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Targeting the apoptotic pathway in chondrosarcoma using recombinant human Apo2L/TRAIL (dulanermin), a dual
Vivek Subbiah1, Robert E Brown, Jamie Buryanek
1The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, Texas 77030, USA. vsubbiah@mdanderson.org
Abstract:
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.
Insights
Dulanermin, a recombinant Apo2L/TRAIL, induced a prolonged response in a refractory chondrosarcoma patient. Acquired resistance was linked to prosurvival protein upregulation, but re-treatment led to no evidence of disease.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chondrosarcoma is a rare bone cancer with limited treatment options for metastatic disease.
- Recombinant human Apo2L/TRAIL (dulanermin) targets death receptors (DR4/DR5) to induce apoptosis.
- Refractory and metastatic chondrosarcoma poses a significant clinical challenge.
Purpose of the Study:
- To report a case of prolonged response to dulanermin in a patient with refractory metastatic chondrosarcoma.
- To investigate the mechanisms underlying response and acquired resistance to dulanermin.
Main Methods:
- A heavily pretreated patient with metastatic chondrosarcoma received dulanermin (8 mg/kg i.v. on days 1-5 every 21 days).
- Tumor tissue was analyzed for death receptor 4 (DR4) expression via immunohistochemistry.
- Expression levels of phosphorylated (p)-NF-κBp65, p-STAT3, p-ERK1/2, p-mTOR, FASN, and Bcl-2 were assessed to explore resistance mechanisms.
Main Results:
- The patient achieved a sustained partial response to dulanermin, with only subcentimeter nodules remaining after 62 months.
- Tumor tissue expressed DR4, potentially enabling the initial response.
- Acquired resistance was associated with upregulation of prosurvival proteins including p-NF-κBp65, p-STAT3, p-ERK1/2, p-mTOR, FASN, and Bcl-2.
- Following disease progression, the patient was restarted on dulanermin and has shown no evidence of disease for 16 months post-surgery.
Conclusions:
- Dulanermin can induce a prolonged response in refractory metastatic chondrosarcoma, with DR4 expression potentially mediating sensitivity.
- Upregulation of prosurvival signaling pathways contributes to acquired resistance.
- Continued treatment with dulanermin, even after progression and surgery, can lead to sustained remission.
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