Antitumor activities and on-target toxicities mediated by a TRAIL receptor agonist following cotreatment with...

Area of Science:

• Oncology
• Cancer Therapeutics
• Pharmacology

Background:

• Novel targeted anticancer therapeutics, including histone deacetylase inhibitors (HDACi) and TRAIL pathway activators, offer new treatment strategies.
• HDACi and TRAIL pathway activators can synergistically induce tumor cell apoptosis and exhibit therapeutic activity in vivo.
• Preclinical models are crucial for evaluating the efficacy and toxicity of novel anticancer regimens.

Purpose of the Study:

• To investigate the efficacy and toxicity of combining the HDACi panobinostat with an anti-TRAIL receptor antibody (MD5-1) in syngeneic preclinical models of human solid cancers.
• To determine if this combination can overcome treatment resistance and eradicate established tumors.
• To identify potential dose-limiting toxicities associated with this combination therapy.

Main Methods:

• Utilized syngeneic preclinical models of human solid cancers in immunocompetent mice.
• Administered panobinostat (HDACi) in combination with the anti-mouse TRAIL receptor antibody MD5-1.
• Assessed tumor eradication, survival, and toxicities, including gastrointestinal adverse events.
• Conducted studies in mice with knockout of the TRAIL receptor to evaluate the role of the receptor in toxicity.

Main Results:

• The combination of panobinostat and MD5-1 eradicated established subcutaneous and orthotopic tumors, while single agents showed minimal effect.
• Dose escalation of panobinostat resulted in on-target MD5-1-mediated gastrointestinal toxicities that were fatal in wild-type mice.
• TRAIL receptor knockout mice tolerated higher doses of the combination therapy, achieving superior tumor clearance without lethal toxicity.
• Syngeneic in vivo models proved effective in predicting antitumor effects and identifying potential side effects.

Conclusions:

• The combination of panobinostat and MD5-1 demonstrates potent antitumor activity in preclinical models.
• On-target TRAIL receptor-mediated gastrointestinal toxicities can limit the therapeutic window of this combination.
• TRAIL receptor knockout models can mitigate toxicity, suggesting a role for receptor targeting in managing side effects.
• These findings highlight the importance of preclinical toxicity studies for novel combination cancer therapies involving HDACi and TRAIL pathway activators.