The discovery of the driver mutation BRAF in melanoma has led to the emergence of new therapeutic treatments resulting in prolonged survival. By combining BRAF inhibitors with MEK inhibitors, median Overall Survival (OS) for patients with metastatic disease is approximately 2 years, which is an improvement by nearly a year and a half over previous therapies. Unfortunately, over 90% of patients will ultimately develop resistance to the targeted therapies and experience disease progression. Several mechanisms of resistance have been identified, including mutant BRAF allele amplification, BRAF splice variation, and activation of MEK1/2. These mechanisms are the focus of intensive research as new drugs emerge to potentially overcome resistance. This review focuses on the discovery of the BRAF mutation, the development of combination targeted therapy, the emergence of resistance to these targeted therapies, and new drugs in development to overcome this resistance

Immune checkpoint inhibitors revive pre-existing immune responses that are suppressed in cancer. To restore innate tumour surveillance that is lost in cancer patients, a tumoricidal agent may have synergistic activity with certain immune checkpoint inhibitors. Herein, we report on our clinical experience using two FDA-approved drugs, trabectedin, a marine derived natural alkaloid with pro-apoptosis and immune modulator properties, in combination with nivolumab, a PD-1 immune checkpoint inhibitor, in advanced Soft Tissue Sarcoma (STS). Twenty-eight heavily pre-treated STS patients received trabectedin (1.5 mg/m2 Continuous Intravenous Infusion, CIV, for 24 hours) every 3 weeks, and nivolumab (3 mg/kg IV over 30 minutes) every 2 weeks. Retrospective analysis of safety/toxicity was conducted using the NIH/NCI CTCAE v.4.03. Tumour responses were assessed by RECIST v1.1 and irRECIST. Histologic subtypes in 28 patients include undifferentiated pleomorphic sarcoma (UPS; n=7), myofibroblastic sarcoma (n=1), leiomyosarcoma (n=6), synovial sarcoma (n=4), liposarcoma (n=6), chondrosarcoma (n=2), and Ewing sarcoma (n=2). All patients had metastatic disease and a median of 4 lines of prior chemotherapy. Safety analysis (n=28): Grade 3 treatment emergent adverse events include anaemia (n=2), fatigue (n=1), decreased platelet count (n=1), decreased granulocyte count (n=1) and increased creatine kinase (n=1). Efficacy analysis (n=22): Twenty-two patients were followed for at least 6 months and their results are reported here. There were 4 partial responses (UPS=1, myxoid liposarcoma=1, chondrosarcoma=1, leiomyosarcoma=1), 12 stable disease and 6 progressive disease, with best overall response rate of 18.2%, median progression free survival (PFS) of >45.4 weeks (range: 10->95 weeks), median Overall Survival (OS) of >66.5 weeks (10->95 weeks), 6 month PFS rate of 68.2%, and 6 month OS rate of 95.4%. Taken together, the data suggest that paired administration of trabectedin and nivolumab is safe, and that this chemo-/immuno therapy approach has synergistic activity that can lead to improved clinical outcomes.

Soft tissue sarcomas (STS) are a group of different diseases that differ in presentation, response to therapies and prognosis. Some new interesting approaches are becoming available in the treatment of locally advanced as well as metastatic disease, leading to an improvement of patient’s survival. Neoadjuvant chemotherapy has the aim to limit the extension of surgery and to improve the systemic control of the disease and it is currently widely accepted. In the metastatic setting the modern concept of histology-driven therapy has overcome the universal use of the combination of Antracyclines and Ifosfamide in all subtypes of STS.

Some recent chemotherapic agents such as Trabectidine, Eribuline, or targeted compounds such as Pazopanib, Imatinib, Crizotinib, and Sunitinib have a defined role in some specific STS. Olaratumab, an anti PDGFRα monoclonal antibody, has recently been approved in combination with Doxorubicin as first line treatment in metastatic STS. Second line treatment is now adopted in many patients and leads to PFS and TTP improvement. Now-a-days the role of supportive care to increase the activity and to reduce toxicity of chemotherapy is well recognized.

Conversely, despite biological evidence supporting the role of immunotherapy in STS, adoptive and anti check point inhibitors therapies failed to show any activity and different further approaches are awaited.

Synovial sarcoma is a rare soft tissue cancer occurring more frequently in adolescent and young adults than older people. The primary sites being the joints of the arms and the legs.

A novel Nutrient Mixture (NM) containing green tea extract, ascorbic acid, lysine, and proline exhibited anti-cancer effects in various cancers. In our earlier studies, the NM considerably reduced the tumor weight and tumor burden in synovial sarcoma. Based on the observation, we investigated whether this phenomenon and the anti-cancer effects were due to the induction of apoptosis. Synovial sarcoma cell line SW982 was cultured in complete DME media and the cells were treated with NM at 0-1000 µg/ml concentration. Cell cytotoxicity was measured by MTT assay, morphology by H&E staining, and the apoptosis by Green Caspases. NM showed no significant cytotoxicity at 100 µg/ml, slight toxicity at 500 µg/ml and maximum at 1000 µg/ml. H&E staining at the NM dose of 100 µg/ml showed a few cellular changes characteristic to apoptosis, while significant changes pertaining to apoptosis morphology were observed at 500 and 1000 µg/ml. Live Green Caspases analysis showed cells in early and late apoptosis with increasing doses of NM. Since there are no satisfactory treatments and cures for synovial sarcoma patients and the 5-year survival rate is low (55-75%), we think that addition of NM could add a new option for the patients of synovial sarcoma and deserves further clinical investigation

Introduction: In sarcoma, no attention has been given to targets beyond the PD-1/PD-L1 axis. We profiled the immune microenvironment of sarcoma with a focus on Undifferentiated Pleomorphic Sarcoma (UPS), to identify novel immunotherapy targets.

Materials and Methods: Microsatellite instability, Tumor Mutation Burden (TMB), PD-L1 IHC and RNA-seq of 395 immune-focused transcripts were performed in 63 sarcomas, including 21 UPS. The expression of each transcript in the 63 sarcomas and a 1295 non-sarcoma solid tumor population was ranked against 167 cases of a diverse solid tumor reference population. The sarcoma (UPS and non-UPS) expression ranks were compared against the expression ranks of the 1295 non-sarcoma tumors using the Wilcoxon Rank-Sum test.

Results: Thirty eight percent and 19% UPS and non-UPS, respectively, were PD-L1 positive by IHC. Microsatellite instability and high TMB were not seen in any specimen. Compared to the 1295 non-sarcoma tumors, the immune therapy targets CD276 (B7-H3) and TGFB1 were significantly over expressed in UPS and non-UPS. The epithelial to mesenchymal transition-related SNAI2, TWIST, and ZEB1 were over expressed in both groups. UPS over expressed PD-L2, CSF1R, CD68 and CD163, while non-UPS over expressed OX40. “Inflamed” sarcomas tended to contain abundant CD8 transcripts and were more frequently PD-L1 IHC positive while “cold” sarcomas tended to be metastatic and non-UPS.

Discussion: A substantial subset of UPS and non-UPS are positive for PD-L1 IHC. The high expression of PD-L2 in UPS suggests that the PD-1/PD-L1 axis may be important in UPS. CD276 (B7-H3) and TGFB1 are other possible immunotherapy targets in sarcoma. CSF1R and OX40 are possible immunotherapy targets in UPS and non-UPS respectively. Myeloid suppression may be an immunosuppressive mechanism in UPS. Epithelial to mesenchymal transition is a possible mechanism of immune suppression in both UPS and non-UPS. Sarcomas can be categorized in “inflamed” and “cold” categories which associate with histological category, metastatic, and PD-L1 status.