Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3Kα/β/δ treatment

Combining immune checkpoint therapy (ICT) and targeted therapy holds great promises for broad and long-lasting anti-cancer therapies. However, combining ICT with anti-PI3K inhibitors have been challenging because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we find that intermittent but not daily dosing of a PI3Kα/β/δ inhibitor, BAY1082439, on Pten-null prostate cancer models could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNα/IFNγ pathway activation, β2-microglubin expression and CXCL10/CCL5 secretion. With its preferential regulatory T cell inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells, most likely via tertiary lymphoid structures. Once primed, tumors remain T cell-inflamed, become responsive to anti-PD-1 therapy and have durable therapeutic effect. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn “cold” tumors into T cell-inflamed ones, paving the way for successful ICT.

Insights on Cancer Cell Inhibition, Subcellular Activities, and Kinase Profile of Phenylacetamides Pending 1H-Imidazol-5-One Variants

Structural changes of small-molecule drugs may bring interesting biological properties, especially in the field of kinase inhibitors. We sought to study tirbanibulin, a first-in-class dual Src kinase (non-ATP competitive)/tubulin inhibitor because there was not enough reporting about its structure–activity relationships (SARs). In particular, the present research is based on the replacement of the outer ring of the biphenyl system of 2-[(1,1′-biphenyl)-4-yl]-N-benzylacetamide, the identified pharmacophore of KX chemotype, with a heterocyclic ring. The newly synthesized compounds showed a range of activities in cell-based anticancer assays, agreeing with a clear SAR profile. The most potent compound, (Z)-N-benzyl-4-[4-(4-methoxybenzylidene)-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl]phenylacetamide (KIM-161), demonstrated cytotoxic IC50 values at 294 and 362 nM against HCT116 colon cancer and HL60 leukemia cell lines, respectively. Profiling of this compound (aqueous solubility, liver microsomal stability, cytochrome P450 inhibition, reactivity with reduced glutathione, and plasma protein binding) confirmed its adequate drug-like properties. Mechanistic studies revealed that this compound does not depend on tubulin or Src kinase inhibition as a factor in forcing HL60 to exit its cell cycle and undergo apoptosis. Instead, KIM-161 downregulated several other kinases such as members of BRK, FLT, and JAK families. It also strongly suppresses signals of ERK1/2, GSK-3α/β, HSP27, and STAT2, while it downregulated AMPKα1 phosphorylation within the HL60 cells. Collectively, these results suggest that phenylacetamide-1H-imidazol-5-one (KIM-161) could be a promising lead compound for further clinical anticancer drug development.

Polydopamine-Coated Copper-Substituted Mesoporous Silica Nanoparticles for Dual Cancer Therapy

Combinational therapy using chemodynamictherapy (CDT) and photothermal therapy (PTT) is known to enhance the therapeutic outcome for cancer treatment. In this study, a biocompatible nano formulation was developed by coating polydopamine (PDA) over doxorubicin (DOX)-loaded copper-substituted mesoporous silica (CuMSN) nanoparticles. PDA coating not only allowed selective photothermal properties with an extended DOX release but also enhanced the water solubility and biocompatibility of the nanocomposites. The nanocomposites displayed a monodispersed shape and pH-dependent release characteristics, with an outstanding photothermal conversion and excellent tumor cell inhibition. The cellular-uptake experiments of CuMSN@DOX@PDA in A549 cells indicated that nanoparticles (NPs) aided in the enhanced DOX uptake in tumor cells compared to free DOX with synergistic anti-cancer effects. Moreover, the cell-viability studies displayed remarkable tumor inhibition in combinational therapy over monotherapy. Thus, the synthesized CuMSN@DOX@PDA NPs can serve as a promising platform for dual cancer therapy.

A Comprehensive Evaluation of ZrC Nanoparticle in Combined Photothermal and Radiation Therapy for Treatment of Triple-Negative Breast Cancer

Because of the difficulty in treating triple-negative breast cancer (TNBC), the search for treatments has never stopped. Treatment opinions remain limited for triple-negative breast cancer (TNBC). The current treatment approach of using photothermal therapy (PTT) is often imprecise and has limited penetration below the surface of the skin. On the other hand, radiation therapy (RT) has its unavoidable disadvantages, such as side effects or ineffectiveness against hypoxic tumor microenvironment (TME). In this study, we proposed the use of ZrC nanoparticles in conjunction with RT/PTT to enhance antitumor and antimetastatic effect. We modified the ZrC nanoparticle with bovine serum albumin (BSA) and folic acid (FA), sizing desirable about 100nm. The photothermal conversion efficiency was calculated to be 40.51% and sensitizer enhancement ration (SER) was 1.8. With addition of ZrC NPs, more DNA were damaged in γ-H2AX and more ROS were detected with immunofluorescence. In vitro and vivo, the combined therapy with ZrC NPS showed the best effect of tumor cell inhibition and safety. Our results provide evidence that the combination of ZrC NPs, PT, and RT is effective in of TNBC, making it a great potential application for cancer therapy in clinic.

NK Cell Anti-Tumor Surveillance in a Myeloid Cell-Shaped Environment

NK cells are innate lymphoid cells endowed with cytotoxic capacity that play key roles in the immune surveillance of tumors. Increasing evidence indicates that NK cell anti-tumor response is shaped by bidirectional interactions with myeloid cell subsets such as dendritic cells (DCs) and macrophages. DC-NK cell crosstalk in the tumor microenvironment (TME) strongly impacts on the overall NK cell anti-tumor response as DCs can affect NK cell survival and optimal activation while, in turn, NK cells can stimulate DCs survival, maturation and tumor infiltration through the release of soluble factors. Similarly, macrophages can either shape NK cell differentiation and function by expressing activating receptor ligands and/or cytokines, or they can contribute to the establishment of an immune-suppressive microenvironment through the expression and secretion of molecules that ultimately lead to NK cell inhibition. Consequently, the exploitation of NK cell interaction with DCs or macrophages in the tumor context may result in an improvement of efficacy of immunotherapeutic approaches.

Investigation of Carboxylic Acid Isosteres for Inhibition of the Human SIRT5 Lysine Deacylase Enzyme

Sirtuin 5 (SIRT5) is a protein lysine deacylase enzyme that regulates diverse biology by hydrolyzing -N-carboxyacyllysine posttranslational modifications in the cell. Inhibition of SIRT5 has been linked to potential treatment of several cancers but potent compounds with activity in cells have been lacking. Here we developed mechanism-based inhibitors that incorporate isosteres of a carboxylic acid residue that is important for high-affinity binding to the enzyme active site. By masking of the tetrazole moiety of the most potent candidate from our initial SAR study, we achieved potent and cytoselective growth inhibition for the treatment of SIRT5-dependent leukemic cancer cell lines in culture. Thus, we provide an efficient, cellularly active small molecule that targets SIRT5, which can help elucidate its function and potential as a future drug target. This work shows that masked biosisosteres of carboxylic acids are viable chemical motifs for the development of inhibitors that target mitochondrial enzymes, which may have applications beyond the sirtuin field.

Ultrafiltration of α-Lactalbumin Protein: Acquaintance of the Filtration Performance by Membrane Structure and Surface Alteration

α-Lactalbumin is an essential protein with multiple roles in physiological and the nutritional functionalities, such as diabetic prevention, blood pressure stabilization, and cancer cell inhibition. In the present work, polyethersulfone (PES)-based membranes were developed by incorporating Pluronic F127 and carbon nanotubes with single- and multi-walled dimensions (Sw-Cnts and Mw-Cnts) as additives. The resulting membranes were evaluated for use in the filtration of α-lactalbumin protein solution. Four series of membranes, including PES pristine membrane, were fabricated via the phase inversion process. The characteristics of the membrane samples were analyzed in terms of morphology, membrane surface hydrophilicity and roughness, and surface chemistry. The characterization results show that the incorporation of additive increased the surface wettability by reducing the surface water contact angle from 80.4° to 64.1° by adding F127 and Mw-Cnt additives. The highest pure water permeability of 135 L/(m2·h·bar) was also exhibited by the PES/F127/Mw-Cnt membrane. The performance of the modified membranes was clearly better than the pristine PSF for α-lactalbumin solution filtration. The permeability of α-lactalbumin solution increased from 9.0 L/(m2·h·bar) for the pristine PES membrane to 10.5, 11.0 and 11.5 L/(m2·h·bar) for membranes loaded with Pluronic F127, Sw-Cnts, and Mw-Cnts, respectively. Those increments corresponded to 17, 22, and 28%. Such increments could be achieved without altering the α-lactalbumin rejections of 80%. Remarkably, the rejection for the membrane loaded with Sw-Cnts even increased to 89%.