Clinical Cancer Research: An Official Journal of the American Association for Cancer Research

PURPOSE: PD-(L)1 blocking antibodies have clinical activity in metastatic non-small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade.Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells were collected from 35 NSCLC patients receiving nivolumab monotherapy...

PURPOSE: BRAF and MEK inhibitors (BRAFi, MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAFV600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T cells therapy (ACT) in melanoma resistant to BRAFi. EXPERIMENTAL DESIGN: Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as PDXs derived from patients...

Purpose: Inducible caspase 9 ( iCasp9 ) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9 -transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies. Patients and Methods: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 106 /kg donor-derived iCasp9 -transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism...

Purpose: Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid-suppressive (GAS) agents such as proton pump inhibitors could affect exposure of pazopanib, and thereby its therapeutic effects. Experimental Design: The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for ≥80% of treatment duration, and subsequently using various thresholds...

A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. While PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in tolerability and antitumor activity that have important implications for the clinic. Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small cell lung cancer...

Studies of Alternative RNA Splicing (ARS) have the potential to provide an abundance of novel targets for development of new biomarkers and therapeutics in oncology, which will be necessary to improve outcomes for cancer patients and mitigate cancer disparities. ARS, a key step in gene expression enabling individual genes to encode multiple proteins, is emerging as a major driver of abnormal phenotypic heterogeneity. Recent studies have begun to identify RNA splicing-related genetic and genomic variation in tumors, oncogenes dysregulated by ARS, RNA splice variants driving race-related cancer aggressiveness and drug response, spliceosome-dependent transformation, and RNA splicing-related immunogenic epitopes in cancer...

PURPOSE: As foremost regulators of cancer-related inflammation and immunotherapeutic resistance, tumor-associated macrophages have garnered major interest as immunotherapeutic drug targets. However, depletory strategies have yielded little benefit in clinical studies to date. An alternative approach is to exploit macrophage plasticity and "reeducate" tumorigenic macrophages towards an immunostimulatory phenotype to activate the host's antitumor immunity. EXPERIMENTAL DESIGN: We investigated the role of macrophage scavenger receptor Clever-1 on tumor growth in multiple mouse cancer models with inflammatory and non-inflammatory characteristics by using conditional knockouts, bone marrow chimeras and cell depletion experiments...

PURPOSE: Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC) commonly bear disruptive mutations in TP53, resulting in treatment resistance. In these patients, direct targeting of p53 has not been successful, but synthetic lethal approaches have promise. Although Aurora A kinase (AURKA) is overexpressed and an oncogenic driver, its inhibition has only modest clinical effects in HPV-negative HNSCC. We explored a novel combination of AURKA and WEE1 inhibition to overcome intrinsic resistance to AURKA inhibition...

PURPOSE: To investigate tolerability, efficacy, and pharmacokinetics/-dynamics (PK/PD) of Debio 1347, a selective fibroblast growth factor receptor (FGFR) Inhibitor. EXPERIMENTAL DESIGN: This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose limiting toxicities (DLTs) were evaluated during the first 4 weeks on treatment, PK/PD post-first dose and after 4 weeks...

Bone metastases are a frequent complication of cancer that are associated with considerable morbidity. Current treatments may temporarily palliate the symptoms of bone metastases, but often fail to delay their progression. Bones provide a permissive environment because they are characterized by dynamic turnover, secreting factors required for bone maintenance but also stimulating the establishment and growth of metastases. Insulin-like growth factors (IGFs) are the most abundant growth factors in bone and are required for normal skeletal development and function...

PURPOSE: Transcriptionally-induced chimeric RNAs are an important emerging area of research into molecular signatures for biomarker and therapeutic target development. Salivary exosomes represent a relatively unexplored but convenient and noninvasive area of cancer biomarker discovery. However, the potential of cancer-derived exosomal chimeric RNAs in saliva as biomarkers is unknown. Here, we explore the potential clinical utility of salivary exosomal GOLM1-NAA35 chimeric RNA (se G-N chiRNA) in esophageal squamous cell carcinoma (ESCC)...

PURPOSE: Biodistribution of bispecific antibodies in patients is largely unknown. We therefore performed a feasibility study in nine patients with advanced gastrointestinal adenocarcinomas to explore AMG 211 biodistribution (also known as MEDI-565), a ~55 kDa bispecific T-cell engager directed against carcinoembryonic antigen on tumor cells and cluster of differentiation 3 (CD3) on T-cells. METHODS: 89Zr-labeled AMG 211 as tracer, was administered alone or with cold AMG 211, for positron emission tomography (PET) imaging before and/or during AMG 211 treatment...

PURPOSE: Thyroid cancer cell lines are valuable models but have been neglected in pan-cancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. EXPERIMENTAL DESIGN: We performed next-generation sequencing and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. RESULTS: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages...

PURPOSE: The B7 homolog 4 (B7-H4, VTCN1 ) is an immune checkpoint molecule that negatively regulates immune responses and is known to be overexpressed in many human cancers. Previously, we generated a mouse anti-human B7-H4 monoclonal antibody that did not have a significant antitumor effect in vivo probably because of molecule instability. In this study, we designed a B7-H4/CD3 bispecific antibody (BsAb) and investigated its antitumor activity in vitro and in vivo using a humanized mouse model...

PURPOSE: We identified for the first time that C8orf76 (chromosome 8 open reading frame 76) is preferentially amplified in gastric cancer (GC). We elucidated its role and clinical significance in gastric carcinogenesis. EXPERIMENTAL DESIGN: The clinical impact of C8orf76 was assessed in 592 GCs. The biological function of C8orf76 was studied in vitro , in vivo and in GC patient-derived organoid models. C8orf76 downstream effector and pathways were identified by RNA-sequencing, ChIP-sequencing, luciferase reporter and electrophoretic mobility shift assay...

PURPOSE: The prognosis of metastatic osteosarcoma continues to be poor. We hypothesized that alpha-emitting, bone-targeting radium 223 dichloride (223 RaCl2 ) can be safely administered to patients with osteosarcoma and that early signals of response or resistance can be assessed by quantitative and qualitative correlative imaging studies and biomarkers. EXPERIMENTAL DESIGN: A 3+3 phase I, dose-escalation trial of 223 RaCl2 (50, 75, and 100 kBq/kg) was designed in recurrent/metastatic osteosarcoma patients aged ≥15 years...

PURPOSE: Mutations in the ligand binding domain (LBD) of estrogen receptor α (ER) confer constitutive transcriptional activity and resistance to endocrine therapies in breast cancer patients. Accumulating clinical data suggest adverse outcome for patients harboring tumors expressing these mutations. We aimed to elucidate mechanisms conferring this aggressive phenotype. EXPERIMENTAL DESIGN: Cells constitutively expressing physiologic levels of ER harboring activating LBD mutations were generated and characterized for viability, invasiveness and tumor formation in vivo...

PURPOSE: Aberrant overexpression of SFN (stratifin) plays an oncogenic role in lung adenocarcinoma. We have shown previously that SKP1, an adapter component of E3 ubiquitin ligase forming a SCF complex, is a unique SFN-binding protein in lung adenocarcinoma cells. EXPERIMENTAL DESIGN: In silico simulation and in vitro mutagenesis analysis were performed to identify the SFN binding domain on SKP1. We examined expression, localization and stability of SKP1 after knockdown of SFN using lung adenocarcinoma cells including A549...

Excision Repair Cross-Complementation Group 1 (ERCC1) participates in the repair of DNA intrastrand adducts and interstrand crosslinks, but its role as a predictive biomarker has never been fully validated. It has now been revealed that p53 mutation status should be considered concomitantly with ERCC1 to predict cisplatin efficacy.

Continuous B cell receptor stimulation by antigens in secondary lymphoid tissues is a key pathogenic mechanism in chronic lymphocytic leukemia. Therapy with ibrutinib mobilizes tissue CLL cells into the peripheral blood, away from tissue antigen. Consequently, mobilized antigen-deprived CLL cells upregulate surface IgM, providing robust evidence for this mechanism of pathogenesis.