bims-drucaf 2020-07-26 papers

bims-drucaf

Biomed News

on Drugs targeting chromatin associated factor in cancer therapy

Issue of 2020–07–26
twelve papers selected by
Tian V. Tian, Vall d’Hebron Institute of Oncology

Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors.
A chemical conjugation of JQ-1 and a TLR7 agonist induces tumoricidal effects in a murine model of melanoma via enhanced immunomodulation.
Targeting BET bromodomain proteins in cancer: The example of lymphomas.
Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment.
Role of H3K9 demethylases in DNA double-strand break repair.
Chemical strategies to overcome resistance against targeted anticancer therapeutics.
Low-dose triptolide enhances antitumor effect of JQ1 on acute myeloid leukemia through inhibiting RNA polymerase II in vitro and in vivo.
Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.
Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets.
BRG1 loss predisposes lung cancers to replicative stress and ATR dependency.
PROTAC: A promising technology for cancer treatment.
Integrating evolutionary dynamics into cancer therapy.

Biomolecules. 2020 Jul 16. pii: E1061. [Epub ahead of print]10(7):

Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors.

Alexandre Perrier, Audrey Didelot, Pierre Laurent-Puig, Hélène Blons, Simon Garinet.

  Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were assessed to better select patients. Although PD-L1 expression remains the only validated marker in clinics, molecular profiling has brought valuable information, showing that the tumor mutation load and microsatellite instability (MSI) status were associated to higher response rates in nearly all cancer types. Moreover, in lung cancer, EGFR and MET mutations, oncogene fusions or STK11 inactivating mutations were associated with low response rates. Cancer progression towards invasive phenotypes that impede immune surveillance relies on complex regulatory networks and cell interactions within the tumor microenvironment. Epigenetic modifications, such as the alteration of histone patterns, chromatin structure, DNA methylation status at specific promoters and changes in microRNA levels, may alter the cell phenotype and reshape the tumor microenvironment, allowing cells to grow and escape from immune surveillance. The objective of this review is to make an update on the identified epigenetic changes that target immune surveillance and, ultimately, ICI responses, such as histone marks, DNA methylation and miR signatures. Translational studies or clinical trials, when available, and potential epigenetic biomarkers will be discussed as perspectives in the context of combination treatment strategies to enhance ICI responses in patients with solid tumors.

Keywords:  cancer; combination approaches; epigenetics; immune checkpoint inhibitors; immunotherapy; predictive biomarkers; resistance mechanisms; tumor immune escape; tumor microenvironment; tumor resistance

DOI:  https://doi.org/10.3390/biom10071061
Int J Cancer. 2020 Jul 19.

A chemical conjugation of JQ-1 and a TLR7 agonist induces tumoricidal effects in a murine model of melanoma via enhanced immunomodulation.

Xiaodong Wang, Bingying Yu, Birong Cao, Ji Zhou, Yongqiang Deng, Zhulin Wang, Guangyi Jin.

  In recent year, inhibitors of the BET bromodomain proteins, such as BRD4 inhibitors, have demonstrated robust antitumor activity. JQ-1, a representative small molecular BRD4 inhibitor, is also effective to block PD-1/PD-L1 signaling by significantly decreasing the PD-L1 expression on tumor cells. However, toxicity of BRD4 inhibitors on lymphoid and hematopoietic tissues limits their clinical usage. In this research, we designed and studied an immunogenic BRD4 inhibitor, SZU-119, by coupling JQ-1 with a TLR7 agonist, SZU-101. In vitro, SZU-119 stimulated the production of cytokines in mouse BMDCs and spleen lymphocytes, and inhibited the expression of PD-L1 in mouse B16 tumor cells. In vivo, SZU-119 suppressed the B16 tumor growth at both injected and uninjected sites, and prolonged the survival time of mice. SZU-119 elevated the number of total CD8+ and IFN-γ+ CD8+ T cells in spleens, with greater CTL cytotoxicity to B16 tumor cells. It was also observed that the infiltration of CD8+ T cells were increased in tumors at both local and distant sites, and the PD-L1 expression was decreased in tumor cells at the primary site. In conclusion, we have demonstrated that SZU-119 activated the innate immune cells, kept efficacy of PD-L1 blockade and abrogated immune toxicity, showing more potent antitumor effects than the simple mixture of SZU-101 and JQ-1 in a mouse melanoma model. Our work provides new insights for the development of anti-melanoma drugs that concurrently target innate and adaptive immunity. This article is protected by copyright. All rights reserved.

Keywords:  JQ-1; Melanoma; PD-L1; TLR7

DOI:  https://doi.org/10.1002/ijc.33222
Pharmacol Ther. 2020 Jul 18. pii: S0163-7258(20)30161-3. [Epub ahead of print] 107631

Targeting BET bromodomain proteins in cancer: The example of lymphomas.

Filippo Spriano, Anastasios Stathis, Francesco Bertoni.

  The Bromo- and Extra-Terminal domain (BET) family proteins act as "readers" of acetylated histones and they are important transcription regulators. BRD2, BRD3, BRD4 and BRDT, part of the BET family, are important in different tumors, where upregulation or translocation often occurs. The potential of targeting BET proteins as anti-cancer treatment originated with data obtained with a first series of compounds, and there are now several data supporting BET inhibition in both solid tumors and hematological malignancies. Despite very positive preclinical data in different tumor types, the clinical results have been so far moderate. Using lymphoma as an example to review the data produced in the laboratory and in the context of the early clinical trials, we discuss the modalities to make BET targeting more efficient both generating novel generation of compounds and by exploring the combination with small molecules affecting various signaling pathways, BCL2, or DNA damage response signaling, but also with additional epigenetic agents and with immunotherapy. We also discuss the mechanisms of resistance and the toxicity profiles so far reported.

Keywords:  BET; BRD2; BRD4; DNA damage response; JQ1; MYC; PROTAC; bromodomain; diffuse large B-cell lymphoma; epigenetics; immuno-oncology; lymphoma

DOI:  https://doi.org/10.1016/j.pharmthera.2020.107631
Cell Mol Immunol. 2020 Jul 22.

Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment.

Xingyi Pan, Lei Zheng.

  Epigenetic regulation of gene expression in cancer cells has been extensively studied in recent decades, resulting in the FDA approval of multiple epigenetic agents for treating different cancer types. Recent studies have revealed novel roles of epigenetic dysregulation in altering the phenotypes of immune cells and tumor-associated stromal cells, including fibroblasts and endothelial cells. As a result, epigenetic dysregulation of these cells reshapes the tumor microenvironment (TME), changing it from an antitumor environment to an immunosuppressive environment. Here, we review recent studies demonstrating how specific epigenetic mechanisms drive aspects of stromal and immune cell differentiation with implications for the development of solid tumor therapeutics, focusing on the pancreatic ductal adenocarcinoma (PDA) TME as a representative of solid tumors. Due to their unique ability to reprogram the TME into a more immunopermissive environment, epigenetic agents have great potential for sensitizing cancer immunotherapy to augment the antitumor response, as an immunopermissive TME is a prerequisite for the success of cancer immunotherapy but is often not developed with solid tumors. The idea of combining epigenetic agents with cancer immunotherapy has been tested both in preclinical settings and in multiple clinical trials. In this review, we highlight the basic biological mechanisms underlying the synergy between epigenetic therapy and immunotherapy and discuss current efforts to translate this knowledge into clinical benefits for patients.

Keywords:  Epigenetics; Immuno-modulation; Tumor microenvironment

DOI:  https://doi.org/10.1038/s41423-020-0505-9
J Cancer Biol. 2020 ;1(1): 10-15

Role of H3K9 demethylases in DNA double-strand break repair.

Hee-Young Jeon, Arif Hussain, Jianfei Qi.

  H3K9 demethylases can remove the repressive H3K9 methylation marks on histones to alter chromatin structure, gene transcription and epigenetic state of cells. By counteracting the function of H3K9 methyltransferases, H3K9 demethylases have been shown to play an important role in numerous biological processes, including diseases such as cancer. Recent evidence points to a key role for some H3K9 demethylases in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR) and/or non-homologous end joining (NHEJ) pathways. Mechanistically, H3K9 demethylases can upregulate the expression of DNA repair factors. They can also be recruited to the DNA damage sites and regulate the recruitment or function of DNA repair factors. Here, we will discuss the role and mechanisms of H3K9 demethylases in the regulation of DSB repair.

Keywords:  DNA damage repair; H3K9; cancer; demethylation; double-strand breaks; epigenetic; histone demethylase

DOI:  https://doi.org/10.46439/cancerbiology.1.003
Nat Chem Biol. 2020 Aug;16(8): 817-825

Chemical strategies to overcome resistance against targeted anticancer therapeutics.

Rudolf Pisa, Tarun M Kapoor.

Emergence of resistance is a major factor limiting the efficacy of molecularly targeted anticancer drugs. Understanding the specific mutations, or other genetic or cellular changes, that confer drug resistance can help in the development of therapeutic strategies with improved efficacies. Here, we outline recent progress in understanding chemotype-specific mechanisms of resistance and present chemical strategies, such as designing drugs with distinct binding modes or using proteolysis targeting chimeras, to overcome resistance. We also discuss how targeting multiple binding sites with bifunctional inhibitors or identifying collateral sensitivity profiles can be exploited to limit the emergence of resistance. Finally, we highlight how incorporating analyses of resistance early in drug development can help with the design and evaluation of therapeutics that can have long-term benefits for patients.

DOI: https://doi.org/10.1038/s41589-020-0596-8
Mol Carcinog. 2020 Jul 21.

Low-dose triptolide enhances antitumor effect of JQ1 on acute myeloid leukemia through inhibiting RNA polymerase II in vitro and in vivo.

Yuanfei Shi, Haijun Zhao, Jing Ye, Zhifeng Li, Manman Deng, Jie Zha, Yong Zhou, Hanyan Zeng, Yun Lin, Xuan Pu, Chengcen Guo, Haihan Song, Yi Qiu, Bing Xu.

  The bromodomain and extra-terminal (BET) domain inhibitor JQ1 exerts potent anticancer activity in various cancer cells. However, the resistance to BET inhibitors in leukemia stem cells limits its implication in acute myeloid leukemia (AML). High concentration of triptolide (TPL) presents anticancer activities but with adverse effects. Here, we investigated whether the combination of low-dose TPL with JQ1 could help to circumvent the dilemma of drug resistance and side effect in treating AML. AML cell lines, primary cells from 10 AML patients with different status, as well as AML mice model were subjected to different treatments and apoptotic related protein expression were evaluated. Data showed that low-dose TPL combined with JQ1 effectively killed AML cell lines and primary cells from AML patients without exerting significantly greater lethal activity against normal cells. Mechanism study revealed that low-dose TPL combined with JQ1 triggered reactive oxygen species production and induced mitochondrial-mediated apoptosis in AML cells, in which the inhibition of RNA polymerase II to downregulate c-Myc was mainly responsible for the enhanced activity of TPL in combination with JQ1. In vivo study presented that cotreatment with low-dose TPL and JQ1 significantly reduced tumor burden of the NOD/SCID mice engrafted with MOLM-13 cells. In conclusion, low-dose TPL enhanced the antitumor effect of JQ1 on AML without increasing the side effects, supporting a potential option for AML treatment.

Keywords:  JQ1; acute myeloid leukemia; low-dose; triptolide

DOI:  https://doi.org/10.1002/mc.23238
Cancer Cell. 2020 Jul 08. pii: S1535-6108(20)30316-0. [Epub ahead of print]

Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.

Nemanja Despot Marjanovic, Matan Hofree, Jason E Chan, David Canner, Katherine Wu, Marianna Trakala, Griffin G Hartmann, Olivia Smith, Jonathan Kim, Kelly Victoria Evans, Anna Hudson, Orr Ashenberg, Caroline B M Porter, Alborz Bejnood, Ayshwarya Subramanian, Kenneth Pitter, Yan Yan, Toni Delroy, Devan R Phillips, Nisargbhai Shah, Ojasvi Chaudhary, Alexander Tsankov, Travis Hollmann, Natasha Rekhtman, Pierre P Massion, John T Poirier, Linas Mazutis, Ruifang Li, Joo-Hyeon Lee, Angelika Amon, Charles M Rudin, Tyler Jacks, Aviv Regev, Tuomas Tammela.

  Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.

Keywords:  cell state transition; lung cancer; plasticity; single-cell transcriptomics; tumor evolution; tumor heterogeneity

DOI:  https://doi.org/10.1016/j.ccell.2020.06.012
Sci Rep. 2020 Jul 21. 10(1): 12027

Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets.

Kendra R Vann, Dhananjaya Pal, Guillermo A Morales, Adam M Burgoyne, Donald L Durden, Tatiana G Kutateladze.

Development of small molecule compounds that target several cancer drivers has shown great therapeutic potential. Here, we developed a new generation of highly potent thienopyranone (TP)-based inhibitors for the BET bromodomains (BDs) of the transcriptional regulator BRD4 that have the ability to simultaneously bind to phosphatidylinositol-3 kinase (PI3K) and/or cyclin-dependent kinases 4/6 (CDK4/6). Analysis of the crystal structures of the complexes, NMR titration experiments and IC50 measurements reveal the molecular basis underlying the inhibitory effects and selectivity of these compounds toward BDs of BRD4. The inhibitors show robust cytotoxic effects in multiple cancer cell lines and induce cell-cycle arrest and apoptosis. We further demonstrate that concurrent disruption of the acetyllysine binding function of BRD4 and the kinase activities of PI3K and CDK4/6 by the TP inhibitor improves efficacy in several cancer models. Together, these findings provide further compelling evidence that these multi-action inhibitors are efficacious and more potent than single inhibitory chemotypes.

DOI: https://doi.org/10.1038/s41598-020-68964-6
Cancer Res. 2020 Jul 20. pii: canres.1744.2020. [Epub ahead of print]

BRG1 loss predisposes lung cancers to replicative stress and ATR dependency.

Manav Gupta, Carla P Concepcion, Caroline G Fahey, Hasmik Keshishian, Arjun Bhutkar, Christine F Brainson, Francisco J Sanchez-Rivera, Patrizia Pessina, Jonathan Y Kim, Antoine Simoneau, Margherita Paschini, Mary C Beytagh, Caroline R Stanclift, Monica Schenone, D R Mani, Chendi Li, Audris Oh, Fei Li, Hai Hu, Angeliki Karatza, Roderick T Bronson, Alice T Shaw, Aaron N Hata, Kwok-Kin Wong, Lee Zou, Steven A Carr, Tyler Jacks, Carla F Kim.

Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers. There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in BRG1 contribute to lung cancer progression. Using a combination of gain- and loss-of-function approaches, we demonstrate that deletion of BRG1 in lung cancer leads to activation of replication stress responses. Single-molecule assessment of replication fork dynamics in BRG1-deficient cells revealed increased origin firing mediated by the pre-licensing protein CDC6. Quantitative mass spectrometry and co-immunoprecipitation assays showed that BRG1-containing SWI/SNF complexes interact with RPA complexes. Lastly, BRG1-deficient lung cancers were sensitive to pharmacological inhibition of ATR. These findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that their dependency on ATR can be leveraged therapeutically and potentially expanded to BRG1-mutant cancers in other tissues.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-1744
Eur J Med Chem. 2020 Jul 15. pii: S0223-5234(20)30511-0. [Epub ahead of print]203 112539

PROTAC: A promising technology for cancer treatment.

Xin Zhou, Ru Dong, Jin-Yang Zhang, Xin Zheng, Li-Ping Sun.

  Proteolysis-targeting chimeric molecules (PROTACs), which attract much more attention today, may be a potential way to treat cancer. PROTACs are made up of ligands of target proteins, E3 ligase recruiting elements and linkers. PROTACs can hijack the intracellular inherent ubiquitin proteasome system in cells to degrade different target proteins. PROTACs targeting different cancer-related proteins have been successfully developed and outperform small inhibitors, the traditional way of treating cancer. In this review, we focus on PROTACs targeting cancer-related proteins and their superiority over inhibitors.

Keywords:  Cancer; PROTACs; Promising treatment

DOI:  https://doi.org/10.1016/j.ejmech.2020.112539
Nat Rev Clin Oncol. 2020 Jul 22.

Integrating evolutionary dynamics into cancer therapy.

Robert A Gatenby, Joel S Brown.

Many effective drugs for metastatic and/or advanced-stage cancers have been developed over the past decade, although the evolution of resistance remains the major barrier to disease control or cure. In large, diverse populations such as the cells that compose metastatic cancers, the emergence of cells that are resistant or that can quickly develop resistance is virtually inevitable and most likely cannot be prevented. However, clinically significant resistance occurs only when the pre-existing resistant phenotypes are able to proliferate extensively, a process governed by eco-evolutionary dynamics. Attempts to disrupt the molecular mechanisms of resistance have generally been unsuccessful in clinical practice. In this Review, we focus on the Darwinian processes driving the eco-evolutionary dynamics of treatment-resistant cancer populations. We describe a variety of evolutionarily informed strategies designed to increase the probability of disease control or cure by anticipating and steering the evolutionary dynamics of acquired resistance.

DOI: https://doi.org/10.1038/s41571-020-0411-1