epidermal-growth-factor and Dermatofibrosarcoma

Cancer literature has consistently described autocrine loops involving growth factors to be important mechanisms for cellular transformation and proliferation in preclinical cancer models. Finally, convincing clinical data exist to implicate autocrine loops as central to the pathogenesis of a malignant condition, largely as a result of the recent development of inhibitors of protein tyrosine kinases important in cell signaling and growth. Although a rare condition, the study of patients with dermatofibrosarcoma protuberans (DFSP) is enriched by data demonstrating strong scientific rationale for its pathogenesis and susceptibility to molecular-based therapies. DFSP is a low-grade sarcoma that responds to treatment with imatinib, an inhibitor of the PDGF receptor tyrosine kinase. This treatment response illustrates the importance of autocrine/paracrine loops involving PDGF and its receptor as the key molecular target in DFSP. New insight into this fundamental biological mechanism sets the scene for the further development of molecular-targeted therapeutic options for cancer.

Topics: Antineoplastic Agents; Autocrine Communication; Benzamides; Dermatofibrosarcoma; Epidermal Growth Factor; ErbB Receptors; Humans; Imatinib Mesylate; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Piperazines; Platelet-Derived Growth Factor; Pyrimidines; Receptor, IGF Type 1; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A

Dermatofibrosarcoma protuberans (DFSP) is a soft-tissue sarcoma characterized by a high risk of local infiltration. The identification of the COL1A1-PDGFB t(17;22) translocation activating the PDGF pathway led to the use of imatinib in unresectable DFSP, with a response rate of 36-80%. Pazopanib is a multitarget tyrosine kinase inhibitor approved for soft-tissue sarcomas. We conducted a phase II study of patients with unresectable DFSP to evaluate the efficacy and safety of pazopanib. Patients received 800 mg of pazopanib daily. The primary endpoint was the objective response rate defined as the reduction of the largest diameter of the tumor by ≥30% at 6 months or at surgery. A total of 23 patients, including one pretreated with imatinib, were enrolled. With a median follow-up of 6.2 months (interquartile range = 5.6-7.8 months), five patients (22%, 95% confidence interval = 7-22%) had a partial response to pazopanib. The best objective response rate was 30% (95% confidence interval = 13-53%) using Response Evaluation Criteria in Solid Tumors. One patient with metastatic DFSP previously treated with imatinib died after 2.4 months. Nine patients (39%) discontinued the treatment owing to adverse events. Pharmacodynamics analyses of tumor samples were conducted: the enrichment of EGF and the EGFR-associated gene panel was associated with resistance, suggesting that EGFR-targeted therapies could be a therapeutic option to explore in DFSP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01059656.

Topics: Adult; Aged; Biomarkers, Tumor; Dermatofibrosarcoma; Drug Resistance, Neoplasm; Epidermal Growth Factor; ErbB Receptors; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Indazoles; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Skin; Skin Neoplasms; Sulfonamides; Tumor Burden

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally aggressive, malignant cutaneous tumor that sparingly presents on the scalp. Dermatofibrosarcomas often result from the formation of a fusion oncogene on translocated or supernumerary ring chromosomes 17 and 22, causing the overexpression of PDGFRbeta driven by the COL1A1 promoter. Because of uncertainty surrounding appropriate treatment of aggressive scalp DFSP, the authors performed an extensive review of the available data from a MEDLINE (Ovid) search to describe the clinical presentation and treatment options for this rare tumor. Their search identified 39 different cases, including the illustrative case presented in this study. Adjuvant therapy for this malignant lesion is not universally established in the literature. In the present case, the authors successfully treated a locally invasive scalp DFSP with presurgical therapy that specifically inhibited the PDGFbeta receptor. Imatinib significantly shrank the DFSP tumor mass, reduced hypervascularity, reduced metabolic activity on PET scanning, and permitted a safe gross-total resection. Although wide excision and Mohs micrographic surgery remain the standard surgical treatments for DFSP, the authors illustrate that presurgical chemotherapeutic treatment by imatinib provides a critical adjunct to traditional therapy.

Topics: Antineoplastic Agents; Benzamides; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 22; Collagen Type I; Collagen Type I, alpha 1 Chain; Dermatofibrosarcoma; Epidermal Growth Factor; Humans; Imatinib Mesylate; Male; Middle Aged; Neurosurgical Procedures; Piperazines; Pyrimidines; Receptor, Platelet-Derived Growth Factor beta; Scalp; Skin Neoplasms; Treatment Outcome