AACR Journals Editors’ Picks for August

The American Association for Cancer Research (AACR) began publishing scientific articles in 1916, and now proudly publishes eight peer-reviewed journals which cover a diverse array of cancer-related topics. The editors from these esteemed journals identify one “must read” article from each issue, and their picks for the month of August are highlighted below. These featured articles are freely available for a limited time.

Journal: Cancer Epidemiology, Biomarkers & Prevention

A Review of Prostate Cancer Genome-Wide Association Studies (GWAS)

This review outlines findings from over 40 prostate cancer genome-wide association studies (GWAS), which have identified approximately 170 common variants. The authors discuss GWAS in non-European populations, GWAS from patients who have received long-term radiotherapy, and the use of common variants to guide a personalized treatment pathway. Furthermore, the authors suggest how this information may be utilized to facilitate the screening and management of prostate cancer.

Journal: Molecular Cancer Research

Epigenetic Targeting of Adipocytes Inhibits High-Grade Serous Ovarian Cancer Cell Migration and Invasion

Because cancer-associated adipocytes foster ovarian tumor progression and invasion, targeting adipocytes may serve as a therapeutic approach for the inhibition of ovarian cancer (OC) metastasis. In this study, the authors found that treating adipocytes with guadecitabine, a hypomethylating agent, decreased the migration and invasion of cocultured OC cells towards adipocytes. Furthermore, guadecitabine-treated adipocytes showed decreased levels of DNA methyltransferase 1 (DNMT1), altered expression of epithelial-mesenchymal transition genes, and upregulation of the tumor suppressor SUSD2. From these results, the authors suggest that targeting adipocytes with hypomethylating agents may alter the tumor microenvironment to decrease OC metastasis.

Journal: Clinical Cancer Research (August 15 issue)

Interferon Gamma Messenger RNA Signature in Tumor Biopsies Predicts Outcomes in Patients with Non-Small Cell Lung Carcinoma or Urothelial Cancer Treated with Durvalumab

In this study, the authors sought to identify messenger RNA (mRNA) signatures that could predict response to the PD-L1 inhibitor durvalumab in patients with non-small cell lung cancer (NSCLC) or urothelial cancer. In patients treated with durvalumab harboring either type of cancer, elevated pretreatment expression levels of four genes (IFNγ, CD274, LAG3, and CXCL9; deemed an IFNγ-positive mRNA signature) were associated with increased overall survival, longer median progression-free survival, and higher overall response rate compared to patients with lower expression of these genes. NSCLC patients with an IFNγ-positive mRNA signature displayed improved survival irrespective of PD-L1 status. The authors posit that this four-gene signature may aid in the identification of patients likely to respond to durvalumab or other PD1/PD-L1 checkpoint inhibitors.

Journal: Cancer Discovery

MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Chromosome instability and aneuploidy are known hallmarks of cancer. In this study, the authors determined that the loss of MACROD2 suppresses poly(ADP-ribose) polymerase 1 (PARP1) activity to impair DNA repair, increase sensitivity to DNA damage, and drive chromosome instability. Depletion of MACROD2 enhanced intestinal tumor growth in a colorectal cancer mouse model and promoted the growth of human colorectal cancer xenografts. From these results, the authors conclude that MACROD2 haploinsufficiency promotes chromosome instability and fosters cancer progression.

Journal: Cancer Research (August 15 issue)

Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations

To identify resistance mechanisms to treatment, the authors evaluated tissues from radical prostatectomies from 18 men treated with neoadjuvant intensive androgen deprivation therapy through the analysis of residual primary prostate cancer foci. In 15 cases, the authors found that multiple foci isolated from the same patient shared a common clonal origin, yet several unique oncogenic alterations were identified in each focus. These results suggest that oncogenic alterations found in primary prostate cancer can be selected for by neoadjuvant intensive androgen deprivation therapy, which can lead to metastatic disease. The authors propose that the identification of aggressive subclones in primary prostate cancer may advise adjuvant strategies to impede recurrence.

Journal: Molecular Cancer Therapeutics

Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice

Inhibitors of the ataxia-telangiectasia mutated (ATM) kinase are promising therapies for the treatment of glioblastoma, yet their clinical utility is limited by their lack of penetration through the blood-brain barrier. In this study, the authors evaluated the efficacy of the ATM inhibitor, AZ32, both in cells and in orthotopic mouse models. AZ32 effectively blocked the DNA damage response and radiosensitized glioblastoma multiforme cells, and exposure of mice to AZ32 and low-dose radiation resulted in a greater than six-fold increase in the level and rate of apoptosis in the brain tumors compared with healthy brains. Data support the development of a blood-brain barrier-penetrating ATM inhibitor for the treatment of glioblastoma.

Journal: Cancer Immunology Research

Primary T Cells From Cutaneous T-cell Lymphoma Skin Explants Display an Exhausted Immune Checkpoint Profile

Cutaneous T-cell lymphomas (CTCL), a type of non-Hodgkin lymphoma characterized by cancerous T cells which accumulate in the skin, have no known curative treatments. In this study, the authors used “explanted biopsies” of CTCL to examine if T cells infiltrate the tumors and how they compare to T cells from normal skin. CTCL samples had more T cells (both CD4+ and CD8+ populations) that expressed the inhibitory checkpoint proteins CTLA-4 and LAG-3 than did normal skin; CD4+ populations from CTCL samples also had more T cells that expressed PD-1, another checkpoint protein. Advanced T3/T4-stage CTCL samples expressed more immune checkpoint and inflammation genes compared with T1/T2 stage CTCL patients or healthy controls. Thus, CTCL T cells show classic signs of exhaustion justifying their identification earlier in the treatment, which could guide the use of checkpoint inhibitors and therapies.

Journal: Cancer Prevention Research

Temporal Efficacy of a Sulforaphane-Based Broccoli Sprout Diet in Prevention of Breast Cancer through Modulation of Epigenetic Mechanisms

In this study, the authors investigated the incorporation of broccoli sprouts, a cruciferous vegetable enriched with the bioactive dietary component and epigenetic modulator sulforaphane, in the pre- and postnatal diets of transgenic mice that can develop breast cancer. Prenatal/maternal diets including broccoli sprouts were the most efficacious in preventing breast cancer development; postnatal early-life consumption of broccoli sprouts displayed protective effects against breast cancer development, but was not as effective as prenatal/maternal diets. Furthermore, adult diets containing broccoli sprouts did not reduce mammary tumorigenesis. These results suggest that ingestion of cruciferous vegetables in the prenatal and early life setting may maximize its chemopreventive effects against human breast cancer.

Journal: Cancer Research (August 1 issue)

Twist1 Regulates Vimentin through Cul2 Circular RNA to Promote EMT in Hepatocellular Carcinoma

Vimentin, an essential component of the cytoskeleton, is overexpressed in various cancers and is a known marker of epithelial-mesenchymal transition (EMT), which plays an important role in cancer metastasis. In this study, the authors show that the transcription factor Twist1 increases the expression of vimentin through the regulation of the Cullin2 (Cul2) circular RNA, circ-10720. Furthermore, knockdown of circ-10720 reduced the expression of vimentin in Twist1-overexpressing hepatocellular carcinoma (HCC) cells and in patient-derived tumor xenograft models of HCC, and silencing of circ-10720 reduced Twist1-induced metastasis in a HCC mouse model. The authors posit that this Twist1-circular RNA-vimentin regulation mechanism may provide a therapeutic target for HCC.

Journal: Clinical Cancer Research (August 1 issue)

Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies

In this study, the authors validated the Guardant360 cell-free tumor DNA sequencing assay using tissue and plasma samples from more than 750 cancer patients. Concordance between Guardant360 and either a validated clinical ddPCR panel or external tumor genotyping results was accurate (positive and negative predictive value greater than 99 percent) and specific (positive predictive value 92 to 100 percent). Furthermore, the test was utilized in 10,593 patients with advanced solid tumors and circulating tumor DNA was detected at a high rate (86 percent of samples). According to the authors, this study establishes the Guardant360 assay to be a clinically effective and accurate genotyping approach for the analysis of cell-free DNA.