Targeting the apoptotic pathway in chondrosarcoma using recombinant human Apo2L/TRAIL (dulanermin), a dual proapoptotic receptor (DR4/DR5) agonist.
Recombinant human Apo2L/TRAIL (dulanermin) is based on the ligand for death receptors (DR4 and DR5), which promotes apoptosis. We report a patient with refractory chondrosarcoma who showed a prolonged response to dulanermin and explore mechanisms of response and resistance. This heavily pretreated patient had progressive metastatic chondrosarcoma to the lung. On dulanermin (8 mg/kg i.v. on days 1-5 in a 21-day cycle), the patient achieved a sustained partial response with only subcentimeter nodules remaining. After 62 months of dulanermin treatment, progressive disease in the lungs was noted, and the patient underwent a resection that confirmed chondrosarcoma. DR4 was detected (immunohistochemistry) in the patient's tumor, which may have enabled the response. However, upregulation of prosurvival proteins, namely, phosphorylated (p)-NF-κBp65 (Ser 536), p-STAT3 (Tyr 705), p-ERK 1/2 (Thr 202/Tyr 204), p-mTOR (Ser 2448), FASN, and Bcl-2, were also detected, which may have provided the underlying mechanisms for acquired dulanermin resistance. The patient was restarted on dulanermin and has continued on this treatment for an additional 16 months since surgery (78 months since initiation of treatment), with his most recent computed tomography (CT) scans showing no evidence of disease.
The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, Texas 77030, USA. vsubbiah@mdanderson.org
Vivek
V
Subbiah
Robert E
RE
Brown
Jamie
J
Buryanek
Jonathan
J
Trent
Avi
A
Ashkenazi
Roy
R
Herbst
Razelle
R
Kurzrock
D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002813:Chondrosarcoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D004252:DNA Mutational Analysis; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D008875:Middle Aged; D040901:Proteomics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013902:Radiography, Thoracic; D053218:Receptors, Death Domain / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
D019253:Proto-Oncogene Proteins c-bcl-2; D053218:Receptors, Death Domain; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human