Metabolic targeting with recombinant methioninase combined with palbociclib regresses a doxorubicin-resistant
Kentaro Igarashi1, Kei Kawaguchi2, Tasuku Kiyuna2
1AntiCancer, Inc, San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan.
Abstract:
Liposarcoma is the most common type of soft tissue sarcoma. Among the subtypes of liposarcoma, dedifferentiated liposarcoma (DDLPS) is recalcitrant and has the lowest survival rate. The aim of the present study is to determine the efficacy of metabolic targeting with recombinant methioninase (rMETase) combined with palbociclib (PAL) against a doxorubicin (DOX)-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model. A resected tumor from a patient with recurrent high-grade DDLPS in the right retroperitoneum was grown orthotopically in the right retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, DOX; G3, PAL; G4, recombinant methioninase (rMETase); G5, PAL combined with rMETase. Tumor length and width were measured both pre- and post-treatment. On day 14 after initiation, all treatments significantly inhibited tumor growth compared to the untreated control except DOX. PAL combined with rMETase was significantly more effective than both DOX, rMETase alone, and PAL alone. Combining PAL and rMETase significantly regressed tumor volume on day 14 after initiation of treatment and was the only treatment to do so. The relative body weight on day 14 compared with day 0 did not significantly differ between each treatment group. The results of the present study indicate the powerful combination of rMETase and PAL should be tested clinically against DDLPS in the near future.
Insights
Combining palbociclib (PAL) and recombinant methioninase (rMETase) effectively treated doxorubicin-resistant dedifferentiated liposarcoma (DDLPS) in a preclinical model. This potent combination significantly regressed tumors, showing promise for future clinical trials in DDLPS patients.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Dedifferentiated liposarcoma (DDLPS) is an aggressive soft tissue sarcoma with poor prognosis.
- Current treatments for DDLPS, including doxorubicin (DOX), often face resistance.
- Metabolic targeting presents a potential therapeutic strategy for recalcitrant cancers.
Purpose of the Study:
- To evaluate the efficacy of combining palbociclib (PAL) with recombinant methioninase (rMETase) against DOX-resistant DDLPS.
- To assess the therapeutic potential of metabolic targeting in a patient-derived orthotopic xenograft (PDOX) model of DDLPS.
Main Methods:
- Established a DDLPS PDOX model using tumor tissue from a recurrent high-grade DDLPS patient.
- Treated randomized PDOX model groups with control, DOX, PAL, rMETase, or PAL + rMETase.
- Monitored tumor growth and relative body weight changes throughout the 14-day treatment period.
Main Results:
- PAL combined with rMETase significantly inhibited tumor growth compared to control and other monotherapies.
- The PAL + rMETase combination was the only treatment to achieve significant tumor volume regression by day 14.
- No significant differences in relative body weight were observed between treatment groups, indicating good tolerability.
Conclusions:
- The combination of palbociclib and recombinant methioninase demonstrates potent anti-tumor activity against doxorubicin-resistant DDLPS.
- Metabolic targeting with PAL and rMETase offers a promising therapeutic strategy for DDLPS.
- Clinical evaluation of the rMETase and PAL combination for DDLPS treatment is warranted.
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