September Editors’ Picks from AACR Journals

As a monthly feature on this blog, we spotlight the 10 articles selected by our editors from each journal issue published by the American Association of Cancer Research (AACR). These journals feature original articles spanning the continuum of cancer research, from basic science discoveries to patient care. To increase access to these studies, articles highlighted here are freely available for a limited time.

In addition to its eight scientific journals, the AACR works to foster the spread of scientific knowledge through a wide variety of meetings. To complement the information presented at the AACR conference on Metabolism and Cancer as well as the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival, the AACR scientific staff is proud to present collections of freely available articles on Metabolism and Cancer as well as Immunotherapy.

Journal: Cancer Discovery

CD38-mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade

While treatment with checkpoint inhibitors has revolutionized the field of oncology, many patients develop resistance to these therapies, thereby limiting their efficacy. In this study, the authors found that tumors from a murine lung cancer model that developed resistance to PD-1 or PD-L1 inhibitors had upregulation of CD38, a cell-surface protein found on many lymphocytes. Both in vivo and in vitro experiments revealed that CD38 inhibits the function of cytotoxic T cells, and that the inhibition of both PD-L1 and CD38 improves antitumor immune responses in tumor-bearing mice. The authors posit that combining CD38 and PD-1/PD-L1 inhibition is a potential strategy for many patients eligible for checkpoint blockade immunotherapy.

Journal: Molecular Cancer Research

Centrosome Linker-induced Tetraploid Segregation Errors Link Rhabdoid Phenotypes and Lethal Colorectal Cancers

Centrosome abnormalities are common in many tumor types, yet their mechanistic link to cancer progression remains to be elucidated. In this study, researchers analyzed tissues from rhabdoid colorectal cancers through whole-exome sequencing and found mutations in the ciliary rootlet coiled-coil (CROCC) gene which encodes for rootletin, an essential protein for centrosome cohesion and separation at the 1p36.13 locus. The researchers also found that the disruption of CROCC expression in colon cancer cells resulted in an aggressive rhabdoid-like phenotype, while the restoration of CROCC in metastatic colorectal cancer cells with lp36.13 deletion corrected centrosome segregation errors. This study provides a mechanistic association between rootletin defects and tetraploid segregation errors in rare colon cancers.

Journal: Cancer Epidemiology, Biomarkers & Prevention

Colorectal Cancer Incidence Trends by Age, Stage, and Racial/Ethnic Group in California, 1990-2014

Utilizing data from the California Cancer Registry, which comprises a diverse racial/ethnic population, the authors investigated trends in colorectal cancer incidence over a 25-year period (1990-2014). Estimates for colorectal cancer (CRC) incidence rates, incidence rate ratios, and triannual percent changes in incidence were calculated based on sex, stage, race/ethnicity, and age at diagnosis. The authors observed increases in the incidence of early-onset CRC in most ethnic/racial groups; increases in the incidence of CRC in Vietnamese and other Southeast Asian groups of screening age (50-74 years); and a decrease in the incidence of CRC among non-Hispanic blacks ages 50 and above (but significantly higher than those in non-Hispanic whites of the same age). Based on these results, the authors advocate for improvements in colorectal cancer awareness, increased access to screening, and early screenings of high-risk populations.

Journal: Clinical Cancer Research (September 15 issue)

Comprehensive Safety Analysis of Venetoclax Monotherapy for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Venetoclax, an oral inhibitor of the protein B-cell leukemia/lymphoma-2 (BCL-2), is an increasingly utilized treatment for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). In this study, a post hoc-integrated safety analysis of venetoclax monotherapy was performed in 350 patients with CLL from three clinical trials, with a median duration of exposure of 16 months. Common grade 3-4 adverse events (AEs) included neutropenia, anemia, and thrombocytopenia; 10 percent of patients discontinued treatment due to AEs and 8 percent of patients died during treatment, most often attributed to disease progression. Results indicate that venetoclax is generally well-tolerated as a long-term therapy for patients with CLL.

Journal: Molecular Cancer Therapeutics

Identification of FDA-approved Oncology Drugs with Selective Potency in High-risk Childhood Ependymoma

Ependymoma (EPN) is the third most common pediatric brain tumor and is often incurable, with few preclinical models to comprehensively assess available treatments. Here, the authors present two human EPN cell lines with high-risk phenotypes, which were subjected to a large-scale comparative screen of FDA-approved oncology drugs, in silico predictions of drug sensitivity, and transcriptome and proteome analyses. The researchers found that fluorinated pyrimidines, retinoids, and a subset of tyrosine kinase inhibitors had EPN-selective anti-tumor effects. The authors suggest that these three classes of oncology drugs may critically inform the design of clinical trials for this pediatric cancer.

Journal: Cancer Research (September 15 issue)

IL1 Receptor Antagonist Controls Transcriptional Signature of Inflammation in Patients with Metastatic Breast Cancer

Inflammation can increase the risk of breast cancer metastasis and treatment resistance, yet the exact mechanisms of cancer promotion are still unknown. In this study, the authors found that the secretion of interleukin (IL)-1β in primary breast cancer samples correlated with disease stage, and that patients with HER2-negative metastatic breast cancer displayed a transcriptional signature dependent on IL-1 as measured in their blood. Furthermore, patients treated with an IL-1 receptor antagonist saw an elimination of this inflammation-associated transcriptional signature and a recovery of cytotoxic programs in their immune cells, assessed in blood. These results suggest that targeting IL-1β may be efficacious in some patients with metastatic breast cancer possessing an IL-1-associated inflammatory signature.

Journal: Cancer Immunology Research

IL35 Hinders Endogenous Antitumor T-Cell Immunity and Responsiveness to Immunotherapy in Pancreatic Cancer

Immunotherapy regimens, while successful in select cancer types, are generally not efficacious in patients with pancreatic ductal adenocarcinoma (PDA). In this study, the authors found that the cytokine interleukin (IL)-35 plays an immunosuppressive role in PDA through the suppression of antitumor T-cell responses, as mouse models deficient in IL35 implanted with pancreatic cancer cells had significantly reduced growth of tumors compared to wild type animals. Furthermore, analysis of tumor-infiltrating immune cells showed that IL35 helped suppress CD4+ effector T cells while expanding regulatory T cells, and IL35-deficient mice had a significant reduction in pancreatic tumor growth, compared with IL35 wild-type animals, when treated with anti-PD-1 immunotherapy. These results suggest a possible synergistic combination of IL35 depletion and anti-PD-1 immunotherapy as a treatment for PDA.

Journal: Cancer Research (September 1 issue)

Inhibition of Rspo-Lgr4 Facilitates Checkpoint Blockade Therapy by Switching Macrophage Polarization

Tumor-associated macrophages (TAMs), a major component of immune cell infiltrate in many tumor types, can play a role in tumor promotion, notably when polarized to the M2 immunosuppressive phenotype. In this study, the authors demonstrate that macrophage M2 polarization is promoted by leucine-rich repeat-containing G-protein coupled receptor 4 (Lgr4) through the Rspo/Lgr4/Erk/Stat3 signaling pathway, and that a mouse model of lung cancer with Lgr4-deficient macrophages had regressed tumor formation and extended survival compared with control mice. Furthermore, inhibition of the Rspo/Lgr4 axis not only decreased tumor growth but synergized with checkpoint inhibition to extend survival in mice bearing melanoma or Lewis lung cancer (LLC) tumors. These results suggest that inhibition of TAM M2 polarization through the Rspo-Lgr4 pathway may help overcome resistance to anti-PD-1 immunotherapy.

Journal: Clinical Cancer Research (September 1 issue)

Magnetic Resonance Imaging of Tumor-Associated Macrophages: Clinical Translation

Tumor-associated macrophages (TAMs), which have been linked to tumor aggressiveness and poor outcome in patients with lymphomas and sarcomas, represent a novel target for TAM-targeted immunotherapy; methods to quantify this biomarker noninvasively represent a clinically unmet need. In this first-in-human clinical trial, researchers investigated the off-label use of the FDA-approved iron supplement ferumoxytol as a tool to enhance the imaging of TAMs through magnetic resonance imaging (MRI). Ferumoxytol-enhanced MRI correlated significantly with TAM density as measured by histopathology in lymphoma and sarcoma patients. The authors advocate for the clinical use of this imaging technique to stratify patients with TAM-rich tumors to TAM-targeted immunotherapy regimens and to monitor response.

Journal: Cancer Prevention Research

Sex-specific Association Between Family History of Diabetes and Risk of Colorectal Cancer: Two Prospective Cohort Studies

While type 2 diabetes is associated with an increased risk of colorectal cancer (CRC), it is unknown if a family history of diabetes can affect CRC risk or alter relevant biomarkers. In this study, the researchers analyzed CRC risk utilizing data from the Nurses’ Health Study and the Health Professionals Follow-up Study and evaluated CRC-related biomarkers in plasma from participants in previous nested case-control studies. While no significant associations were observed in women, men with a family history of diabetes had reduced levels of CRC-related biomarkers (estradiol, sex hormone binding globulin, and adiponectin) and had an increased risk of CRC, with the highest risk occurring in men younger than 60 years. These results suggest that a family history of diabetes may help identify individuals at risk of developing CRC.

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