From the Journals: Editors’ Picks for September
As we welcome the fall season, it’s time for our September edition of Editors’ Picks, a monthly collection of articles hand-picked by the editors of the eight scientific journals published by the AACR. This month, articles span from an assessment of a first-in-class antibody-drug conjugate targeting the antigen CD205 in xenograft models, to results from a clinical trial evaluating the dual inhibition of VEGFR2 and MET in patients with advanced solid tumors. Read on to learn about this month’s selections, which are freely available for a limited time.
Journal: Clinical Cancer Research (September 1 issue)
A Phase Ib/II Study of Ramucirumab in Combination with Emibetuzumab in Patients with Advanced Cancer
Inhibition of the cell-surface receptor VEGFR2 can attenuate tumor growth and block angiogenesis, but resistance to this therapeutic strategy can develop due to the activation of the receptor tyrosine kinase MET. This phase Ib/II clinical trial evaluated the combination of the VEGFR2 inhibitor ramucirumab with the MET inhibitor emibetuzumab in 97 patients with advanced solid tumors. Across all tumor types evaluated, five partial responses were observed, representing 5.2 percent of patients. For patients with hepatocellular carcinoma (HCC), the overall response rate, disease control rate, and progression-free survival (PFS) were 6.7 percent, 60 percent, and 5.42 months, respectively; among these patients, those with tumors with high expression of MET had roughly a threefold increase in PFS compared to those with low MET expression (8.1 months compared with 2.8 months, respectively). The authors conclude that MET expression may help to identify patients who would benefit most from this combinatorial treatment in select tumor types. This article was highlighted in this issue.
Journal: Cancer Immunology Research
Mesothelin is overexpressed in more than 75 percent of high-grade serous ovarian cancer (HGSOC) tumors and has limited expression in healthy cells, representing a potential therapeutic target for this hard-to-treat disease. In this study, the authors engineered CD8+ T cells to express T-cell receptors specific for mesothelin and evaluated their efficacy in human ovarian cancer cell lines and in murine ovarian tumors. They found that human engineered T cells were effective against three distinct HGSOC cell lines, and that repeated doses of murine engineered T cells could prolong the survival of tumor-bearing mice. The authors conclude that engineered adoptive T-cell therapy may have clinical applicability in patients with late-stage HGSOC. This article was featured on the cover of this issue.
Journal: Clinical Cancer Research (September 15 issue)
Activin A is a member of the TGFβ family that plays an important role in growth, differentiation, and cancer cachexia. This first-in-human phase I clinical trial evaluated the safety and early efficacy of the Activin A inhibitor STM 434 in 32 patients with advanced solid tumors. While no responses were observed among the 30 evaluable patients, the stable disease rate among patients with granulosa cell ovarian cancer was 80 percent, and increases in both total lean body mass and 6-minute walk test distance were observed in most cohorts. The authors conclude that inhibition of Activin A should be explored in other clinical settings, such as improving muscle wasting and cancer cachexia. The article was highlighted in this issue, and a commentary discussing this article can be found here.
Journal: Cancer Discovery
Innate αβ T cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming
Because pancreatic tumors are often nonimmunogenic, the study of unconventional T lymphocyte populations that infiltrate this tumor type may provide novel treatment insights for this deadly disease. In this study, the authors found that innate CD3+TCRαβ+CD4–CD8–NK1.1– T cells (innate αβ T cells) represented roughly 10 percent of the infiltrating T-cell population in both the murine and human pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment, and that adoptive transfer of these innate αβ T cells protect against PDAC tumor growth in vitro. The researchers found that PDAC-associated innate αβ T cells induce CCR5-dependent immunogenic macrophage polarization, enhance effector CD4+ and CD8+ T-cell function, and facilitate tumor protection. The authors conclude that this unique population of innate αβ T cells should be considered as a target for immunotherapy. This article was featured on the cover and was highlighted in this issue. A commentary discussing this article can be found here.
Journal: Molecular Cancer Therapeutics
MEN1309/OBT076, a First-In-Class Antibody–Drug Conjugate Targeting CD205 in Solid Tumors
The transmembrane glycoprotein CD205 (previously known as lymphocyte antigen 75) is overexpressed in a variety of solid tumor types and has a rapid internalization rate, making it an ideal target for antibody-drug conjugate (ADC) therapy. In this study, the authors describe the activity of the CD205-targeting ADC, MEN1309/OBT076, in both in vitro and in vivo settings. The ADC showed selective and potent cytotoxic effects against tumor cells with either low or high CD205 expression and potent antitumor activity resulting in complete tumor regressions in bladder, pancreatic, and triple-negative breast cancer xenograft models. These data supported the clinical development of MEN1309/OBT076, and a first-in-human clinical trial evaluating this ADC in patients with CD205-positive metastatic solid tumors and relapsed/refractory non-Hodgkin lymphoma is currently ongoing. This article was featured on the cover and was highlighted in this issue.
Journal: Cancer Prevention Research
The carbohydrates and related biomarkers (CARB) study was a randomized, controlled crossover feeding trial, where 80 normal-weight or overweight/obese participants each consumed two controlled diets differing in glycemic load to investigate if such diets were associated with modulation of cancer risk biomarkers. In this study, the authors utilized a proteomics approach to investigate if the consumption of a low- or high-glycemic diet altered proteins in plasma taken from the participants in the CARB trial. Only among participants with a high body fat mass, the researchers observed overrepresentation of cancer-related pathways involved with DNA repair, DNA replication, cell cycle, the adaptive immune system, and WNT signaling. The authors conclude that the physiological impact of consuming a low- or high-glycemic diet may depend on an individual’s fat mass, and that dietary recommendations related to cancer prevention should consider an individual’s adiposity. This article was featured on the cover of this issue.
Journal: Cancer Epidemiology, Biomarkers & Prevention
The addition of rurality information at the census tract level into the Surveillance, Epidemiology, and End Results (SEER) database would improve etiologic and surveillance studies, but whether this addition would increase the risk of revealing individual patients’ identity, especially since a census tract-based socioeconomic status (SES) quintile has already been added, has yet to be determined. In this study, the authors calculated the percentage of census tracts and cancer cases that could be uniquely identified following the addition of two indicators of census tract-level rurality, the U.S. Department of Agriculture’s Rural Urban Commuting Area (RUCA) codes and the U.S. Census data on the percentage of the population living in nonurban areas, into the SEER database along with a census-tract SES variable. The researchers found that the risk of disclosure was low; less than 0.03 percent of census tracts and less than 0.03 percent of cancer cases were uniquely identifiable. The authors note that a specialized SEER 18 database that includes RUCA and Census rurality measures is available for research use upon request. This article was highlighted in this issue.
Journal: Molecular Cancer Research
Even though cisplatin is an effective, first-line chemotherapeutic option, it has a high level of toxicity which can culminate in chemotherapy-induced peripheral neuropathy (CIPN), negatively impacting a patient’s quality of life and potentially requiring the reduction or cessation of treatment. In this study, the authors created an immunocompetent tumor-bearing CIPN mouse model and evaluated tumor and host responses to a therapeutic combination consisting of cisplatin and Y-27632, an inhibitor of the Rho/ROCK pathway. Not only did Y-27632 enhance the antineoplastic effects of cisplatin in both in vitro and in vivo settings, it also prevented the cisplatin-induced loss of epidermal nerve fibers, protecting tumor-bearing mice from reduced touch sensation brought on by cisplatin treatment. Further, proteomic analyses revealed that Y-27632 decreased NF-κB hyperactivation in footpad tissues, suggesting that targeting the RhoA-NF-κB axis may help to ameliorate CIPN. This article was highlighted and featured on the cover of this issue.
Journal: Cancer Research (September 1 issue)
Focal adhesion kinase (FAK) is an ubiquitously expressed tyrosine kinase that is essential for angiogenesis, yet how the phosphorylation of FAK at tyrosine residues Y397 and Y861 regulate tumor angiogenesis has not been fully explored. In this study, the authors studied mice with inducible endothelial cell-specific non-phosphorylatable tyrosine mutations. Following the subcutaneous injection of melanoma or lung carcinoma cells, the researchers found that mice with homozygous Y397F FAK mutations had reduced tumor growth and angiogenesis as compared with controls, but mice with homozygous Y861F FAK mutations had normal tumor growth and only a transient reduction of angiogenesis. Mechanistically, the researchers found that FAK-Y397F endothelial cells had disrupted FAK-Src interactions, increased expression of Tie-2, and decreased activation of β1-integrin, while FAK-Y861F endothelial cells maintained FAK-Src interactions, had decreased expression of Tie-2, and had enhanced activation of β1-integrin. These results suggest that the phosphorylation of these two tyrosine residues differentially regulate tumor angiogenesis. This article was featured on the cover of this issue.
Journal: Cancer Research (September 15 issue)
Current noninvasive intravital imaging methods to map tumor hypoxia lack high spatial and temporal resolution, hindering accurate assessment of dynamic oxygen behavior. In this study, the authors utilized volumetric multispectral optoacoustic tomography (vMSOT), a label-free method that generates real-time, three-dimensional images in biological tissues, to characterize acute and cyclic hypoxia in a murine model of breast cancer. The authors could segment the murine tumors into three distinct subregions – the tumor rim, hypoxic core, and normoxic core – and could map their individual responses to oxygen stress. These results suggest that vMSOT could be a valuable tool to advance the imaging of cancer and help inform clinical decisions on therapeutic interventions. This article was featured on the cover of this issue, and a related commentary discussing this article can be found here.
