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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 66,801 bioRxiv papers from 294,138 authors.

Most downloaded bioRxiv papers, since beginning of last month

in category cancer biology

2,186 results found. For more information, click each entry to expand.

61: Tumor neoantigen heterogeneity thresholds provide a time window for combination immunotherapy
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Posted to bioRxiv 30 Oct 2019

Tumor neoantigen heterogeneity thresholds provide a time window for combination immunotherapy
124 downloads cancer biology

Guim Aguade Gorgorio, Ricard Sole

Following the advent of immunotherapy as a possible cure for cancer, remarkable insight has been gained on the role of mutational load and neoantigens as key ingredients in T cell recognition of malignancies. However, not all highly mutational tumors react to immune therapies, and even initial success is often followed by eventual relapse. Recent research points out that high heterogeneity in the neoantigen landscape of a tumor might be key in understanding the failure of immune surveillance. In this work we present a mathematical framework able to describe how neoantigen distributions shape the immune response. Modeling T cell reactivity as a function of antigen dominancy and distribution across a tumor indicates the existence of a diversity threshold beyond which T cells fail at controling heterogeneous cancer growth. Furthermore, an analytical estimate for the evolution of average antigen clonality indicates rapid increases in epitope heterogeneity in early malignancy growth. In this scenario, we propose that therapies targeting the tumor prior to immunotherapy can reduce neoantigen heterogeneity, and postulate the existence of a time window, before tumor relapse due to \textit{de novo} resistance, rendering immunotherapy more effective.

62: Extracting Biological Insights from the Project Achilles Genome-Scale CRISPR Screens in Cancer Cell Lines
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Posted to bioRxiv 31 Jul 2019

Extracting Biological Insights from the Project Achilles Genome-Scale CRISPR Screens in Cancer Cell Lines
123 downloads cancer biology

Joshua M Dempster, Jordan Rossen, Mariya Kazachkova, Joshua Pan, Guillaume Kugener, David E Root, Aviad Tsherniak

One of the main goals of the Cancer Dependency Map project is to systematically identify cancer vulnerabilities across cancer types to accelerate therapeutic discovery. Project Achilles serves this goal through the in vitro study of genetic dependencies in cancer cell lines using CRISPR/Cas9 (and, previously, RNAi) loss-of-function screens. The project is committed to the public release of its experimental results quarterly on the DepMap Portal (https://depmap.org), on a pre-publication basis. As the experiment has evolved, data processing procedures have changed. Here we present the current and projected Achilles processing pipeline, including recent improvements and the analyses that led us to adopt them, spanning data releases from early 2018 to the first quarter of 2020. Notable changes include quality control metrics, calculation of probabilities of dependency, and correction for screen quality and other biases. Developing and improving methods for extracting biologically-meaningful scores from Achilles experiments is an ongoing process, and we will continue to evaluate and revise data processing procedures to produce the best results.

63: convertibleCARs: A chimeric antigen receptor system for flexible control of activity and antigen targeting
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Posted to bioRxiv 09 Jul 2019

convertibleCARs: A chimeric antigen receptor system for flexible control of activity and antigen targeting
122 downloads cancer biology

Kyle Landgraf, Steven R. Williams, Daniel Steiger, Dana Gebhart, Stephen Lok, David W. Martin, Kole T. Roybal, Kaman Chan Kim

We have developed a chimeric antigen receptor (CAR) platform that functions as a modular system to address limitations of current CAR therapies. An inert form of the NKG2D extracellular domain (iNKG2D) was used as the ectodomain of the CAR to generate convertibleCAR-T cells. These cells were activated only when an immunological synapse was formed with an antigenic target, mediated by a bispecific adaptor comprised of an iNKG2D-exclusive ULBP2-based ligand fused to an antigen-targeting antibody (MicAbody). Efficacy against Raji tumors in NSG mice was dependent upon doses of both a rituximab-based MicAbody and convertibleCAR-T cells. We have also demonstrated that the exclusive ligand-receptor partnering enabled the targeted delivery of a mutant form of IL-2 to exclusively promote the expansion of convertibleCAR-T cells in vitro and in vivo. By altering the Fv domains of the MicAbody or the payload fused to the orthogonal ligand, convertibleCAR-T cells can be readily targeted or regulated.

64: Metastatic function of METTL18 in breast cancer via actin methylation and Src
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Posted to bioRxiv 05 Nov 2019

Metastatic function of METTL18 in breast cancer via actin methylation and Src
120 downloads cancer biology

Han Gyung Kim, Ji Hye Kim, Woo Seok Yang, Jae Gwang Park, Yong Gyu Lee, Eunji Kim, Yo Han Hong, Minkyeong Jo, Chae Young Lee, Shi Hyung Kim, Nak Yoon Sung, Young-Su Yi, Zubair Ahmed Ratan, Sunggyu Kim, Byong Chul Yoo, Sung-Ung Kang, Young Bong Kim, Sangmin Kim, Hyun-June Paik, Jeong Eon Lee, Seok Jin Nam, Narayanan Parameswaran, Jeung-Whan Han, Jae Youl Cho

Here, We report another type of actin histidine methyltransferase, METTL18, that regulates the metastatic potential of breast cancer in human. Among methyltransferases, METTL18 was highly amplified in human breast cancer. Particularly, poor prognosis was associated with high expression of METTL18 in HER2-negative breast cancer patients. This gene product was found to be a critical component of metastatic responses. Loss of METTL18 expression significantly reduced metastatic responses of breast tumor cells both in vitro and in vivo. It was observed that METTL18 increased actin polymerization, upregulated complex formation with HSP90AA1 and Src, enhanced the activity of an intermediate form of Src with tyrosine phosphorylation at both Y416 and Y527, and induced cellular metastatic responses, including morphological change, migration, and invasion of MDA-MB-231 cells in vitro and in mice. Methylated actin at His73 served as a critical site for interaction with HSP90AA1 and Src to activate p85/PI3K and STAT3. Our findings suggest that METTL18 plays critical roles in metastatic responses of HER2-negative breast cancer cells via actin polymerization and the generation of an intermediate form of Src.

65: Oxygen-responsive p53 tetramer-octamer switch controls cell fate
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Posted to bioRxiv 16 Nov 2019

Oxygen-responsive p53 tetramer-octamer switch controls cell fate
119 downloads cancer biology

Shashank Taxak, Uttam Pati

Solid tumors require an efficient decision-making mechanism to progress through a gradient of hypoxia. Here, we show that an oxygen-sensory p53 tetramer-octamer switch makes cell decision for survival or death in variable hypoxia. Trapping homo-oligomers from biosynthesis cycle, we found a metastable p53 tetramer in cells. Under the operation of switch, tetramer segregates the p53 character of a tumor suppressor and promoter. The p53 switch generates a pattern of its on-off state in time that is specific to the strength of hypoxia. A bidirectional tetramer-octamer conversion in on state decides the restoration of basal state by forward and programs apoptosis upon the reverse shift via p53-MDM2 loop. However, reversible dimer-tetramer transitions in off state trigger chaperoning of HIF-1 complex by tetramer in forward and oncogenic gain-of-function by prion-like dimers in reverse direction. Temporal on-off patterns calibrate stabilized p53 pool by defining the abundance of dimer, tetramer and octamer that ultimately decides diverse cellular outcomes in hypoxia. Through multi-chromophore FRET, we further show that chaperoning of HIF-1 may modulate angiogenesis through a possible flip-flop of the p53T-HIF-1 complex upon DNA. Our results demonstrate how p53 can sense oxygen and act upon its homo-oligomerization states to control cell fate in hypoxic tumors.

66: Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses - implications for the management of irAEs
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Posted to bioRxiv 08 Oct 2018

Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses - implications for the management of irAEs
116 downloads cancer biology

Arianna Draghi, Troels Holz Borch, Haja Dominike Radic, Christopher Aled Chamberlain, Aishwarya Gokuldass, Inge Marie Svane, Marco Donia

Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune-related adverse events (irAEs). Immunosuppression with high doses of corticosteroids or, in refractory cases, with tumor necrosis factor (TNF) antagonists, are the mainstay of treatment for irAEs. It is currently unknown what is the impact of corticosteroids and anti-TNF on the activity of antitumor T cells. In this study, the influences of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10 to 125 mg prednisolone) and infliximab (anti-TNF) on the activation and killing ability of tumor-infiltrating lymphocytes (TILs) was tested in vitro. Overall, dexamethasone at low or intermediate/high dose impaired the activation (respectively -46% and -62%) and tumor-killing ability (respectively -48% and -53%) of tumor-specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T cell activation (-20%) and tumor killing (-10%). A brief resting following exposure to dexamethasone was sufficient to rescue the in vitro activity of TILs. In conclusion, clinically-relevant doses of infliximab only influenced to a lesser extent the activity of tumor-specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. These data support steroid-sparing strategies and early initiation of anti-TNF for the treatment of irAEs in immuno-oncology.

67: A consensus molecular classification of muscle-invasive bladder cancer
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Posted to bioRxiv 07 Dec 2018

A consensus molecular classification of muscle-invasive bladder cancer
114 downloads cancer biology

Aurelie Kamoun, Aurélien de Reyniès, Yves Allory, Gottfrid Sjödahl, A. Gordon Robertson, Roland Seiler, Katherine A Hoadley, Hikmat Al-Ahmadie, Woonyoung Choi, Clarice S. Groeneveld, Mauro A. A. Castro, Jacqueline Fontugne, Pontus Eriksson, Qianxing Mo, Jordan Kardos, Alexandre Zlotta, Arndt Hartmann, Colin P. Dinney, Joaquim Bellmunt, Thomas Powles, Núria Malats, Keith S. Chan, William Y. Kim, David J McConkey, Peter C. Black, Lars Dyrskjot, Mattias Höglund, Seth P. Lerner, Francisco X Real, François Radvanyi, The Bladder Cancer Molecular Taxonomy Group

Muscle-Invasive Bladder Cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, yielding diverse sets of subtypes. This diversity hampers the clinical application of such knowledge. Here, we report the results of a large international effort to reach a consensus on MIBC molecular subtypes. Using 1750 MIBC transcriptomes and a network-based analysis of six independent MIBC classification systems, we identified a consensus set of six molecular classes: Luminal Papillary (24%), Luminal Non-Specified (8%), Luminal Unstable (15%), Stroma-rich (15%), Basal/Squamous (35%), and Neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics. This consensus system offers a robust framework that will enable testing and validating predictive biomarkers in future clinical trials.

68: A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of Diffuse Large B-cell Lymphoma
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Posted to bioRxiv 07 Nov 2019

A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of Diffuse Large B-cell Lymphoma
114 downloads cancer biology

Kohta Miyawaki, Koji Kato, Takeshi Sugio, Kensuke Sasaki, Hiroaki Miyoshi, Yuichiro Semba, Yoshikane Kikushige, Yasuo Mori, Yuya Kunisaki, Hiromi Iwasaki, Toshihiro Miyamoto, Frank C Kuo, Jon C. Aster, Koichi Ohshima, Takahiro Maeda, Koichi Akashi

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using highly-sensitive transcriptome profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of ″unfavorable″ molecular signatures.

69: Attenuated Salmonella typhimurium cancer therapy has direct effects on the tumor epithelium in colorectal cancer
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Posted to bioRxiv 21 Aug 2019

Attenuated Salmonella typhimurium cancer therapy has direct effects on the tumor epithelium in colorectal cancer
110 downloads cancer biology

Kendle M Maslowski, Masumi Takahashi, Yumiko Nakanishi, Gillian M Mackie, Isabel Everard, Alastair Copland, Hirotsugu Oda, Takashi Kanaya, Hiroshi Ohno

Bacterial cancer therapy (BCT) shows great promise for treatment of solid tumors, yet basic mechanisms of bacterial-induced tumor suppression remain undefined. The intestinal epithelium is the natural route of infection for Salmonella and thus harbors innate immune defenses which protect against infection. Attenuated strains of Salmonella enterica serovar Typhimurium ( S Tm) have commonly been used in mouse models of BCT, largely with the use of xenograft and orthotopic transplant cancer models. We aimed to better understand the tumor epithelium-targeted mechanisms of BCT by using mouse models of intestinal tumorigenesis and tumor organoid cultures to assess the effectiveness and mechanisms of treatment with aromatase A-deficient S Tm ( STmΔ aroA ). STmΔ aroA delivered by oral gavage could significantly reduce tumor burden and tumor load in both a colitis-associated colon cancer model (CAC) and in Apcmin/+ mice. STmΔ aroA colonization of tumors caused alterations in transcription of mRNAs associated with epithelial−mesenchymal transition as well as metabolic and cell cycle-related transcripts. Metabolomic analysis of tumors demonstrated alteration in the metabolic environment of STmΔ aroA -treated tumors, suggesting STmΔ aroA imposes metabolic competition on the tumor. Use of tumor organoid cultures in vitro demonstrated that STmΔ aroA can directly affect the tumor epithelium with alterations in transcripts and metabolites similar to in vivo -treated tumors. Thereby, we demonstrate that bacterial cancer therapy is efficacious in autochthonous intestinal cancer models, that BCT imposes metabolic competition, and that BCT has direct effects on the tumor epithelium, which have not previously been appreciated.

70: Inference of tumor cell-specific transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection of cancer
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Posted to bioRxiv 30 Oct 2018

Inference of tumor cell-specific transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection of cancer
110 downloads cancer biology

Peter Ulz, Samantha Perakis, Qing Zhou, Tina Moser, Jelena Belic, Isaac Lazzeri, Albert Wölfler, Armin Zebisch, Armin Gerger, Gunda Pristauz, Edgar Petru, Brandon White, Charles E.S. Roberts, John St. John, Michael G Schimek, Jochen B Geigl, Thomas Bauernhofer, Heinz Sill, Christoph Bock, Ellen Heitzer, Michael R Speicher

Deregulation of transcription factors (TFs) is an important driver of tumorigenesis. We developed and validated a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyzed whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a newly developed bioinformatics pipeline that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observed patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of early detection of colorectal carcinomas. Our approach for mapping tumor-specific transcription factor binding in vivo based on blood samples makes a key part of the noncoding genome amenable to clinical analysis.

71: The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis
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Posted to bioRxiv 08 Nov 2019

The Hippo pathway oncoprotein YAP promotes melanoma cell invasion and spontaneous metastasis
108 downloads cancer biology

Xiaomeng Zhang, Lie Yang, Pacman Szeto, Youfang Zhang, Kaushalya Amarasinghe, Jason Li, Catriona McLean, Mark Shackleton, Kieran Harvey

Melanoma is a deadly form of skin cancer that accounts for a disproportionally large proportion of cancer-related deaths in younger people. Compared to most other skin cancers, a feature of melanoma is its high metastatic capacity, although molecular mechanisms that confer this are not well understood. The Hippo pathway is a key regulator of organ growth and cell fate that is deregulated in many cancers. To analyse the Hippo pathway in cutaneous melanoma, we generated a transcriptional signature of pathway activity in melanoma cells. Hippo-mediated transcriptional activity varied in melanoma cell lines but failed to cluster with known genetic drivers of melanomagenesis such as BRAF and NRAS mutation status. Instead, it correlated strongly with published gene expression profiles linked to melanoma cell invasiveness. Consistent with this, the central Hippo oncogene, YAP, was both necessary and sufficient for melanoma cell invasion in vitro. In in vivo murine studies, YAP promoted spontaneous melanoma metastasis, whilst the growth of YAP-expressing primary tumours was impeded. Finally, we identified the YAP target genes AXL, THBS1 and CYR61 as key mediators of YAP-induced melanoma cell invasion. These data suggest that the Hippo pathway is a critical regulator of melanoma metastasis.

72: Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers
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Posted to bioRxiv 15 Nov 2019

Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers
105 downloads cancer biology

Bing He, Peng Gao, Yang-yang Ding, Chia-hui Chen, Gregory Chen, Changya Chen, Hannah Kim, Sarah K. Tasian, Stephen P Hunger, Kai Tan

Interpreting the function of noncoding mutations in cancer genomes remains a major challenge. Here we developed a computational framework to identify risk noncoding mutations of all classes by joint analysis of mutation and gene expression data. We identified thousands of SNVs/small indels and structural variants as candidate risk mutations in five major pediatric cancers. We experimentally validated the oncogenic role of CHD4 overexpression via enhancer hijacking in B-ALL. We observed a general exclusivity of coding and noncoding mutations affecting the same genes and pathways. We showed that integrated mutation signatures can help define novel patient subtypes with different clinical outcomes. Our study introduces a general strategy to systematically identify and characterize the full spectrum of noncoding mutations in cancers.

73: Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response
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Posted to bioRxiv 09 Nov 2019

Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response
105 downloads cancer biology

Ping Zhang, Isaac Kitchen-Smith, Lingyun Xiong, Giovanni Stracquadanio, Katherine Brown, Philipp Richter, Marsha Wallace, Elisabeth Bond, Natasha Sahgal, Samantha Moore, Svanhild Nornes, Sarah De Val, Mirvat Surakhy, David Sims, Xuting Wang, Douglas A Bell, Jorge Zeron-Medina, Yanyan Jiang, Anderson Ryan, Joanna Selfe, Janet Shipley, Siddhartha Kar, Paul Pharoah, Chey Loveday, Rick Jansen, Lukasz F. Grochola, Claire Palles, Andrew Protheroe, Val Millar, Daniel Ebner, Meghana Pagadala, Sarah P Blagden, Tim Maughan, Enric Domingo, Ian Tomlinson, Clare Turnbull, Hannah Carter, Gareth Bond

Insights into oncogenesis derived from cancer susceptibility loci could facilitate better cancer management and treatment through precision oncology. However, therapeutic applications have thus far been limited by our current lack of understanding regarding both their interactions with somatic cancer driver mutations and their influence on tumorigenesis. Here, by integrating germline datasets relating to cancer susceptibility with tumour data capturing somatically-acquired genetic variation, we provide evidence that single nucleotide polymorphism (SNPs) and somatic mutations in the p53 tumor suppressor pathway can interact to influence cancer development, progression and treatment response. We go on to provide human genetic evidence of a tumor-promoting role for the pro-survival activities of p53, which supports the development of more effective therapy combinations through their inhibition in cancers retaining wild-type p53.

74: PARPi synthetic lethality derives from replication-associated single-stranded DNA gaps
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Posted to bioRxiv 25 Sep 2019

PARPi synthetic lethality derives from replication-associated single-stranded DNA gaps
102 downloads cancer biology

Ke Cong, Arne Nedergaard Kousholt, Min Peng, Nicholas J Panzarino, Wei Ting Chelsea Lee, Sumeet Nayak, John Krais, Jennifer Calvo, Matt Bere, Eli Rothenberg, Neil Johnson, Jos Jonkers, Sharon Cantor

BRCA1 or BRCA2 (BRCA)-deficient tumor cells have defects in DNA double strand break repair by homologous recombination (HR) and fork protection (FP) that are thought to underlie the sensitivity to poly(ADP-ribose) polymerase inhibitor (PARPi). Given the recent finding that PARPi accelerates DNA replication, it was proposed that high speed DNA replication leads to DNA double strand breaks (DSBs). Here, we tested the alternative hypothesis that PARPi sensitivity in BRCA deficient cells results from combined replication dysfunction that causes a lethal accumulation of replication-associated single-stranded DNA (ssDNA) gaps. In support of a gap toxicity threshold, PARPi-induced ssDNA gaps accumulate more excessively in BRCA deficient cells and are suppressed in de novo and genetic models of PARPi resistance while defects in HR or FP often lack this correlation. We also uncouple replication speed from lethality. The clear link between PARPi sensitivity and ssDNA gaps provides a new paradigm for understanding synthetic lethal interactions.

75: Modeling adaptive therapy in non-muscle invasive bladder cancer
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Posted to bioRxiv 06 Nov 2019

Modeling adaptive therapy in non-muscle invasive bladder cancer
102 downloads cancer biology

Meghan C Ferrall-Fairbanks, Gregory Kimmel, Mik Black, Rafael Bravo, Oana Deac, Pierre Martinez, Maggie Myers, Fereshteh Nazari, Ana Osojnik, Hemachander Subramanian, Yannick Viossat, Freddie Whiting, Roger Li, Karen M. Mann, Philipp M Altrock

Bladder cancer is the 9th most commonly diagnosed cancer. Nearly half of patients with early stage bladder cancer treated with the immune-stimulating agent BCG have disease recurrence, while 13% progress to invasive bladder cancer. Here we explored the potential of tumor mutational heterogeneity and the role of pro- and anti-inflammatory cytokines to identify different subtypes of bladder cancer that may predict therapeutic response to BCG. Further, we used mathematical modeling of dosing strategies to infer tumor response to varying doses and time schedules f BCG administration. As a proof-of-concept, present adaptive therapy scheduling of BCG as a viable strategy to control tumor size and minimize recurrence.

76: IMPDH inhibitors for anti-tumor therapy in tuberous sclerosis complex
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Posted to bioRxiv 11 Nov 2019

IMPDH inhibitors for anti-tumor therapy in tuberous sclerosis complex
100 downloads cancer biology

Alexander J. Valvezan, Spencer K Miller, Molly C McNamara, Margaret E Torrence, John M Asara, Elizabeth P Henske, Brendan D. Manning

Purpose: mTORC1 is a master regulator of anabolic cell growth and proliferation that is activated in the majority of human tumors. We recently demonstrated that elevated mTORC1 activity in cells and tumors can confer dependence on IMPDH, the rate-limiting enzyme in de novo guanylate nucleotide synthesis, to support increased ribosome biogenesis and cell viability. Pharmacological agents that inhibit IMPDH, such as mizoribine and mycophenolic acid (CellCept), are in wide clinical use as immunosuppressants. However, whether these agents can be repurposed for anti-tumor therapy requires further investigation in preclinical models, including direct comparisons to identify the best candidate(s) for advancement. Experimental Design: Distinct IMPDH inhibitors were tested on cell and mouse tumor models of tuberous sclerosis complex (TSC), a genetic tumor syndrome featuring widespread lesions with uncontrolled mTORC1 activity. Growth and viability were assessed in cells and tumors lacking the TSC2 tumor suppressor, together with drug pharmacokinetics and pharmacodynamics, target inhibition, and effects on tumor, tissue, and plasma metabolic biomarkers. Results: Mizoribine, used throughout Asia, exhibited greater selectivity in specifically targeting TSC2-deficient cells with active mTORC1 compared to the FDA-approved IMPDH inhibitors mycophenolic acid or ribavirin, or approved inhibitors of other nucleotide synthesis enzymes. In distinct tumor models, mizoribine demonstrated robust anti-tumor efficacy that is superior to mycophenolic acid, despite similar immunosuppressive effects. Conclusions: These results provide pre-clinical rationale for repurposing mizoribine as an antitumor agent in tumors with active mTORC1, such as in TSC. Our findings also suggest that IMPDH inhibitors should be revisited in cancer models where MMF has shown modest efficacy.

77: The repertoire of serous ovarian cancer non-genetic heterogeneity revealed by single-cell sequencing of normal fallopian tube epithelial cells
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Posted to bioRxiv 17 Jun 2019

The repertoire of serous ovarian cancer non-genetic heterogeneity revealed by single-cell sequencing of normal fallopian tube epithelial cells
98 downloads cancer biology

Zhiyuan Hu, Mara Artibani, Abdulkhaliq Alsaadi, Nina Wietek, Matteo Morotti, Laura Santana Gonzalez, Salma El-Sahhar, Mohammad KaramiNejadRanjbar, Garry Mallett, Tingyan Shi, Kenta Masuda, Yiyan Zheng, Kay Chong, Stephen Damato, Sunanda Dhar, Riccardo Garruto Campanile, Hooman Soleymani majd, Vincenzo Cerundolo, Tatjana Sauka-Spengler, Christopher Yau, Ahmed Ashour Ahmed

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH can be accurately measured when informed by the molecular signatures of the normal cells of origin. We surveyed the transcriptomes of ~ 4000 normal fallopian tube epithelial (FTE) cells, the cells of origin of serous ovarian cancer (SOC), and identified six FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH that was previously unrecognized. Importantly, NGH-based stratification of ~1700 tumors robustly predicted survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.

78: Defective Nucleotide Catabolism Defines a Subset of Cancers Sensitive to Purine Nucleoside Phosphorylase Inhibition
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Posted to bioRxiv 29 Oct 2019

Defective Nucleotide Catabolism Defines a Subset of Cancers Sensitive to Purine Nucleoside Phosphorylase Inhibition
98 downloads cancer biology

Evan R Abt, Vincent Lok, Thuc M Le, Soumya Poddar, Woosuk Kim, Joseph R Capri, Gabriel Abril-Rodriguez, Johannes Czernin, Timothy R Donahue, Thomas Mehrling, Antoni Ribas, Caius G Radu

Small molecule inhibitors of purine nucleoside phosphorylase (PNP) have been explored as a treatment strategy for leukemia and lymphoma, however, the determinants of response to this class of drugs are incompletely understood. PNP inhibitors impair cell proliferation by preventing catabolism of the nucleoside deoxyguanosine (dG) which induces toxic imbalances amongst intracellular deoxyribonucleotide triphosphate (dNTP) pools following its phosphorylation and trapping by nucleoside kinases. We hypothesized that differential nucleoside uptake or catabolism defines cancer cell lines as either sensitive or resistant to PNP inhibition. Among cancer cell lines we found that T-cell acute lymphoblastic leukemia (T-ALL) cells are uniquely and acutely sensitive to PNP inhibition whereas the B-cell leukemia and solid tumor models are completely resistant. We determined that although the nucleoside scavenging kinase deoxycytidine kinase (dCK) was active in all cells tested, PNP inhibitors only induced dGTP pool increases in sensitive models. By evaluating the expression of key genes involved in nucleotide scavenging, biosynthesis, and phosphohydrolysis in a panel of sensitive and resistant cell lines we found that the dNTP phosphohydrolase SAM histidine aspartate containing protein 1 (SAMHD1) was exclusively expressed in resistant models. Using CRISPR/Cas9 SAMHD1 knockout cell lines, we verified that PNP inhibitor sensitivity is a function of SAMHD1 expression and determined that the pharmacological inhibition of dCK or genetic restoration of SAMHD1 conferred resistance to PNP inhibition. Importantly, we determined that low expression of SAMHD1 is not limited to T-ALL as subset of established and primary solid tumors models are SAMHD1-deficient. These solid tumor models were consistently acutely sensitive to PNP inhibitors which indicates that the utility of PNP inhibitors extends beyond hematological malignancies. Additionally, we found that deoxycytidine (dC) can limit the anti-proliferative effects of PNP inhibitors by competing with dG for phosphorylation by dCK but this effect can be overcome by expression of dC-catabolizing gene cytidine deaminase (CDA). Collectively, these results indicate that SAMHD1, dCK and CDA are critical biomarkers that must be used to stratify patients in clinical trials evaluating pharmacological PNP inhibition.

79: Development of a novel preclinical glioblastoma mouse model and therapeutic impact of IRE1 inhibition
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Posted to bioRxiv 14 Nov 2019

Development of a novel preclinical glioblastoma mouse model and therapeutic impact of IRE1 inhibition
97 downloads cancer biology

Pierre-Jean Le Reste, Raphael Pineau, Juhi Samal, Gwenaele Jegou, Stephanie Lhomond, Adrienne M Gorman, Afshin Samali, John B Patterson, Qinping Zeng, Abhay Pandit, Marc AUBRY, Nicolas Soriano, Amandine Etcheverry, Jean Mosser, Tony Avril, eric chevet

Glioblastoma multiforme (GBM) is the most severe primary brain cancer. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy patients survival post diagnosis remains short. A limitation for success in finding novel improved therapeutic options for such dismal disease partly lies in the lack of a relevant animal model that accurately recapitulates patient disease and standard of care. In the present study, we have developed a novel immunocompetent GBM model that includes tumor surgery and a radio/chemotherapy regimen resembling the Stupp protocol and have used this model to test the impact of the pharmacological inhibition of the endoplasmic reticulum (ER) stress sensor IRE1, on treatment efficacy.

80: Reprogrammed mRNA translation drives metabolic response to therapeutic targeting of ribosome biogenesis
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Posted to bioRxiv 20 Nov 2019

Reprogrammed mRNA translation drives metabolic response to therapeutic targeting of ribosome biogenesis
97 downloads cancer biology

Eric P Kusnadi, Anna S Trigos, Carleen Cullinane, David L Goode, Ola S Larsson, Jennifer R Devlin, Keefe T Chan, David P DeSouza, Malcolm J. McConville, Grant A McArthur, George Thomas, Elaine Sanij, Gretchen Poortinga, Ross D Hannan, Katherine M Hannan, Jian Kang, Richard B Pearson

Elevated ribosome biogenesis in oncogene-driven cancers is commonly targeted by DNA-damaging cytotoxic drugs. Our first-in-man trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA Polymerase I transcription, revealed single agent efficacy in refractory blood cancers. Here we show that the marked improvement in the in vivo efficacy of CX-5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this co-treatment is driven by translational re-wiring that results in dysregulated cellular metabolism and a cAMP-dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies identify the molecular mechanisms responsible for the acute regulation of the translational apparatus and its functional adaptation upon selective drug-induced pressure, and will facilitate the rational design of more effective regimens for Pol I-directed ribosome targeting therapies.

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