A vaccine that targets tumor neoantigens may improve the effectiveness of nivolumab. A trial that included patients with metastatic melanoma, non–small cell lung cancer, and bladder cancer found that progression-free survival was longer than in historical controls. The vaccine also stimulated tumor-specific T cells.
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We report the emergence of the novel MEK1V211D gatekeeper mutation in a patient with BRAFK601E colon cancer treated with the allosteric MEK inhibitor binimetinib and the anti-EGFR antibody panitumumab. The MEK1V211D mutation concurrently occurs in the same cell with BRAFK601E and leads to RAF-independent activity but remains regulated by RAF. The V211D mutation causes resistance to binimetinib by both increasing the catalytic activity of MEK1 and reducing its affinity for the drug. Moreover, the...
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A phase I trial reported positive results for an antibody–drug conjugate that targets HER2-positive tumors. Trastuzumab duocarmazine, which kills tumor cells by causing DNA damage, induced partial responses in 33% of patients whose tumors were resistant to the approved antibody–drug conjugate trastuzumab emtansine. The drug caused fatigue, neutropenia, pneumonitis, and eye-related side effects.
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Glioblastoma ranks among the most aggressive and lethal of all human cancers. Functionally defined glioma stem cells (GSC) contribute to this poor prognosis by driving therapeutic resistance and maintaining cellular heterogeneity. To understand the molecular processes essential for GSC maintenance and tumorigenicity, we interrogated the superenhancer landscapes of primary glioblastoma specimens and in vitro GSCs. GSCs epigenetically upregulated ELOVL2, a key polyunsaturated fatty-acid synthesis enzyme....
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The FDA granted accelerated approval to selinexor plus low-dose dexamethasone for triple-class refractory multiple myeloma, despite an advisory panel's concerns about the drug's toxicity and the lack of randomized clinical data.
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Summary:In this issue of Cancer Discovery, Gu and colleagues developed a mouse model of myeloproliferative neoplasm driven by NrasG12D and Ezh2–/–, which cooperated to induce malignant transformation and metabolic reprogramming of leukemic stem cells at least in part through loss of normal epigenetic regulation of gene expression. Furthermore, their findings point to Ezh1 and branched chain amino acid metabolism as biological dependencies and potential therapeutic targets in myeloid neoplasms. See...
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The function of PTEN in the cytoplasm largely depends on its lipid-phosphatase activity, though which it antagonizes the PI3K–AKT oncogenic pathway. However, molecular mechanisms underlying the role of PTEN in the nucleus remain largely elusive. Here, we report that DNA double-strand breaks (DSB) promote PTEN interaction with MDC1 upon ATM-dependent phosphorylation of T/S398-PTEN. Importantly, DNA DSBs enhance NSD2 (MMSET/WHSC1)-mediated dimethylation of PTEN at K349, which is recognized by the tudor...
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Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores...
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Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ+CD4–CD8–NK1.1– innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ~10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαβTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαβTs...
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Loss of p53 caused increased neutrophil levels and systemic inflammation in mice with breast tumors.
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Ferroptotic cell death is mediated by cell contact and Hippo pathway members, including NF2 and YAP.
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Researchers have developed a KRAS inhibitor, BI-2852, that inhibits ERK phosphorylation and reduces proliferation of KRAS-mutant cancer cells. A drug based on the molecule may be effective in patients who don't respond to the KRASG12C inhibitors currently in clinical trials.
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A previously unknown sterol binding pocket was found in the crystal structure of active Smoothened.
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C19MC is part of an oncogenic circuit that drives embryonal brain tumors with multilayered rosettes.
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The oncoprotein HER2 inhibits the cGAS–STING-mediated innate immune response to cytosolic DNA.
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The G9a/DNMT methyltransferase inhibitor CM-272 causes tumor regression in bladder cancer.
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The immune response to checkpoint blockade is associated with recruitment of new T cells, not preexisting TILs.
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The experimental RET inhibitor BLU-667 appears safe and effective in patients with RET-altered thyroid cancers, according to findings presented at the 2019 American Society of Clinical Oncology Annual Meeting. In the phase II ARROW trial, the drug elicited responses in 56% of patients with advanced RET-mutated medullary thyroid cancer and five out of six patients with papillary thyroid cancer and was associated with mild side effects.
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Cyclic GMP–AMP synthase (cGAS) causes cell death when mitosis is prolonged.
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In a phase I/II study, chimeric antigen receptor T cells produced complete remissions in 88% of patients with refractory or relapsed follicular lymphoma, all of whom remained in remission after a median of 2 years of follow-up. The treatment induced cytokine release syndrome and neurotoxicity in 50% of patients, but none developed side effects more severe than grade 2.
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AML cells not expressing ligands of NKG2D had leukemic stem cell (LSC) activity linked to immune evasion.
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The novel drug SM-88 seems to be a promising therapy for previously treated patients with advanced pancreatic ductal adenocarcinoma. In a phase II trial, the modified dysfunctional tyrosine derivative was well tolerated and elicited responses or led to stable disease in 44% of patients.
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BRCA1–BARD1 promotes fork protection independently of the canonical BRCA1–PALB2–BRCA2–RAD51 pathway.
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A blood test being developed by Grail may not only detect early-stage cancers, but also determine where those cancers originate: In an ongoing study, the methylation-based assay detected 55.1% of cancers across types and stages and correctly identified the tissue of origin in 90.2% of cases.
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Tisagenlecleucel has an acceptable safety profile and showed preliminary evidence of CNS efficacy.
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SCNC patterns of gene expression, methylation, and mutations are convergent.
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Purpose:Circulating tumor DNA (ctDNA) provides a novel approach for detecting tumor burden and predicting clinical outcomes of hepatocellular carcinoma (HCC). Here, we performed a thorough evaluation of HCC circulating genetic features and further fully integrated them to build a robust strategy for HCC monitoring and prognostic outcome assessment. Experimental Design:We performed target sequencing and low-coverage whole-genome sequencing on plasma samples collected from 34 long-term follow-up patients...
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Purpose:Both gain-of-function enhancer of zeste homolog 2 (EZH2) mutations and inactivating histone acetyltransferases mutations, such as CREBBP and EP300, have been implicated in the pathogenesis of germinal center (GC)–derived lymphomas. We hypothesized that direct inhibition of EZH2 and histone deacetyltransferase (HDAC) would be synergistic in GC-derived lymphomas. Experimental Design:Lymphoma cell lines (n = 21) were exposed to GSK126, an EZH2 inhibitor, and romidepsin, a pan-HDAC inhibitor....
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Purpose:As a main rate-limiting subunit of the 2-oxoglutarate dehydrogenase multienzyme complex, oxoglutarate dehydrogenase like (OGDHL) is involved in the tricarboxylic acid cycle, and frequently downregulated in human carcinoma and suppresses tumor growth. However, little is known about the role of OGDHL in human cancer, especially pancreatic cancer. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by OGDHL modulating pancreatic cancer progression. Experimental...
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Purpose:Clinically aggressive meningiomas (MGMs) are rare but treatment-resistant tumors in need for more effective therapies. Because tumor-infiltrating T lymphocytes (TILs) are essential for successful immunotherapy, we assessed TIL numbers and their activation status in primary (p-) and recurrent (r-) meningiomas and their impact on survival. Experimental Design:Presence of TILs was analyzed in 202 clinically well-annotated cases (n = 123 pMGMs and n = 79 rMGMs) focusing on higher-grade meningiomas...
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Purpose:We examined the prognostic impact of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) detected at the time of surgery in 742 untreated patients with early breast cancer. Experimental Design:DTCs in bone marrow were enumerated using the EPCAM-based immunomagnetic enrichment and flow cytometry (IE/FC) assay. CTCs in blood were enumerated either by IE/FC or CellSearch. Median follow-up was 7.1 years for distant recurrence-free survival (DRFS) and 9.1 years for breast cancer–specific...
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Purpose:Approximately 10% of patients with mismatch repair–proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer. Experimental Design:We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal...
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Purpose:Lung fibrosis is a major side effect experienced by patients after lung cancer radiotherapy. However, effective protection strategies and underlying treatment targets remain unclear. In an effort to improve clinical outcomes, pharmacologic treatment of fibrosis is becoming increasingly popular; however, no ideal therapeutic strategy is yet available. Experimental Design:We used a mouse model to irradiate high focal (90 or 75 Gy) to 3-mm volume of the left lung. Lung tissues of mice were...
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Purpose:With recent advancements in personalized medicine, biopsies must contain sufficient tumor for histologic diagnosis and molecular testing. However, inadvertent biopsy of tumor-associated fibrosis compromises tumor yield, resulting in delayed diagnoses and/or repeat procedures when additional tumor is needed. The ability to differentiate tumor from fibrosis intraprocedurally during biopsy could significantly increase tumor yield. Polarization-sensitive optical coherence tomography (PS-OCT)...
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Purpose:Regarding cancer antigen 125 (CA-125) longitudinal kinetics during chemotherapy, the actual predictive value of the Gynecologic Cancer Intergroup (GCIG) CA-125 response criterion is questioned. The modeled CA-125 elimination rate constant KELIM exhibited higher prognostic value in patients with recurrent ovarian cancer enrolled in the CALYPSO trial. The objective was to validate the higher predictive and prognostic values of KELIM during first-line treatments. Experimental Design:Data from...
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Purpose:This study was aimed at evaluating the feasibility, safety, immunologic and clinical responses in patients with follicular lymphoma treated with monocyte-derived dendritic cells generated in the presence of IFNα and GM-CSF (IFN-DC) in combination with low doses of rituximab. Patients and Methods:Firstly, we analyzed in vitro and in vivo the immunologic properties of IFN-DC against follicular lymphoma. Thus, we performed a phase I trial in 8 patients with refractory and relapsed follicular...
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Purpose:Intratumoral hypoxia and immunity have been correlated with patient outcome in various tumor settings. However, these factors are not currently considered for treatment selection in head and neck cancer (HNC) due to lack of validated biomarkers. Here we sought to develop a hypoxia-immune classifier with potential application in patient prognostication and prediction of response to targeted therapy. Experimental Design:A 54-gene hypoxia-immune signature was constructed on the basis of literature...
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