Wed Jul 01, 2020 10:06
Abstract Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60‐500 copies in the 5′‐untranslated region of NOTCH2NLC . The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long‐read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92‐138)....
Tue Jun 30, 2020 14:43
Circulating tumor DNA (ctDNA) may be a useful biomarker for minimal residual disease (MRD) in patients with early-stage non–small cell lung cancer—and MRD may be a good predictor of relapse. In the TRACERx study, a ctDNA assay confirmed MRD negativity in more than 99% of patients—and detected MRD in patients who relapsed before their disease was picked up by standard imaging.
Wed Jul 01, 2020 10:05
USP22 positively regulated transcription factor FOXP3 activity in mouse regulatory T (Treg) cells.
Wed Jul 01, 2020 10:05
Findings from the KEYNOTE-177 study indicate that pembrolizumab is superior to the current standard of care, significantly improving progression-free survival when deployed up front to treat patients with metastatic DNA mismatch repair/microsatellite instability–high colorectal cancer.
Wed Jul 01, 2020 10:05
Anticancer PP2A activators facilitated assembly of holoenzymes with unique regulatory subunits.
Wed Jul 01, 2020 10:05
Olaparib has solidified its place as a standard maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer who have BRCA mutations. In the phase III SOLO 2 trial, the drug extended overall survival by more than a year in these patients compared with a placebo.
Wed Jul 01, 2020 10:05
Loss of the gluconeogenic enzyme FBP1 promoted hepatocellular carcinoma development in mice.
Wed Jul 01, 2020 10:05
Maintenance immunotherapy following chemotherapy may improve survival in advanced urothelial cancer. In the phase III JAVELIN Bladder 100 trial, patients treated with the PD-L1 inhibitor avelumab plus best supportive care after first-line chemotherapy had significantly longer overall survival and progression-free survival than those who received best supportive care alone.
Wed Jul 01, 2020 10:05
Early reports suggest that tocilizumab, an IL6 receptor–blocking antibody used to manage toxicities associated with chimeric antigen receptor T-cell therapy, may help control cytokine storms in people infected with COVID-19. Preliminary data from randomized trials are less clear-cut.
Wed Jul 01, 2020 10:05
Unlike melanomas and colorectal cancers with a high tumor mutation burden, hypermutated gliomas generally do not respond to checkpoint blockade, a study concludes. Hypermutation shortens patient survival, and the results suggest that it occurs because of selective pressure from the chemotherapeutic temozolomide.
Wed Jul 01, 2020 10:05
T-cell exhaustion was a four-stage process; the transition to terminal exhaustion was irreversible.
Wed Jul 01, 2020 10:05
Neoadjuvant immune checkpoint inhibition is gaining ground as a treatment strategy for early-stage, operable cancers. The list of potentially responsive tumor types now includes Merkel cell carcinoma; recent findings from an arm of the I-SPY2 trial also support the utility of this approach in HER2-negative breast cancer.
Wed Jul 01, 2020 10:05
In pediatric central nervous system cancer models, locoregional CAR T-cell delivery was effective.
Wed Jul 01, 2020 10:05
Wed Jul 01, 2020 10:05
Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSC). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine cross-talk between PSCs and PDAC is orchestrated by the utilization of specific transporters. PSCs utilize SLC1A4 and other transporters to rapidly exchange...
Wed Jul 01, 2020 10:05
Loss-of-function mutations of EZH2, the enzymatic component of PRC2, have been associated with poor outcome and chemotherapy resistance in T-cell acute lymphoblastic leukemia (T-ALL). Using isogenic T-ALL cells, with and without CRISPR/Cas9–induced EZH2-inactivating mutations, we performed a cell-based synthetic lethal drug screen. EZH2-deficient cells exhibited increased sensitivity to structurally diverse inhibitors of CHK1, an interaction that could be validated genetically. Furthermore, small-molecule...
Wed Jul 01, 2020 10:05
To study genetic factors influencing the progression and therapeutic responses of advanced prostate cancer, we developed a fast and flexible system that introduces genetic alterations relevant to human disease directly into the prostate glands of mice using tissue electroporation. These electroporation-based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional germline models and, by modeling genetic factors linked to late-stage human disease, can produce tumors...
Wed Jul 01, 2020 10:05
Glioblastoma (GBM), an incurable tumor, remains difficult to model and more importantly to treat due to its genetic/epigenetic heterogeneity and plasticity across cellular states. The ability of current tumor models to recapitulate the cellular states found in primary tumors remains unexplored. To address this issue, we compared single-cell RNA sequencing of tumor cells from 5 patients across four patient-specific glioblastoma stem cell (GSC)–derived model types, including glioma spheres, tumor...
Wed Jul 01, 2020 10:05
Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific...
Wed Jul 01, 2020 10:05
Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/β-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in approximately 26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment...
Wed Jul 01, 2020 10:05
Aberrant MET signaling can drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET gene amplification, mutation, rearrangement, and overexpression. Improvements in biomarker discovery and testing have more recently enabled the selection of patients with MET-dependent cancers for treatment with potent, specific, and novel MET-targeting therapies. We review the known oncologic processes that activate MET, discuss therapeutic strategies for MET-dependent...
Wed Jul 01, 2020 10:05
Summary: The mapping of SARS-CoV-2 human protein–protein interactions by Gordon and colleagues revealed druggable targets that are hijacked by the virus. Here, we highlight several oncogenic pathways identified at the host–virus interface of SARS-CoV-2 to enable cancer biologists to apply their knowledge for rapid drug repurposing to treat COVID-19, and help inform the response to potential long-term complications of the disease.
Wed Jul 01, 2020 10:05
The FDA has greenlighted selpercatinib, the first targeted therapy for RET-altered non–small cell lung cancer (NSCLC) and certain types of thyroid cancer. Another RET inhibitor, pralsetinib, has been submitted for approval to treat NSCLC. Both drugs have shown effectiveness in treating brain metastases.
Wed Jul 01, 2020 10:05
Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;Trp53–/– PDAC mouse model, gain-of-function screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed...
Wed Jul 01, 2020 10:05
Patients with cancer are presumed to be at increased risk from COVID-19 infection–related fatality due to underlying malignancy, treatment-related immunosuppression, or increased comorbidities. A total of 218 COVID-19–positive patients from March 18, 2020, to April 8, 2020, with a malignant diagnosis were identified. A total of 61 (28%) patients with cancer died from COVID-19 with a case fatality rate (CFR) of 37% (20/54) for hematologic malignancies and 25% (41/164) for solid malignancies. Six...
Wed Jul 01, 2020 10:05
Summary: In this issue, Hou and colleagues present their exciting work demonstrating that, through remodeling of the local tumor microenvironment (TME), pancreatic ductal adenocarcinoma forms a tumor-supportive niche capable of liberating cancer cells from dependence on oncogenic KRAS signaling. Through extensive experimentation both in vitro and in vivo, the authors reveal that the HDAC5–CCL2 axis drives the recruitment of tumor-associated macrophages to the TME to provide trophic signaling. ...
Wed Jul 01, 2020 10:05
Summary: In this issue, Pine and colleagues compared single-cell RNA-sequencing data across four distinct types of glioblastoma stem cell–derived tumor models, reinforcing the importance of a three-dimensional microenvironment for accurate recapitulation of cellular states. See related article by Pine et al., p. 964.
Wed Jul 01, 2020 10:05
Summary: The coronavirus SARS-CoV-2 has created a global pandemic that has killed more than a quarter million people since December 2019, halted commerce, and disrupted our ability to research cancer in the laboratory and clinic and care for our patients. A return to a functioning society can be facilitated by the active participation of cancer researchers to diagnose and treat SARS-CoV-2–infected patients, and the direct and indirect benefits of our involvement cannot be overstated.
Wed Jul 01, 2020 10:05
Whether metastases were seeded mono- or polyclonally depended on cancer site and treatment.
Wed Jul 01, 2020 10:05
p53-pathway activation, inactivating TP53 mutations, and DNA damage were common with Cas9 expression.
Wed Jul 01, 2020 10:05
Summary: In this issue of Cancer Discovery, Clarke and colleagues define the genetic landscape of infantile cerebral high-grade gliomas, which frequently contain alterations in the MAPK pathway, as well as recurrent gene fusions in receptor tyrosine kinases (ALK, ROS1, MET) and neurotrophic receptor kinases (NTRK1–3). Combining their multi-omic profiling data with functional preclinical and clinical studies, this large multi-institutional study provides strong rationale for future classification...
Wed Jul 01, 2020 10:05
Most prostate luminal cells that survive androgen deprivation can contribute to organ regeneration.
Wed Jul 01, 2020 10:05
Anti–PD-1 was safe to add to anti-HER2 plus chemotherapy in HER2-positive esophagogastric cancers.
Wed Jul 01, 2020 10:05
Trastuzumab deruxtecan may be effective in solid cancers in addition to breast cancer. In a randomized phase II trial of HER2-positive gastric and gastroesophageal junction cancers, the agent significantly extended overall survival and progression-free survival compared with standard chemotherapy. It also elicited high response rates in phase II trials of HER2-mutant non–small cell lung cancer and HER2-positive colorectal cancer.
Wed Jul 01, 2020 10:05
Ezh2-mutant germinal center B cells depended on follicular dendritic cells rather than Tfh cells.
Wed Jul 01, 2020 10:05
Colorectal cancer cells lost biosynthetic capabilities in an irreversible differentiation process.
Wed Jul 01, 2020 10:05
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