Sets of modular proteins enabled targeting of cells with specific combinations of surface markers.
Thu Oct 01, 2020 10:05
Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring...
Thu Oct 01, 2020 10:05
Monocytes in the tumor microenvironment that expressed TREM2 hampered antitumor immunity.
Thu Oct 01, 2020 10:05
The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin–driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor MECOM (EVI1) compared with leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a...
Thu Oct 01, 2020 10:05
Inosine produced by the gut microbe Bifidobacterium pseudolongum enhanced anti-CTLA4's efficacy.
Thu Oct 01, 2020 10:05
Reversion mutations in BRCA1 or BRCA2 are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codified, and analyzed more than 300 reversions. This identified reversion "hotspots" and "deserts" in regions encoding the N and C terminus, respectively, of BRCA2, suggesting that pathogenic mutations in these regions may be at higher or lower risk of reversion. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared...
Thu Oct 01, 2020 10:05
Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated...
Thu Oct 01, 2020 10:05
Circadian rhythms integrate many physiological pathways, helping organisms to align the timing of various internal processes to daily cycles in the external environment. Disrupted circadian rhythmicity is a prominent feature of modern society, and has been designated as a probable carcinogen. Here, we review multiple studies, in humans and animal models, that suggest a causal effect between circadian disruption and increased risk of cancer. We also discuss the complexity of this connection, which...
Thu Oct 01, 2020 10:05
Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using...
Thu Oct 01, 2020 10:05
Summary: In this issue, Miyabayashi and colleagues describe a novel intraductal model of pancreatic cancer that allows modeling of the transcriptional subtypes of pancreatic cancer. Using this model, they are able to observe subtype switching driven by the microenvironment, a process at least partially mediated by RAS signaling. See related article by Miyabayashi et al., p. 1566.
Thu Oct 01, 2020 10:05
The overall response rate was 19.4% in patients who received ripretinib as a second-line therapy.
Thu Oct 01, 2020 10:05
Summary: In this issue of Cancer Discovery, Pennycuick and colleagues comprehensively evaluate the immune contexture of progressive and regressive lesions in squamous pulmonary premalignancy. The authors dissect the molecular features of these lesions and the potential pathways of immune escape operative in progression to invasive cancer. See related article by Pennycuick et al., p. 1489.
Thu Oct 01, 2020 10:05
Lysosome-targeting chimeras (LYTAC) directed extracellular and membrane proteins to lysosomes.
Thu Oct 01, 2020 10:05
Methylmalonic acid (MMA) from older donors' sera promoted cancer-cell invasiveness and metastasis.
Thu Oct 01, 2020 10:05
Debio 1143 plus chemoradiotherapy improved head and neck squamous cell carcinoma disease control.
Thu Oct 01, 2020 10:05
Although single hotspot mutations in oncogenes have been the focus of much research, the clinical relevance of oncogenes with multiple mutations—now shown to be common—has only recently come into the spotlight.
Thu Oct 01, 2020 10:05
Edward Chu, MD; Hans-Joachim Scholl, MD, PhD; and Nadia Harbeck, MD, PhD, are highlighted.
Thu Oct 01, 2020 10:05
Depleting serine hindered tumor growth by promoting synthesis of toxic 1-deoxydihydroceramide.
Thu Oct 01, 2020 10:05
Summary: Cancer research and cancer care require deliberate attention to racial diversity. Here we comment on the ongoing issues of diversity and racism in cancer research.
Thu Oct 01, 2020 10:05
Several retrospective studies have examined whether patients with cancer who develop COVID-19 may be at risk of more severe viral disease if their therapy includes immune checkpoint inhibition. Although the data are not uniform, for now, halting or modifying cancer treatment decisions is unnecessary; meanwhile, vigilance with testing for COVID-19 in this population is recommended.
Thu Oct 01, 2020 10:05
Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers.
Thu Oct 01, 2020 10:05
The National Lung Matrix Trial, an umbrella trial of targeted therapies in non–small cell lung cancer, revealed that most drugs prescribed based on specific genomic aberrations showed little efficacy, but new approaches could bolster precision medicine.
Thu Oct 01, 2020 10:05
The SARS-CoV-2 pandemic significantly affected oncology practice across the globe. There is uncertainty as to the contribution of patients' demographics and oncologic features to severity and mortality from COVID-19 and little guidance as to the role of anticancer and anti–COVID-19 therapy in this population. In a multicenter study of 890 patients with cancer with confirmed COVID-19, we demonstrated a worsening gradient of mortality from breast cancer to hematologic malignancies and showed that...
Thu Oct 01, 2020 10:05
The Research to Accelerate Cures and Equity for Children Act recently went into effect, potentially paving the way for more drug development in pediatric cancers. The legislation will tighten the requirements for testing cancer agents used in adults to treat malignancies in children when there is a shared molecular target.
Thu Oct 01, 2020 10:05
Gilead announced plans in July to pay $300 million for a 49.9% stake in Tizona Therapeutics, with the option to buy the rest of the company for $1.25 billion. Whether Gilead follows through with the acquisition will hinge on how well Tizona's investigational HLA-G inhibitor, TTX-080, fares in early-stage clinical trials.
Thu Oct 01, 2020 10:05
A deformed leg bone from a 76-million-year-old fossil offers the first histologically confirmed example of a malignant tumor diagnosed in a dinosaur. The paleontologic findings could narrow the oncologic search for genomic drivers of osteosarcoma today.
Thu Oct 01, 2020 10:05
Summary: In this issue of Cancer Discovery, Cai and colleagues delineate a new mechanism that links cell of origin, the transcription factor EVI1, apoptotic priming, and therapeutic susceptibility in mixed lineage leukemia–rearranged acute myeloid leukemia. These findings establish a cell of origin–dependent program that may be leveraged by therapeutic combinations to overcome drug resistance in chemoresistant leukemias. See related article by Cai et al., p. 1500.
Thu Oct 01, 2020 10:05
Relapses driven by chemoresistant leukemic cell populations are the main cause of mortality for patients with acute myeloid leukemia (AML). Here, we show that the ectonucleotidase CD39 (ENTPD1) is upregulated in cytarabine-resistant leukemic cells from both AML cell lines and patient samples in vivo and in vitro. CD39 cell-surface expression and activity is increased in patients with AML upon chemotherapy compared with diagnosis, and enrichment in CD39-expressing blasts is a marker of adverse...
Thu Oct 01, 2020 10:05
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts....
Thu Oct 01, 2020 10:05
The WNT pathway is a fundamental regulator of intestinal homeostasis, and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer. To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that although WNT suppression blocks tumor growth in most organoid and in vivo colorectal cancer models, the accumulation of colorectal cancer–associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal...
Thu Oct 01, 2020 10:05
A mouse study suggests that daily doses of a CSF1R inhibitor after radiation therapy can reduce the likelihood of glioblastoma recurrence. Mice that received the inhibitor lived more than twice as long as control animals, and only 20% of them developed recurrent tumors, whereas all control animals did.
Thu Oct 01, 2020 10:05
Type I and II antibodies bound CD20 with different stoichiometry and recognized different epitopes.
Thu Oct 01, 2020 10:05
Three studies elucidate the proteomic and genomic characteristics of lung cancer and suggest new ways to treat the disease. The first study found distinct mutation patterns in Taiwanese patients, most of whom had never smoked. The second study, which included only Chinese patients, identified three groups with different prognoses. The third study of an international group of patients uncovered three new targets for drug development.
Thu Oct 01, 2020 10:05
The clade of human papillomavirus (HPV) infecting tumor cells influenced epigenetics genome-wide.
Thu Oct 01, 2020 10:05
An FDA advisory committee recommended approval of belantamab mafodotin, a first-in-class BCMA-targeted therapy, to treat patients with multiple myeloma refractory to several other drugs. Agency officials had raised concerns about the high incidence of corneal disease linked to the therapy, but clinical experts felt that the demonstrated benefits outweighed the risks of ocular toxicity.
Thu Oct 01, 2020 10:05
New androgen receptor binding sites acquired with metastasis overlapped with those in fetal tissue.
Thu Oct 01, 2020 10:05
An RNA vaccine against nonmutated, shared tumor antigens promoted T-cell responses in melanoma.
Thu Oct 01, 2020 10:05
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