tbuckley/cabot-search huggingface dataset:
Abstract 1107: Cell state diversity promotes metastasis through heterotypic cluster formation in melanoma
Authors: Nathaniel R. Campbell, Maomao Zhang, Maayan Baron, Silja Heilmann, Maxime Deforet, Lorenza Ferretti, Ting-Hsiang Huang, Mitchell P. Levesque, Itai Yanai, Joao B. Xavier, Richard M. White
Journal: Cancer Research (2020)

Abstract Metastasis is the primary cause of cancer death, yet we know little about what determines its timing and aggressiveness. In melanoma, transcriptional profiling has revealed multiple co-existing cell states, including proliferative (PRO) versus invasive (INV) subpopulations that have been posited to represent a “go or grow” tradeoff in the etiology of metastasis. Although both of these populations are present in primary tumors and metastases, little is known about how they physically interact with each other in tumor dissemination. We use a combination of melanoma modeling in zebrafish and human validation to demonstrate that these subpopulations form spatially structured heterotypic clusters that cooperate in the seeding of metastasis. We unexpectedly found that INV cells were tightly adherent to each other and formed large tumor cell clusters. Mixing of PRO and INV cells generated heterotypic clusters, composed of a dense central core of INV cells surrounded by a rim of PRO cells. Using intravital imaging, we identified metastatic cooperation between these two subpopulations, in which the INV cells facilitated the earlier spread of the less metastatic PRO cells via collective extravasation. Mechanistically, we identified the TFAP2 family of neural crest transcription factors to be a master regulator of both clustering and the PRO/INV states. Knockout of TFAP2 from melanoma cells reduced proliferation but increased clustering and metastasis. TFAP2 loss resulted in increased expression of cell adhesion molecules, providing a mechanistic basis for cluster formation. Our data suggest a coherent framework for the co-existence of these two divergent cell populations in melanoma, in which differing cell states form heterotypic clusters that promote collective metastasis via cell-cell cooperation. Citation Format: Nathaniel R. Campbell, Maomao Zhang, Maayan Baron, Silja Heilmann, Maxime Deforet, Lorenza Ferretti, Ting-Hsiang Huang, Mitchell P. Levesque, Itai Yanai, Joao B. Xavier, Richard M. White. Cell state diversity promotes metastasis through heterotypic cluster formation in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1107.
Abstract CT187: Pembrolizumab and nanoparticle albumin bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC)
Authors: Patrizia Giannatempo, Daniele Raggi, Elena Farè, Laura Marandino, Marco Bandini, Maurizio Colecchia, Filippo Pederzoli, Giuseppina Calareso, Russell Madison, Francesco Monopoli, Giusy Russo, Roberto Ferrara, Filippo De Braud, Francesco Montorsi, Andrea Necchi
Journal: Cancer Research (2020)

Abstract Methods: In an open-label, single-arm, phase 2 trial, pts receive pembro 200 mg intravenously (IV) on D1 and 125 mg/m2 IV nPtx on D1 and D8, every 3 weeks, until disease progression (PD) or onset of unacceptable toxicity. Key inclusion criteria are: predominant UC histology, failure of ≤2 platinum-based CT for metastatic disease. Response is evaluated by RECIST v.1.1 criteria every 2 cycles. Biomarkers include PD-L1 expression with the combined positive score (CPS) and comprehensive genomic profiling on tumor and blood samples (FoundationONE and FoundationACT assay). The primary endpoint of the study is the progression-free survival (PFS). The target is to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). Results: Between 01 and 12/2019, PEANUT study enrolled 63 pts evaluable for the study endpoint: 24% female, median age 69 y (IQR 61-73); 75% had failed 1 prior systemic therapy vs 25% 2 prior therapies; 35% had ECOG-performance status 1; 33% had liver metastases. The median TMB was 6.9 mut/Mb. After median follow-up of 5 months, 33 pts have relapsed (52%). The median PFS was 5 months (95%CI: 4-not achieved). The confirmed objective response-rate (ORR) was 44.4% (95%CI: 0.34 to 0.55): 19 partial responses and 9 complete responses (14.4%). Grade 3-4 treatment-related adverse events (TRAE) were seen in 14 pts (22%). Most common any-grade TRAE included alopecia (76%), neutropenia (33.3%), and asthenia (33%). Permanent interruption of treatment (nPtx only) was seen in 9 pts (14.2%) due to toxicity. Neither TMB nor CPS were significantly associated with PFS on univariable analyses. Conclusions: Preliminary results from PEANUT study demonstrated a promising PFS and a clinically meaningful ORR in II-III line setting of advanced UC. Updated data, including mature OS, duration of response and biomarkers will be presented. Citation Format: Patrizia Giannatempo, Daniele Raggi, Elena Farè, Laura Marandino, Marco Bandini, Maurizio Colecchia, Filippo Pederzoli, Giuseppina Calareso, Russell Madison, Francesco Monopoli, Giusy Russo, Roberto Ferrara, Filippo De Braud, Francesco Montorsi, Andrea Necchi. Pembrolizumab and nanoparticle albumin bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT187.
Effect of midodrine versus placebo on time to vasopressor discontinuation in patients with persistent hypotension in the intensive care unit (MIDAS): an international randomised clinical trial
Authors: Peter Santer, Matthew H. Anstey, Maria D. Patrocínio, Bradley Wibrow, Bijan Teja, Denys Shay, Shahzad Shaefi, Charles S. Parsons, Timothy T. Houle, Matthias Eikermann, Peter Santer, Matthew H. Anstey, Maria D. Patrocínio, Bradley Wibrow, Bijan Teja, Denys Shay, Shahzad Shaefi, Charles S. Parsons, Timothy T. Houle, Matthias Eikermann, Kwok M. Ho, Stefan J. Schaller, Tharusan Thevathasan, Lea Albrecht, Stephanie Grabitz, Khushi Chhangani, Pauline Y. Ng, Alexander Levine, Alan DiBiasio, Robert Palmer, Erina Myers, Rashmi Rauniyar, Todd Sarge, Flora Scheffenbichler, Alok Gupta
Journal: Intensive Care Medicine (2020)
Abstract 2116: Strength of immune selection in tumors varies with sex and age
Authors: Andrea Castro, Rachel M. Pyke, Maurizio Zanetti, Hannah Carter
Journal: Cancer Research (2020)

Abstract Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. Recent studies demonstrated poorer response rates in female and younger melanoma patients. Although immune responses differ with sex and age, the role of MHC-based immune selection in this context is unknown. We found that tumors in younger and female individuals accumulated more poorly presented driver mutations than those in older and male patients, despite no differences in MHC genotype. Younger patients showed strongest effects of MHC-based driver mutation selection, with younger females showing compounded effects and nearly twice as much MHC-II based selection. This study presents the first evidence that strength of immune selection during tumor development varies with sex and age, and may influence the availability of mutant peptides capable of driving effective response to immune checkpoint inhibitor therapy. Citation Format: Andrea Castro, Rachel M. Pyke, Maurizio Zanetti, Hannah Carter. Strength of immune selection in tumors varies with sex and age [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2116.
Abstract 3579: Pimozide combined with paclitaxel demonstrates a significant antitumor effect in head and neck squamous cell carcinoma
Authors: Shintaro Nakamura, Hiroyuki Ozawa, Juntaro Yamasaki, Shogo Okazaki, Momoko Yoshikawa, Tomoya Soma, Seiji Asoda, Osamu Nagano, Mariko Sekimizu, Shin Saito, Keisuke Yoshihama, Takuya Mikoshiba, Kaoru Ogawa, Hideyuki Saya
Journal: Cancer Research (2020)

Abstract Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer in the world. Despite the development of various treatments, the five-year survival rate for HNSCC is about 50-60% and has not been improved in recent years. Immune checkpoint inhibitors are promising, but the effect of those is limited. The development of new reagents having different mechanisms against tumor progression is still needed. From the result of drug screening, Pimozide (PMZ), an antipsychotic drug used for the treatment of schizophrenia and chronic psychosis, demonstrated a strong antitumor ability to HNSCC cells expressing high level of CD44v. In this study, we examined the combined effects of PMZ and paclitaxel (PTX) for HNSCC cells. Methods: Using HNSCC cell lines (FaDu, Detroit562, HSC-2, OSC-19), the antitumor effects of PTX, PMZ, and the combination of PTX and PMZ were evaluated by MTS assay. Moreover, the reactive oxygen species (ROS) expression level under each drug administration was measured by flow cytometry. Moreover, PTX, PMZ (0.45mg/kg), PMZ (1mg/kg), PTX+PMZ were administered to the xenograft model by OSC-19. The tumor was resected after those treatments. The expression of CD44v, ALDH3A1, and NRF2 was evaluated by immunohistochemistry (IHC) of FFPE tissues from those extracted tumors. Results: PMZ single-agent inhibited tumor growth in various tumor cell lines, and the antitumor effect was enhanced by concomitant use of PTX. PMZ, which significantly increased ROS of tumor cells, was more effective than PTX in OSC-19, which was a chemoresistant cell line expressing high CD44v. Xenograft model exhibited that tumor growth was suppressed in PTX+PMZ group than in PTX and PMZ single-agent group. IHC staining revealed that PMZ administration restrained CD44v expression, and ALDH3A1 expression markedly decreased in PMZ treated tumors, but not in PTX treated tumors. Conclusions: PMZ dramatically induced ROS production in tumor cells. These data suggest that aldehyde produced by ROS might suppress HNSCC tumor growth. The results from this study indicated that PMZ could be a novel therapeutic reagent for HNSCC in combination with existing anticancer drugs. Citation Format: Shintaro Nakamura, Hiroyuki Ozawa, Juntaro Yamasaki, Shogo Okazaki, Momoko Yoshikawa, Tomoya Soma, Seiji Asoda, Osamu Nagano, Mariko Sekimizu, Shin Saito, Keisuke Yoshihama, Takuya Mikoshiba, Kaoru Ogawa, Hideyuki Saya. Pimozide combined with paclitaxel demonstrates a significant antitumor effect in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3579.
Abstract 2148: Screening of cancer-reactive T cells in lymph nodes in colorectal cancer patients
Authors: Kazuma Kiyotani, Kazumi Okamura, Satoshi Nagayama, Yusuke Nakamura
Journal: Cancer Research (2020)

Abstract Tumor draining lymph nodes (TDLNs) are located in the routes of lymphatic drainage from a primary tumor and have the highest metastasis in various types of solid tumors. TDLNs are considered as a tissue to activate the antitumor immunity, where antigen-specific effector T cells are generated and released to the blood stream. These effector T cells then infiltrate into the tumor site and attack cancer cells. However, it has not been investigated whether cancer-reactive T cells are present in lymph nodes. Through T cell receptor (TCR) repertoire analysis of cancer tissues and total 203 regional lymph nodes from 23 colorectal cancer patients, we previously found that regional lymph nodes, especially metastasis-positive lymph nodes, contain T cells with TCR shared with primary cancer tissues. In this study, we collected surgically-resected fresh cancer tissues and total 12 regional lymph nodes from 4 colorectal cancer patients. From these freshly-obtained cancer tissues and lymph nodes, we isolated single cells and then cultured T cells and patient-derived cancer cells. We co-cultured each of T cells from the 12 lymph nodes with autologous cancer cells, and examined their cancer-reactivity using IFN-γ ELISPOT assay. Six among the 7 metastasis-positive lymph nodes, shows significant production of INF-γ, suggesting the presence of cancer-reactive T cells in the lymph nodes. We also detected cancer-reactive T cells in 3 out of 5 metastasis-negative lymph nodes. In FACS analysis, we found the proportion of TIM3+ cells in CD8+PD1+ T cells were lower in T cells in lymph nodes compared to T cells in primary tumor. These data suggest that lymph nodes may be a good source of T cells for cancer immunotherapy. Citation Format: Kazuma Kiyotani, Kazumi Okamura, Satoshi Nagayama, Yusuke Nakamura. Screening of cancer-reactive T cells in lymph nodes in colorectal cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2148.
Open abdomen management for severe peritonitis in elderly. Results from the prospective International Register of Open Abdomen (IROA): Cohort study
Authors: Stefano Rausei, Vincenzo Pappalardo, Marco Ceresoli, Fausto Catena, Massimo Sartelli, Massimo Chiarugi, Yoram Kluger, Andrew Kirkpatrick, Luca Ansaloni, Federico Coccolini, Giulia Montori, Fracensco Salvetti, Paola Fugazzola, Ionut Negoi, Monica Zese, Savino Occhionorelli, Sergei Shlyapnikov, Andrew Kirkpatrick, Zaza Demetrashvili, Daniele Dondossola, Orestis Ioannidis, Giuseppe Novelli, Mirco Nacoti, Desmond Khor, Kenji Inaba, Demetrios Demetriades, Torsten Kaussen, Asri Che Jusoh, Wagih Ghannam, Boris Sakakushev, Ohad Guetta, Agron Dogjani, Stefano Costa, Sandeep Singh, Dimitrios Damaskos, Arda Isik, Kuo-Ching Yuan, Francesco Trotta, Stefano Rausei, Aleix Martinez-Perez, Giovanni Bellanova, Vinicius Cordeiro Fonseca, Fernando Hernández, Athanasios Marinis, Wellington Fernandes, Martha Quiodettis, Miklosh Bala, Andras Vereczkei, Rafael Curado, Gustavo Pereira Fraga, Bruno M. Pereira, Mahir Gachabayov, Guillermo Perez Chagerben, Miguel Leon Arellano, Sefa Ozyazici, Gianluca Costa, Tugan Tezcaner, Matteo Porta, Yousheng Li, Faruk Karateke, Dimitrios Manatakis, Federico Mariani, Federico Lora, Ivan Sahderov, Boyko Atanasov, Sergio Zegarra, Luca Fattori, Rao Ivatury, Jimmy Xiao, Yoram Kluger, Andrea Lippi, Mario Improta, Francesca Gubbiotti, Andrey Zharikov, Vincent Dubuisson, Michael Sugrue
Journal: International Journal of Surgery (2020)
Abstract 1042: Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833
Authors: Eric T. Gangl, Roshini Markandu, Pradeep Sharma, Andy Sykes, Petar Pop-Damkov, Pablo Morentin Gutierrez, James S. Scott, Dermot F. McGinnity, Adrian J. Fretland, Teresa Klinowska
Journal: Cancer Research (2020)

Abstract AZD9833 is a potent, orally delivered, non-steroidal selective estrogen receptor degrader (SERD) that both antagonizes and degrades ERα. It is currently in clinical testing for the treatment of ER+ metastatic breast cancer (SERENA-1; NCT03616587). While ER is a clinically validated target, sustained inhibition of the target via oral delivery has proven an elusive goal. Despite intensive research, no oral SERD options are currently approved. Poor pharmacokinetic (PK) properties and/or short half-life (t ½) are often underlying features that limit oral SERD candidates from once or twice daily dose regimens. AZD9833 is a clinical stage next generation oral SERD that may overcome these challenges. The pre-clinical PK properties of AZD9833 are consistent with once daily oral dosing in patients and are reported herein. AZD9833 is a low molecular weight (&amp;lt;500 Da), low lipophilicity (logD &amp;lt;3) base with good permeability characteristics. High volume of distribution (6-13 L/kg) and high bioavailability were observed in preclinical species. The in vitro hepatic metabolic clearance (CLint) for AZD9833 varied across species and were found to be nonlinear as a function of concentration. This nonlinear behaviour most strongly manifested in dog where in vivo bioavailability was &amp;lt;2 or 95 %F depending on dose. To explain these observations, detailed in vitro mechanistic studies were conducted and physiologically based PK (PBPK) models were created. Cytochrome P450 phenotyping studies suggest dog clearance is mediated by CYP2D15 whereas CYP3A is the dominant P450 isoform responsible for clearance in human. In vitro CLint vs. concentration studies exhibited a low Km in dog (0.2 μM) relative to human (2 μM) and other species. To further our understanding, we constructed PBPK models which demonstrated that the dose dependent exposures in dog were predictable. The human model suggests that nonlinear behaviour will manifest well above predicted efficacious doses. Modeling also allowed us to assess the potential for drug-drug interactions with likely co-medications such as CDK 4/6 inhibitors. The PBPK predictions of good human exposure and long t ½ are being explored in the ongoing clinical trial. Citation Format: Eric T. Gangl, Roshini Markandu, Pradeep Sharma, Andy Sykes, Petar Pop-Damkov, Pablo Morentin Gutierrez, James S. Scott, Dermot F. McGinnity, Adrian J. Fretland, Teresa Klinowska. Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1042.
DEVELOPMENT AND VALIDATION OF THREE PRELIMINARY MRI SACROILIAC JOINT COMPOSITE STRUCTURAL DAMAGE SCORES IN A 5-YEAR LONGITUDINAL STUDY OF PATIENTS WITH AXIAL SPONDYLOARTHRITIS
Authors: M. Wetterslev, Mikkel Østergaard, I. J. Sørensen, Ulrich Weber, Anne Gitte Loft, Gina Birgitte Kollerup, L Juul, G. Thamsborg, O. Madsen, J. Møllenbach Møller, Susanne Juhl Pedersen
Journal: Annals of the Rheumatic Diseases (2020)
Abstract 1190: Comparison of cumulative incidence rates of colorectal cancer among Asians and Pacific Islanders (API) populations in Guam, Hawai'i, and the United States
Authors: Grazyna Badowski
Journal: Cancer Research (2020)

Abstract Background: Colorectal cancer is one of 4 most common cancers on Guam, Hawai'i (HI) and the US. However, incidence rates vary between ethnic groups and location. Objective: The objective of the study was to compare cumulative incidence rates (CIRs) among ethnic groups in Guam, HI, and the US; specifically, Chamorros in Guam, Filipinos in Guam, HI and the US, and Native Hawaiians in HI and the US. CIRs are weighted sums of age-specific incidence rates therefore they can be used for comparisons between populations. They are relatively stable and thus provide a good estimate of cumulative risk of cancer. Methods: This study included all colorectal cancer cases (n=562) reported to the Guam Cancer Registry and all colorectal cancer cases (n=253,782) reported to the Surveillance, Epidemiology, and End Results (SEER) 9-Registry from 2000 to 2014. Cumulative incidence rates were calculated for three time periods: 2000-2004, 2005-2009, and 2010-2014 and compared by age, ethnicity and location. Results: Differences were seen in CIRs by time-period, age, ethnicity, and location. For all three time periods: 2000-2004, 2005-2009, 2010-2014, the lifetime cumulative incidence rates (age 0-79) were highest for Hawai'i (5.7%, 5.4%, and 5.3% respectively), followed by the US (5.2%, 4.5%, and 3.7%) and Guam (4.3%, 3.3%, and 3.6%). Interestingly, there were large differences in lifetime CIRs between Filipinos in HI, Filipinos in the US and Filipinos on Guam (i.e. 6.5%, 3.7%, and 2.4% respectively in 2005-2009). The Chamorros on Guam had the rate at least 1.5 times higher than Filipinos on Guam (4.3 % vs 3.3%) and close to the rate of Native Hawaiians in HI (4.9%). Overall, there was downward trend for the lifetime CIRs over time. Only for the Filipinos in HI, the rates went up. However, early onset CIRs (age 0-49) went up across all locations and ethnic groups. Conclusions: Disparities in colorectal cancer incidence were identified. Further study is needed to examine how exposure to risk factors and screening changes with immigration and how this variation contributes to the incidence disparities. Citation Format: Grazyna Badowski. Comparison of cumulative incidence rates of colorectal cancer among Asians and Pacific Islanders (API) populations in Guam, Hawai'i, and the United States [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1190.
Abstract 5262: Identifying the role of AXL in fusion kinase inhibitor resistant non-small cell lung cancer
Authors: Tara Peters, Anastasios Dimou, Anh Le, Robert Doebele
Journal: Cancer Research (2020)

Abstract Chromosomal rearrangements involving ALK, ROS1, RET and others generate novel fusion kinases which comprise approximately 10% of the oncogenic drivers in lung adenocarcinoma. Several tyrosine kinase inhibitors (TKIs) are approved or in development for each of these oncogenes and have shown marked clinical improvement for patients, but resistance inevitably occurs, a significant proportion of which is not currently druggable. AXL is a receptor tyrosine kinase that is often upregulated in resistant cancers in response to both chemotherapy and targeted therapies such as EGFR inhibitors. AXL can promote resistance to targeted therapy by signaling through the MAPK and Akt pathways or heterodimerizing with other receptors to maintain growth and survival signaling. However, the role of AXL in mediating resistance to ALK, ROS1, and RET TKIs is not well understood. In screening our unique panel of patient-derived lung adenocarcinoma cell lines harboring ALK, ROS1 or RET gene fusions, we found elevated AXL expression was correlated with resistance to cognate TKIs, as well as mesenchymal features including spindle morphology and vimentin expression. Combining the AXL inhibitor R428 with TKI treatment, such as crizotinib for ALK and ROS1 driven cell lines, was effective at inhibiting colony formation and wound healing in fusion kinase inhibitor resistant cell lines. Combination treatment downregulates Akt phosphorylation in resistant cells, and we found the resistant cell lines were also more sensitive to PI3K inhibition than cell lines that are still sensitive to their specific TKI. Interestingly, we also identified AXL cross talk with other receptor tyrosine kinases. In a RET inhibitor resistant model expression of both AXL and EGFR are elevated and the receptors interact, which can be disrupted upon EGF stimulation, to drive resistance. Collectively, we show that AXL upregulation is a common marker of TKI resistance among ALK, ROS1, and RET fusion kinase driven lung adenocarcinoma models, and provide rationale for AXL as a clinical target for combination therapy to overcome drug resistance. Citation Format: Tara Peters, Anastasios Dimou, Anh Le, Robert Doebele. Identifying the role of AXL in fusion kinase inhibitor resistant non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5262.