bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2612: Anti-Tigit induces T cell mediated anti-tumor immune response and combines with immune checkpoint inhibitors to enhance strong and long term anti-tumor immunity
Authors: Srivastava Minu K. , Yun Rui , Mayes Erin , Yu Janice , Jie Hyun-Bae , Axelrod Fumiko , Xie Ming-Hong , Monteon Jorge , Lam Andrew , Ji May , Liu Yuwang , Lewicki John , Hoey Tim , Gurney Austin , Park Angie Inkyung 
Published: July 2017

Abstract
TIGIT (T cell immunoreceptor with Ig and ITIM domains) has been recently described as an inhibitory receptor which blocks CD8 T cell-mediated anti-tumor immune responses. We have generated an anti-mouse TIGIT antibody (313R12) to evaluate drug efficacy and mechanism of action in pre-clinical tumor models. Anti-TIGIT as a single agent promoted an anti-tumor immune response in multiple syngeneic mouse tumor models. Anti-TIGIT enhanced tumor specific T cell responses, particularly of the Th1 type and reduced Th2 type responses and also increased the function of cytotoxic T cells. Furthermore, anti-TIGIT displayed combination activity with immune checkpoint inhibitors anti-PD1 and anti-PDL1 in inhibiting tumor growth, promoting complete tumor rejection and significantly increasing mouse survival in the murine CT26 colon carcinoma model as compared to controls and single agents alone. Mice “cured” with anti-TIGIT/anti-PDL1 or anti-TIGIT/anti-PD1 combination treatments did not form tumors upon subsequent re-challenges with increasing number of CT26 tumor cells, suggesting the existence of immunologic memory. IL2 and tumor-specific IFN-γ production by splenic T cells were increased in mice who responded to combination treatment compared to controls. Additionally, both effector and memory CD8+ T cell frequencies were increased within the total CD8+ T cell population in responding mice. We also demonstrated a systemic increase in tumor-specific CD8 T cells after anti-TIGIT/anti-PDL1 combination treatment compared to controls. Therefore, these results suggest that co-targeting of TIGIT and PD1 or PDL1 may be an effective and durable cancer therapy by increasing T cell-mediated anti-tumor immune responses and promoting long-term immunological memory.
Citation Format: Minu K. Srivastava, Rui Yun, Erin Mayes, Janice Yu, Hyun-Bae Jie, Fumiko Axelrod, Ming-Hong Xie, Jorge Monteon, Andrew Lam, May Ji, Yuwang Liu, John Lewicki, Tim Hoey, Austin Gurney, Angie Inkyung Park. Anti-Tigit induces T cell mediated anti-tumor immune response and combines with immune checkpoint inhibitors to enhance strong and long term anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2612. doi:10.1158/1538-7445.AM2017-2612
Abstract 2743: Comparison of enhanced Tagged-Amplicon Sequencing and digital PCR for circulating tumor DNA analysis in advanced breast cancer
Authors: Garcia-Murillas Isaac , Beanney Matthew , Epstein Michael , Howarth Karen , Lawson Andrew , Hrebien Sarah , Green Emma , Rosenfeld Nitzan , Turner Nick 
Published: July 2017

Abstract
Background Circulating tumor DNA (ctDNA) analysis allows non-invasive detection of tumor mutations and amplifications in advanced breast cancer. Multiple technologies have been developed to analyse ctDNA and here we compared two leading ctDNA detection technologies, enhanced Tagged-Amplicon Sequencing™ (eTAm-Seq™) and digital PCR (dPCR) assays, in advanced breast cancer.
Methods We recruited a cohort of 35 women with advanced breast cancer, of whom 23 had two separate blood samples taken in a standard EDTA tube processed immediately or in preservative Streck tubes processed up to 120 hours after venipuncture. Digital PCR was conducted with assays for hotspot actionable mutations in 3 known drivers in breast cancer: PIK3CA exon 9 and 20, ESR1 ligand binding domain and AKT1 (c.49G&gt;A; p.E17K), and ctDNA sequencing was conducted with eTAm-Seq method using a 35-gene panel including cancer hotspots, entire coding regions and copy number variants (CNVs).
Results Across both assays, 37 mutations were detected in 35 patients, with PIK3CA mutation in 13 patients (37%), ESR1 mutations in 10 patients (29%), and no AKT1 mutations. ESR1 mutations were polyclonal in 8 patients, with ctDNA eTAm-Seq method revealing substantially more diversity in mutations, with up to 8 individual mutations detected in a patient. There was 96.15% agreement for PIK3CA mutation detection between assays (Kappa 0.89, 95% CI 0.743 to 1.000), 100% agreement for ESR1 mutations (Kappa 1.00, 95% CI 1.000 to 1.000). There was very high correlation in mutation allele frequency between eTAm-Seq and dPCR (r=0.93, 95%CI 0.86 to 0.96, p&lt;0.0001). The sensitivity and specificity for HER2 amplification detection by eTAm-Seq was 100% compared to tumor HER2 status. Comparison of immediate processing and Streck tubes revealed 97.92% agreement (Kappa 0.95, 95% CI 0.868 to 1.000) for mutation calling.
Conclusions This study demonstrates that ctDNA analysis using eTAmSeq and dPCR have very high agreement in mutation detection in patients with advanced breast cancer patients. Streck tubes present a robust alternative to immediate processing of samples. eTAm-Seq and digital PCR have high clinical validity in mutation detection.
Citation Format: Isaac Garcia-Murillas, Matthew Beanney, Michael Epstein, Karen Howarth, Andrew Lawson, Sarah Hrebien, Emma Green, Nitzan Rosenfeld, Nick Turner. Comparison of enhanced Tagged-Amplicon Sequencing and digital PCR for circulating tumor DNA analysis in advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2743. doi:10.1158/1538-7445.AM2017-2743
Abstract 283: Establishing the predominant type of leukemia among patients attending the Uganda Cancer Institute
Authors: Nsubuga Gerald 
Published: July 2017

Abstract
Introduction: Leukemia is a cancer of white blood cells. It is characterized by an abnormal accumulation of WBC in the bone marrow which leads to bone marrow failure and is manifested in form of anemia and thrombocytopenia. This arises from neoplastic transformation usually of a single cell. There are four common types of leukemia: 1) Acute lymphoblastic leukemia (ALL); 2) Acute myeloblastic leukemia (AML); 3) Chronic lymphocytic leukemia (CLL); and Chronic myeloid/myclocytic leukemia (CML).
Methods: The study was designed to find out the predominant type of leukemia. 80 leukemia cases which comprised of all bone marrow aspirates and peripheral blood slide results with specific age, sex and ward of the patients was analyzed in the hematology laboratory.
Results: The study was revealed that leukemia occurred in following order of types of predominant that is AML 15 (18.75%), CLL 12(15%) and least type was CML 11(13.75%). The result also showed that the most affected age group by all age. Brackets of (01-20) years. From the study a male preponderance (M: F) of 4:3 was found in cases of ALL. The study emphasizes that special staining techniques be adopted in diagnosing and typing of leukemia.
Conclusions: From the results presented, ALL is the predominant type of leukemia affecting children and young adults. AML was found to affect children, young adults, and adults. CLL and CML were found to occur at the same incidence, the elderly (61-70 and 71-80 years). Other types were rare in these age group similarly CLL and CML were rare in children and young adults.
Note: This abstract was not presented at the meeting.
Citation Format: Gerald Nsubuga. Establishing the predominant type of leukemia among patients attending the Uganda Cancer Institute [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 283. doi:10.1158/1538-7445.AM2017-283
Abstract 3023: The antitumor activity of immunotoxins is enhanced by tofacitinib
Authors: Simon Nathan , Antignani Antonella , Hewitt Stephen , Gadina Massimo , Onda Masanori , Alewine Christine , Fitzgerald David Joseph 
Published: July 2017

Abstract
Treatment outcomes of certain aggressive cancers have not improved significantly in the last decade, necessitating development of new therapies. Recombinant immunotoxins (IT) are fusion proteins consisting of the enzymatic domain of a cytotoxin linked to an antibody fragment targeting a cellular surface protein. While the combination of selective targeting and potent cell-killing make ITs well suited for targeted cancer therapy, clinical experience has indicated that patients can generate anti-toxin neutralizing antibodies after one cycle of treatment. Mice treated with the FDA-approved JAK inhibitor, tofacitinib, produced significantly lower anti-toxin antibody titers, suggesting that tofacitinib could be used in combination with immunotoxins to improve therapeutic efficacy. Accordingly, the combination of tofacitinib and IT was tested both in vitro and in vivo using two models of aggressive human cancers: pancreatic ductal adenocarcinoma and triple-negative breast cancer. In vitro combination studies examined the effects on oncogenic signaling pathways and looked for enhancement of cytotoxic potency. Results demonstrated some tofacitinib-mediated inhibition of key signaling pathways but no enhancement of immunotoxin killing. By contrast, when xenograft tumor models were challenged, immunotoxin activity was enhanced greatly by co-treating with tofacitinib. Tofacinib treatments alone did not demonstrate any antitumor activity. The combination of tofacitinib and immunotoxin decreased tumor growth and extended survival compared to either treatment alone. Examination of post-treatment tumor samples and sera from mice indicated that JAK inhibition resulted in alterations of the tumor microenvironment, including a decrease in cancer-promoting cytokine levels and reductions in recruitment of suppressive immune cells to tumor tissue. This study demonstrates that the inhibition of the JAK-STAT pathway can significantly enhance the ability of cytotoxin-based therapeutic agents to elicit anti-tumor effects through alteration of the tumor microenvironment.
Citation Format: Nathan Simon, Antonella Antignani, Stephen Hewitt, Massimo Gadina, Masanori Onda, Christine Alewine, David Joseph Fitzgerald. The antitumor activity of immunotoxins is enhanced by tofacitinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3023. doi:10.1158/1538-7445.AM2017-3023
Abstract 3095: The development of CPI as a novel, next-generation DNA-targeting payload for ADCs
Authors: Kahler Jennifer , Dougher Maureen , Xu Jane , Doroski Matthew , Maderna Andreas , Dushin Russell , Thibault Stephane , Leal Mauricio , Katragadda Madan , O'Donnell Christopher J. , Sung Matthew , Sapra Puja 
Published: July 2017

Abstract
DNA targeting drugs represent one of cornerstones of anti-cancer therapy for both hematologic and solid tumor indications. Low potency anti-DNA compounds (e.g. platins, anthracyclines) are included in many standard-of-care (SOC) regimens, however their modest activity and overall toxicity profiles limit their therapeutic potential. To increase the therapeutic window for DNA-damaging agents, high potency anti-DNA compounds with enhanced anti-tumor activity have been delivered to tumors as payloads of targeting modalities such as antibody-drug conjugates (ADCs). Herein, we describe the development of a novel DNA-damaging compound comprised of a dimeric structure of cyclopropylpyrrolo[e]indolones (CPIs) that was designed to alkylate DNA and generate toxic interstrand crosslinks (ICLs). In response to the CPI-induced formation of ICLs, CPI treatment of cells primarily activates the Fancomia anemia DNA damage response pathway, whereas other successful DNA-damaging ADC payloads such as calicheamicin activate double-strand break response pathways. CPI shows ~860-fold greater potency than calicheamicin in a panel of cell lines derived from a broad spectrum of tumor indications. Importantly, this new CPI payload retains potent activity in calicheamicin- and SOC-resistant tumor models (including overcoming overexpression of drug efflux pumps). When evaluated as payloads on anti-CD33 targeting ADCs, the CPI conjugate showed dramatically improved efficacy over the corresponding calicheamicin conjugates in MDR+ tumor models. As a site-specific conjugate, the CPI ADC shows enhanced in vivo stability and possesses a wider therapeutic window than the corresponding conventional calicheamicin conjugate and other leading DNA-damaging conjugates on the CD33 platform.
Citation Format: Jennifer Kahler, Maureen Dougher, Jane Xu, Matthew Doroski, Andreas Maderna, Russell Dushin, Stephane Thibault, Mauricio Leal, Madan Katragadda, Christopher J. O'Donnell, Matthew Sung, Puja Sapra. The development of CPI as a novel, next-generation DNA-targeting payload for ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3095. doi:10.1158/1538-7445.AM2017-3095
Abstract 3103: Nanoengineered mesenchymal stem cells for targeted lung cancer therapy
Authors: Prabha Swayam , Sadhukha Tanmoy , Layek Buddhadev 
Published: July 2017

Abstract
Solid tumors are characterized by increased interstitial fluid pressure and enhanced solid stress, contributing to poor intra–tumoral penetration of nano drug carriers. This offsets the benefits of enhanced permeation and retention effect often attributed to these drug carriers. We have developed a novel cell based targeting approach using mesenchymal stem cells (MSCs) as cellular drug carriers. MSCs have been indicated in the tumor-targeted therapy owing to their selective ability to home to tumors. Our work is focused on non–genetic modification of MSCs by incorporating nanoparticles loaded with chemotherapeutics to create cellular drug depots capable of homing to tumors and releasing drugs over a sustained period of time. Nano–engineered MSCs were manufactured by incubating MSCs with 100µg/mL of paclitaxel loaded (18.5% w/w paclitaxel) PLGA nanoparticles for 4 hours at 37°C without affecting their viability and migration potential. Anti-cancer efficacy of nano-engineered MSCs was evaluated in the A549 lung tumor model. Bioluminescence imaging was used to monitor tumor growth. Animals that developed tumors (lung bioluminescence between 0.5 x 106 – 1 x 106 photons/sec) were randomly divided into different treatment groups. Animals received 1 million nano-engineered MSCs (equivalent to 5 mg/kg of paclitaxel) or 106 MSCs that were either unmodified or loaded with equivalent concentration of blank nanoparticles. The animals were then re-dosed with half the initial dose of MSCs every two weeks. Additional groups of animals received three doses of 40 mg/kg of nanoparticle-encapsulated or free paclitaxel once every week. Treatment with nano-engineered MSCs resulted in a significant inhibition of the lung tumor growth (p &lt; 0.01) compared to that with other controls. It was interesting to note that despite being dosed at a significantly lower concentration of paclitaxel (~17.5 mg/kg vs. 120 mg/kg total dose), nano-engineered MSCs were significantly more effective than free paclitaxel or paclitaxel nanoparticles, suggesting better delivery to the tumor. The biodistribution studies and pharmacokinetic analysis indicated a rapid migration and enhanced retention of the nano–engineered MSCs to the lung tumors. Our studies demonstrated that nano-engineered MSCs are efficient carriers for tumor-specific drug delivery. Funding: R01EB022558
Citation Format: Swayam Prabha, Tanmoy Sadhukha, Buddhadev Layek. Nanoengineered mesenchymal stem cells for targeted lung cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3103. doi:10.1158/1538-7445.AM2017-3103
Abstract 3143: FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation
Authors: Tong Jingshan , Tan Shuai , Zou Fangdong , Yu Jian , Zhang Lin 
Published: July 2017

Abstract
Colorectal cancer (CRC), the second leading cause of cancer-related deaths in the US, has been treated with targeted therapies. However, the mechanisms of differential responses and resistance of CRCs to targeted therapies are not well understood. In this study, we found that genetic alterations of FBW7, an E3 ubiquitin ligase and a tumor suppressor frequently mutated in CRCs, contribute to resistance to targeted therapies. CRC cells containing FBW7 inactivating mutations are insensitive to clinically used multi-kinase inhibitors of RAS/RAF/MEK/ERK signaling, including regorafenib and sorafenib. In contrast, sensitivity to these agents is not affected by oncogenic mutations in KRAS, BRAF, PIK3CA, or p53. These cells are defective in apoptosis due to blocked degradation of Mcl-1, a pro-survival Bcl-2 family protein. Deleting FBW7 in FBW7-wild-type CRC cells abolishes Mcl-1 degradation and recapitulates the in vitro and in vivo drug resistance phenotypes of FBW7-mutant cells. CRC cells selected for regorafenib resistance have progressive enrichment of pre-existing FBW7 hotspot mutations, and are cross-resistant to other targeted drugs that induce Mcl-1 degradation. Furthermore, a selective Mcl-1 inhibitor restores regorafenib sensitivity in CRC cells with intrinsic or acquired resistance. Together, our results demonstrate FBW7 mutational status as a key genetic determinant of CRC response to targeted therapies, and Mcl-1 as an attractive therapeutic target.
Citation Format: Jingshan Tong, Shuai Tan, Fangdong Zou, Jian Yu, Lin Zhang. FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3143. doi:10.1158/1538-7445.AM2017-3143
Abstract 3144: Prediction of ALK mutations associated with acquired resistance to lorlatinib
Authors: Yoda Satoshi , Dardaei Leila , Singh Manrose , Engelman Jeffrey A. , Shaw Alice T. , Hata Aaron N. 
Published: July 2017

Abstract
Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non-small cell lung cancer. They are currently treated with the first-generation ALK inhibitor crizotnib followed by more potent, second-generation ALK inhibitors, such as ceritinib, alectinib, or brigatinib. We reported different spectrums of ALK resistance mutations in the biopsies from patients progressing on these drugs. G1202R mutation was found more frequently after treatment with second generation ALK inhibitors. In addition to these drugs, the third-generation ALK inhibitor lorlatinib is currently being evaluated in phase 2 clinical trial. Ba/F3 models indicated that all single ALK mutants are sensitive to lorlatinib and some compound ALK mutations are resistant to lorlatinib. In this study, we performed accelerated mutagenesis screen on Ba/F3 models to predict the resistance mutations which potentially emerge in the patients treated with lorlatinib. Briefly, Ba/F3 cells expressing wild type EML4-ALK or mutant EML4-ALK containing C1156Y, F1174C, L1196M, G1202R, or G1269A were exposed to N-ethyl-N-nitrosourea (ENU). After a 24-hour incubation in normal media, the cells were seeded in 96-well plates and incubated in lorlatinib for 4 weeks. ALK kinase domain was sequenced in clones growing in lorlatinib to identify possible new mutations. As a result, Ba/F3 cells harboring wild type EML4-ALK did not show any mutation on ALK kinase domain. Crizotinib was used as a control to validate the efficiency of mutagenesis. We identified eight different mutations in clones growing in crizotinib, and those were reflecting the spectrum of mutations in the crizotinib-treated patients. Ba/F3 cells with mutant EML4-ALK showed additional compound mutations after incubation with lorlatinib. Those mutations included L1196M + L1198F and G1202R + L1198F which showed high resistance to lorlatinib in Ba/F3 models. Ba/F3 cells with different mutant EML4-ALK showed a distinct spectrum and different frequency of additional mutations. In conclusion, this study predicted that no single mutation would emerge to confer resistance to lorlatinib. Thus, compound mutations and ALK-independent mechanisms become essential mechanisms for lorlatinib resistance.
Citation Format: Satoshi Yoda, Leila Dardaei, Manrose Singh, Jeffrey A. Engelman, Alice T. Shaw, Aaron N. Hata. Prediction of ALK mutations associated with acquired resistance to lorlatinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3144. doi:10.1158/1538-7445.AM2017-3144
Abstract 3148: Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer
Authors: Yoshida Ryohei , Sasaki Takaaki , Okumura Shunsuke , Ohsaki Yoshinobu 
Published: July 2017

Abstract
Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in around 3%-5% non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, Crizotinib, and recently the more highly potent Alectinib and Ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines. Src signaling was identified as an Alectinib resistance mechanism, and combination treatment with ALK and Src inhibitors was highly effective for inhibiting the growth of ALK inhibitor resistant cells in vitro and in mouse xenograft models. Furthermore, phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling was effectively blocked by inhibiting Src in Alectinib resistant cells. Finally, we showed that the combined use of ALK and Src inhibitors inhibited the growth of other ALK-NSCLC cell lines, including those that were Ceritinib or Lorlatinib resistant. Our data suggest that targeting Src signaling may be an effective approach to the treatment of ALK–NSCLC with acquired resistance to ALK inhibitors.
Citation Format: Ryohei Yoshida, Takaaki Sasaki, Shunsuke Okumura, Yoshinobu Ohsaki. Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3148. doi:10.1158/1538-7445.AM2017-3148