Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors Publication date: Available online 7 November 2019 Source: Cancer Cell Author(s): Amaury Leruste, Jimena Tosello, Rodrigo Nalio Ramos, Arnault Tauziède-Espariat, Solène Brohard, Zhi-Yan Han, Kevin Beccaria, Mamy Andrianteranagna, Pamela Caudana, Jovan Nikolic, Céline Chauvin, Leticia Laura Niborski, Valeria Manriquez, Wilfrid Richer, Julien Masliah-Planchon, Sandrine Grossetête-Lalami, Mylene Bohec, Sonia Lameiras, Sylvain Baulande, Celio Pouponnot Summary Rhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1, leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8+ T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation. Graphical Abstract

Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy Publication date: Available online 31 October 2019 Source: Cancer Cell Author(s): Huiying Han, Atul D. Jain, Mihai I. Truica, Javier Izquierdo-Ferrer, Jonathan F. Anker, Barbara Lysy, Vinay Sagar, Yi Luan, Zachary R. Chalmers, Kenji Unno, Hanlin Mok, Rajita Vatapalli, Young A. Yoo, Yara Rodriguez, Irawati Kandela, J. Brandon Parker, Debabrata Chakravarti, Rama K. Mishra, Gary E. Schiltz, Sarki A. Abdulkadir Summary Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents. Graphical Abstract

Paradigms for Precision Medicine in Epichaperome Cancer Therapy Publication date: Available online 24 October 2019 Source: Cancer Cell Author(s): Nagavarakishore Pillarsetty, Komal Jhaveri, Tony Taldone, Eloisi Caldas-Lopes, Blesida Punzalan, Suhasini Joshi, Alexander Bolaender, Mohammad M. Uddin, Anna Rodina, Pengrong Yan, Anson Ku, Thomas Ku, Smit K. Shah, Serge Lyashchenko, Eva Burnazi, Tai Wang, Nicolas Lecomte, Yelena Janjigian, Anas Younes, Connie W. Batlevi Summary Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients' tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection. We thus provide preclinical and clinical evidence in the use of this theranostic platform for precision medicine targeting of the aberrant properties of protein networks. Graphical Abstract

Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer Publication date: Available online 24 October 2019 Source: Cancer Cell Author(s): Victor Quereda, Simon Bayle, Francesca Vena, Sylvia M. Frydman, Andrii Monastyrskyi, William R. Roush, Derek R. Duckett Summary Epigenetic regulation enables tumors to respond to changing environments during tumor progression and metastases and facilitates treatment resistance. Targeting chromatin modifiers or catalytic effectors of transcription is an emerging anti-cancer strategy. The cyclin-dependent kinases (CDKs) 12 and 13 phosphorylate the C-terminal domain of RNA polymerase II, regulating transcription and co-transcriptional processes. Here we report the development of SR-4835, a highly selective dual inhibitor of CDK12 and CDK13, which disables triple-negative breast cancer (TNBC) cells. Mechanistically, inhibition or loss of CDK12/CDK13 triggers intronic polyadenylation site cleavage that suppresses the expression of core DNA damage response proteins. This provokes a “BRCAness” phenotype that results in deficiencies in DNA damage repair, promoting synergy with DNA-damaging chemotherapy and PARP inhibitors. Graphical Abstract

Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG Publication date: Available online 17 October 2019 Source: Cancer Cell Author(s): Jamie N. Anastas, Barry M. Zee, Jay H. Kalin, Mirhee Kim, Robyn Guo, Sanda Alexandrescu, Mario Andres Blanco, Stefanie Giera, Shawn M. Gillespie, Jayanta Das, Muzhou Wu, Sarah Nocco, Dennis M. Bonal, Quang-De Nguyen, Mario L. Suva, Bradley E. Bernstein, Rhoda Alani, Todd R. Golub, Philip A. Cole, Mariella G. Filbin Summary H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs. Graphical Abstract

ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures Publication date: Available online 17 October 2019 Source: Cancer Cell Author(s): Zulekha A. Qadeer, David Valle-Garcia, Dan Hasson, Zhen Sun, April Cook, Christie Nguyen, Aroa Soriano, Anqi Ma, Lyra M. Griffiths, Maged Zeineldin, Dan Filipescu, Luz Jubierre, Asif Chowdhury, Orla Deevy, Xiang Chen, David B. Finkelstein, Armita Bahrami, Elizabeth Stewart, Sara Federico, Soledad Gallego Summary ATRX alterations occur at high frequency in neuroblastoma of adolescents and young adults. Particularly intriguing are the large N-terminal deletions of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) that generate in-frame fusion (IFF) proteins devoid of key chromatin interaction domains, while retaining the SWI/SNF-like helicase region. We demonstrate that ATRX IFF proteins are redistributed from H3K9me3-enriched chromatin to promoters of active genes and identify REST as an ATRX IFF target whose activation promotes silencing of neuronal differentiation genes. We further show that ATRX IFF cells display sensitivity to EZH2 inhibitors, due to derepression of neurogenesis genes, including a subset of REST targets. Taken together, we demonstrate that ATRX structural alterations are not loss-of-function and put forward EZH2 inhibitors as a potential therapy for ATRX IFF neuroblastoma. Graphical Abstract

Toward the Early Detection of Cancer by Decoding the Epigenetic and Environmental Fingerprints of Cell-Free DNA Publication date: 14 October 2019 Source: Cancer Cell, Volume 36, Issue 4 Author(s): Ymke van der Pol, Florent Mouliere Widespread adaptation of liquid biopsy for the early detection of cancer has yet to reach clinical utility. Circulating tumor DNA is commonly detected though the presence of genetic alterations, but only a minor fraction of tumor-derived cell-free DNA (cfDNA) fragments exhibit mutations. The cellular processes occurring in cancer development mark the chromatin. These epigenetic marks are reflected by modifications in the cfDNA methylation, fragment size, and structure. In this review, we describe how going beyond DNA sequence information alone, by analyzing cfDNA epigenetic and immune signatures, boosts the potential of liquid biopsy for the early detection of cancer.

Acquired Resistance Is Oncogene and Drug Agnostic Publication date: 14 October 2019 Source: Cancer Cell, Volume 36, Issue 4 Author(s): Robert C. Doebele Recent approvals of TRK inhibitors have demonstrated the success of a tumor agnostic approach to oncogene-targeted therapy across cancers. Collective data from acquired resistance studies suggest that resistance mechanisms, which include both kinase domain mutations and bypass signaling via RTK-RAS-RAF-MAPK pathways, frequently recur regardless of tumor type, oncogene, and drug.

Thrown for a Loop: Awakening BORIS to Evade ALK Inhibition Therapy Publication date: 14 October 2019 Source: Cancer Cell, Volume 36, Issue 4 Author(s): Esther R. Berko, Yael P. Mossé Mechanisms of acquired resistance to ALK inhibition therapy in neuroblastoma have not yet been elucidated. In a recent issue of Nature, Debruyne et al. demonstrate that resistant MYCN-amplified ALK-mutated neuroblastoma cells overexpress BORIS, resulting in wide-ranging changes in chromatin interaction and transcriptional reprogramming.

PRC2 Plays Red Light, Green Light with MHC-I and CD8+ T Cells Publication date: 14 October 2019 Source: Cancer Cell, Volume 36, Issue 4 Author(s): Johnathan R. Whetstine In this issue of Cancer Cell, Burr et al. report that PRC2 plays a conserved role in silencing antigen presentation and processing genes and, in turn, CD8+ T cell activation. Furthermore, PRC2-targeted therapeutics overcome gene silencing and promote tumor clearance by cytotoxic T cells.