The estrogen receptor (ER/ESR1) is expressed in a majority of breast cancers and drugs that inhibit ER signaling are the cornerstone of breast cancer pharmacotherapy. Currently, aromatase inhibitors are the frontline endocrine interventions of choice although their durability in metastatic disease is limited by activating point mutations within the ligand binding domain (LBD) of ESR1 that permit ligand independent activation of the receptor. It has been suggested that the most commonly occurring...
Thu May 07, 2020 16:59
Clear cell renal cell carcinoma (ccRCC) remains a common cause of cancer mortality. Better understanding of ccRCC molecular drivers resulted in the development of anti-angiogenic therapies that block the blood vessels that supply tumors with nutrients for growth and metastasis. Unfortunately, most ccRCC patients eventually become resistant to initial treatments creating a need for alternative treatment options. We investigated the role of the small GTPase Rac1 in ccRCC. Analysis of ccRCC clinical...
Tue May 05, 2020 17:57
Multiple myeloma (MM) is a plasma cell malignancy that grows in the bone marrow (BM). The major population of cells in the BM is represented by neutrophils and they can form neutrophil extracellular traps (NETs). Here, we investigated whether MM cells induce NET formation and whether targeting this process would delay MM progression. We demonstrated that murine and human MM cells stimulate citrullination of histone H3 and NET formation by neutrophils and that this process is abrogated by pharmacological...
Tue May 05, 2020 17:57
Tumor-associated M2-macrophages are one of the most abundant immunosuppressive cell types in the PDAC TME. However, the molecular mechanisms responsible for the generation of M2-macrophages are unclear. Here we demonstrated that overexpression of DCLK1-isoform2 in AsPC1 and MIA PaCa2 cells resulted in the polarization of M1-macrophages towards an M2-phenotype via secreted chemokines/cytokines. These M2-macrophages enhanced parental PDAC cell migration, invasion, and self-renewal and this was associated...
Tue May 05, 2020 17:57
Novel therapeutic strategies are urgently required for the clinical management of chemoresistant ovarian carcinoma, which is the most lethal of the gynecological malignancies. MicroRNAs (miRNAs) hold promise because they play a critical role in determining the cell phenotype by regulating several hundreds of targets, which could constitute vulnerabilities of cancer cells. A combination of gain of function miRNA screening and real-time continuous cell monitoring allows the identification of miRNAs...
Tue May 05, 2020 17:57
KIT or PDGFRA gain-of-function mutations are the primary drivers of gastrointestinal stromal tumor (GIST) growth and progression throughout the disease course. The PI3K/mTOR pathway is critically involved in the transduction of KIT/PDGFRA oncogenic signaling regardless of the type of primary and secondary mutations, and therefore emerges as a relevant targetable node in GIST biology. We evaluated in GIST preclinical models the anti-tumor activity of copanlisib, a novel pan-class-I PI3K inhibitor...
Tue May 05, 2020 17:57
Treatment response assessment for patients with advanced solid tumors is complex and existing methods require greater precision. Current guidelines rely on imaging, which has known limitations, including the time required to show a deterministic change in target lesions. Serial changes in whole-genome (WG) circulating tumor DNA (ctDNA) were used to assess response or resistance to treatment early in the treatment course. 96 patients with advanced cancer were prospectively enrolled (91 analyzed and...
Tue May 05, 2020 17:57
The MYC oncogene is frequently amplified in Medulloblastoma (MB) patients, particularly in Group 3 patients, who have the worst prognosis. MTOR signaling-driven deregulated protein synthesis is very common in various cancers including MB that can promote MYC stabilization. As a transcription factor, MYC itself is further known to regulate transcription of several components of protein synthesis machinery, leading to an enhanced protein synthesis rate and proliferation. Thus, inhibiting enhanced protein...
Tue May 05, 2020 17:57
The PI3K-AKT pathway has pleiotropic effects, and its inhibition has long been of interest in the management of prostate cancer, where a compensatory increase in PI3K signaling has been reported following Androgen Receptor (AR) blockade. Prostate cancer cells can also bypass AR blockade through induction of other hormone receptors, in particular the glucocorticoid receptor (GR). Here we demonstrate that AKT inhibition significantly decreases cell proliferation through both cytostatic and cytotoxic...
Tue May 05, 2020 17:57
Despite a growing body of knowledge about the genomic landscape of Ewing sarcoma (ES), translation of basic discoveries into targeted therapies and significant clinical gains has remained elusive. Recent insights have revealed that the oncogenic transcription factor EWS-FLI1 can impact ES cellular metabolism, regulating expression of 3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in de novo serine synthesis. Here, we have examined the importance of serine metabolism in ES tumorigenesis...
Tue May 05, 2020 17:57
Most osteosarcoma (OS) patients have subclinical pulmonary micrometastases at diagnosis. Mounting evidence suggests that macrophages facilitate metastasis. As the epidermal growth factor receptor (EGFR) has been implicated in carcinoma-macrophage crosstalk, in this study we asked whether gefitinib, an EGFR inhibitor, reduces OS invasion and metastatic outgrowth using the K7M2-Balb/c syngeneic murine model. Macrophages enhanced OS invasion in vitro, which was suppressed by gefitinib. Oral gefitinib...
Tue May 05, 2020 17:57
NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET selective bromodomain inhibitors have demonstrated on-target activity in NMC patients, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective...
Tue May 05, 2020 17:57
Bevacizumab is the molecular-targeted agent used for the antiangiogenic therapy of metastatic colorectal cancer. But some patients are resistant to bevacizumab, it needs an effective biomarker to predict the prognosis and responses of metastatic colorectal cancer (mCRC) to bevacizumab therapy. In this work, we developed a qualitative transcriptional signature to individually predict the response of bevacizumab in mCRC patients. Firstly, using mCRC samples treated with bevacizumab, we detected differentially...
Tue May 05, 2020 17:57
Fibroblast growth factor receptors (FGFR) are commonly altered in non-small cell lung cancer (NSCLC). FGFRs activate multiple pathways including RAS/RAF/MAPK, PI3K/AKT and STAT, which may play a role in the cellular response to radiation. We investigated the effects of combining the selective FGFR 1-3 tyrosine kinase inhibitor AZD4547 with radiation in cell line and xenograft models of NSCLC. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, autophagy, cell cycle,...
Tue May 05, 2020 17:57
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