Several molecular imaging modalities have been evaluated in the management of Merkel cell carcinoma (MCC), a rare and aggressive tumor with a high tendency to metastasize. Continuous progress in the field of molecular imaging might improve management in these patients. The authors review the current modalities and their impact on MCC in this brief review article.
Triple-negative breast cancer (TNBC) is the most challenging subtype to treat due to the lack of estrogen receptor, progesterone receptor, and HER2 expression, which excludes the usage of directed targeted therapy against them. Promising therapeutic targets are the hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR), which expression is frequently elevated in TNBC. Inhibitors of these receptors used as monotherapy are often ineffective. Due to that, we studied the efficacy of combined therapy targeting MET and EGFR simultaneously. Two TNBC cell lines were treated with lapatinib (a dual EGFR and HER2 inhibitor), foretinib (a MET inhibitor), or a combination of the two. After the inhibitors treatment, we verified the cell viability (XTT assay), distribution of the cell cycle phases, the activation of signaling pathways (Western blotting), distribution of invadopodia, fluorescent gelatin digestion (immunofluorescence), and the invasion capacity of cells. A combination of foretinib and lapatinib effectively reduced the viability of examined cells, led to G2/M arrest and reduction of pAKT. There was also a decreasein number of invadopodia formed by cells, their ability to digest gelatin and reduction of cells migration/invasion capacity. Therapy targeting of both EGFR and MET receptors was much more effective against tested cells than monotherapy. We selected a combination of drugs that could be successfully used against this breast cancer subtype.
Background: Oral cancer is one of the most prevalent cancers worldwide. Despite that the oral cavity is easily accessible for clinical examinations, oral cancers are often not promptly diagnosed. Furthermore, to date no effective biomarkers are available for oral cancer. Therefore, there is an urgent need to identify novel biomarkers able to improve both diagnostic and prognostic strategies. In this context, the development of innovative high-throughput technologies for molecular and epigenetics analyses has generated a huge amount of data that may be used for the identification of new cancer biomarkers. Methods: In the present study, GEO DataSets and TCGA miRNA profiling datasets were analyzed in order to identify miRNAs with diagnostic and prognostic significance. Furthermore, several computational approaches were adopted to establish the functional roles of these miRNAs. Results: The analysis of datasets allowed for the identification of 11 miRNAs with a potential diagnostic role for oral cancer. Additionally, eight miRNAs associated with patients' prognosis were also identified; six miRNAs predictive of patients' overall survival (OS) and one, hsa-miR-let.7i-3p, associated with tumor recurrence. Conclusion: The integrated analysis of different miRNA expression datasets allows for the identification of a set of miRNAs that, after validation, may be used for the early detection of oral cancers.
The question of whether anesthetic, analgesic or other perioperative intervention during cancer resection surgery might influence long-term oncologic outcomes has generated much attention over the past 13 years. A wealth of experimental and observational clinical data have been published, but the results of prospective, randomized clinical trials are awaited. The European Union supports a pan-European network of researchers, clinicians and industry partners engaged in this question (COST Action 15204: Euro-Periscope). In this narrative review, members of the Euro-Periscope network briefly summarize the current state of evidence pertaining to the potential effects of the most commonly deployed anesthetic and analgesic techniques and other non-surgical interventions during cancer resection surgery on tumor recurrence or metastasis.
Even though more than 350,000 men die from prostate cancer every year, broad-based screening for the disease remains a controversial topic. Guidelines demand that the only commonly accepted screening tool, prostate-specific antigen (PSA) testing, must be followed by prostate biopsy if results are elevated. Due to the procedure’s low positive predictive value (PPV), however, over 80% of biopsies are performed on healthy men or men with clinically insignificant cancer-prompting calls for new ways of vetting equivocal PSA readings prior to the procedure. Responding to the challenge, the present study investigated the diagnostic potential of tumour-associated circulating endothelial cells (tCECs), which have previously been described as a novel, blood-based biomarker for clinically significant cancers. Specifically, the objective was to determine the diagnostic accuracy of a tCEC-based blood test to detect clinically significant prostate cancer (defined as Gleason score ≥ 3 + 4) in high-risk patients. Performed in a blinded, prospective, single-centre set-up, it compared a novel tCEC index test with transrectal ultrasound-guided biopsy biopsy as a reference on a total of 170 patients and found that a tCEC add-on test will almost double the PPV of a standalone PSA test (32% vs. 17%; p = 0.0012), while retaining a negative predictive value above 90%.
A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and the nuclear transport protein XPO1 in overcoming endocrine resistance. Selinexor (SEL), an XPO1 antagonist, has been evaluated in multiple late stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Our transcriptomics analysis showed that 4-Hydroxytamoxifen (4-OHT), SEL alone or their combination induced differential Akt signaling- and metabolism-associated gene expression profiles. Western blot analysis in endocrine resistant cell lines and xenograft models validated differential Akt phosphorylation. Using the Seahorse metabolic profiler, we showed that ERα-XPO1 targeting changed the metabolic phenotype of TAM-resistant breast cancer cells from an energetic to a quiescent profile. This finding demonstrated that combined targeting of XPO1 and ERα rewired the metabolic pathways and shut down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies to improve therapy response in relapsed ERα (+) tumors, our findings show great promise for uncovering the role that ERα-XPO1 crosstalk plays in reducing cancer recurrences.
Metastatic disease from uveal melanoma occurs in almost 50% of patients suffering from this ocular tumour, with median survival from development of symptoms being around 1 year. In contrast to cutaneous melanoma, kinase inhibitors and immune checkpoint inhibitors are usually ineffective in patients with metastatic uveal melanoma. Tebentafusp is a novel form of immunotherapy based on the immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) platform, which comprises a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment. The T cell receptor domain of tebentafusp targets cells present a human leukocyte antigen-A*02:01 complexed with a peptide derived from the melanoma-associated antigen gp100, which is expressed strongly by melanoma cells, weakly by normal melanocytes and minimally by other tissues. The anti-CD3 domain recruits CD3+ T cells (and, indirectly, other immune cells), redirecting these to the melanoma cells. The most common adverse events with tebentafusp are manageable and usually transient. Early survival data in patients with metastatic uveal melanoma are promising when considered alongside historical data. Based on these encouraging results, a randomised study comparing tebentafusp to investigator’s choice of therapy in metastatic uveal melanoma is ongoing.
Circulating tumor cells (CTCs) hold great promise with regard to prognosis, treatment optimization, and monitoring of breast cancer patients. Single CTC transcriptome profiling might help reveal valuable information concerning intra-patient heterogeneity relevant to therapeutic interventions. In this study, we combined Diagnostic Leukapheresis (DLA), which is a microfluidic enrichment using the ParsortixTM system, micromanipulation with CellCelectorTM and subsequent single cell multi-marker transcriptome profiling. First, a PCR panel consisting of 30 different endocrine resistance and phenotypic marker genes was validated for single cell profiling by using different breast cancer cell lines. Second, this panel was applied to characterize uncultured and cultured CTCs, which were enriched from a cryopreserved DLA product obtained from a patient suffering from metastatic breast cancer resistant to endocrine therapy. Gene expression profiles of both CTC populations uncovered inter CTC heterogeneity for transcripts, which are associated with response or resistance to endocrine therapy (e.g., ESR1, HER2, FGFR1). Hierarchical clustering revealed CTC subpopulations with different expressions of transcripts regarding the CTCs' differential phenotypes (EpCAM, CD44, CD24, MYC, MUC1) and of transcripts involved in endocrine signaling pathways (FOXO, PTEN). Moreover, ER-positive CTCs exhibited significant higher expression of Cyclin D1, which might be relevant for CDK4/6 inhibitor therapies. Overall, gene expression profiles of uncultured and cultured CTCs resulted in a partly combined grouping. Our findings demonstrate that multi-marker RNA profiling of enriched single uncultured CTCs and cultured CTCs form cryopreserved DLA samples may provide important insights into intra-patient heterogeneity relevant for targeted therapies and therapy resistance.
Cannabidiol, a major non-psychotomimetic compound derived from Cannabis sativa, is a potential therapeutic agent for a variety of diseases such as inflammatory diseases, chronic neurodegenerative diseases, and cancers. Here, we found that the combination of cannabidiol and TNF-related apoptosis-inducing ligand (TRAIL) produces synergistic antitumor effects in vitro. However, this synergistic effect was not observed in normal colonic cells. The levels of ER stress-related proteins, including C/EBP homologous protein (CHOP) and phosphorylated protein kinase RNA-like ER kinase (PERK) were increased in treatment of cannabidiol. Cannabidiol enhanced significantly DR5 expression by ER stress. Knockdown of DR5 decreased the combined effect of cannabidiol and TRAIL. Additionally, the combination of TRAIL and cannabidiol decreased tumor growth in xenograft models. Our studies demonstrate that cannabidiol enhances TRAIL-induced apoptosis by upregulating DR5 and suggests that cannabidiol is a novel agent for increasing sensitivity to TRAIL.
Triple-negative breast cancer (TNBC) is a complex disease associated with the aggressive phenotype and poor prognosis. TNBC harbors heterogeneous molecular subtypes with no approved specific targeted therapy. It has been reported that HER receptors are overexpressed in breast cancer including TNBC. In this study, we evaluated the efficacy of varlitinib, a reversible small molecule pan-HER inhibitor in TNBC. Our results showed that varlitinib reduced cell viability and induced cell apoptosis in most TNBC cell lines but not in MDA-MB-231 cells. MEK and ERK inhibition overcame resistance to varlitinib in MDA-MB-231 cells. Varlitinib inhibited HER signaling which led to inhibition of migration, invasion and mammosphere formation of TNBC cells as well as significant suppression of tumor growth of MDA-MB-468 xenograft mouse model. In summary, these results suggest that HER signaling plays an important role in TNBC progression and that pan-HER inhibition is potentially an effective treatment for TNBC patients.