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Journal Cancer Discov

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Toward a New Molecular Taxonomy of Diffuse Large B-cell Lymphoma.

Daisuke Ennishi, Eric D Hsi, Christian Steidl, David W Scott,

Diffuse large B-cell lymphoma (DLBCL) represents a grouping of clinically and biologically heterogeneous tumors. Application of advanced molecular technology has significantly expanded our knowledge of DLBCL pathobiology, allowing identification of subgroups with common, potentially targetable, biological themes. Here, we review the recent molecular analyses that could provide a paradigm shift ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Fusing the Genetic Landscape of Infantile High-Grade Gliomas.

Frank Szulzewsky, Patrick J Cimino,

In this issue of Cancer Discovery, Clarke and colleagues define the genetic landscape of infantile cerebral high-grade gliomas, which frequently contain alterations in the MAPK pathway, as well as recurrent gene fusions in receptor tyrosine kinases (ALK, ROS1, MET) and neurotrophic receptor kinases (NTRK1-3). Combining their multi-omic profiling data with ... Read more >>

Cancer Discov (Cancer discovery)
[2020, 10(7):904-906]

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Utility of Human-Derived Models for Glioblastoma.

Xujun Luo, William A Weiss,

In this issue, Pine and colleagues compared single-cell RNA-sequencing data across four distinct types of glioblastoma stem cell-derived tumor models, reinforcing the importance of a three-dimensional microenvironment for accurate recapitulation of cellular states.See related article by Pine et al., p. 964. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, 10(7):907-909]

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Disparities Persist in Cancer Careers.

Minority scientists-especially Black scientists-have long been underrepresented in the oncology workforce, likely due to a low number of minority students starting and continuing careers in science and medicine. Although progress has been made through government programs that offer students of all ages opportunities to explore careers in oncology, more work ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition.

Sheng F Cai, S Haihua Chu, Aaron D Goldberg, Salma Parvin, Richard P Koche, Jacob L Glass, Eytan M Stein, Martin S Tallman, Filiz Sen, Christopher A Famulare, Monica Cusan, Chun-Hao Huang, Chun-Wei Chen, Lihua Zou, Keith B Cordner, Nicole L DelGaudio, Vidushi Durani, Mitali Kini, Madison Rex, Helen S Tian, Johannes Zuber, Timour Baslan, Scott W Lowe, Hugh Y Rienhoff, Anthony Letai, Ross L Levine, Scott A Armstrong,

The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor Evi1 compared to leukemias derived from ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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It Takes a Village to Overcome KRAS Dependence in Pancreatic Cancer.

Ryan M Carr, Martin E Fernandez-Zapico,

In this issue, Hou and colleagues present their exciting work demonstrating that, through remodeling of the local tumor microenvironment (TME), pancreatic ductal adenocarcinoma forms a tumor-supportive niche capable of liberating cancer cells from dependence on oncogenic KRAS signaling. Through extensive experimentation both in vitro and in vivo, the authors reveal ... Read more >>

Cancer Discov (Cancer discovery)
[2020, 10(7):910-912]

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Poly(ADP-ribose) glycohydrolase inhibition sequesters NAD+ to potentiate the metabolic lethality of alkylating chemotherapy in IDH mutant tumor cells.

Hiroaki Nagashima, Christine K Lee, Kensuke Tateishi, Fumi Higuchi, Megha Subramanian, Seamus Rafferty, Lisa Melamed, Julie J Miller, Hiroaki Wakimoto, Daniel P Cahill,

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. Poly(ADP-ribose) polymerases (PARPs) catalyze oligomerization of NAD+ monomers into poly(ADP-ribose) (PAR) chains during cellular response ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Berzosertib May Synergize with Gemcitabine in Serous Ovarian Cancer.

Berzosertib upped survival in those with platinum-resistant tumors and short platinum-free intervals. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Senolytic CAR T Cells Targeting uPAR Treat Lung Cancer in Mice.

In mice, senescence-targeted CAR T cells extended survival in lung cancer and improved liver fibrosis. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Tiragolumab Impresses in Multiple Trials.

The TIGIT inhibitor tiragolumab, alone or in combination with the PD-L1 inhibitor atezolizumab, may be effective against solid cancers. In phase I and II trials, the agent achieved statistically significant results in multiple solid malignancies-most notably non-small cell lung cancer. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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The IDH1 Inhibitor Ivosidenib May Slow IDH1-Mutant Glioma Progression.

Ivosidenib, an inhibitor of mutant IDH1, was safe and showed early evidence of efficacy in glioma. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Targeting CD19-CD22 Aids Younger Patients with ALL.

In a phase I trial of chimeric antigen receptor T cells targeting CD19 and CD22 in younger patients with relapsed or refractory B-cell acute lymphoblastic leukemia, toxicity was manageable, and five of 12 patients had complete responses. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition.

Bryan Ngo, Eugenie Kim, Victoria Osorio-Vasquez, Sophia Doll, Sophia Bustraan, Roger J Liang, Alba Luengo, Shawn M Davidson, Ahmed Ali, Gino B Ferraro, Grant M Fischer, Roozbeh Eskandari, Diane S Kang, Jing Ni, Ariana Plasger, Vinagolu K Rajasekhar, Edward R Kastenhuber, Sarah Bacha, Roshan K Sriram, Benjamin D Stein, Samuel F Bakhoum, Matija Snuderl, Paolo Cotzia, John H Healey, Nello Mainolfi, Vipin Suri, Adam Friedman, Mark Manfredi, David M Sabatini, Drew R Jones, Min Yu, Jean J Zhao, Rakesh K Jain, Kayvan R Keshari, Michael A Davies, Matthew G Vander Heiden, Eva Hernando, Matthias Mann, Lewis C Cantley, Michael E Pacold,

A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Diffuse Large B-cell Lymphoma Responds to Tafasitamab plus Lenalidomide.

Patients with relapsed or refractory diffuse large B-cell lymphoma responded to a novel combination. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Dendritic Cells Form Synapses to Transfer Tumor Antigens to Each Other.

Tumor antigen-loaded vesicles were transferred between dendritic cells for presentation to T cells. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Correction: Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors.

Cancer Discov (Cancer discovery)
[2020, 10(7):1078]

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Neutrophil Extracellular Traps Attract Metastatic Cells to New Sites.

DNA-protein complexes called neutrophil extracellular traps were chemoattractants for metastatic cells. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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T Cells Targeting MAGE-A4 Shrink Tumors.

Autologous T cells engineered to target the MAGE-A4 cancer testis antigen successfully shrank a wide range of solid tumors with a manageable toxicity profile. In a phase I trial, the therapy, ADP-A2M4, showed the most promise in synovial sarcoma, yielding a disease control rate of around 90%. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Tumors Appear Rife with Bacterial Lodgers.

Intracellular bacteria are widespread in tumors throughout the body, forming distinct populations that may play a critical role in shaping the microenvironment of cancers, according to a comprehensive survey of more than 1,000 tumor microbiomes across seven cancer types. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Lineage reversion drives WNT independence in intestinal cancer.

Teng Han, Sukanya Goswami, Yang Hu, Fanying Tang, Maria Paz Zafra, Charles Murphy, Zhen Cao, John T Poirier, Ekta Khurana, Olivier Elemento, Jaclyn F Hechtman, Karuna Ganesh, Rona Yaeger, Lukas E Dow,

The WNT pathway is a fundamental regulator of intestinal homeostasis and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer (CRC). To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that while WNT suppression blocks tumor growth in most ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Epigenetic switch-induced viral mimicry evasion in chemotherapy resistant breast cancer.

Genevieve Deblois, Seyed Ali Madani Tonekaboni, Giacomo Grillo, Constanza Martinez, Yunchi Ingrid Kao, Felicia Tai, Ilias Ettayebi, Anne-Marie Fortier, Paul Savage, Alexandra N Fedor, Xiaojing Liu, Paul Guilhamon, Evelyne Lima-Fernandes, Alex Murison, Hellen Kuasne, Wail Ba-Alawi, David W Cescon, Cheryl H Arrowsmith, Daniel D De Carvalho, Benjamin Haibe-Kains, Jason W Locasale, Morag Park, Mathieu Lupien,

Tumor progression upon treatment arises from pre-existing resistant and/or adaptation of persister cancer cells committing to an expansion phase. Here, we show that evasion from viral mimicry response allows the growth of taxane-resistant triple-negative breast cancer (TNBC). This is enabled by an epigenetic state adapted to taxane-induced metabolic stress, where ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Phase I trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib and AKT inhibitor capivasertib in patients with BRCA1/2 and non-BRCA1/2 mutant cancers.

Timothy A Yap, Rebecca Kristeleit, Vasiliki Michalarea, Stephen J Pettitt, Joline S J Lim, Suzanne Carreira, Desamparados Roda, Rowan Miller, Ruth Riisnaes, Susana Miranda, Ines Figueiredo, Daniel Nava Rodrigues, Sarah Ward, Ruth Matthews, Mona Parmar, Alison Turner, Nina Tunariu, Neha Chopra, Heidrun Gevensleben, Nicholas C Turner, Ruth Ruddle, Florence I Raynaud, Shaun A Decordova, Karen E Swales, Laura Finneran, Emma Hall, Paul Rugman, Justin P O Lindemann, Andrew Foxley, Christopher J Lord, Udai Banerji, Ruth Plummer, Bristi Basu, Juanita S Lopez, Yvette Drew, Johann S de Bono,

Preclinical studies have demonstrated synergy between poly(ADP-ribose) polymerase (PARP) and phosphatidylinositol-3-kinase (PI3K)/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose-escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Tucatinib Is Active Against Brain Metastases in HER2+ Breast Cancer.

The small-molecule tyrosine kinase inhibitor tucatinib outperformed placebo against brain metastases. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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AMG 510 Shows Activity beyond NSCLC.

The latest results from the CodeBreak 100 trial evaluating AMG 510 indicate that this first-in-class KRAS inhibitor, having shown promise in non-small cell lung cancer, is modestly active in several other types of solid tumors, including colorectal cancer. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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Partitioning into Phase-Separated Condensates Mediates Drug Activity.

Anticancer drugs' ability to concentrate in condensates containing their targets affected activity. ... Read more >>

Cancer Discov (Cancer discovery)
[2020, :]

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