Prostate cancer (PCa) has become the most common cancer among males in Europe and the USA. Adoptive immunotherapy appears a promising strategy to control the advanced stages of the disease by specifically targeting the tumor, in particular through chimeric antigen receptor T (CAR-T) cell therapy. Despite the advancements of CAR-T technology in the treatment of hematological malignancies, solid tumors still represent a challenge. To overcome current limits, other cellular effectors than T lymphocytes are under study as possible candidates for CAR-engineered cancer immunotherapy. A novel approach involves the NK-92 cell line, which mediates strong cytotoxic responses against a variety of tumor cells but has no effect on non-malignant healthy counterparts. Here, we report a novel therapeutic approach against PCa based on engineering of NK-92 cells with a CAR recognizing the human prostate-specific membrane antigen (PSMA), which is overexpressed in prostatic neoplastic cells. More importantly, the potential utility of NK-92/CAR cells to treat PCa has not yet been explored. Upon CAR transduction, NK-92/CAR cells acquired high and specific lytic activity against PSMA-expressing prostate cancer cells in vitro, and also underwent degranulation and produced high levels of IFN-γ in response to antigen recognition. Lethal irradiation of the effectors, a safety measure requested for the clinical application of retargeted NK-92 cells, fully abrogated replication but did not impact on phenotype and short-term functionality. PSMA-specific recognition and antitumor activity were retained in vivo, as adoptive transfer of irradiated NK-92/CAR cells in prostate cancer-bearing mice restrained tumor growth and improved survival. Anti-PSMA CAR-modified NK-92 cells represent a universal, off-the-shelf, renewable, and cost-effective product endowed with relevant potentialities as a therapeutic approach for PCa immunotherapy.

Recently, prostate-specific membrane antigen (PSMA) has gained momentum in tumor nuclear molecular imaging as an excellent target for both the diagnosis and therapy of prostate cancer. Since 2008, after years of preclinical research efforts, a plentitude of radiolabeled compounds mainly based on low molecular weight PSMA inhibitors (PSMA-i) have been described for imaging and theranostic applications, and some of them have been transferred to the clinic. Most of these compounds include radiometals (e.g., ⁶⁸Ga, ⁶⁴Cu, ¹⁷⁷Lu) for positron emission tomography (PET) imaging or endoradiotherapy. Nowadays, although the development of new PET tracers has caused a significant drop in single-photon emission tomography (SPECT) research programs and the development of new technetium-99m (^99mTc) tracers is rare, this radionuclide remains the best atom for SPECT imaging owing to its ideal physical decay properties, convenient availability, and rich and versatile coordination chemistry. Indeed, ^99mTc still plays a relevant role in diagnostic nuclear medicine, as the number of clinical examinations based on ^99mTc outscores that of PET agents and ^99mTc-PSMA SPECT/CT may be a cost-effective alternative for ⁶⁸Ga-PSMA PET/CT. This review aims to give an overview of the specific features of the developed [^99mTc]Tc-tagged PSMA agents with particular attention to [^99mTc]Tc-PSMA-i. The chemical and pharmacological properties of the latter will be compared and discussed, highlighting the pros and cons with respect to [⁶⁸Ga]Ga-PSMA11.

Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors.

A novel orally active water-soluble Inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Anastasia De Luca1, *, Debora Carpanese2, *, Maria Cristina Rapanotti3, Tara Mayte Suarez Viguria3, Maria Antonietta Forgione4, Dante Rotili4, Chiara Fulci1, Egidio Iorio5, Luigi Quintieri6, Sergio Chimenti7, Luca Bianchi7, Antonio Rosato2, 8, Anna Maria Caccuri1 1Department of Experimental Medicine and Surgery, University of Tor Vergata, 00133 Rome, Italy 2Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy 3Department of Laboratory Medicine, University of Tor Vergata, 00133 Rome, Italy 4Department of Drug Chemistry and Technologies, “Sapienza” University, 00185 Rome, Italy 5Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy 6Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy 7Department of Dermatology, University of Tor Vergata, 00133 Rome, Italy 8Istituto Oncologico Veneto IOV-IRCCS, 35128 Padova, Italy *These authors have contributed equally to this work Correspondence to: Anna Maria Caccuri, email: caccuri@uniroma2.it Antonio Rosato, email: antonio.rosato@unipd.it Keywords: melanoma, 6-((7-nitrobenzo[c][1,2,5]oxadiazoles, c-Jun N-terminal kinase, antimetastatic properties, glutathione transferase P1-1 Received: July 25, 2016 Accepted: December 27, 2016 Published: January 17, 2017 ABSTRACT The novel nitrobenzoxadiazole (NBD) derivative MC3181 is endowed with remarkable therapeutic activity in mice bearing both sensitive and vemurafenib-resistant human melanoma xenografts. Here, we report that subtoxic concentrations of this compound significantly reduced invasiveness of BRAF-V600D mutated WM115 and WM266.4 melanoma cell lines derived from the primary lesion and related skin metastasis of the same patient, respectively. The strong antimetastatic activity of MC3181 was observed in both 2D monolayer cultures and 3D multicellular tumor spheroids, and confirmed in vivo by the significant decrease in the number of B16-F10 melanoma lung metastases in drug-treated mice. Our data also show that MC3181 affects the lactate production in the high glycolytic WM266.4 cell line. To unveil the MC3181 mechanism of action, we analyzed the ability of MC3181 to affect the degree of activation of different MAPK pathways, as well as the expression/activity levels of several proteins involved in angiogenesis, invasion, and survival (i.e. AP2, MCAM/MUC18, N-cadherin, VEGF and MMP-2). Our data disclosed both a decrease of the phospho-active form of JNK and an increased expression of the transcription factor AP2, events that occur in the very early phase of drug treatment and may be responsible of the antimetastatic effects of MC3181.