The Emerging Role of c-Met in Carcinogenesis and Clinical Implications as a Possible Therapeutic Target.

BACKGROUND: c-MET is a receptor tyrosine kinase receptor (RTK) for the hepatocyte growth factor (HGF). The binding of HGF to c-MET regulates several cellular functions: differentiation, proliferation, epithelial cell motility, angiogenesis, and epithelial-mesenchymal transition (EMT). Moreover, it is known to be involved in carcinogenesis. Comprehension of HGF-c-MET signaling pathway might have important clinical consequences allowing to predict prognosis, response to treatment, and survival rates based on its expression and dysregulation. Discussion. c-MET represents a useful molecular target for novel engineered drugs. Several clinical trials are underway for various solid tumors and the development of new specific monoclonal antibodies depends on the recent knowledge about the definite c-MET role in each different malignance. Recent clinical trials based on c-MET molecular targets result in good safety profile and represent a promising therapeutic strategy for solid cancers, in monotherapy or in combination with other target drugs. CONCLUSION: The list of cell surface receptors crosslinking with the c-MET signaling is constantly growing, highlighting the importance of this pathway for personalized target therapy. Research on the combination of c-MET inhibitors with other drugs will hopefully lead to discovery of new effective treatment options.

Immune cell labelling and tracking: implications for adoptive cell transfer therapies.

BACKGROUND: The understanding of the role of different immune cell subsets that infiltrate tumors can help researchers in developing new targeted immunotherapies to reactivate or reprogram them against cancer. In addition to conventional drugs, new cell-based therapies, like adoptive cell transfer, proved to be successful in humans. Indeed, after the approval of anti-CD19 CAR-T cell therapy, researchers are trying to extend this approach to other cancer or cell types. MAIN BODY: This review focuses on the different approaches to non-invasively monitor the biodistribution, trafficking and fate of immune therapeutic cells, evaluating their efficacy at preclinical and clinical stages. PubMed and Scopus databases were searched for published articles on the imaging of cell tracking in humans and preclinical models. CONCLUSION: Labelling specific immune cell subtypes with specific radiopharmaceuticals, contrast agents or optical probes can elucidate new biological mechanisms or predict therapeutic outcome of adoptive cell transfer therapies. To date, no technique is considered the gold standard to image immune cells in adoptive cell transfer therapies.

First-line systemic therapy for metastatic castration-sensitive prostate cancer: An updated systematic review with novel findings.

Although both docetaxel and androgen-receptor-axis-targeted (ARAT) agents have yielded survival improvements in combination with androgen deprivation therapy (ADT) compared to ADT alone in metastatic castration-sensitive prostate cancer (mCSPC) patients, the optimal therapeutic choice remains to be established. We analyzed estimates of the hazard ratios for death (OS-HRs) in patients treated in the first-line setting enrolled in the GETUG-AFU15, CHAARTED, STAMPEDE, LATITUDE, ENZAMET, and TITAN trials. Overall, men with mCSPC receiving ADT with vs. without either an ARAT agent or docetaxel as first-line systemic therapy showed a pooled OS-HR of 0.69 (95 % CI: 0.61-0.78), with significant heterogeneity (p = 0.045, I2 = 52.5 %). Network meta-analysis showed an OS-HR in patients receiving an ARAT agent vs. docetaxel of 0.78 (95 %CI: 0.67-0.91). In conclusion, the evidence analysed indicates that an ARAT agent may provide improved OS outcomes compared to docetaxel. Prospective randomized trials are warranted.

Assessment of Total, PTEN-, and AR-V7+ Circulating Tumor Cell Count by Flow Cytometry in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Enzalutamide.

INTRODUCTION: Metastatic castration-resistant prostate cancer (mCRPC) is a deadly disease. Enzalutamide is an oral second-generation anti-androgen that is active in mCRPC. Circulating tumor cells (CTC) count correlates with overall survival (OS) in mCRPC, whereas detection of the androgen-receptor splice variant 7 (AR-V7) in CTC predicts poor response to oral second-generation anti-androgens. Also, loss of PTEN (phosphatase and tensin homolog) in CTC is a biomarker of poor prognosis in mCRPC. PATIENTS AND METHODS: In this translational study, we employed flow cytometry to assess total, PTEN-, and AR-V7+ CTC count per 7.5 mL of whole blood in a prospective cohort of patients with mCRPC receiving enzalutamide. RESULTS: CTCs were assessed in a total of 45 men with mCRPC at baseline and at 12 weeks. Overall, CTC, PTEN- CTC, and AR-V7+ CTC detection rate was high, at baseline, with 84.4%, 71.1%, and 51.1% of samples showing at least 1 cell/7.5-mL blood, respectively, and after 3 months, with 93.3%, 64.4%, and 77.7% of samples showing at least 1 cell/7.5-mL blood, respectively. Median radiographic progression-free survival (rPFS) and OS were 6 (95% confidence interval [CI], 5.6-9) and 14.3 (95% CI, 12.8-20.3) months, respectively. Median (interquartile range) total CTC count at baseline was 5 (3; 8), whereas median (interquartile range) PTEN- CTC count was 2 (0; 4) and median (interquartile range) AR-V7+ CTC count was 1 (0; 3). At baseline, ≥ 5 versus < 5 total CTC count was associated with worse rPFS (hazard ratio [HR], 2.35; 95% CI, 1.14-4.84; P= .021) and OS (HR, 3.08; 95% CI, 1.45-6.54; P = .003), whereas ≥ 2 versus < 2 PTEN- CTC count was associated with worse rPFS (HR, 3.96; 95% CI, 1.8-8.72; P= .001) and OS (HR, 2.36; 95% CI, 1.12-5; P= .025). Finally, ≥ 1 versus < 1 AR-V7+ CTC count was also associated with worse rPFS (HR, 5.05; 95% CI, 2.4-10.64; P< .001) and OS (HR, 2.25; 95% CI, 1.1-4.58; P= .026). CONCLUSIONS: Despite multiple limitations, including the small sample size, our preliminary study suggests that assessment of CTC via flow cytometry may provide potentially useful prognostic and predictive information in advanced prostate cancer. Further studies are warranted. Micro-Abstract: In this study, men with metastatic castration-resistant prostate cancer, scheduled to start enzalutamide, were assessed for circulating tumor cell count and molecular characterization (total, PTEN-, and AR-V7+ circulating tumor cell count) by the use of flow cytometry. We found that flow cytometry could be used to enumerate circulating tumor cells, but also to assess molecular biomarkers on their surface.

Radiopharmaceuticals for Breast Cancer and Neuroendocrine Tumors: Two Examples of How Tissue Characterization May Influence the Choice of Therapy.

Molecular medicine has gained clinical relevance for the detection and staging of oncological diseases, to guide therapy decision making and for therapy follow-up due to the availability of new highly sensitive hybrid imaging camera systems and the development of new tailored radiopharmaceuticals that target specific molecules. The knowledge of the expression of different receptors on the primary tumor and on metastases is important for both therapeutic and prognostic purposes and several approaches are available aiming to achieve personalized medicine in different oncological diseases. In this review, we describe the use of specific radiopharmaceuticals to image and predict therapy response in breast cancer and neuroendocrine tumors since they represent a paradigmatic example of the importance of tumoral characterization of hormonal receptors in order to plan a tailored treatment. The most attractive radiopharmaceuticals for breast cancer are 16α-[18F]-fluoro-17ß-estradiol for PET assessment of the estrogen expression, radiolabeled monoclonal antibody trastuzumab to image the human epidermal growth factor receptor 2, but also the imaging of androgen receptors with [18F]-fluorodihydrotestosterone.