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Journal Cancer Res.

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Generalized additive mixed modeling of longitudinal tumor growth reduces bias and improves decision making in translational oncology.

William F Forrest, Bruno Alicke, Oleg Mayba, Magdalena Osinska, Michal Jakubczak, Pawel Piatkowski, Lech Choniawko, Alice Starr, Stephen E Gould,

Scientists working in translational oncology regularly conduct multi-group studies of mice with serially measured tumors. Longitudinal data collected can feature mid-study dropouts and complex nonlinear temporal response patterns. Parametric statistical models such as ones assuming exponential growth are useful for summarizing tumor volume over ranges for which the growth model ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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EpCAM signaling promotes tumor progression and protein stability of PD-L1 through the EGFR pathway.

Hao-Nien Chen, Kang-Hao Liang, Jun-Kai Lai, Chun-Hsin Lan, Mei-Ying Liao, Shao-Hsi Hung, Yi-Ting Chuang, Kai-Chi Chen, William Wei-Fu Tsuei, Han-Chung Wu,

Although EpCAM has previously been shown to promote tumor progression, the underlying mechanisms remain largely unknown. Here we report that the EGF-like domain I within the extracellular domain of EpCAM (EpEX) binds EGFR, activating both AKT and MAPK signaling to inhibit FOXO3a function and stabilize PD-L1 protein, respectively. Treatment with ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Futibatinib is a novel irreversible FGFR 1-4 inhibitor that shows selective antitumor activity against FGFR-deregulated tumors.

Hiroshi Sootome, Hidenori Fujita, Kenjiro Ito, Hiroaki Ochiiwa, Yayoi Fujioka, Kimihiro Ito, Akihiro Miura, Takeshi Sagara, Satoru Ito, Hirokazu Ohsawa, Sachie Otsuki, Kaoru Funabashi, Masakazu Yashiro, Kenichi Matsuo, Kazuhiko Yonekura, Hiroshi Hirai,

Fibroblast growth factor receptor (FGFR) signaling is deregulated in many human cancers and FGFR is considered a valid target in FGFR-deregulated tumors. Here we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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EZH2-targeted therapies in cancer: hype or a reality.

Marie-Lisa Eich, James E Ferguson, Sooryanarayana Varambally,

Next-generation genomic sequencing has identified multiple novel molecular alterations in cancer. Since the identification of DNA methylation and histone modification, it has become evident that genes encoding epigenetic modifiers that locally and globally regulate gene expression play a crucial role in normal development and cancer progression. The histone methyltransferase enhancer ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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A circle RNA regulatory axis promotes lung squamous metastasis via CDR1-mediated regulation of Golgi trafficking.

Emily B Harrison, Alessandro Porrello, Brittany M Bowman, Adam R Belanger, Gabriella Yacovone, Salma H Azam, Ian A Windham, Subrata K Ghosh, Menglin Wang, Nick McKenzie, Trent A Waugh, Amanda E D Van Swearingen, Stephanie M Cohen, Devon G Allen, Tyler J Goodwin, Teresa Mascenik, James E Bear, Sarah Cohen, Scott H Randell, Pierre P Massion, Michael B Major, Leaf Huang, Chad V Pecot,

Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis. Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of circRNA is through miRNA sponging, we found that miR-671-5p more potently silenced an ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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FGFR1 is critical for Rbl2 loss-driven tumor development and requires PLCG1 activation for continued growth of small cell lung cancer.

Kee-Beom Kim, Youngchul Kim, Christopher J Rivard, Dong-Wook Kim, Kwon-Sik Park,

Small cell lung cancer (SCLC) remains a recalcitrant disease where limited therapeutic options have not improved overall survival and approved targeted therapies are lacking. Amplification of the tyrosine kinase receptor FGFR1 (fibroblast growth factor receptor 1) is one of the few actionable alterations found in the SCLC genome. However, efforts ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Chromothripsis in human breast cancer.

Michiel Bolkestein, John K L Wong, Verena Thewes, Verena Körber, Mario Hlevnjak, Shaymaa Elgaafary, Markus Schulze, Felix K F Kommoss, Hans-Peter Sinn, Tobias Anzeneder, Steffen Hirsch, Frauke Devens, Petra Schröter, Thomas Höfer, Andreas Schneeweiss, Peter Lichter, Marc Zapatka, Aurélie Ernst,

Chromothripsis is a form of genome instability by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosomes. Widely assumed to be an early event in tumor development, this phenomenon plays a prominent role in tumor onset. In this study, an analysis of chromothripsis ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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NSD3-induced methylation of H3K36 activates NOTCH signaling to drive breast tumor initiation and metastatic progression.

Ga-Young Jeong, Mi Kyung Park, Hee-Joo Choi, Hee Woon An, Young-Un Park, Hyung-Jun Choi, Jin Park, Hyung-Yong Kim, Taekwon Son, Ho Lee, Kyueng-Whan Min, Young-Ha Oh, Jeong-Yeon Lee, Gu Kong,

Histone methyltransferase NSD3 is frequently dysregulated in human cancers, yet the epigenetic role of NSD3 during cancer development remains elusive. Here we report that NSD3-induced methylation of H3K36 is crucial for breast tumor initiation and metastasis. In breast cancer patients, elevated expression of NSD3 was associated with recurrence, distant metastasis, ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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FAM46C and FNDC3A are multiple myeloma tumor suppressors that act in concert to impair clearing of protein aggregates and autophagy.

Nicola Manfrini, Marilena Mancino, Annarita Miluzio, Stefania Oliveto, Matteo Balestra, Piera Calamita, Roberta Alfieri, Riccardo L Rossi, Marco Sassoè-Pognetto, Chiara Salio, Alessandro Cuomo, Tiziana Bonaldi, Marcello Manfredi, Emilio Marengo, Elia Ranzato, Simona Martinotti, Davide Cittaro, Giovanni Tonon, Stefano Biffo,

Multiple myeloma (MM) is a plasma cell neoplasm characterized by the production of unfolded immunoglobulins which cause endoplasmic reticulum (ER) stress and sensitivity to proteasome inhibition. The genomic landscape of MM is characterized by the loss of several genes rarely mutated in other cancers that may underline specific weaknesses of ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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PET reporter gene imaging and ganciclovir-mediated ablation of chimeric antigen receptor T-cells in solid tumors.

Surya Murty, Louai Labanieh, Tara Murty, Gayatri Gowrishankar, Tom Haywood, Israt S Alam, Corinne Beinat, Elise Robinson, Amin Aalipour, Dorota D Klysz, Jennifer R Cochran, Robbie G Majzner, Crystal L Mackall, Sanjiv S Gambhir,

Imaging strategies to monitor chimeric antigen receptor (CAR) T-cell biodistribution and proliferation harbor the potential to facilitate clinical translation for the treatment of both liquid and solid tumors. Additionally, the potential adverse effects of CAR T-cells highlight the need for mechanisms to modulate CAR T-cell activity. The herpes simplex virus ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Glutamate is a non-invasive metabolic biomarker of IDH1 mutant glioma response to temozolomide treatment.

Elavarasan Subramani, Marina Radoul, Chloe Najac, Georgios Batsios, Abigail R Molloy, Donghyun Hong, Anne Marie Gillespie, Romelyn Delos Santos, Pavithra Viswanath, Joseph F Costello, Russell O Pieper, Sabrina M Ronen,

Although lower-grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1 mutant patients are increasingly being treated with temozolomide (TMZ), but early detection of response remains a challenge and there is a need for complementary ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Targeting CDK12 for cancer therapy: function, mechanism, and drug discovery.

Hui Liu, Kangdong Liu, Zigang Dong,

Cyclin dependent kinase 12 (CDK12) is a member of the CDK family of proteins (CDK) and is critical for cancer development. Years of study into CDK12 have generated much information regarding the intricacy of its function and mechanism as well as inhibitors against it for oncological research. However, there remains ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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CD122-selective IL-2 complexes reduce immunosuppression, promote Treg fragility, and sensitize tumor response to PD-L1 blockade.

Justin M Drerup, Yilun Deng, Sri Lakshmi Pandeswara, Álvaro S Padrón, Ryan M Reyes, Xinyue Zhang, Jenny Mendez, Aijie Liu, Curtis A Clark, Wanjiao Chen, José R Conejo-Garcia, Vincent Hurez, Harshita Gupta, Tyler J Curiel,

The IL-2 receptor (IL-2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Tregs) and anti-tumor T cells. Here we used IL-2Rβ-selective IL-2/anti-IL-2 complexes (IL-2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer (OC) model. Despite strong tumor rejection, IL-2c unexpectedly lowered ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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CRISPR/Cas9-Mediated Point Mutation in Nkx3.1 Prolongs Protein Half-Life and Reverses Effects Nkx3.1 Allelic Loss.

Cai Bowen, Maho Shibata, Hailan Zhang, Sarah K Bergren, Michael M Shen, Edward P Gelmann,

NKX3.1 is the most commonly deleted gene in prostate cancer and is a gatekeeper suppressor. NKX3.1 is haploinsufficient, and pathogenic reduction in protein levels may result from genetic loss, decreased transcription, and increased protein degradation caused by inflammation or PTEN loss. NKX3.1 acts by retarding proliferation, activating antioxidants, and enhancing ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Cancers from novel Pole mutant mouse models provide insights into polymerase-mediated hypermutagenesis and immune checkpoint blockade.

Melissa A Galati, Karl P Hodel, Miki S Gams, Sumedha Sudhaman, Taylor Bridge, Walter J Zahurancik, Nathan A Ungerleider, Vivian S Park, Ayse B Ercan, Lazar Joksimovic, Iram Siddiqui, Robert Siddaway, Melissa Edwards, Richard de Borja, Dana Elshaer, Jiil Chung, Victoria J Forster, Nuno M Nunes, Melyssa Aronson, Xia Wang, Jagadeesh Ramdas, Andrea Seeley, Tomasz Sarosiek, Gavin P Dunn, Jonathan N Byrd, Oz Mordechai, Carol Durno, Alberto Martin, Adam Shlien, Eric Bouffet, Zucai Suo, James G Jackson, Cynthia E Hawkins, Cynthia J Guidos, Zachary F Pursell, Uri Tabori,

POLE mutations are a major cause of hypermutant cancers, yet questions remain regarding mechanisms of tumorigenesis, genotype-phenotype correlation, and therapeutic considerations. In this study, we establish mouse models harboring cancer-associated POLE mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation in vivo independent of their exonuclease ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Integrating mathematical modeling with high throughput imaging explains how polyploid populations behave in nutrient-sparse environments.

Gregory J Kimmel, Mark Dane, Laura M Heiser, Philipp M Altrock, Noemi Andor,

Breast cancer progresses in a multistep process from primary tumor growth and stroma invasion to metastasis. Nutrient-limiting environments promote chemotaxis with aggressive morphologies characteristic of invasion. It is unknown how co-existing cells differ in their response to nutrient limitations and how this impacts invasion of the metapopulation as a whole. ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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ERG-mediated coregulator complex formation maintains androgen receptor signaling in prostate cancer.

Neel Shah, Nikolas Kesten, Alba Font-Tello, Matthew E K Chang, Raga Vadhi, Klothilda Lim, Mark R Flory, Paloma Cejas, Hisham Mohammed, Henry W Long, Myles Brown,

The TMPRSS2-ERG fusion is the most common genomic rearrangement in human prostate cancer. However, in established adenocarcinoma, it is unknown how the ERG oncogene promotes a cancerous phenotype and maintains downstream androgen receptor (AR) signaling pathways. In this study, we utilized a murine prostate organoid system to explore the effects ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Searching for Goldilocks: How evolution and ecology can help uncover more effective patient-specific chemotherapies.

Derek S Park, Kimberly A Luddy, Mark Robertson-Tessi, Cliona O'Farrelly, Robert A Gatenby, Alexander R A Anderson,

Deaths from cancer are mostly due to metastatic disease that becomes resistant to therapy. A mainstay treatment for many cancers is chemotherapy for which the dosing strategy is primarily limited by patient toxicity. While this Maximum Tolerated Dose (MTD) approach builds upon the intuitively appealing principle that maximum therapeutic benefit ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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The inhibitor of apoptosis protein Livin confers resistance to Fas-mediated immune cytotoxicity in refractory lymphoma.

Eiji Sugihara, Norisato Hashimoto, Satoru Osuka, Takatsune Shimizu, Sayaka Ueno, Shogo Okazaki, Tomonori Yaguchi, Yutaka Kawakami, Kenjiro Kosaki, Taka-Aki Sato, Shinichiro Okamoto, Hideyuki Saya,

Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Breast cancer cell detection and characterization from breast milk-derived cells.

Poornima Bhat-Nakshatri, Brijesh Kumar, Ed Simpson, Kandice K Ludwig, Mary L Cox, Hongyu Gao, Yunlong Liu, Harikrishna Nakshatri,

Radiologic techniques remain the main method for early detection for breast cancer and are critical to achieve a favorable outcome from cancer. However, more sensitive detection methods to complement radiologic techniques are needed to enhance early detection and treatment strategies. Using our recently established culturing method that allows propagation of ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Iron and cancer: 2020 Vision.

Suzy V Torti, Frank M Torti,

New and provocative insights into the relationships between iron and cancer have been uncovered in recent years. These include delineation of connections that link cellular iron to DNA repair, genomic integrity, and oncogenic signaling as well as the discovery of ferroptosis, a novel iron-dependent form of cell death. In parallel, ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Genomic and Epigenomic Landscaping Defines New Therapeutic Targets for Adenosquamous Carcinoma of the Pancreas.

Elizabeth Lenkiewicz, Smriti Malasi, Tara L Hogenson, Luis F Flores, Whitney Barham, William J Phillips, Alexander S Roesler, Kendall R Chambers, Nirakar Rajbhandari, Akimasa Hayashi, Corina E Antal, Michael Downes, Paul M Grandgenett, Michael A Hollingsworth, Derek Cridebring, Yuning Xiong, Jeong-Heon Lee, Zhenqing Ye, Huihuang Yan, Matthew C Hernandez, Jennifer L Leiting, Ronald M Evans, Tamas Ordog, Mark J Truty, Mitesh J Borad, Tannishtha Reya, Daniel D Von Hoff, Martin E Fernandez-Zapico, Michael T Barrett,

Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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The Alternative Splicing Factor MBNL1 Inhibits Glioblastoma Tumor Initiation and Progression by Reducing Hypoxia-Induced Stemness.

Dillon M Voss, Anthony Sloan, Raffaella Spina, Heather M Ames, Eli E Bar,

Muscleblind-like-proteins (MBNL) belong to a family of tissue-specific regulators of RNA metabolism that control pre-messenger RNA-splicing (AS). Inactivation of MBNL causes an adult-to-fetal AS transition, resulting in the development of myotonic dystrophy. We have previously shown that the aggressive brain cancer glioblastoma (GBM) maintains stem-like features (GSC) through hypoxia-induced responses. ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Allosteric SHP2 inhibitor IACS-13909 overcomes EGFR-dependent and EGFR-independent resistance mechanisms towards osimertinib.

Yuting Sun, Brooke A Meyers, Barbara Czako, Paul Leonard, Faika Mseeh, Angela L Harris, Qi Wu, Sarah Johnson, Connor A Parker, Jason B Cross, Maria Emilia Di Francesco, Benjamin J Bivona, Christopher A Bristow, Jason P Burke, Caroline C Carrillo, Christopher L Carroll, Qing Chang, Ningping Feng, Guang Gao, Sonal Gera, Virginia Giuliani, Justin K Huang, Yongying Jiang, Zhijun Kang, Jeffrey J Kovacs, Chiu-Yi Liu, Anastasia M Lopez, Xiaoyan Ma, Pijus K Mandal, Timothy McAfoos, Meredith A Miller, Robert A Mullinax, Michael Peoples, Vandhana Ramamoorthy, Sahil Seth, Nakia D Spencer, Erika Suzuki, Christopher C Williams, Simon S Yu, Andy M Zuniga, Giulio F Draetta, Joseph R Marszalek, Timothy P Heffernan, Nancy E Kohl, Philip Jones,

Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors (TKI) ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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Association of Pathological Complete Response with Long-Term Survival Outcomes in Triple-Negative Breast Cancer: A Meta-analysis.

Min Huang, Joyce O'Shaughnessy, Jing Zhao, Amin Haiderali, Javier Cortés, Scott D Ramsey, Andrew Briggs, Peter Hu, Vassiliki Karantza, Gursel Aktan, Cynthia Z Qi, Chenyang Gu, Jipan Xie, Muhan Yuan, John Cook, Michael Untch, Peter Schmid, Peter A Fasching,

Pathological complete response (pCR) following neoadjuvant therapy has been associated with improved event-free survival (EFS) and overall survival (OS) in early-stage breast cancer (BC). The magnitude of this association varies by BC subtype, yet further research focusing on subtype-specific populations is limited. Here we provide an updated and comprehensive evaluation ... Read more >>

Cancer Res. (Cancer research)
[2020, :]

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