Chemotherapy For Melanoma Research Articles

The Wdr5-H3K4me3 Epigenetic Axis Regulates Pancreatic Tumor Immunogenicity and Immune Suppression.

The WDR5/MLL1-H3K4me3 epigenetic axis is often activated in both tumor cells and tumor-infiltrating immune cells to drive various cellular responses in the tumor microenvironment and has been extensively studied in hematopoietic cancer, but its respective functions in tumor cells and immune cells in the context of tumor growth regulation of solid tumor is still incompletely understood. We report here that WDR5 exhibits a higher expression level in human pancreatic tumor tissues compared with adjacent normal pancreas. Moreover, WDR5 expression is negatively correlated with patients' response to chemotherapy or immunotherapy in human colon cancer and melanoma. However, WDR5 expression is positively correlated with the HLA level in human cancer cells, and H3K4me3 enrichment is observed at the promoter region of the HLA-A, HLA-B, and HLA-C genes in pancreatic cancer cells. Using mouse tumor cell lines and in vivo tumor models, we determined that WDR5 deficiency or inhibition significantly represses MHC I expression in vitro and in vivo in pancreatic tumor cells. Mechanistically, we determine that WDR5 deficiency inhibits H3K4me3 deposition at the MHC I (H2K) promoter region to repress MHC I (H2K) transcription. On the other hand, WDR5 depletion leads to the effective downregulation of immune checkpoints and immunosuppressive cytokines, including TGFβ and IL6, in the pancreatic tumor microenvironments. Our data determine that WDR5 not only regulates tumor cell immunogenicity to suppress tumor growth but also activates immune suppressive pathways to promote tumor immune evasion. Selective activation of the WDR5-MHC I pathway and/or selective inhibition of the WDR5-immune checkpoint and WDR5-cytokine pathways should be considered in WDR5-based epigenetic cancer immunotherapy.

Pigmentary complications of chemotherapy for metastatic melanoma

Pigmentary complications of chemotherapy for metastatic melanoma

Synthesis of folate targeted theranostic cubosomal platform for co-delivery of bismuth oxide and doxorubicin to melanoma in vitro and in vivo

Liquid crystalline nanoparticles (LCNPs) have gained much attention in cancer nanomedicines due to their unique features such as high surface area, storage stability, and sustained-release profile. In the current study, a novel LCNP for co-encapsulation of Bi2O3 and hydrophilic doxorubicin (DOX) was fabricated and functionalized with folic acid (FA) to achieve efficient tumor targeting toward CT-scan imaging and chemotherapy of melanoma in vitro and in vivo. LCNPs Bi2O3 NPs were prepared using glycerol monooleate-pluronic F-127 (GMO/PF127/water). Firstly, GMO/water were homogenized to prepare LC gel. Then, the stabilizer aqueous solution (PF127/Bi2O3/DOX) was added to the prepared LC gel and homogenized using homogenization and ultrasonication. The formulated NPs exhibited superior stability with encapsulation efficiency. High cytotoxicity and cellular internalization of the FA-Bi2O3-DOX-NPs were observed in comparison with Bi2O3-DOX-NPs and the free DOX in folate-receptor (FR) overexpressing cells (B16F10) in vitro. Moreover, ideal tumor suppression with increased survival rate were observed in tumorized mice treated with FA–Bi2O3-DOX-NPs compared to those treated with non-targeted one. On the other hand, the CT-imaging ability of the Bi2O3-DOX-NPs was tested inB16F10 tumor-bearing mice. The obtained data indicated a high potential of the developed targeted theranostic FA-Bi2O3-DOX-NPs for diagnostics and treatment of melanoma.

Platinum nanozyme co-loaded reactive oxygen species-responsive prodrug integrated with dissolvable microneedle for chemotherapy and photodynamic therapy of melanoma

Melanoma, the most aggressive form of skin cancer, is characterized by an increasing incidence rate. However, conventional treatment methods such as surgery, chemotherapy, radiotherapy, and immunotherapy have limitations that hinder their widespread application. In this study, we aim to develop a platinum nanozyme (PtNP) co-loaded reactive oxygen species (ROS)-responsive prodrug integrated with dissolvable microneedle for chemotherapy and photodynamic therapy of melanoma. The utilization of microneedle can significantly enhance the efficiency of transdermal drug delivery while improving treatment efficacy and minimizing toxic side effects. The nanodrug system incorporates a prodrug composed of chemotherapeutic agent, photosensitizer, and ROS-responsive chemical bond. Upon laser irradiation, it generates ROS for effective photodynamic therapy while precisely controlling the release behavior of camptothecin (CPT) within the prodrug formulation. Furthermore, PtNP in the nanodrug exhibits nanozyme-like activity by catalyzing the decomposition of hydrogen peroxide into oxygen to overcome hypoxia-related challenges and enhance the effectiveness of photodynamic therapy. The integration of the nanodrug complex with dissolvable microneedle presents a synergistic approach for the combined delivery of chemotherapy and photodynamic therapy to melanoma patients, offering novel strategies and avenues for clinical treatment.

A Novel Trypsin Kunitz-Type Inhibitor from Cajanus cajan Leaves and Its Inhibitory Activity on New Cancer Serine Proteases and Its Effect on Tumor Cell Growth.

A novel trypsin inhibitor from Cajanus cajan (TIC) fresh leaves was partially purified by affinity chromatography. SDS-PAGE revealed one band with about 15kDa with expressive trypsin inhibitor activity by zymography. TIC showed high affinity for trypsin (Ki = 1.617μM) and was a competitive inhibitor for this serine protease. TIC activity was maintained after 24h of treatment at 70°C, after 1h treatments with different pH values, and β-mercaptoethanol increasing concentrations, and demonstrated expressive structural stability. However, the activity of TIC was affected in the presence of oxidizing agents. In order to study the effect of TIC on secreted serine proteases, as well as on the cell culture growth curve, SK-MEL-28 metastatic human melanoma cell line and CaCo-2 colon adenocarcinoma was grown in supplemented DMEM, and the extracellular fractions were submitted salting out and affinity chromatography to obtain new secreted serine proteases. TIC inhibited almost completely, 96 to 89%, the activity of these serine proteases and reduced the melanoma and colon adenocarcinoma cells growth of 48 and 77% respectively. Besides, it is the first time that a trypsin inhibitor was isolated and characterized from C. cajan leaves and cancer serine proteases were isolated and partial characterized from SK-MEL-28 and CaCo-2 cancer cell lines. Furthermore, TIC shown to be potent inhibitor of tumor protease affecting cell growth, and can be one potential drug candidate to be employed in chemotherapy of melanoma and colon adenocarcinoma.

Self-supplying Cu2+ and H2O2 synergistically enhancing disulfiram-mediated melanoma chemotherapy.

Disulfiram (DSF) can target and kill cancer cells by disrupting cellular degradation of extruded proteins and has therefore received particular attention for its tumor chemotherapeutic potential. However, the uncontrollable Cu2+/DSF ratio reduces the efficacy of DSF-mediated chemotherapy. Herein, self-supplying Cu2+ and oxidative stress synergistically enhanced DSF-mediated chemotherapy is proposed for melanoma-based on PVP-coated CuO2 nanodots (CPNDs). Once ingested, DSF is broken down to diethyldithiocarbamate (DTC), which is delivered into a tumor via the circulation. Under the acidic tumor microenvironment, CPNDs produce sufficient Cu2+ and H2O2. DTC readily chelates Cu2+ ions to generate CuET, which shows antitumor efficacy. CuET-mediated chemotherapy can be enhanced by H2O2. Sufficient Cu2+ generation can guarantee the maximum efficacy of DSF-mediated chemotherapy. Furthermore, released Cu2+ can be reduced to Cu+ by glutathione (GSH) and O2- in tumor cells, and Cu+ can react with H2O2 to generate toxic hydroxyl radicals (·OH) via a Fenton-like reaction, promoting the efficacy of CuET. Therefore, this study hypothesizes that employing CPNDs instead of Cu2+ ions could enhance DSF-mediated melanoma chemotherapy, providing a simple but efficient strategy for achieving chemotherapeutic efficacy.

Nanocomposite hydrogels in skin cancer medicine.

Skin cancer is one of the most common malignancies in white populations. The therapy strategy is important in skin cancer treatment, depending on several criteria such as stage, size, and localization. Removal of cancerous tissue following anticancer therapeutic administration is considered as gold standard in skin cancer treatment. However, annually rising drug resistance, local inflammation, and ineffective treatment result in a reduction in the effectiveness of the patient's treatment. Nanotechnology has emerged as a prospective in the field of skin cancer medicine, offering innovative, promising solutions for therapeutic procedures and targeted drug delivery. Different nanomaterials are investigated for their potential in skin cancer treatment. Nanohydrogels as a hybrid material, have gained considerable attention due to their unique biomedical and pharmaceutical properties, such as biocompatibility, high water content, and tunable physicochemical characteristics. The principal problem with common skin melanoma chemotherapy is the strong side effects because therapeutics used for treatment do not distinguish cancer cells from healthy cells. Nanohydrogels, as a new-generation, versatile system with the possession of dual characteristics of hydrogels and nanoparticles have shown great potential in targeted delivery in cancer therapy thanks to the possibility of their various modifications, and by that overcome problems with side effects of treatment. This scientific review provides an analysis of the current state of research on nanohydrogels in skin cancer medicine, highlighting their design principles, synthesis methods, and applications in drug delivery, imaging, and combination therapies.

Protocatechuic aldehyde acts synergistically with dacarbazine to augment DNA double-strand breaks and promote apoptosis in cutaneous melanoma cells

BackgroundDespite rapid developments in immunotherapy and targeted therapy, dacarbazine (DTIC)-based chemotherapy still has been placed at the first-line for advanced melanoma patients who are after failure of immunotherapy or targeted therapy. However, the limited response rate and survival benefit challenge the DTIC-based chemotherapy for advanced melanoma patients.MethodsTwo melanoma cell lines, A375 and SK-MEL-28 were cultured with PA and DTIC over a range of concentrations for 72 h and the cell viabilities were detected by CCK8 assay. The Bliss model and ZIP model were used for calculating the synergistic effect of PA and DTIC. DNA double-strand breaks in the two cell lines were examined by the Comet assay, and cell apoptosis was analyzed by flow cytometry. The short hairpin RNA (shRNA)-mediated knockdown, Real-time polymerase chain reaction (RT-PCR) and Western blot were performed for molecular analysis.ResultsIn the present study, we report that Protocatechuic aldehyde (PA) synergistically enhances the cytotoxicity of DTIC to two melanoma cell lines, A375 and SK-MEL-28. The combination of PA and DTIC augments DNA double-strand breaks and increases cell apoptosis. Further mechanism study reveals that PA destabilizes MGMT protein (O-6-Methylguanine-DNA Methyltransferase) through the ubiquitin-proteasome process and directly repairs DTIC-induced genetic lesions. Knockdown of MGMT compromises the synergistic effect between PA and DTIC.ConclusionOur study demonstrates that the bioactive compound, Protocatechuic aldehyde, synergistically promotes the cytotoxicity of DTIC to melanoma cells through destabilization of MGMT protein. It could be a potential candidate for melanoma chemotherapy.

Morusinol extracted from Morus alba induces cell cycle arrest and apoptosis via inhibition of DNA damage response in melanoma by CHK1 degradation through the ubiquitin-proteasome pathway

BackgroudFlavonoids have a variety of biological activities, such as anti-inflammation, anti-tumor, anti-thrombosis and so on. Morusinol, as a novel isoprene flavonoid extracted from Morus alba root barks, has the effects of anti-arterial thrombosis and anti-inflammatory in previous studies. However, the anti-cancer mechanism of morusinol remains unclear. PurposeIn present study, we mainly studied the anti-tumor effect of morusinol and its mode of action in melanoma. MethodsThe anti-cancer effect of morusinol on melanoma were evaluated by using the MTT, EdU, plate clone formation and soft agar assay. Flow cytometry was used for detecting cell cycle and apoptosis. The ɣ-H2AX immunofluorescence and the alkaline comet assay were used to detect DNA damage and the Western blotting analysis was used to investigate the expressions of DNA-damage related proteins. Ubiquitination and turnover of CHK1 were also detected by using the immunoprecipitation assay. The cell line-derived xenograft (CDX) mouse models were used in vivo to evaluate the effect of morusinol on tumorigenicity. ResultsWe demonstrated that morusinol not only had the ability to inhibit cell proliferation, but also induced cell cycle arrest at G0/G1 phase, caspase-dependent apoptosis and DNA damage in human melanoma cells. In addition, morusinol effectively inhibited the growth of melanoma xenografts in vivo. More strikingly, CHK1, which played an important role in maintaining the integrity of cell cycle, genomic stability and cell viability, was down-regulated in a dose- and time-dependent manner after morusinol treatment. Further research showed that CHK1 was degraded by the ubiquitin-proteasome pathway. Whereafter, morusinol-induced cell cycle arrest, apoptosis and DNA damage were partially salvaged by overexpressing CHK1 in melanoma cell lines. Herein, further experiments demonstrated that morusinol increased the sensitivity of dacarbazine (DTIC) to chemotherapy for melanoma in vitro and in vivo. ConclusionMorusinol induces CHK1 degradation through the ubiquitin-proteasome pathway, thereby inducing cell cycle arrest, apoptosis and DNA damage response in melanoma. Our study firstly provided a theoretical basis for morusinol to be a candidate drug for clinical treatment of cancer, such as melanoma, alone or combinated with dacarbazine.

Malignant Melanoma of the Anorectal Region: A Case Study and Review of the Contemporary Treatment Options

Aims: Anorectal melanoma, an uncommon malignancy of mucosal origin accounts for 0.05 per cent of all colorectal malignancies and 1 per cent of tumours of the anal canal. The typical clinical presentation includes local pain, palpable mass, bleeding, change in bowel habits, and weight loss. The symptoms are somewhat nondescript and unremarkable and can be easily confused with other conditions native to the region. Hence, a careful and timely assessment is imperative in treating this condition.
 Presentation of Case: A case involving a 54-year-old male who presented with a 3-month history of rectal bleeding and pain. Further assessment revealed a malignant melanoma of the anal canal. After undergoing laparoscopic abdominoperineal resection, the patient was on 6 cycles of dacarbazine. He was subsequently found to have liver metastasis. He subsequently started oral Temozolomide for 2 cycles. He has been on close follow-up for the last 6 months and the disease has not progressed since.
 Discussion: The course of evaluation in suspected cases of anorectal melanoma is a rectal examination, biopsy and histopathologic examination. Immunohistochemistry aids in the confirmation of the diagnosis. Laparoscopic abdominoperineal resection demonstrates good response rates. Adjuvant chemotherapy in anorectal melanoma can be given in patients following surgical resection of the primary anorectal tumour and with a high risk of recurrence. Targeted therapies like c-kit inhibitors, BRAF inhibitors, anti- CTLA-4 antibodies and anti-PD-1 antibodies can also be used.
 Conclusion: Melanomas of the anorectal region present a diagnostic dilemma and carry poor prognoses. Despite an aggressive management approach, the disease maintains an average five-year survival rate of 20%.

Lipopeptide liposomes-loaded hydrogel for multistage transdermal chemotherapy of melanoma

Transdermal administration of chemotherapeutics into tumor tissues may be an effective treatment to reduce toxic side effects and improve patient compliance for melanoma. Herein, we report a multistage transdermal drug delivery system for chemotherapy of melanoma. In this system, dendritic lipopeptide (DLP) modified multistage targeted liposomes (Mtlip) were incorporated into the hydrogel matrix to achieve localized and sustained drug release; Ultra-deformability of Mtlip can pass through dense stratum corneum to the epidermis where melanoma is located; Virus-mimicking Mtlip enhances the payload in tumor tissues by high permeability; The positive charged Mtlip can improve cell uptake efficiency and selectively accumulate into mitochondria to increases toxic. The efficacy of this type of multistage targeted liposomes loaded hydrogel in treating melanoma was systematically evaluated both in vitro and in vivo.

Prodrug and Glucose Oxidase Coloaded Photodynamic Hydrogels for Combinational Therapy of Melanoma.

With the advantages of high safety and selectivity, photodynamic therapy (PDT) has been widely used for cancer treatments, while the anticancer efficacy is often limited because of its relying on oxygen concentrations. Therefore, sole PDT fails to achieve the desired therapeutic effect for hypoxic tumors. To address this issue, we herein report the construction of prodrug and glucose oxidase (GOx) coloaded alginate (ALG) hydrogels for PDT-combined chemotherapy of melanoma. The hydrogels are in situ formed in tumor sites after injection of ALG solution containing semiconducting polymer nanoparticles, hypoxia-responsive prodrug tirapazamine (TPZ), and GOx, which is based on chelation of ALG by endogenous Ca2+. Due to the presence of semiconducting polymer nanoparticles acting as photosensitizers, the hydrogels mediate PDT to produce singlet oxygen (1O2) for directly killing tumor cells, in which oxygen is consumed to create a more hypoxic tumor microenvironment. Moreover, the loaded GOx within hydrogels can deplete oxygen to further aggravate tumor hypoxia. As such, TPZ is effectively activated by hypoxia to cause cancer cell death via chemotherapy. Thus, the hydrogels with laser irradiation achieve a combinational action of PDT with chemotherapy to almost completely eradicate tumors, leading to a much higher therapeutic efficacy relative to sole PDT. This study will provide a promising injectable hydrogel platform for effective treatments of cancer.

Red Blood Cell Membrane-Camouflaged Gold Nanoparticles for Treatment of Melanoma.

Background Patients with melanoma have poor response and low long-term survival to conventional cisplatin (CP). Recently, biomimetic nanoparticles have played a significant role in tumor therapy. The purpose of this study was to mechanistically evaluate the effect of red blood cell membrane camouflaged gold nanoparticles loaded with CP (RBCm@AuNPs-CP) on enhancing chemotherapy in melanoma. Methods Treated B16-F10 cells with RBCm@AuNPs-CP, the antimelanoma effect in vitro was explored by detecting cell viability, apoptosis rate, level of reactive oxygen species (ROS), and singlet oxygen. RBCm@AuNPs-CP was injected into the melanoma-bearing mice via tail vein, and the target-ability, therapeutic effect, and toxicity were detected in melanoma tumor-bearing mice. Results RBCm@AuNPs-CP had an antiproliferation and apoptosis-inducing effect on B16-F10 cells, which might be mediated by oxidative stress of ROS, and its effect was significantly enhanced compared with the CP treatment group. In vivo experiments suggested the same outcome, with better target-ability of RBCm@AuNPs-CP. Conclusion The erythrocyte camouflage nanosystem RBCm@AuNPs-CP exhibited well passive tumor target-ability and promoted apoptosis of melanocytes by inducing ROS. RBCm@AuNPs-CP as a novel safe and effective targeted drug delivery system may provide a promising choice for the treatment of melanoma.

Monensin synergizes with chemotherapy in uveal melanoma through suppressing RhoA

Objective Uveal melanoma (UM) is the common primary cancer of the eye and new treatments are needed. Substantial evidence has shown that an antibiotic monensin is an attractive candidate for the development of anti-cancer drug. In this study, we investigated the potential of repositioning monensin for the treatment of UM in the pre-clinical setting. Materials and Methods Cellular activity assays were performed using multiple cell lines representing UM models with different cellular origins and genetic profiling and normal cells as control. Combination studies were performed using Chou-Talalay method. Mechanism studies were performed using immunoblotting and ELISA. Results Monensin was effective against all tested UM cell lines and less effective against normal fibroblast cells. Monensin induced G0/G1 arrest and thus decreased S phase, leading to UM cell growth inhibition. It also inhibited migration and induced apoptosis in UM cells. In addition, the combination of monensin and dacarbazine was synergistic in targeting UM cells. Our mechanistic studies showed that monensin specifically decreased activity of RhoA without affecting other small GTPases, such as Ras and Rac1. Consistently, monensin decreased phosphorylation of downstream effectors of RhoA signaling, including ROCK, MYPT1 and MLC. Rescue studies using RhoA activator calpeptin showed that calpeptin significantly abolished the inhibitory effects of monensin on RhoA activity, proliferation, migration and survival, confirming that RhoA is the target of monensin in UM cells. Conclusions Our study demonstrates that monensin is a potent inhibitor of UM and synergizes with chemotherapy, via suppressing RhoA activity and RhoA-mediated signaling. Our findings suggest that monensin may be a potential lead compound for further development into a drug for UM treatment.

Anticancer Activity of Amantadine and Evaluation of Its Interactions with Selected Cytostatics in Relation to Human Melanoma Cells.

Patients with Parkinson’s disease are prone to a higher incidence of melanoma. Amantadine (an anti-Parkinson drug) possesses the antiproliferative potential that can be favorable when combined with other chemotherapeutics. Cisplatin (CDDP) and mitoxantrone (MTO) are drugs used in melanoma chemotherapy, but they have many side effects. (1) Clinical observations revealed a high incidence of malignant melanoma in patients with Parkinson’s disease. Amantadine as an anti-Parkinson drug alleviates symptoms of Parkinson’s disease and theoretically, it should have anti-melanoma properties. (2) To characterize the interaction profile for combinations of amantadine with CDDP and MTO in four human melanoma cell lines (A375, SK-MEL 28, FM55P and FM55M2), type I isobolographic analysis was used in the MTT test. (3) Amantadine produces the anti-proliferative effects in various melanoma cell lines. Flow cytometry analysis indicated that amantadine induced apoptosis and G1/S phase cell cycle arrest. Western blotting analysis showed that amantadine markedly decreased cyclin-D1 protein levels and increased p21 levels. Additionally, amantadine significantly increased the Bax/Bcl-2 ratio. The combined application of amantadine with CDDP at the fixed-ratio of 1:1 exerted an additive interaction in the four studied cell lines in the MTT test. In contrast, the combination of amantadine with MTO (ratio of 1:1) produced synergistic interaction in the FM55M2 cell line in the MTT (* p < 0.05). The combination of amantadine with MTO was also additive in the remaining tested cell lines (A375, FM55P and SK-MEL28) in the MTT test. (4) Amantadine combined with MTO exerted the most desirable synergistic interaction, as assessed isobolographically. Additionally, the exposure of melanoma cell lines to amantadine in combination with CDDP or MTO augmented the induction of apoptosis mediated by amantadine alone.

Inhibition of NOS1 promotes the interferon response of melanoma cells

BackgroundNOS1 expression predicts poor prognosis in patients with melanoma. However, the molecular function of NOS1 in the type I IFN response and immune escape of melanoma is still unknown.MethodsThe CRISPR/Cas9 system was used to generate NOS1-knockout melanoma cells and the biological characteristics of NOS1-knockout cells were evaluated by MTT assay, clonogenic assay, EdU assay, and flow cytometric assay. The effect on tumor growth was tested in BALB/c-nu and C57BL/6 mouse models. The gene expression profiles were detected with Affymetrix microarray and RNA-seq and KEGG (Kyoto Encyclopedia of Genes and Genomes) and CLUE GO analysis was done. The clinical data and transcriptional profiles of melanoma patients from the public database TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus, GSE32611) were analyzed by Qlucore Omics Explorer.ResultsNOS1 deletion suppressed the proliferation of melanoma A375 cells in culture, blocked cell cycling at the G0/G1 phase, and decreased the tumor growth in lung metastasis nodes in a B16 melanoma xenograft mouse model. Moreover, NOS1 knockout increased the infiltration of CD3+ immune cells in tumors. The transcriptomics analysis identified 2203 differential expression genes (DEGs) after NOS1 deletion. These DEGs indicated that NOS1 deletion downregulated mostly metabolic functions but upregulated immune response pathways. After inhibiting with NOS1 inhibitor N-PLA, melanoma cells significantly increased the response to IFNupalpha by upregulation expression of IFNupalpha simulation genes (ISGs), especially the components in innate immune signaling, JAK-STAT, and TOLL-LIKE pathway. Furthermore, these NOS1-regulating immune genes (NOS1-ISGs) worked as a signature to predict poor overall survival and lower response to chemotherapy in melanoma patients.ConclusionThese findings provided a transcriptional evidence of NOS1 promotion on tumor growth, which is correlated with metabolic regulation and immune escape in melanoma cells.

Outcomes From Cytotoxic Chemotherapy Following Progression on Immunotherapy in Metastatic Melanoma: An Institutional Case-Series.

IntroductionThe role of chemotherapy in the management of advanced melanoma is limited due to low response rates and short survival. Improved outcomes to chemotherapy administered after immunotherapy for metastatic melanoma and other solid tumors have been reported. We studied the outcomes of subjects treated at the University of Virginia (UVA) with chemotherapy following progression on prior systemic immunotherapy and compared the results with the existing literature.Materials and MethodsSubjects were identified through an institutional database of patients treated with immunotherapy at UVA. Demographic, pathologic and clinical factors were collected, along with dates of therapy, investigator-assessed best response as per Response Evaluation Criteria for Solid Tumors version 1.1 and dates of death or last follow up. Kaplan-Meier survival estimates and log-rank tests were used to perform time to event analysis of progression free survival and overall survival.ResultsForty-five patients were identified who met the inclusion criteria including 24 men and 21 women with a median age of 61 years. All patients had received at least one line of immunotherapy including 64.4% with prior anti-PD1 treatment. The cytotoxic chemotherapy regimens used included carboplatin with paclitaxel (55.6%), temozolomide (31.1%) and nab-paclitaxel (13.3%). The overall response rate for cytotoxic chemotherapy 22.2% and the disease control rate was 35.6%. The median progression-free survival was 1.7 months and median overall survival was 4.7 months. Nineteen (42.2%) patients survived greater than 6 months and seven (15.5%) patients survived over 12 months. Fourteen patients were able to proceed to further therapy.DiscussionOur results reveal that receipt of immunotherapy prior to chemotherapy for metastatic melanoma does not appear to improve the benefit of chemotherapy. The palliation of symptoms, maintenance of performance status and disease control may be valuable for some patients during this time of robust research and discovery for metastatic melanoma.

Dacarbazine-Loaded Targeted Polymeric Nanoparticles for Enhancing Malignant Melanoma Therapy

Dacarbazine (DTIC) dominates chemotherapy for malignant melanoma (MM). However, the hydrophobicity, photosensitivity, instability, and toxicity to normal cells of DTIC limit its efficacy in treating MM. In the present study, we constructed star-shaped block polymers nanoparticles (NPs) based on Cholic acid -poly (lactide-co-glycolide)-b-polyethylene glycol (CA-PLGA-b-PEG) for DTIC encapsulation and MM targeted therapy. DTIC-loaded CA-PLGA-b-PEG NPs (DTIC-NPs) were employed to increase the drug loading and achieve control release of DTIC, followed by further modification with nucleic acid aptamer AS1411 (DTIC-NPs-Apt), which played an important role for active targeted therapy of MM. In vitro, DTIC-NPs-Apt showed good pH-responsive release and the strongest cytotoxicity to A875 cells compared with DTIC-NPs and free DTIC. In vivo results demonstrated that the versatile DTIC-NPs-Apt can actively target the site of MM and exhibited excellent anti-tumor effects with no obvious side effects. Overall, this research provided multi-functional NPs, which endow a new option for the treatment of MM.

Differences in and verification of genetic alterations in chemotherapy and immunotherapy for metastatic melanoma.

Background: Metastatic melanoma has poor therapeutic response and may present resistance to chemotherapy or immunotherapy. Significant differences are observed in the survival time of patients with metastatic melanoma based on the administration of chemotherapy or immunotherapy; thus, we have explored the important role of specific differential genes between the two therapies in their effect on treatment response in melanoma.Methods: Metastatic melanoma gene expression data (RNAseq, mutation and methylation) and patient clinical information were downloaded from The Cancer Genome Atlas database and grouped according to chemotherapy or immunotherapy. The differentially expressed genes of the two groups were further screened for signature genes through a protein–protein interaction network and Lasso-Cox regression model. Then, differences in the treatment response, overall survival, mutation and methylation of characteristic genes were compared. Finally, western blot and real-time qPCR technology were used to detect the expression differences of the signature genes in metastatic melanoma tumor tissues in patients undergoing chemotherapy and immunotherapy.Results: The overall survival of the chemotherapy-based treatment group was significantly higher than that of the immunotherapy-based group. The immune infiltration level of immature dendritic cells (DCs) in the chemotherapy group was significantly higher than that in the immunotherapy group. Finally, seven signature genes were selected: CCKBR, KCNJ11, NMU, MMP13, ITGA10, IGFBP1 and CEACAM5. The results of these signature genes were significantly differentiated between the chemotherapy and immunotherapy groups in terms of overall survival and disease progression in response to treatment. In addition, differences in the expression of these genes were verified by western blot and real-time qPCR.Conclusion: In this study, significant differences in the expression of signature genes were verified. The findings indicate that immature DCs with potential application value should be considered and high mutation sites of signature genes should be identified to reduce the occurrence of treatment resistance.

NK Cells in the Tumor Microenvironment as New Potential Players Mediating Chemotherapy Effects in Metastatic Melanoma.

Until the last decade, chemotherapy was the standard treatment for metastatic cutaneous melanoma, even with poor results. The introduction of immune checkpoints inhibitors (ICIs) radically changed the outcome, increasing 5-year survival from 5% to 60%. However, there is still a large portion of unresponsive patients that would need further therapies. NK cells are skin-resident innate cytotoxic lymphocytes that recognize and kill virus-infected as well as cancer cells thanks to a balance between inhibitory and activating signals delivered by surface molecules expressed by the target. Since NK cells are equipped with cytotoxic machinery but lack of antigen restriction and needing to be primed, they are nowadays gaining attention as an alternative to T cells to be exploited in immunotherapy. However, their usage suffers of the same limitations reported for T cells, that is the loss of immunogenicity by target cells and the difficulty to penetrate and be activated in the suppressive tumor microenvironment (TME). Several evidence showed that chemotherapy used in metastatic melanoma therapy possess immunomodulatory properties that may restore NK cells functions within TME. Here, we will discuss the capability of such chemotherapeutics to: i) up-regulate melanoma cells susceptibility to NK cell-mediated killing, ii) promote NK cells infiltration within TME, iii) target other immune cell subsets that affect NK cells activities. Alongside traditional systemic melanoma chemotherapy, a new pharmacological strategy based on nanocarriers loaded with chemotherapeutics is developing. The use of nanotechnologies represents a very promising approach to improve drug tolerability and effectiveness thanks to the targeted delivery of the therapeutic molecules. Here, we will also discuss the recent developments in using nanocarriers to deliver anti-cancer drugs within the melanoma microenvironment in order to improve chemotherapeutics effects. Overall, we highlight the possibility to use standard chemotherapeutics, possibly delivered by nanosystems, to enhance NK cells anti-tumor cytotoxicity. Combined with immunotherapies targeting NK cells, this may represent a valuable alternative approach to treat those patients that do not respond to current ICIs.