bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-113: Immune-mediated anti-tumor activity with a clinical stage BET bromodomain inhibitor ODM-207 in pre-clinical models
Authors: Deshpande Pratima , Babu Ravi Krishna , Vadnal Prashant Yallappa , Jaleel Mahaboobi , Ramachandra Murali , Abbineni Chandrasekhar , Samajdar Susanta , Moilanen Anu-Maarit , Kallio Pekka 
Published: July 2017

Abstract
Background: ODM-207 is a potent and selective BET inhibitor that is structurally unrelated to the benzodiazepine-based inhibitors including JQ1, I-BET762, and OTX015. Phase I clinical trials have now been initiated with this agent based on its potent anti-tumor activity in various in vitro and in vivo models of hematologic malignancies and solid tumors. In view of the recent publications implicating a role for BET protein BRD4 in the suppression of PD-L1 expression, an immune checkpoint ligand for PD-1, we sought to evaluate ODM-207 for its effect on immune-mediated anti-tumor efficacy in pre-clinical models.
Methods and Results: Mouse splenocytes were stimulated with anti-CD3 and anti-CD28 in the presence or absence of ODM-207 for four days and changes in immune cell population were analyzed by FACS. Results revealed an increase in the level of activated cytotoxic CD8+ T cells as indicated by increased intracellular IFNγ and granzyme B with ODM-207 treatment. After confirming the lack of direct anti-proliferative activity on the mouse colon carcinoma cell line CT26, in vivo evaluation of ODM-207 was carried out in the syngeneic CT26 subcutaneous tumor model established in BALB/c mice. Daily oral administration of ODM-207 at 30 mg/kg was well tolerated in this model and resulted in a statistically significant inhibition of tumor growth. Interestingly, the tumor growth inhibition observed with ODM-207 was comparable to that with a commercially available anti-mouse PD1 antibody. Studies to characterize the immune changes in the tumor and anti-tumor activity of ODM-207 in combination with an anti-mouse PD1 antibody are currently underway and the results will be presented.
Conclusions: In summary, these studies demonstrate the anti-tumor activity of BET inhibitor in a syngeneic model of colon carcinoma in the absence of a direct anti-proliferative activity on tumor cells. Observed tumor growth inhibition correlated with the in vitro activation of cytotoxic CD8+ T cells supporting the immune-mediated effect leading to tumor growth inhibition. In view of the remarkable success with the immune-based therapeutic approaches, these findings are relevant in devising appropriate strategies for the continued clinical development of ODM-207.
Citation Format: Pratima Deshpande, Ravi Krishna Babu, Prashant Yallappa Vadnal, Mahaboobi Jaleel, Murali Ramachandra, Chandrasekhar Abbineni, Susanta Samajdar, Anu-Maarit Moilanen, Pekka Kallio. Immune-mediated anti-tumor activity with a clinical stage BET bromodomain inhibitor ODM-207 in pre-clinical models [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 LB-113. doi:10.1158/1538-7445.AM2017-LB-113
Abstract LB-115: TPRKB dependency in p53-deficient cancers
Authors: VanDenBerg Kelly , Goswami Moloy , Wang Lei Lucy , Singh Bhavneet , Weiss Travis , Han Sumin , Rhodes Dan , Feng Felix , Tomlins Scott 
Published: July 2017

Abstract
TP53 (p53) is an extensively studied tumor suppressor mutated in approximately 50% of all cancers. Identification of vulnerabilities imposed by p53 alterations may enable effective targeted therapy development. Thus, this study aimed to identify and characterize novel vulnerabilities in this context. Through analyzing shRNA screening data from the Broad Institute’s Project Achilles, we identified TPRKB, a poorly characterized member of the tRNA-modifying EKC/KEOPS complex, as the most significant vulnerability in p53 mutated cancer cell lines. In vitro, across multiple benign-immortalized and cancer cell lines, we confirmed that TPRKB knockdown in p53-deficient cells significantly inhibited proliferation, while there was little to no effect in p53 wild-type cells. Furthermore, p53 reintroduction into TPRKB-sensitive p53-null cells resulted in loss of TPRKB sensitivity, confirming the importance of p53 status in this context. To determine whether this response was unique to TPRKB or a result of impairment of the EKC/KEOPS complex, we knocked down other members of the complex: PRPK, OSGEP, and LAGE3. PRPK loss showed minor changes between p53 wild type versus deficient cells; while OSGEP and LAGE3 loss resulted in a significant decrease regardless of p53 status. For the first time, we have demonstrated a potential role for TPRKB in cancer, and our results suggest that effects of TPRKB knockdown in p53-deficient cancer cells may be independent of its role in the EKC/KEOPS complex.
Citation Format: Kelly VanDenBerg, Moloy Goswami, Lei Lucy Wang, Bhavneet Singh, Travis Weiss, Sumin Han, Dan Rhodes, Felix Feng, Scott Tomlins. TPRKB dependency in p53-deficient cancers [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 LB-115. doi:10.1158/1538-7445.AM2017-LB-115
Abstract LB-121: ACK in BRAF inhibitor resistance
Authors: Ji Zhenyu , Tsao Hensin , Hannes Mikula , Njauw Jenny , Kumar Raj 
Published: July 2017

Abstract
BRAF inhibition by the small-molecule drug vemurafenib or dabrafenib achieves enormous success in the treatment of melanoma. However, melanoma patients lose their responsiveness after 6 months of treatment. Activation of receptor tyrosine kinase (RTK) was found in vemurafenib resistant melanomas and considered as a critical factor contributing to vemurafenib resistance. We hypothesize that the quick relapse after BRAFi therapy is at least partly due to the off targets of these drugs. Using trans-cyclooctene(TCO) moiety conjugated vemurafenib to treat melanoma cells in culture, we were able to confirm that ACK is a bona-fide intracellular target of vemurafenib. ACK, a protein kinase that regulates turnover of EGFR and other RTKs, was then identified to be downregulated in melanoma cells after short term vemurafenib treatment. Furthermore, ACK protein was reduced in multiple vemurafenib resistant melanoma cells. To prove ACK downregulation plays a role in vemurafenib resistance development, we knocked down ACK by shRNA. We found that ACK reduction delays EGFR degradation speed and increases EGFR protein expression. Since EGFR overexpression has been demonstrated as one important driver of vemurafenib resistance, we expected ACK reduction by shRNA would lead to BRAFi resistance, which was then confirmed by viability assay. During the development of BRAFi resistance, MITF is lost, which is accompanied by overexpression of growth factors and cytokines. We proved that higher resistance to vemurafenib can be induced by combination of ACK reduction and addition of EGFR ligands and cytokines. Our data suggest that EGFR activation in vemurafenib resistant melanoma is mediated by a combination of ACK and MITF downregulation, which lead to RTK and growth factor/cytokine upregulation. ACK binding and downregulation by BRAFi might be the first step toward resistance and a loophole inherent in these compounds themselves. Thus, optimizing BRAFi to ensure more selectivity should be a critical step further to improve the long-term benefits of this class of drugs.
Note: This abstract was not presented at the meeting.
Citation Format: Zhenyu Ji, Hensin Tsao, Mikula Hannes, Jenny Njauw, Raj Kumar. ACK in BRAF inhibitor resistance [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 LB-121. doi:10.1158/1538-7445.AM2017-LB-121
Abstract LB-123: Identification of the molecular mechanisms of resistance to NTRK inhibitors and the potential therapeutic strategies in NTRK1-rearranged cancers
Authors: Katayama Ryohei , Fuse Miho J. , Oh-hara Tomoko , Ogura Hayato , Fujita Naoya 
Published: July 2017

Abstract
Neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangement leads to constitutive activation of NTRK1, which induces high transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non-small-cell lung cancer, and colorectal cancer. Although there are currently no clinically available inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKIs), such as entrectinib and LOXO-101, are in clinical trials. To identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance, we examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Then, acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea (ENU) mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. After identifying the resistance mechanisms, we performed drug screening with small-molecular inhibitors to overcome the resistance. As the results, we identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R. As a result of drug screening, we found that cabozantinib and a few TKIs effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants, both of which showed resistance to entrectinib or LOXO101. Furthermore, cabozantinib with an insulin growth factor receptor type 1 (IGF1R) inhibitor such as OSI906 could overcome bypass pathway-mediated resistance. Thus, in this study, we developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement. In addition, we found drugs and a combination therapy to overcome the identified resistance to NTRK1-TKI.
Citation Format: Ryohei Katayama, Miho J. Fuse, Tomoko Oh-hara, Hayato Ogura, Naoya Fujita. Identification of the molecular mechanisms of resistance to NTRK inhibitors and the potential therapeutic strategies in NTRK1-rearranged cancers [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 LB-123. doi:10.1158/1538-7445.AM2017-LB-123
Abstract LB-124: COP1 E3 ligase modulates response to oncogenic MAPK pathway inhibition
Authors: Mayekar Manasi K. , Bivona Trever 
Published: July 2017

Abstract
Oncogenic activation of the RAS-MAPK pathway is the underlying cause of the majority of lung adenocarcinomas. In these tumors, RAS-MAPK pathway activation occurs via diverse genetic alterations in upstream receptor tyrosine kinases such as EGFR and ALK as well as in RAS, BRAF, MEK and RAS GTPase activating protein (GAP) and tumor suppressor, NF1. Therapies targeting components of the RAS-MAPK pathway can lead to initial tumor responses in many patients. But most patients show only a partial response and many do not respond at all despite the presence of a RAS-MAPK pathway-activating genetic lesion in the tumor. Hence, it is critical to understand the molecular basis of response and resistance to targeted therapies acting against the RAS-MAPK pathway in lung adenocarcinomas in order to improve patient survival. We conducted a genetic screen to identify modifiers of response to MAPK pathway inhibition in lung cancer. Our genetic screen uncovered the E3 ubiquitin ligase COP1/RFWD2 as a novel genetic modifier. We found that depletion of COP1 and members of its complex, as well proteasomal subunits, confers resistance to RAS-MAPK pathway inhibition in human lung adenocarcinoma cells with oncogenically-activated MAPK pathway. Since two critical MAPK pathway effectors c-Jun and ETV1 have been shown to be targets of COP1 E3 ligase complex-mediated proteosomal degradation, we tested if depletion of COP1 alters the levels of phosphorylated c-Jun and ETV1. Intriguingly, we did not observe a substantial impact of COP1 depletion on the levels of these effectors. Based on these observations, we hypothesize that depletion of COP1 confers resistance to MAPK pathway inhibition in RAS-MAPK pathway driven lung adenocarcinomas through accumulation of a novel protein substrate(s) that allows the survival and/or proliferation of these cells upon MAPK pathway inhibition. We will uncover the mechanism of resistance by identifying this substrate(s) of COP1 whose accumulation facilitates cell survival and/or proliferation upon MAPK pathway inhibition. This work will improve our understanding of the molecular basis of tumor cell resilience during initial treatment as well as of primary treatment resistance. Additionally, it could lead to identification of a novel biomarker for predicting response to MAPK pathway inhibitor therapy and a therapeutic target(s) that could be co-targeted with MAPK pathway signaling to improve the patient response in MAPK pathway driven lung adenocarcinomas.
Citation Format: Manasi K. Mayekar, Trever Bivona. COP1 E3 ligase modulates response to oncogenic MAPK pathway inhibition [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 LB-124. doi:10.1158/1538-7445.AM2017-LB-124
Abstract LB-129: NDAT and P-bi-TAT formulations of tetraiodothyroacetic acid (tetrac) induce devascularization, necrosis and apoptosis in glioblastoma xenografts
Authors: Davis Paul J. , Thangirala Sudha , Sell Stewart , Hercbergs Aleck , Mousa Shaker A. 
Published: July 2017

Abstract
Thyroid hormone as L-thyroxine (T4) has been reported to stimulate proliferation of multiple glioma cell lines in vitro and there is clinical evidence that medical induction of hypothyroidism slows growth of glioblastoma multiforme (GBM). The proliferative action of T4 on glioma cells is initiated at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone (T4) derivative that blocks T4 action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) or to two polyethylene glycol (PEG) molecules (P-bi-TAT) that increase the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of U87 MG GBM xenografts, NDAT administered daily for 10 days s.c. as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p &lt;0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p &lt;0.001). There was no intratumoral hemorrhage. There was extensive cellular necrosis in treated tumors attributable to devascularization. Cells not necrotic in treated xenografts exhibited apoptosis, so that 80% of cells were either necrotic or apoptotic, compared to controls (p &lt;0.001). Induction of apoptosis in cancer cells is a well-described quality of NDAT. P-bi-TAT treatment resulted in similar results after 20 days of treatment, but included a 21-day off-treatment follow-up after therapy. Xenografts achieved a 95% volume loss in the off-treatment, follow-up phase (P &lt; 0.001). In summary, systemic NDAT and P-bi-TAT have been shown to be effective by multiple mechanisms in treatment of GBM xenografts.
Citation Format: Paul J. Davis, Sudha Thangirala, Stewart Sell, Aleck Hercbergs, Shaker A. Mousa. NDAT and P-bi-TAT formulations of tetraiodothyroacetic acid (tetrac) induce devascularization, necrosis and apoptosis in glioblastoma xenografts [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 LB-129. doi:10.1158/1538-7445.AM2017-LB-129
Abstract LB-136: Characterization of residual Basal Cell Carcinoma after vismodegib treatment
Authors: Biehs Brian , Dijkgraaf Gerrit J. , Alicke Bruno , Peale Franklin , Gould Stephen E. , Sauvage Frederic J. de 
Published: July 2017

Abstract
We have generated a mouse model of Superficial Basal Cell Carcinoma (BCC) to study the effect of the Smoothened inhibitor vismodegib in vivo. Despite the potency of vimodegib in blocking Hedgehog (Hh) signaling and efficacy in treatment of BCC, residual disease persists in the mouse model. To better understand the Biology of BCC and the potential mechanisms maintaining BCC during treatment, we profiled isolated untreated as well as residual tumors. We found that treated tumors change their transcriptional program to resemble the cells of skin and hair follicle structures like the Interfollicular Epidermis (IFE) and Isthmus, both of which harbor stem cell compartments. Consistent with these findings, residual disease lacks expression of epidermal differentiation markers and initiates growth upon cessation of treatment. While Wnt signaling is clearly required for BCC initiation in mouse models, we show that Wnt signaling is down-regulated in untreated full-blown disease and subsequently strongly induced in the treated tumors. We hypothesize that re-initiation of the Wnt pathway maintains BCC and study the effect of blocking both Wnt and Hh pathways with combined treatment of vismodegib and Wnt inhibitors.
Citation Format: Brian Biehs, Gerrit J. Dijkgraaf, Bruno Alicke, Franklin Peale, Stephen E. Gould, Frederic J. de Sauvage. Characterization of residual Basal Cell Carcinoma after vismodegib treatment [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 LB-136. doi:10.1158/1538-7445.AM2017-LB-136
Abstract LB-140: Inhibition of cancer stemness sensitizes colorectal cancer to immune checkpoint inhibitors
Authors: Gao Yuan , Li Youzhi , Hsu Eric , Wang Yuxin , Huang Janet , Brooks Emily , Li Chiang J. 
Published: July 2017

Abstract
Cancer stem cells (CSCs), a highly malignant tumor cell subpopulation capable of self-renewal, are considered to be fundamentally responsible for malignant growth and tumor recurrence. Emerging evidences indicate that CSCs and CSC pathways, such as STAT3, beta-Catenin, CD44 and Nanog pathway, are involved in the immune evasion in cancers. With the exception of a small percentage of colorectal cancers (CRC) patients that display microsatellite instability (MSI), the vast majority of CRC patients have been found to be resistant to immune checkpoint therapies. BBI-608 (napabucasin) is an orally-administered first-in-class cancer stemness inhibitor that works by targeting STAT3, which lead to inhibition of multiple cancer stemness pathways, including Stat3 and β-catenin pathways. In this study, we investigate the effect of cancer stemness inhibition on sensitizing CRC to immune checkpoint inhibitors in preclinical models. In the syngeneic tumor model, anti-PD-1 antibody monotherapy produced low level and temporary antitumor activity with rapid development of complete resistance to anti-PD1 in the MSS CT26 CRC model. The anti-PD-1 antibody treated CT26 tumors exhibited increased p-STAT3 activation and overexpression of a variety of stemness factors, including Nanog, CD44 and CD133, as well as enrichment of sphere-forming stemness-high cancer cells. BBI-608 was able to reduce basal as well as anti-PD1-induced STAT3 activation and other CSC features within CT26 tumors. Combination of stemness inhibitor BBI-608 with anti-PD-1 antibody to treat CT26 tumors led to tumor complete response (CR) virtually in all treated CT26 tumors with 40% of the mice remain tumor-free for 30 days following treatment termination. This combination also had a synergistic effect on the influx of tumor infiltrating CD8+ T cells, which likely contributed to the rapid tumor regression. Finally, mice CR-induced by BBI-608 and anti-PD-1 antibody were able to reject CT26 tumors upon rechallenge, but not the unrelated breast cancer 4T1 tumors. Our data suggests cancer stemness pathways contribute to immunotherapy resistance in MSS CRC and inhibition of cancer stemness by BBI-608 sensitizes colorectal cancer to immune checkpoint inhibition. This study provides compelling preclinical evidence to support the investigation of the combination of BBI608 with immune checkpoint inhibitors in CRC.
Citation Format: Yuan Gao, Youzhi Li, Eric Hsu, Yuxin Wang, Janet Huang, Emily Brooks, Chiang J. Li. Inhibition of cancer stemness sensitizes colorectal cancer to immune checkpoint inhibitors [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 LB-140. doi:10.1158/1538-7445.AM2017-LB-140
Abstract LB-149: ITGA1 marks pre-malignant pancreatic lesions and drives stem-like cell survival and TGFβ/collagen-induced therapy resistance and metastasis in pancreatic cancer
Authors: Kim Sa La , Gharibi Armen , Molnar Justin , Brambilla Daniel , Adamian Yvess , Hoover Malachia , Lin Joy , Hong Julie , Kelber Jonathan A. 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of few malignancies to have single-digit 5-year survival rates at &lt;7%. This dismal prognosis is due in part to the limited ability of clinicians to make pre-metastatic diagnoses and effectively treat localized pancreatic tumors. Thus, there is a dire need to improve early detection methods and identify new therapeutic targets for abrogating PDAC progression. To this end, we mined our previously published pseudopodium-enriched (PDE) protein/phosphoprotein datasets to identify novel PDAC-specific biomarkers and/or therapeutic targets. We discovered that 37 of the top 100 PDE proteins are frequently upregulated in human pancreatic cancer and other tumor types. Integrin alpha 1 (ITGA1) was of primary interest because its high expression in pancreatic cancer precursor lesions may provide a path toward earlier diagnoses, while targeting its cell surface function may abrogate tumor-stroma interactions known to exacerbate PDAC. In this regard, the expression of ITGA1-specific collagens within the pancreatic cancer microenvironment significantly correlates with indicators of poor patient prognosis such as high tumor grade, p53/SMAD4 mutation status and erlotinib resistance. Depleting ITGA1 from PDAC cells revealed that it is required for collagen-induced migration and survival. We further demonstrate that collagen induces PDAC cell attachment and spreading in an ITGA1-dependent manner. Notably, collagen/ITGA1 signaling promotes the survival of ALDH1-positive stem-like cells and cooperates with TGFβ to drive gemcitabine resistance. Finally, we report that increased ITGA1 expression in PDAC tissue indicates the presence of epithelial-mesenchymal transition (EMT) and that ITGA1 is required for TGFβ/collagen-induced EMT and hepatotropic metastasis. Our data suggest that ITGA1 is a new biomarker for PDAC initiation and, when targeted, can sensitize tumors to available chemotherapies to suppress the growth of pancreatic tumors at primary and metastatic sites.
Citation Format: Sa La Kim, Armen Gharibi, Justin Molnar, Daniel Brambilla, Yvess Adamian, Malachia Hoover, Joy Lin, Julie Hong, Jonathan A. Kelber. ITGA1 marks pre-malignant pancreatic lesions and drives stem-like cell survival and TGFβ/collagen-induced therapy resistance and metastasis in pancreatic 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 LB-149. doi:10.1158/1538-7445.AM2017-LB-149