Mismatch repair (MMR)–deficient tumors exhibit proteome-wide protein instability and aggregation.
Fri May 01, 2020 10:05
Mutations in protein-coding genes are well established as the basis for human cancer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage–associated...
Fri May 01, 2020 10:05
Monoubiquitinated FANCI and FANCD2 constitute the ID complex, which forms a sliding clamp on DNA.
Fri May 01, 2020 10:05
The pks+E. coli metabolite colibactin caused a unique mutational signature in intestinal organoids.
Fri May 01, 2020 10:05
A new method called MicroMapping can identify nanoscale protein–protein interactions on live cells.
Fri May 01, 2020 10:05
A cluster of dendritic cells (termed mregDCs), observed in humans and mice, restricted antitumor immunity.
Fri May 01, 2020 10:05
Patients with HPV16+ cervical cancer and high T-cell responses to an HPV16 vaccine survived longer.
Fri May 01, 2020 10:05
Antoni Ribas, MD, PhD, and Gillian Leng, MBChB, are featured.
Fri May 01, 2020 10:05
The FGFR2b inhibitor bemarituzumab was effective in high-FGFR2b gastroesophageal adenocarcinoma.
Fri May 01, 2020 10:05
As the COVID-19 pandemic worsens, the clinical cancer community is grappling with how to continue providing access to experimental but potentially lifesaving therapies while keeping immunocompromised patients safe. To that end, cancer centers are making changes to their clinical trial programs, while pharmaceutical companies are deciding how—or whether—trials should continue.
Fri May 01, 2020 10:05
Pemigatinib was effective in patients with cholangiocarcinomas with FGFR2 fusions or rearrangements.
Fri May 01, 2020 10:05
Thermo Fisher Scientific announced plans in March to acquire Qiagen in a $11.5 billion deal that could bring morediagnostic offeringsand sample-preparation technologies to one of the world's leading manufacturers of scientific instruments, research services, and laboratory consumables.
Fri May 01, 2020 10:05
Summary:The first basket clinical trial testing the BRAF inhibitor vemurafenib resulted in evidence of activity in 13 unique cancer types with BRAFV600 mutations, but the response rates were variable. Therefore, different cancer histologies with the same driver oncogene display different degrees of oncogenic pathway addiction. See related article by Subbiah et al., p. 657.
Fri May 01, 2020 10:05
Human macrophages equipped with chimeric antigen receptor constructs infiltrate solid tumors, ingest malignant tissue, and stimulate adaptive immunity in mouse models. Several new biotech companies are racing to bring the technology into clinical trials.
Fri May 01, 2020 10:05
Summary:In this issue of Cancer Discovery, Li and colleagues provide a blueprint for the identification and functional validation of cancer-associated mutations in noncoding regions of the genome. Integration of whole-genome sequencing and high-throughput epigenome editing screens is starting to reveal the extent to which noncoding genetic lesions contribute to cancer. See related article by Li et al., p. 724.
Fri May 01, 2020 10:05
Chlorotoxin, a small peptide component of scorpion venom, may help pinpoint glioblastoma cells for destruction when engineered into a chimeric antigen receptor T-cell therapy. The concept has shown efficacy in mice, without off-target toxicity, and will soon be assessed in patients.
Fri May 01, 2020 10:05
BRAFV600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAFV600 mutations have historically been considered a clear demonstration of tumor lineage context–dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort "basket"...
Fri May 01, 2020 10:05
A large international study found that the composition of the intestinal microbiome can predict clinical outcomes in patients undergoing allogenic hematopoietic-cell transplant (HCT) for blood cancers. The findings may help assess patients' transplantation-related mortality risk and aid in developing interventions to prevent or mitigate microbiome changes that affect HCT outcomes.
Fri May 01, 2020 10:05
Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These...
Fri May 01, 2020 10:05
Insufficient reactivity against cells with low antigen density has emerged as an important cause of chimeric antigen receptor (CAR) T-cell resistance. Little is known about factors that modulate the threshold for antigen recognition. We demonstrate that CD19 CAR activity is dependent upon antigen density and that the CAR construct in axicabtagene ciloleucel (CD19-CD28) outperforms that in tisagenlecleucel (CD19-4-1BB) against antigen-low tumors. Enhancing signal strength by including additional immunoreceptor...
Fri May 01, 2020 10:05
As cancer researchers shutter their labs to comply with COVID-19–related work restrictions, some are turning their attention, resources, and technical know-how to the challenge of tackling the deadly coronavirus.
Fri May 01, 2020 10:05
Fri May 01, 2020 10:05
Fri May 01, 2020 10:05
Purpose:Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non–small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated...
Fri May 01, 2020 10:05
Recent FDA approvals of regimens targeting programmed death 1 (PD-1) in combination with anti-CTLA-4 or with VEGF tyrosine kinase inhibitors are reshaping front-line therapy for metastatic kidney cancer. In parallel, therapeutics specific for programmed death ligand 1 (PD-L1), one of the two major ligands for PD-1, are under continued investigation. Surprisingly, not all PD-1 and PD-L1 agents lead to similar clinical outcomes, potentially due to biological differences in the cellular expression and...
Fri May 01, 2020 10:05
Purpose:Gastrointestinal cancers remain areas of high unmet need despite advances in targeted and immunotherapies. Here, we demonstrate potent, tumor-selective efficacy with PF-07062119, a T-cell engaging CD3 bispecific targeting tumors expressing Guanylyl Cyclase C (GUCY2C), which is expressed widely across colorectal cancer and other gastrointestinal malignancies. In addition, to address immune evasion mechanisms, we explore combinations with immune checkpoint blockade agents and with antiangiogenesis...
Fri May 01, 2020 10:05
Purpose:In the phase III DUO trial, duvelisib, an oral dual PI3K-, inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% (P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after...
Fri May 01, 2020 10:05
The impact on survival of steroids and TNFα blockade to treat immune-related toxicity from checkpoint blockade with ipilimumab, nivolumab/pembrolizumab, or combined ipilimumab and nivolumab was assessed using data from a large national database. Using steroids was associated with better survival than the use of TNFα-blocking antibodies such as infliximab. See related article by Verheijden et al., p. 2268
Fri May 01, 2020 10:05
Purpose:Radium-223 is approved for metastatic castration-resistant prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the...
Fri May 01, 2020 10:05
Purpose:We hypothesized that the combination of a local stimulus for activating tumor-specific T cells and an anti-immunosuppressant would improve treatment of gliomas. Virally encoded IL15Rα-IL15 as the T-cell activating stimulus and a prostaglandin synthesis inhibitor as the anti-immunosuppressant were combined with adoptive transfer of tumor-specific T cells. Experimental Design:Two oncolytic poxviruses, vvDD vaccinia virus and myxoma virus, were each engineered to express the fusion protein...
Fri May 01, 2020 10:05
Purpose:Preclinical data demonstrating androgen receptor (AR)–positive (AR+) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR+ (≥10%) breast cancer. Patients and Methods:Phase Ib patients [estrogen...
Fri May 01, 2020 10:05
Purpose:Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown. Experimental Design:Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analyzed the association between severe toxicity and overall survival (OS) in 1,250 patients with advanced melanoma who were treated with immune checkpoint inhibitors...
Fri May 01, 2020 10:05
Purpose:KEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) investigated the efficacy and safety of pembrolizumab across multiple cancers. We present results from patients with previously treated advanced well-differentiated neuroendocrine tumors (NET). Patients and Methods:Pembrolizumab 200 mg was administered every 3 weeks for 2 years or until progression, intolerable toxicity, or physician/patient decision. Tumor imaging was performed every 9 weeks for the first year and then every 12 weeks....
Fri May 01, 2020 10:05
Purpose:There are several agents in early clinical trials targeting components of the adenosine pathway including A2AR and CD73. The identification of cancers with a significant adenosine drive is critical to understand the potential for these molecules. However, it is challenging to measure tumor adenosine levels at scale, thus novel, clinically tractable biomarkers are needed. Experimental Design:We generated a gene expression signature for the adenosine signaling using regulatory networks derived...
Fri May 01, 2020 10:05
Purpose:Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC. Experimental Design:Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor–positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR)....
Fri May 01, 2020 10:05
Purpose:Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action. Experimental Design:We evaluated the anti-MM activity of the fully human BCMAxCD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated. Results:We show that JNJ-7957 has potent activity against...
Fri May 01, 2020 10:05
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