bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4882: Identification and optimization of chemical inhibitors that directly target KRAS G12D mutant
Authors: Tian Xiaohong , Geng Guoyan , Wu Jian Hui 
Published: August 2018

Abstract
KRAS mutations are enriched in three lethal cancers, such as pancreatic ductal adenocarcinoma (PDAC) (&gt; 90% of cases), colorectal cancer (CRC) (~50%) and lung cancer (~25%). Within these cancers, specific KRAS mutations dominate. KRAS G12D is the most common mutation in pancreatic and colorectal cancer. To date, accumulating studies have firmly established that constitutive activation of KRAS mutants is a driver of PDAC and CRC. Inhibitors of the downstream components of KRAS signaling only have limited success. Due to the high affinity of KRAS with GTP and no other obvious binding pocket on the KRAS surface for the design of inhibitors, KRAS has been considered ‘undruggable' for a long period of time. As a breakthrough, a novel direct inhibitor of the KRASG12C mutant was discovered in 2013, which forms a covalent bond with the cysteine at residue 12. However, such KRASG12C inhibitor is inactive against the G12D mutant as there is no Cysteine at residue 12. In this project, we have learnt from the excellent work of the G12C inhibitors and identified a novel compound as a direct inhibitor of the KRASG12D mutant. Importantly, this compound is active against the G12D mutant, but inactive against the KRAR wild-type. We demonstrated that our compound at 10 uM significantly inhibits the KRAS signaling in PANC10.05 pancreatic cancer cells and SNU-C2B colorectal cancer cells, both of which express endogenous KRASG12D mutant.
Citation Format: Xiaohong Tian, Guoyan Geng, Jian Hui Wu. Identification and optimization of chemical inhibitors that directly target KRAS G12D mutant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4882.
Abstract 4897: An acquired vulnerability of drug resistant melanoma with therapeutic potential
Authors: Oliveira Rodrigo Leite de 
Published: August 2018

Abstract
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance, which is frequently caused by reactivation of the Mitogen Activated Protein Kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor (HDACi) vorinostat represses SLC7A11 that leads to a lethal increase in the already elevated levels of ROS in drug-resistant cells, thereby causing selective apoptotic death of only the drug resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with HDACi in mice results in a dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor resistant melanoma, we find that HDACi can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.
Citation Format: Rodrigo Leite de Oliveira. An acquired vulnerability of drug resistant melanoma with therapeutic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4897.
Abstract 4899: Establishment and characterization of SN-38 resistant metastatic colorectal cancer cells (SW620/SN100) reveals an ABCG2 (BCRP) transport mediated resistance
Authors: Barbuti Anna Maria , Chen Zhe-Sheng 
Published: August 2018

Abstract
Despite advances in anticancer drug research, chemotherapy options and response rates for metastatic colorectal cancer (mCRC) are poor. Irinotecan, a topoisomerase I inhibitor, is a commonly used chemotherapy against mCRC as a single agent, or in combination with other anti-cancer drugs such as fluorouracil and leucovorin. However, acquired resistance to chemotherapy, especially in metastatic patients, is a critical cause of treatment failure.
Multi-drug resistance (MDR) in cancer is a major challenge to chemotherapy success. Mechanisms of MDR involve deliberate alteration in cellular expression, function, and/or responses of the cancer. One of the most notable mechanism of MDR is an increased cellular drug efflux through up-regulation of membrane ATP-binding cassette (ABC) transporters.
To investigate a new and clinically relevant mechanism of MDR in mCRC cells, SN-38 (the potent and active metabolite of irinotecan) was regularly administered to SW620 cells with drug-free intervals to reflect a drug induced resistance to treatment. Through cytotoxicity and western blotting assays on the newly formed SW620/SN100 cells, we discovered ABCG2 (BCRP) to be the main mechanism of SN-38 resistance, with no alterations in the topoisomerase I, ABCB1 (P-gp) or ABCC1 (MRP1). These results confirmed our initial hypothesis, given SN-38 is a known substrate of ABCG2. This discovery of SN-38 induced efflux in mCRC is of a larger importance because this mechanism not only limits the efficacy of the chemotherapy, but also poses a threat to the efficacy of a variety of pharmacologically dissimilar drugs which are substrates of ABCG2.
As treatments for mCRC continue to be investigated it is important to also continue investigating resistant mechanisms of these drugs. More discoveries of MDR mechanisms which are specific to cancer patient populations will offer superior diagnosis, proper treatment regimens and greater prognosis for patient success.
Citation Format: Anna Maria Barbuti, Zhe-Sheng Chen. Establishment and characterization of SN-38 resistant metastatic colorectal cancer cells (SW620/SN100) reveals an ABCG2 (BCRP) transport mediated resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4899.
Abstract 4903: AXL inhibition overcomes erlotinib resistance in AXL-activated non-small cell lung cancer cells
Authors: Wang Feng 
Published: August 2018

Abstract
Mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) are present in 10-35% patients with NSCLC. In patients with EGFR-mutated NSCLC, EGFR tyrosine kinase inhibitors, including erlotinib, have demonstrated excellent initial responses. However, despite improved outcomes observed in patients treated with EGFR TKIs, most patients eventually develop drug resistance. We and others recently demonstrated that the activation of oncogene AXL is necessary to confers erlotinib resistance in both cell and mouse models as well as in human tumor tissues. While genetic aberrations affecting AXL appear rare, we recently identified two patients with EGFR-mutated lung cancer who simultaneously harbor AXL A273V or AXL V289M mutation. Both patients were resistant to erlotinib treatment (one case of primary and one case of acquired resistance). In this study, we first evaluated whether these AXL mutations conferred resistance to erlotinib treatment. Using HCC827 and PC-9 NSCLC cell lines stably expressing the AXL A273V or V289M mutation, we confirmed that AXL A273V significantly increased resistance to erlotinib treatment. Subsequently we also conducted a preclinical study to test if a new AXL inhibitor MGCD265 could overcome such erlotinib resistance in NSCLC cells. Using an in vitro MTS assay, we first validated that administration of MGCD265 in combination with erlotinib significantly inhibited the viability of erlotinib-resistant HCC827-ER cells, compared to erlotinib- or MGCD265-alone treatment. Through conducting an array of cell functional studies, we found that combination of MGCD265 and erlotinib significantly decreased cell cycle progression in S phase, enhanced apoptosis, and repressed cell migration relative to single-agent erlotinib or MGCD265 treatment in HCC827-ER cells. We further performed RNA-sequencing to evaluate the gene expression profile and the cellular pathways altered in cells treated with erlotinib alone, MGCD265 alone or a combination of erlotinib and MGCD265. RNA-sequencing analysis identified that several groups of genes involved in cell survival inhibition or apoptosis promotion were upregulated, whereas genes involved in cell cycle process, DNA replication or cancer metabolism were downregulated in cells treated with the combination of erlotinib and MGCD265. Taken together, our results indicated that AXL mutations may confer resistance to EGFR TKI treatment, and effective blockade of the AXL pathway may represent a novel strategy to overcome erlotinib resistance for the treatment of NSCLC patients.
Citation Format: Feng Wang. AXL inhibition overcomes erlotinib resistance in AXL-activated non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4903.
Abstract 4917: Tipifarnib is highly active in HRAS mutant lung squamous carcinoma tumor models
Authors: Kessler Linda , Scholz Catherine , Gualberto Antonio , Liu Yi , Burrows Francis 
Published: August 2018

Abstract
Genomic profiling of squamous tumors has revealed important similarities between lung squamous cell carcinoma (LSCC) and head and neck squamous cell carcinoma (HNSCC). For instance, HRAS is the most commonly mutated RAS species in both LSCC and HNSCC, observed in approximately 2% and 5% of cases, respectively (TCGA, Nature 2013). Tipifarnib is a potent and selective inhibitor of farnesyltransferase (FT) that catalyzes the post-translational attachment of farnesyl groups to proteins that require localization to the inner cell membrane. Although all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. With limited treatment options, LSCC and HNSCC remain a significant unmet medical need. Recent evidence supports the clinical utility of tipifarnib for treatment of patients with HRAS-mutant HNSCC, and we present herein data supporting a potential utility of tipifarnib in the treatment of HRAS-mutant LSCC. We have characterized the antitumor activity of tipifarnib in CDX and PDX models of squamous cell carcinoma with activating HRAS mutations. Tipifarnib displayed robust antitumor activity in the majority of these models, including lung and head and neck tumors. Six of seven HRAS-mutant lung SCC PDX models responded to tipifarnib treatment with the majority either fully growth-inhibited or undergoing partial or complete regression. Importantly, even LSCC PDX tumors resistant to chemotherapy responded to tipifarnib, suggesting tipifarnib has the potential to offer clinical benefit in patients relapsed or refractory to standard therapies. The activity of tipifarnib in LSCC models is quite similar to that seen in HNSCC PDX models, where tipifarnib also induced regressions consistent with those observed in patients enrolled in the ongoing Phase 2 study in HRAS-mutant SCCHN patients (NCT02383927), including patients refractory to chemotherapy, cetuximab and/or immunotherapy. These data demonstrate that HRAS is a targetable mutation in lung SCC as well as in HNSCC and illustrate the potential for tipifarnib in the treatment of additional HRAS-mutant squamous cell carcinomas.
Citation Format: Linda Kessler, Catherine Scholz, Antonio Gualberto, Yi Liu, Francis Burrows. Tipifarnib is highly active in HRAS mutant lung squamous carcinoma tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4917.
Abstract 4918: Pharmacokinetics and toxicity studies of AT1965, a B-cell activating immunotherapy
Authors: Sengupta Aniruddha , Samarla Mallik , Pandey Manoj , Sarkar Arindam , Roy Monideepa , Sengupta Shiladitya 
Published: August 2018

Abstract
Introduction: Cancer immunotherapy is the emerging paradigm in the search for a cure for cancer. AT1965 is a novel therapeutic that demonstrates remarkable anti-tumor activity across different preclinical tumor models, mediated through the activation of B-cells. In this study, we have evaluated the metabolism, pharmacokinetics (PK) and toxicity of AT1965 in rodent and non-rodent species.
Methods: AT1965 metabolism was studied in rodent, canine and primate liver microsomes. The PK of AT1965 was determined in 4T1 tumor bearing female Balb/c mice; female Sprague Dawley rats and female Beagle dogs at a variety of doses and schedules following single intravenous (i.v) injections. The extent and duration of the exposure was monitored over 120 hours in mice and rats, and till 192 hours in dogs, post dosing. Concentrations of AT1965 in plasma samples were determined either by LC-MS/MS or Atomic Absorption Spectroscopy. The toxicity of AT1965 in male and female Sprague Dawley Rats following single dose i.v. administration of 43.7, 87.4 and 174.8 mg/kg dosage of AT1965 were examined. During toxicity studies, clinical health status was observed daily for 14 days after treatment, followed by necropsy.
Results: AT1965 metabolism evaluated in mouse, rat, dog, monkey and human liver microsomes indicated high stability across all species. PK studies reveal that AT1965 exhibited a high exposure, slow systemic clearance and a proportional increase in dose normalized exposure across species. The elimination half-life (T1/2) varied from 34-40 hours in tumor-bearing mice to 29-44 hours in rats and ~ 66 hours in dogs. The excretion of AT1965 was predominantly through hepatobiliary route, with minimal renal clearance. Single i.v. administered acute dose toxicity studies for AT1965 reveal 87.4 mg/kg and 174.8 mg/kg as MTD and toxic doses respectively in rats.
Conclusion: The excellent pharmacokinetic profile of AT1965 showing high exposure and enhanced elimination half-life tested across species, in addition to striking antitumor activity coupled with low toxicity in multiple rodent tumor models, provide a compelling rationale for the development of AT1965 as a novel immunotherapeutic agent in the clinic.
Citation Format: Aniruddha Sengupta, Mallik Samarla, Manoj Pandey, Arindam Sarkar, Monideepa Roy, Shiladitya Sengupta. Pharmacokinetics and toxicity studies of AT1965, a B-cell activating immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4918.
Abstract 4930: Epicatechin alleviates DOX-induced cardiovascular toxicity and improves its cytotoxic profile against breast cancer cells
Authors: Alshehri Ohoud Y. , Alabbasi Fahad A. , Mahmoud Islam F. , Abu-Sharib Alaa T. , El-Bassossy Hany M. , Abdallah Hossam A. , Al-Abd Ahmed M. 
Published: August 2018

Abstract
Epicatechin (EPI) has a well known and robust antioxidant properties which could alleviate drug-induced cardiovascular toxicities. On the other side, Doxorubicin (DOX) is a cornerstone anticancer drug used to treat breast cancer. However, DOX-induced cardiovascular complications might limit its treatment course continuation. Herein, we evaluated cardiovascular protective effects of EPI against DOX in-vivo and ex-vivo using isolated aortic ring preparation; meanwhile we assessed the potential ameliorating effects of EPI against DOX-induced cytotoxicity in breast cancer cells. Animals were given DOX (12 mg/kg, single IV injection) which induced cardiac ischemia appeared as increased QT and QTc intervals (1.8 folds for both). EPI (12 mg/kg, orally for 6 days) completely aborted DOX-induced cardiac ischemia and corrected all ECG abnormalities. Using isolated aortic ring preparation, DOX (10µM) impaired aortic ring vasodilatation and induced excessive vasoconstriction. Co-incubation of EPI (10µM) with DOX (10µM) entirely blocked DOX-induced impaired aortic ring vasodilatation, without affecting DOX-induced elevated vasoconstriction. EPI (10µM) combination with DOX in MDA-MB-231, MCF7 and T47D breast cancer cells significantly decreased the IC50‘s from 70.0±17.3 to 44.0±14.0 nM, from 554.0±30 to 240.0±10.0 nM and from 700.0±36.0 to 561.0±170 nM, respectively. Under hypoxic condition, EPI (10µM) significantly increased DOX cytotoxicity against MCF-7 cells and decreased its IC50 from 8.9±1.2 to 6.1±1.9 μM. This effect could be partially attributed to the inhibitory effect of EPI to P-glycoprotein (P-gp) and related efflux protein which would enhance DOX intracellular concentration. EPI increased the intracellular accumulation of rhodamine (P-gp probe) within MDA-MB-231 cells by 3-4 folds at concentration range from 3 to 100 μM. Moreover, EPI combination with DOX significantly increased cell apoptosis and necrosis assessed by annexin-V/FITC. However, EPI did not influence DOX effect on cell cycle distribution. In conclusion, EPI possesses potential cardiovascular protective effects against DOX. Meanwhile, EPI does not interfere with DOX-induced cytotoxic profile against breast cancer cells.
Citation Format: Ohoud Y. Alshehri, Fahad A. Alabbasi, Islam F. Mahmoud, Alaa T. Abu-Sharib, Hany M. El-Bassossy, Hossam A. Abdallah, Ahmed M. Al-Abd. Epicatechin alleviates DOX-induced cardiovascular toxicity and improves its cytotoxic profile against breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4930.
Abstract 4932: Neuro-endocrine negative SCLC is mostly RB1 WT and may be sensitive to CDK4/6 inhibition, especially if CCND1 is amplified
Authors: Sonkin Dmitriy , Thomas Anish , Teicher Beverly A. 
Published: August 2018

Abstract
Background: Small cell lung cancer (SCLC) is an aggressive form of lung cancer with limited therapeutic options, a very high mortality rate and is characterized, in most cases, by neuroendocrine features. A small but important subset of SCLC has intact RB1, however, other characteristics of this subset are not well-defined. Here we aim to characterize underlying genomics of SCLC cell lines with functional RB1.
Methods: To comprehensively assess the underlying genomics of SCLC cell lines with functional RB1, we examined 52 SCLC cell lines from the Cancer Cell Line Encyclopedia (CCLE) collection. We also integrated CCLE SCLC genomics data with drug sensitivity data from NCI SCLC screen of 420 approved and investigational oncology drugs.
Results: Out of 7 neuro-endocrine lineage marker-negative SCLC lines, 6 were RB1 WT. Out of 42 neuro-endocrine lineage marker-positive SCLC cell lines, 3 were RB1 WT. Two RB1 WT SCLC cell lines with CCND1 amplification were sensitive to CDK4/6 inhibitor. Oncogenic alterations in genes such as KRAS, NRAS, SMARCA4, and CDKN2A are rare in SCLC; however, these genes were altered in 7 of 9 RB1 WT SCLC cell lines.
Conclusions: Neuro-endocrine lineage marker-negative SCLC are enriched for RB1 WT and may be sensitive to CDK4/6 inhibition especially in context of CCND1 amplification. Neuro-endocrine lineage marker-negative SCLC cell lines are associated with low DLL3 expression. Therefore, RB1 WT SCLC are less likely to respond to DLL3 targeted drugs. However, this may present the opportunity to identify patients with WT RB1 among patients screened for DLL3 ADC clinical trials and having no or very low DLL3 expression.
Citation Format: Dmitriy Sonkin, Anish Thomas, Beverly A. Teicher. Neuro-endocrine negative SCLC is mostly RB1 WT and may be sensitive to CDK4/6 inhibition, especially if CCND1 is amplified [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4932.
Abstract 4964: Metabolically activated macrophages mediate obesity-driven TNBC progression
Authors: Tiwari Payal , Blank Ariane , Cui Chang , Schoenfelt Kelly , Khan Seema A. , Rosner Marsha R. , Becker Lev 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) patients have the poor prognosis due to their high metastatic potential and lack of targeted therapies. Emerging epidemiological data suggest that obesity is associated with increased incidence of more aggressive triple-negative breast cancer; however, mechanisms are unclear. During obesity, adipocytes within breast tissues recruit macrophages. M2-like macrophages can exacerbate TNBC progression; however, obese breast tissue is reported to be enriched with M1-like adipose tissue macrophages (ATMs), which are anti-tumorigenic. These results raise a paradox: how does obesity promote tumor progression if it activates an anti-tumorigenic macrophage phenotype?
Here we show that obesity promotes a distinct pro-inflammatory phenotype (metabolically activated macrophages; MMe) in breast ATMs, which promotes TNBC progression. We showed that ATMs isolated from obese women express cell surface markers of MMe (CD36, ABCA1) but not M1 (CD38, CD319) macrophages. We further found that pretreating TNBC cells with MMe (but not M1) derived conditioned media increase tumorsphere growth, and frequency of tumor-incidence when injected into mice in limited dilutions. Remarkably, we saw the same effect with obesity on tumor-incidence in both spontaneous and syngeneic TNBC mouse models. Moreover, blocking cytokine expression specifically in MMe using myeloid specific genetic knockout mice diminishes the effect of obesity on tumor-incidence. Interestingly, a subset of these MMe-secreted cytokines shared a common signal transducer, gp130, which led us to investigate the role of gp130 in tumors. Knocking down gp130 in cancer cells inhibits the MMe-induced stat-3 phosphorylation and tumorsphere growth in vitro, and diminishes the MMe-mediated effect of obesity on tumor-incidence in mice. Together these findings suggest that obesity-induced metabolically activated macrophages (MMe) in breast adipose tissue secrete inflammatory cytokines that promotes the TNBC tumor-progression by activating gp130 in cancer cells.
A comprehensive understanding of the signaling mechanism(s) involved in metabolic activation of mammary ATMs would enable development of targeted therapies towards this specific pro-tumorigenic macrophage phenotype, thereby leaving the immune system of cancer patients intact.
Citation Format: Payal Tiwari, Ariane Blank, Chang Cui, Kelly Schoenfelt, Seema A. Khan, Marsha R. Rosner, Lev Becker. Metabolically activated macrophages mediate obesity-driven TNBC progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4964.