Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90101 ‘CREATE’

Abstract

EORTC 90101, NCT01524926.

Genomics, Morphoproteomics, and Treatment Patterns of Patients with Alveolar Soft Part Sarcoma and Response to Multiple Experimental Therapies

“…In that regard, morphoproteomic analysis provides the following correlative insights into the biology of ASPS: (i) ASPL-TFE 3 fusion protein in ASPS binds to the MET promoter and induces the expression of c-Met tyrosine kinase and the finding of phosphorylated c-Met indicates that it has been activated by HGF, its ligand (24); (ii) FAS expression represents a correlate to c-Met pathway signaling because inhibition of FAS posttranscriptionally downregulates c-Met expression (25); and (iii) the constitutive activation of the signal transducer and activation of transcription (STAT)3 pathway in the tumor cells in the form of phosphorylation of STAT3 on tyrosine 705 with translocation to the nucleus represents a potential autocrine mechanism in providing HGF, the ligand for c-Met given the role of c-src-STAT3 pathway activation as a transcriptional activator of HGF (26,27) and further correlates with the previous demonstration of activation of platelet-derived growth factor receptor signaling in ASPS (9,28), which in turn is consistent with the activation of p-STAT3 (Tyr 705) via the src-STAT3 pathway (29). These observations provide therapeutic targets for relatively low toxicity agents in patients with ASPS, such as crizotinib to interfere with the HGF/c-Met signaling pathway and angiogenesis (11), pazopanib to participate in the inhibition of angiogenesis by VEGF (30,31), and metformin to downregulate FAS and to interfere in c-Met-driven tumorigenesis (32,33) and prevent the phosphorylation/activation of the STAT3 pathway (34,35). Interestingly, the role of metformin is complex with different concentrations in the preclinical studies that support its mechanism of action [5-10 mmol/L metformin (32); 0.5-2 mmol/L (33), and 1.25-5 mmol/L metformin (34)].…”

“…The above mentioned upregulation of angiogenesis transcripts provided evidence for using tyrosine kinase inhibitors (TKI) directed at VEGF. Clinical trials using TKIs, such as, sunitinib (9), cediranib (10), pazopanib (11,12), and crizotinib (11), have demonstrated activity and have shown clinical responses. Importantly, cediranib performed favorably against placebo showing a 21% response rate versus 0% in placebo with a corresponding progressionfree survival of 10.8 months compared with 3.7 months with placebo (13).…”

Establishment and Characterization of Histologically and Molecularly Stable Soft-tissue Sarcoma Xenograft Models for Biological Studies and Preclinical Drug Testing

“…Because of the rarity and heterogeneity of sarcomas, most studies pool different subtypes of STS together and include only a relatively small number of patients with specific entities, each subtype characterized by unique disease biology, clinical behavior, and response to treatment, as one of the reasons for the somewhat unpredictable outcome of clinical trials in sarcoma. At present, the field is moving toward exploring specific drugs in rationally selected biological entities, as illustrated by large prospective trials performed exclusively in the more common liposarcoma and leiomyosarcomas (12,13) or by more recent trials in ultrarare STS variants (14)(15)(16)(17). To provide a rationale for such trials, there is a need to have reliable sarcoma research models that match the clinical behavior of the respective sarcoma subtype and its sensitivity or resistance to a given experimental agent.…”

Alveolar soft‐part sarcoma: Case demonstrating principles for uncommon vascular lesions

“…Cytotoxic chemotherapy seems to be ineffective and thus complete surgical resection is the treatment of choice in localized disease . In metastatic settings, there are emerging promising systemic options including angiogenesis inhibitors and programmed cell death protein 1 (PD‐1) checkpoint inhibitors …”