Breaking Insights Highlights from Recent Cancer Literature

Cancer Research Breaking Insights Highlights from Recent Cancer Literature

GSH Homeostasis Disruption in ARID1A-Deﬁcient Cells Offers a Targetable Vulnerability

ARID1A is a SWI/SNF chromatin-remodeling factor. Mutations in ARID1A are frequently found in a number of cancers. Ogiwara and colleagues have identified a vulnerability in ARID1A-deficient tumors where loss of the antioxidant glutathione (GSH) led to increased production of reactive oxygen species and cell death. The authors found that ARID1A-deficient tumors were selectively sensitive to pharmacological inhibition of GSH function or synthesis. They also showed that ARID1A maintained GSH homeostasis by increasing transcription of the cystine transporter SLC7A11. Cystine uptake is essential for the synthesis of GSH and the authors proposed that the resulting reduced basal levels of GSH in ARID1A-deficient cells makes them more vulnerable to disruption of GSH homeostasis. Expert Commentary: Pharmacological inhibition of glutamate-cysteine ligase synthetase, the rate- limiting enzyme in the GSH synthesis pathway, provides a potential treatment option for tumors with combined loss of ARID1A and SLC7A11. (Image courtesy of Wikimedia Commons.) Ogiwara H, Takahashi K, Sasaki M, Kuroda T, Yoshida H, Watanabe R, et al. Targeting the vulnerability of glutathione metabolism in ARID1A-deficient cancers. Cancer Cell 2019;35:177-190.e8. doi: 10.1016/j.ccell.2018.12.009.

Tumor-in-a-Dish Approach to Precision Medicine

Metastasis is a chief cause of cancer-related deaths. A major hurdle in developing antimetastatic therapies is the shortage of effective and representative preclinical models to study and develop targeted therapies that prevent or treat metastatic disease. Ramamoorthy and colleagues developed a multicellular lung organoid that mimics the lung microenvironment and named it primitive lung-in-a-dish (PLiD). They then grew colon or ovarian cancer cell lines in PLiD and named it "metastatic tumor-in-a-dish" (mTiD). Using this model, they tested several standard-of-care chemotherapeutic agents. They also used primary patient-derived colon or ovarian tumor cells and corroborated the patient's response to therapy with that of the mTiD cultures in vitro. Expert Commentary: The lung organoid culture described exhibits characteristics of a normal human lung to study the biology of metastatic disease and to evaluate therapeutic interventions. This approach has signiﬁcant utility in precision/personalized medicine, coupling a phenotypic screen with pharmacogenetics to identify the ideal therapeutic agent. (Image from cited article courtesy of the publisher.) Ramamoorthy P, Thomas SM, Kaushik G, Subramaniam D, Chastain KM, Dhar A, et al. Metastatic tumor-in-a-dish, a novel multicellular organoid to study lung colonization and predict therapeutic response. Cancer Research; Published ﬁrst January 23, 2019; doi: 10.1158/0008-5472.CAN-18-2602.

The Transcriptional Repressor REST Drives Chromatin Compaction

The RE1-silencing transcription factor (REST) is a transcriptional repressor of neuronal differentiation, which acts as a scaffold to recruit chromatin remodeling enzymes. Dobson and colleagues examined the role REST plays as a regulator of Sonic hedgehog (SHH) signaling during the differentiation of cerebellar granular neuron progenitors (CGNP). REST activity was correlated with decreased survival in a subset of SHH subgroup medulloblastoma patients. They generated a CGNP-expressing transgenic REST mouse model and þ used it to increase the tumorigenic characteristics of a Ptch1 / mouse model for medulloblastoma and showed that REST increased SHH signaling in a manner dependent on the epigenetic repression of the Ptch1 locus. Further, by attenuating expression of the PTEN locus, they showed that REST increased AKT activity, which has previously been shown to drive increased metastases in medulloblastoma. Expert Commentary: REST represses key regulators of SHH signaling. Thus, targeting components of this repressor complex may provide a therapeutic approach for a subset of medulloblastoma patients. (Image courtesy of Wikimedia Commons.) Dobson THW, Tao RH, Swaminathan J, Maegawa S, Shaik S, Bravo-Alegria J, et al. Transcriptional repressor REST drives lineage stage–speciﬁc chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma. Sci Signal 2019;12. doi: 10.1126/scisignal.aan8680. www.aacrjournals.org 1017

Regulatory T Cells See Distinct Antigenic Targets in Tumors

Regulatory T cells (Treg) suppress cancer-specific immune responses, however, the antigenic specificity of these tumor-infiltrating Tregs remains elusive. Analyzing tumors, Ahmadzadeh and colleagues þ showed no overlap between 90% of T-cell receptors (TCR) on Tregs and CD4 effector T cells (Teff). Comparing TCRs from Tregs in peripheral blood and tumors, they showed that all tumor-infiltrating Treg TCRs were also present in blood. These data showed that tumor-infiltrating Tregs came from the circulating pool of Tregs, expanding locally in tumors rather than arising from conversion of Teffs into Tregs in tumors. Finally, using an in silico TCR alpha and beta chain pairing algorithm (pairSEQ), they tested Treg TCR specificity by transducing patient T cells with the newly defined TCRs. Remarkably, many Treg TCRs responded to mutated neoantigens in cancers. Expert Commentary: Identification of antigenic targets of tumor-infiltrating Tregs and the TCRs that recognize them reveals a new source of TCRs for TCR-modified adoptive T-cell therapies. (Image courtesy of Wikimedia Commons.) þ Ahmadzadeh M, Pasetto A, Jia L, Deniger DC, Stanovic S, Robbins PF, et al. Tumor-infiltrating human CD4 regulatory T cells display a distinct TCR repertoire and exhibit tumor and neoantigen reactivity. Sci Immunol 2019;4. doi: 10.1126/sciimmunol. aao4310.

Mutational Load and Immunotherapy

Immune checkpoint inhibitors are beneﬁcial for some patients with metastatic cancer, however, there is a great need for predictive biomarkers. Samstein and colleagues analyzed tumor mutational burden (TMB) as a potential biomarker to predict clinical responses. The authors examined clinical and genomic data from 1662 advanced cancer patients treated with immune checkpoint inhibitors, as well as 5371 patients who did not receive this treatment. Using targeted next-generating sequencing on all samples, the authors found that higher somatic TMB was associated with better overall survival among all patients. Importantly, the TMB cut points associated with better survival varied among cancer types. Expert Commentary: This study indicates that tumor mutational burden across a variety of cancer types is associated with higher survival in patients receiving immune checkpoint inhibitor therapy. However, the deﬁnition of high tumor mutational burden may not be universal across all cancer types. (Image courtesy of Wikimedia Commons.) Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 2019;51:202-6.

Targeting Lsd1 in MYC-GFI1-Driven Group 3 Medulloblastoma

Lee and colleagues previously showed that MYC cooperates with the GFI family of oncogenes to drive a specific subtype of Group 3 medulloblastoma, however, targeting GFI1/1b has been a major challenge. To discern the events leading to tumorigenesis in MYC-GFI-driven Group 3 medulloblastoma, the authors generated a Group 3 medulloblastoma murine model with a floxed allele of GFI1 and showed that administration of Cre resulted in tumor regression. They next performed coimmunoprecipitation of known GFI1 interactors and identified the enzyme lysine demethylase 1 (Lsd1) as a physical interactor of GFI1. Pathway analysis of MYC-GFI1-driven medulloblastoma suggested that downregulation of several genes was involved in neuronal differentiation; overexpression of one of these genes, Fbxo5, a key driver of neuronal differentiation, inhibited tumorigenesis. Finally, genetic knockdown of Lsd1 suppressed transformation of MYC-GFI1 neural stem cells and targeting Lsd1 using small molecular inhibitors resulted in prolonged survival in vivo. Expert Commentary: Despite tremendous advances in the genomics of medulloblastoma, many of the lesions identified are not clearly actionable. This simple and logical study suggests that GFI-driven medulloblastoma, comprising a substantial portion of high-risk Group 3 tumors, can be targeted through an actionable physical interactor rather than the oncogene itself. (Image courtesy of Wikimedia Commons.) Lee C, Rudneva VA, Erkek S, Zapatka M, Chau LQ, Tacheva-Grigorova SK, et al. Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma. Nature Commun 2019;10:332. doi: 10.1038/s41467-018-08269-5.

Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the ﬁndings described.

1018 Cancer Research

Cancer Res 2019;79:1017-1018.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/79/6/1017

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