces BRCAness and potent synergy with PARP inhibition in neuroendocrine prostate and small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2607.
Abstract 2608: Pre-clinical evaluation of small molecule CHK2 inhibitor, ART-122 combined with olaparib in BRCA wild type tumors
Authors: Baik Taegon , Park Chaeun , Kang Young Woo , Joh Danny , Lee Ha-Young , Park Sojung , Hwang Supyong , Kim In Ki , Kim Jong Oh 
Published: June 2022

Abstract
Background: PARP inhibitors are widely used for BRCA-mutant cancers, but often tumors become resistant to PARP inhibitors. The resistance develops through various mechanisms, including BRCA1/2 reversion mutation. Several publications have suggested that CHK2 inhibition could help overcome the resistance to PARP inhibitors. We discovered a novel small molecule CHK2 inhibitor, ART-122, and conducted a series of experiments to explore the rationale for combining a PARP inhibitor and ART-122 to treat the BRCA wild-type ovarian and breast tumors.
Results: In the LanthaScreen࣪ Kinase assay, ART-122 was shown to have the IC50 values of 0.57 nM and 10.85 nM, for CHK2 and CHK1, respectively. We observed the strong synergy between ART-122 and olaparib in the mouse xenograft model using the MDA-MB-231 cancer cells (BRCA1/2 wild type, triple-negative breast cancer cells). Animals were treated with 50 mg/kg olaparib on days 1-5, 30 mg/kg ART-122 on days 1-2 each week for 3 weeks, or both therapies. The result demonstrated approximately 41% reduction in tumor volume in mice treated with the combination therapy compared to the vehicle group. Animals treated with either of the single-agent therapies showed tumor growth similar to the vehicle group. We did not observe apparent toxicity or significant body weight differences among the animals. Additionally, the synergism between ART-122 and olaparib was confirmed in other cancer cell lines, including several BRCA wild-type and BRCA mutant cells lines such as CaOV3, SK-OV-3, UWB1.289, UWB1.289 with BRCA overexpression, HCC1937, MDA-MB-436, and MCF7.
Conclusion: The combination of ART-122 and Olaparib demonstrated a synergistic effect in BRCA wild-type ovarian and breast tumor cell lines. In the mouse xenograft model, the CHK2 inhibitor ART-122 sensitized BRCA1/2 wild-type tumor cells MDA-MB-231 to olaparib treatment. The data provide a strong rationale for the further development of ART-122 as a therapeutic agent.
Citation Format: Taegon Baik, Chaeun Park, Young Woo Kang, Danny Joh, Ha-Young Lee, Sojung Park, Supyong Hwang, In Ki Kim, Jong Oh Kim. Pre-clinical evaluation of small molecule CHK2 inhibitor, ART-122 combined with olaparib in BRCA wild type tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2608.
Abstract 2681: Novel and selective inhibitors of KRASG12D
Authors: Bhavar Prashant Kashinath , Surampudi Uday Kumar , Sarma Partha Pratim , Shidore Mahesh Mohan , Kshirsagar Anuj Ramesh 
Published: June 2022

Abstract
RAS proteins are family of small GTP-binding proteins that play a major role in regulating cellular responses such as proliferation, differentiation, migration, and cell growth. RAS proteins function as molecular switches, cycling between inactive (GDP-bound) and active (GTP-bound) states, which relay cellular signals in response to extracellular stimuli. Aberrant RAS signaling plays a role in up to 30% of all human cancers, with the highest incidence occurring in carcinomas of the pancreas (63–90%), colon (36–50%), and lung (19–30%). Targeting the inactive, GDP bound KRASG12C has been a promising approach for generating novel anti RAS therapies, which is validated by the approval of AMG 510 (Lumakras) by the FDA. It is also known that KRASG12D also retains GTPase activity. Consequently, KRASG12D is one of the most important chemotherapeutic drug targets. KRASG12D is commonly observed in pancreatic cancer. Here we describe preclinical profile of a potent, selective, in-vivo tool compound, VRTX144. VRTX144 was potent in HPAC cell line, representing pancreatic adenocarcinoma, and a panel of KRASG12D mutated cell lines. It was found to be several folds less active in non-KRASG12D mutant cell lines. In vitro combination strategies with other targeted therapies such as EGFR, SHP2 and CDK4/6 inhibitor is also being investigated. VRTX144 exhibited low propensity for metabolism in microsomes, and has high protein bound. VRTX144 was found to have no adverse effect in hERG upto 10 uM.
Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Mahesh Mohan Shidore, Anuj Ramesh Kshirsagar. Novel and selective inhibitors of KRASG12D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2681.