Sarcopenia, the degenerative and systemic loss of skeletal muscle mass, is a multifactorial syndrome reflecting frailty, poor general health status, and the possible presence of cancer cachexia. Here, we aimed to investigate the effect of sarcopenia on the efficacy of pembrolizumab in patients with advanced urothelial carcinoma (aUC). This retrospective study included 28 patients with aUC treated with pembrolizumab as a second or later-line therapy. Sarcopenia was determined based on computed tomography...
Tue Jul 28, 2020 03:00
Colorectal cancer (CRC) is a commonly diagnosed type of cancer globally. The molecular mechanism by which peiminine suppressed the progression of CRC is not fully addressed. The viability was assessed through cell counting kit 8 assay. Colony formation assay was used to analyze the colony formation ability. The metastasis was evaluated by transwell migration and invasion assays. Quantitative real-time PCR was performed to measure the expression of LINC00659 and miR-760 in CRC cells. The binding sites...
Tue Jul 28, 2020 03:00
British Journal of Cancer, Published online: 04 August 2020; doi:10.1038/s41416-020-1018-0Suppressive myeloid cells are expanded by biliary tract cancer-derived cytokines in vitro and associate with aggressive disease
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British Journal of Cancer, Published online: 04 August 2020; doi:10.1038/s41416-020-1001-9Miliary breast cancer brain metastasis: a rare and aggressive form of central nervous system metastasis
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British Journal of Cancer, Published online: 04 August 2020; doi:10.1038/s41416-020-1008-2Central nervous system miliary metastasis in breast cancer: a case series analysis and proposed identification criteria of a rare metastasis subtype
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Modified PD-1 incorporating an unnatural amino acid covalently bound PD-L1 to shrink tumors in vivo.
Mon Aug 03, 2020 10:05
A liquid biopsy–based method, dubbed EV-CLUE, discerned breast cancer invasiveness and metastasis.
Mon Aug 03, 2020 10:05
Autologous T cells engineered to target the MAGE-A4 cancer testis antigen successfully shrank a wide range of solid tumors with a manageable toxicity profile. In a phase I trial, the therapy, ADP-A2M4, showed the most promise in synovial sarcoma, yielding a disease control rate of around 90%.
Mon Aug 03, 2020 10:05
Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to...
Mon Aug 03, 2020 10:05
Following the failure of several OX40 agonist antibody candidates, findings from an early-stage trial suggest a way forward to activate the costimulatory receptor. In the trial, intratumoral injections of mRNA encoding the OX40 ligand yielded favorable immunologic and molecular effects in patients.
Mon Aug 03, 2020 10:05
Posterior fossa A (PFA) ependymomas required a hypoxic environment to maintain their epigenomes.
Mon Aug 03, 2020 10:05
In recent months, the COVID-19 pandemic has caused many institutions to pause routine cancer screenings—delays that may not be problematic for patients but can create challenges for healthcare providers.
Mon Aug 03, 2020 10:05
Summary: In this issue of Cancer Discovery, Bayik and colleagues demonstrated sexual dimorphism in accumulation of different populations of myeloid-derived suppressor cells in glioblastoma and showed that they could be targeted by different agents. See related article by Bayik et al., p. 1210.
Mon Aug 03, 2020 10:05
Anticancer drugs' ability to concentrate in condensates containing their targets affected activity.
Mon Aug 03, 2020 10:05
Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct contributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network...
Mon Aug 03, 2020 10:05
Ivosidenib, an inhibitor of mutant IDH1, was safe and showed early evidence of efficacy in glioma.
Mon Aug 03, 2020 10:05
The small-molecule tyrosine kinase inhibitor tucatinib outperformed placebo against brain metastases.
Mon Aug 03, 2020 10:05
Metabolites produced in cancer cells interfered with resolution of DNA double-strand breaks.
Mon Aug 03, 2020 10:05
Transcytosis from cancer cells into fibroblasts triggered the cGAS–STING pathway.
Mon Aug 03, 2020 10:05
MTOR was a critical node modulating stress-induced mutagenesis (SIM) in cancer in vitro and in vivo.
Mon Aug 03, 2020 10:05
Summary: The discovery of covalent inhibitors of KRASG12C has led to promising clinical results in lung cancer, but disappointing response rates in colon cancer. In this issue of Cancer Discovery, Misale and colleagues identify high endogenous EGFR activity as the underlying mechanism of intrinsic resistance, which can be overcome by anti-EGFR antibody coadministration. See related article by Amodio et al., p. 1129.
Mon Aug 03, 2020 10:05
Deficiency of dendritic cell–expressed PD-L1 reduced tumor growth and increased T-cell infiltration.
Mon Aug 03, 2020 10:05
The coronavirus disease 2019 (COVID-19) pandemic has led to dramatic changes in oncology practice. It is currently unknown whether programmed death 1 (PD-1) blockade therapy affects severity of illness from COVID-19 in patients with cancer. To address this uncertainty, we examined consecutive patients with lung cancers who were diagnosed with COVID-19 and examined severity on the basis of no or prior receipt of PD-1 blockade. Overall, the severity of COVID-19 in patients with lung cancer was high,...
Mon Aug 03, 2020 10:05
Tumor antigen–loaded vesicles were transferred between dendritic cells for presentation to T cells.
Mon Aug 03, 2020 10:05
Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor–positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells...
Mon Aug 03, 2020 10:05
IL18 engineered not to bind a decoy receptor, but not normal IL18, had antitumor efficacy in mice.
Mon Aug 03, 2020 10:05
In a phase I trial of chimeric antigen receptor T cells targeting CD19 and CD22 in younger patients with relapsed or refractory B-cell acute lymphoblastic leukemia, toxicity was manageable, and five of 12 patients had complete responses.
Mon Aug 03, 2020 10:05
DNA–protein complexes called neutrophil extracellular traps were chemoattractants for metastatic cells.
Mon Aug 03, 2020 10:05
Oxaliplatin caused ileal apoptosis and Tfh-cell enrichment and perturbed microbiota in colon cancer.
Mon Aug 03, 2020 10:05
Mutagen-induced DNA lesions were not all resolved prior to mitosis, yielding mutational strand bias.
Mon Aug 03, 2020 10:05
Gain-of-function variants of the E3 ubiquitin ligase WWP1 increased cancer susceptibility.
Mon Aug 03, 2020 10:05
Patients with relapsed or refractory diffuse large B-cell lymphoma responded to a novel combination.
Mon Aug 03, 2020 10:05
Berzosertib upped survival in those with platinum-resistant tumors and short platinum-free intervals.
Mon Aug 03, 2020 10:05
Preliminary clinical data for ARV-110, a proteolysis-targeting chimera that flags the androgen receptor for degradation, indicate that the drug is safe and shows some efficacy in men with metastatic castration-resistant prostate cancer.
Mon Aug 03, 2020 10:05
In mice, senescence-targeted CAR T cells extended survival in lung cancer and improved liver fibrosis.
Mon Aug 03, 2020 10:05
The latest results from the CodeBreak 100 trial evaluating AMG 510 indicate that this first-in-class KRAS inhibitor, having shown promise in non–small cell lung cancer, is modestly active in several other types of solid tumors, including colorectal cancer.
Mon Aug 03, 2020 10:05
Summary: In this issue of Cancer Discovery, Diab and colleagues demonstrate in a phase I trial enrolling 38 patients diagnosed with advanced solid tumors that combining the pegylated IL2 bempegaldesleukin with an anti–PD-1 mAb is safe, with an overall response rate of 59.5%. This compelling clinical activity is supported by the potent immune proliferation and activation of circulating T and natural killer cells with a >4-fold increase in the CD8/regulatory T-cell ratio in tumors, independent...
Mon Aug 03, 2020 10:05
Intracellular bacteria are widespread in tumors throughout the body, forming distinct populations that may play a critical role in shaping the microenvironment of cancers, according to a comprehensive survey of more than 1,000 tumor microbiomes across seven cancer types.
Mon Aug 03, 2020 10:05
Among more than 200 BAP1-mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a BAP1 mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic BAP1 mutations. Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual...
Mon Aug 03, 2020 10:05
A personalized cancer vaccine, when combined with the PD-L1 inhibitor atezolizumab, has shown early promise in patients with solid cancers: In a phase Ib trial, the therapy induced neoantigen-specific T-cell responses—and elicited complete or partial tumor eradication in some patients.
Mon Aug 03, 2020 10:05
Most patients with KRASG12C–mutant non–small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRASG12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRASG12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation...
Mon Aug 03, 2020 10:05
The TIGIT inhibitor tiragolumab, alone or in combination with the PD-L1 inhibitor atezolizumab, may be effective against solid cancers. In phase I and II trials, the agent achieved statistically significant results in multiple solid malignancies—most notably non–small cell lung cancer.
Mon Aug 03, 2020 10:05
This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non–small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related...
Mon Aug 03, 2020 10:05
EGFR exon 20 insertion driver mutations (Exon20ins) in non–small cell lung cancer (NSCLC) are insensitive to EGFR tyrosine kinase inhibitors (TKI). Amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR–MET, has shown preclinical activity in TKI-sensitive EGFR-mutated NSCLC models and in an ongoing first-in-human study in patients with advanced NSCLC. However, the activity of amivantamab in Exon20ins-driven tumors has not yet been described. Ba/F3 cells and patient-derived cells/organoids/xenograft...
Mon Aug 03, 2020 10:05
Minority scientists—especially Black scientists—have long been underrepresented in the oncology workforce, likely due to a low number of minority students starting and continuing careers in science and medicine. Although progress has been made through government programs that offer students of all ages opportunities to explore careers in oncology, more work is needed to promote diversity.
Mon Aug 03, 2020 10:05
Inactivation of the tumor suppressor lipid phosphatase INPP4B is common in triple-negative breast cancer (TNBC). We generated a genetically engineered TNBC mouse model deficient in INPP4B. We found a dose-dependent increase in tumor incidence in INPP4B homozygous and heterozygous knockout mice compared with wild-type (WT), supporting a role for INPP4B as a tumor suppressor in TNBC. Tumors derived from INPP4B knockout mice are enriched for AKT and MEK gene signatures. Consequently, mice with INPP4B...
Mon Aug 03, 2020 10:05
Abstract Although intake of highly sugary foods is considered to be a potential risk factor for colorectal cancer through hyperinsulinemia, the association of sugar intake and colorectal adenoma, a precursor lesion to most colorectal cancer, is poorly understood, particularly in Asian populations. We conducted a cross‐sectional study in a Japanese population to investigate the association between dietary sugar intake and the prevalence of colorectal adenoma. Study subjects were selected from participants...
Sun Aug 02, 2020 17:09
Purpose: We assessed plasma circulating tumor DNA (ctDNA) level as a prognostic marker for progression-free survival (PFS) following first-line metastatic colorectal cancer (mCRC) therapy. Experimental Design: The Sequencing Triplet With Avastin and Maintenance (STEAM) was a randomized, phase II trial investigating efficacy of bevacizumab (BEV) plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) and 5-fluorouracil/leucovorin/irinotecan (FOLFIRI), administered concurrently or sequentially,...
Mon Aug 03, 2020 10:05
Purpose: For patients with refractory/relapsed Hodgkin lymphoma (roughly 20% of total cases), few effective therapeutic options exist. Currently, brentuximab vedotin (BV), a drug-conjugated anti-CD30 antibody, is one of the most effective approved therapy agents for these patients. However, many patients do not achieve complete remission and ultimately develop BV-resistant disease, necessitating a more detailed understanding of the molecular circuitry that drives BV sensitivity and the mechanism...
Mon Aug 03, 2020 10:05
A study was presented in which sarcomas were microinjected simultaneously with several drugs to study the pharmacodynamic response after resection. This platform may represent a future way of probing efficacy of anticancer agents in the relevant model system: human tumors. See related article by Gundle et al., p. 3958
Mon Aug 03, 2020 10:05
Purpose: A major challenge in ductal carcinoma in situ (DCIS) treatment is selection of the most appropriate therapeutic approach for individual patients. We conducted an external prospective–retrospective clinical validation of a DCIS biologic risk signature, DCISionRT, in a population-based observational cohort of women diagnosed with DCIS and treated with breast-conserving surgery (BCS). Experimental Design: Participants were 455 health plan members of Kaiser Permanente Northwest diagnosed...
Mon Aug 03, 2020 10:05
Treating BCR-ABL–positive chronic myeloid leukemia remains impeded by the development of clinical resistance to imatinib. It has been demonstrated that berberine, a plant alkaloid, has activity against imatinib-resistant BCR-ABL mutants by inducing autophagic degradation of BCR-ABL, thereby preventing the acquisition of drug-resistant mutations. See related article by Yin et al., p. 4040
Mon Aug 03, 2020 10:05
Purpose: Aggressive variant prostate cancer (AVPC) represents a clinical subset distinguished by therapy resistance and poor prognosis, linked to combined losses of the tumor suppressor genes (TSG) PTEN, RB1, and TP53. Circulating tumor cells (CTC) provide a minimally invasive opportunity for identification and molecular characterization of AVPC. We aimed to evaluate the incidence and clinical significance of compound (2+)TSG losses and genomic instability in prostate cancer CTC, and to expand...
Mon Aug 03, 2020 10:05
The development of the most successful cancer immunotherapies in solid tumors, immune-checkpoint blockade, has focused on factors regulating T-cell activation. Until recently, the field has maintained a predominately T-cell centric view of immunotherapy, leaving aside the impact of innate immunity and especially myeloid cells. Dendritic cells (DC) are dominant partners of T cells, necessary for initiation of adaptive immune responses. Emerging evidence supports a broader role for DCs in tumors including...
Mon Aug 03, 2020 10:05
Purpose: Several groups have reported a prevalence of human cytomegalovirus (CMV) in glioblastoma close to 100%. Previously, we reported that treatment with the antiviral drug valganciclovir as an add-on to standard therapy significantly prolonged survival in 50 patients with glioblastoma. Here, we present an updated retrospective analysis that includes an additional 52 patients. Experimental Design: From December 2006 to November 2019, 102 patients with newly diagnosed glioblastoma received...
Mon Aug 03, 2020 10:05
Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy. In almost all cases, it is associated with somatic and often germline pathogenic variants in SMARCA4, which encodes for the SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin remodeling complex. Approximately 20% of human cancers possess pathogenic variants in at least one SWI/SNF subunit. Because of their role in regulating many important cellular processes including transcriptional...
Mon Aug 03, 2020 10:05
Purpose: We pursued genomic analysis of an exceptional responder with non–small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets. Experimental Design: In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate...
Mon Aug 03, 2020 10:05
Purpose: The safety and efficacy of ibrutinib, a once-daily Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was demonstrated in this phase Ib/II study. Extended follow-up up to 8 years is described, representing the longest follow-up for single-agent ibrutinib, or any BTK inhibitor, to date. Patients and Methods: Phase Ib/II PCYC-1102 (NCT01105247) and extension study PCYC-1103 (NCT01109069) included patients receiving single-agent...
Mon Aug 03, 2020 10:05
Purpose: Although cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly extend tumor response in patients with metastatic estrogen receptor–positive (ER+) breast cancer, relapse is almost inevitable. This may, in part, reflect the failure of CDK4/6 inhibitors to induce apoptotic cell death. We therefore evaluated combination therapy with ABT-199 (venetoclax), a potent and selective BCL2 inhibitor. Experimental Design: BCL2 family member expression was assessed following treatment...
Mon Aug 03, 2020 10:05
Purpose: Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002. Patients and Methods: Eligible patients had stage III to IV or recurrent disease....
Mon Aug 03, 2020 10:05
Purpose: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. Patients and Methods: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver...
Mon Aug 03, 2020 10:05
Purpose: Clinical trials with immune checkpoint inhibition in sarcomas have demonstrated minimal response. Here, we interrogated the tumor microenvironment (TME) of two contrasting soft-tissue sarcomas (STS), rhabdomyosarcomas and undifferentiated pleomorphic sarcomas (UPS), with differing genetic underpinnings and responses to immune checkpoint inhibition to understand the mechanisms that lead to response. Experimental Design: Utilizing fresh and formalin-fixed, paraffin-embedded tissue...
Mon Aug 03, 2020 10:05
Purpose: The activating mutation AKT1E17K occurs in approximately 7% of estrogen receptor–positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1E17K-mutant ER+ MBC. Patients and Methods: Patients with an AKT1E17K mutation, detected by local (next-generation sequencing) or central...
Mon Aug 03, 2020 10:05
Purpose: Imatinib, the breakpoint cluster region protein (BCR)/Abelson murine leukemia viral oncogene homolog (ABL) inhibitor, is widely used to treat chronic myeloid leukemia (CML). However, imatinib resistance develops in many patients. Therefore, new drugs with improved therapeutic effects are urgently needed. Berberine (BBR) is a potent BCR-ABL inhibitor for imatinib-sensitive and -resistant CML. Experimental Design: Protein structure analysis and virtual screening were used to identify...
Mon Aug 03, 2020 10:05
Purpose: A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously...
Mon Aug 03, 2020 10:05
Purpose: Brain involvement occurs in the majority of patients with metastatic melanoma. The potential of circulating tumor DNA (ctDNA) for surveillance and monitoring systemic therapy response in patients with melanoma brain metastases merits investigation. Experimental Design: This study examined circulating BRAF, NRAS, and c-KIT mutations in patients with melanoma with active brain metastases receiving PD-1 inhibitor–based therapy. Intracranial and extracranial disease volumes were measured...
Mon Aug 03, 2020 10:05
Purpose: Treatment of multiple myeloma has evolved tremendously and optimal utilization of available therapies will ensure maximal patient benefits. Patients and Methods: We report the Southwest Oncology Group randomized phase II trial (S1304) comparing twice weekly low-dose (27 mg/m2; arm 1) to high-dose carfilzomib (56 mg/m2; arm 2), both with dexamethasone, administered for 12 cycles (11 months) for relapsed and/or refractory multiple myeloma with up to six prior lines of therapy (NCT01903811)....
Mon Aug 03, 2020 10:05
Purpose: Diffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, Activin A receptor type I (ACVR1)-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy. Experimental Design: We utilized the Sleeping Beauty transposase system to generate an endogenous mouse model of mACVR1 brainstem glioma. Histology was used to characterize and validate the model. We performed RNA-sequencing...
Mon Aug 03, 2020 10:05
Purpose: Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. Patients and Methods: In two prospective phase I studies, adult patients with advanced GPC3+ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective...
Mon Aug 03, 2020 10:05
Purpose: Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer. Experimental Design: We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDO) from resected colorectal cancer liver metastases. Drug sensitivity testing (n = 40 clinically relevant agents) and gene expression...
Mon Aug 03, 2020 10:05
Purpose: Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing real-time visualization of tumors and vital structures during...
Mon Aug 03, 2020 10:05
Purpose: DNA damage response and repair (DDR) gene alterations are associated with increased tumor-infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with clinical outcomes to programmed death ligand 1 [PD-(L)1] blockade in non–small cell lung cancer (NSCLC) is unknown. Experimental Design: Tumors from patients treated with PD-(L)1 inhibitors were analyzed using targeted next-generation sequencing...
Mon Aug 03, 2020 10:05
Purpose: Probody therapeutic CX-072 is a protease-activatable antibody that is cross-reactive with murine and human programmed death-ligand 1 (PD-L1). CX-072 can be activated in vivo by proteases present in the tumor microenvironment, thereby potentially reducing peripheral, anti–PD-L1-mediated toxicities. To study its targeting of PD-L1–expressing tissues, we radiolabeled CX-072 with the PET isotope zirconium-89 (89Zr). Experimental Design: 89Zr-labeled CX-072, nonspecific Probody control...
Mon Aug 03, 2020 10:05
Purpose: With the increased prevalence in checkpoint therapy resistance, there remains a significant unmet need for additional therapies for patients with relapsing or refractory cancer. We have developed FS222, a bispecific tetravalent antibody targeting CD137 and PD-L1, to induce T-cell activation to eradicate tumors without the current toxicity and efficacy limitations seen in the clinic. Experimental Design: A bispecific antibody (FS222) was developed by engineering CD137 antigen–binding...
Mon Aug 03, 2020 10:05
Publication date: Available online 2 August 2020Source: Critical Reviews in Oncology/HematologyAuthor(s): Massimiliano Camilli, Marco Lombardi, Giovanni Maria Vescovo, Marco Giuseppe Del Buono, Mattia Galli, Nadia Aspromonte, Giuseppe Biondi Zoccai, Giampaolo Niccoli, Rocco A. Montone, Filippo Crea, Giorgio Minotti
Mon Aug 03, 2020 18:10
Abstract To investigate the difference among patients, family members, physicians, and nurses in their ability to identify malnutrition risk in patients with thoracic cancer. The enrolled patients were evaluated by the NRS2002 nutritional risk scale. The patient-centered groups, including the patient, the primary caretaker, the physician, and the nurse, were given a questionnaire on their knowledge and understanding of nutrition therapy in cancer treatment. The incidence rate...
Mon Aug 03, 2020 03:00
Non-small cell lung cancer (NSCLC) cells derived intracellular and extracellular programmed cell death ligand 1 (PD-L1) promoted cancer progression and drug resistance, and facilitated tumor immune evasion. Ho...
Mon Aug 03, 2020 03:00
Collagens are the most abundant proteins in extra cellular matrix and important components of tumor microenvironment. Recent studies have showed that aberrant expression of collagens can influence tumor cell b...
Mon Aug 03, 2020 03:00
Colorectal cancer (CRC) is one of the most common malignancies, and it’s expected that the CRC burden will substantially increase in the next two decades. New biomarkers for targeted treatment and associated m...
Mon Aug 03, 2020 03:00
Abstract The outbreak of pneumonia caused by novel coronavirus (SARS-CoV-2) in Wuhan, China, at the end of 2019 quickly escalated into a global health emergency. Since its outbreak until the 29th of April 2020, the pandemic has affected more than 3 million of people and caused 207,973 deaths globally. SARS-CoV-2 belongs to the β-coronavirus genus of the Coronavirus family, and it shares the same subfamily with severe acute respiratory syndrome-associated coronavirus (SARS-CoV)...
Mon Aug 03, 2020 03:00
PI3K/AKT/mTOR pathway hyperactivation is frequent in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). To model inhibition of mTOR, pre-T LBL tumor development was monitored in mice with T-lymphocyte-specific, constitutively-active AKT (Lck-MyrAkt2) that were either crossed to mTOR knock-down (KD) mice or treated with the mTOR inhibitor, everolimus. Lck-MyrAkt2;mTOR KD mice lived significantly longer than Lck-MyrAkt2;mTOR wild-type (WT) mice, although both groups ultimately developed thymic...
Mon Aug 03, 2020 19:29
Regorafenib is a tyrosine kinase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of chemotherapy-refractory metastatic colorectal cancer (mCRC) patients. Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity. Here we report biomarker results from LCCC1029, a randomized, placebo controlled, phase II trial of chemotherapy ± regorafenib in second-line mCRC patients. A panel of 20 soluble protein biomarkers...
Mon Aug 03, 2020 19:29
The approval of ado-trastuzumab emtansine (T-DM1) in HER2+ metastatic breast cancer validated HER2 as a target for HER2-specific antibody-drug conjugates (ADC). Despite its demonstrated clinical efficacy, certain inherent properties within T-DM1 hamper this compound from achieving the full potential of targeting HER2-expressing solid tumors with ADCs. Here, we detail the discovery of PF-06804103, an anti-HER2 ADC designed to have a widened therapeutic window compared to T-DM1. We utilized an empirical...
Mon Aug 03, 2020 19:29
Small molecule inhibitors targeting mutant epidermal growth factor receptor (EGFR) are standard of care in non-small cell lung cancer (NSCLC), but acquired resistance invariably develops through mutations in EGFR or through activation of compensatory pathways such as cMet. Amivantamab (JNJ-61186372) is an anti-EGFR and anti-cMet bispecific low fucose antibody with enhanced Fc function designed to treat tumors driven by activated EGFR and/or cMet signaling. Potent in vivo anti-tumor efficacy is observed...
Mon Aug 03, 2020 19:29
Higher tumor mutational burden (TMB) has been correlated with response to checkpoint blockade immunotherapy. However, it is unclear whether TMB independently serves as a prognostic biomarker for outcomes in immunotherapy-naïve patients. Here we evaluated the relationship between TMB and overall survival in 1,415 immunotherapy-naïve patients with diverse advanced malignancies. TMB was studied both as a tiered variable (low ≤5 mutations/Mb, intermediate >5 and <20, high ≥20 and <50, and...
Mon Aug 03, 2020 19:29
Uveal melanoma is a rare and aggressive cancer that originates in the eye. Currently, there are no approved targeted therapies and very few effective treatments for this cancer. While activating mutations in the G protein alpha subunits, GNAQ and GNA11, are key genetic drivers of the disease, few additional drug targets have been identified. Recently, studies have identified context specific roles for the mammalian SWI/SNF chromatin remodeling complexes (also known as BAF/PBAF) in various cancer...
Mon Aug 03, 2020 19:29
Despite unprecedented advances in the treatment of cancer through the use of immune checkpoint blockade, responses are not universal and alternative strategies are needed to enhance responses to ICB. We have shown previously that a novel polyamine blocking therapy (PBT), consisting of co-treatment with α-difluoromethylornithine (DFMO) to block polyamine biosynthesis and a Trimer polyamine transport inhibitor, decreases myeloid-derived suppressor cells (MDSC) and M2-like tumor-associated macrophages...
Mon Aug 03, 2020 19:29
To investigate the feasibility of a knowledge-based automated intensity-modulated radiation therapy (IMRT) planning technique for locally advanced nasopharyngeal carcinoma (NPC) radiotherapy.
Mon Aug 03, 2020 03:00
Mechanisms underlying the ability of hepatitis C virus (HCV) to establish persistent infections and induce progressive liver disease remain poorly understood. HCV is one of several positive-stranded RNA viruses capable of establishing persistence in their immunocompetent vertebrate hosts, an attribute associated with formation of large scale RNA structure in their genomic RNA. We developed novel methods to analyse and visualise genome-scale ordered RNA structure (GORS) predicted from the increasingly...
Mon Aug 03, 2020 21:43
Programmed Cell Death 4 (PDCD4) protein is a tumour suppressor that inhibits translation through the mTOR dependent initiation factor EIF4A, but its functional role and mRNA targets in neurons remain largely unknown. Our work identified that PDCD4 is highly expressed in axons and dendrites of CNS and PNS neurons, with loss and gain of function experiments in cortical and dorsal root ganglia primary neurons demonstrating the capacity of PDCD4 to negatively control axonal growth. To explore PDCD4 transcriptome...
Mon Aug 03, 2020 21:43
Chaperone proteins --- the most disordered among all protein groups --- help RNAs fold into their functional structure by destabilizing misfolded configurations or stabilizing the functional ones. But disentangling the mechanism underlying RNA chaperoning is challenging, mostly due to inherent disorder of the chaperones and the transient nature of their interactions with RNA. In particular, it is unclear how specific the interactions are and what role is played by amino acid charge and polarity...
Mon Aug 03, 2020 20:21
Abstract Background and purpose Radiotherapy (RT) is persistently gaining significance in the treatment of pediatric tumors. However, individual features of a growing body and multifocal stages complicate this approach. Tomotherapy offers advantages in the treatment of anatomically complex tumors with low risks of side effects. Here we report on toxicity incidence and outcome of tomotherapy with a focus on multitarget RT (mtRT). ...
Mon Aug 03, 2020 03:00
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