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Revitalizing PI3K Inhibitors for PET/CT Imaging and Radionuclide Therapy of Multiple Cancers
Hongyi Huang1, Shouguo Peng1, Quan Zuo1
1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Abstract:
Phosphoinositide 3-kinase (PI3K) dysregulation drives tumorigenesis through regulation of cell cycle progression and survival. Several small molecular inhibitors targeting PI3K have been approved for tumor treatment. However, these inhibitors exposed unexpected severe off-tumor toxicity, leading to poor patient prognosis. Radiopharmaceuticals based on radiolabeled PI3K inhibitors for targeted internal radionuclide therapy offer a revitalized therapeutic approach to reduced pharmacological toxicity. Herein, we rationally designed and synthesized four bifunctional radiolabeled small-molecule chimeras based on the PI3K inhibitor IMM-H012, denoted as [68Ga]Ga/[177Lu]Lu-P(1-4). Among them, radiolabeled P4 demonstrated superior pharmacodynamic and pharmacokinetic profiles in multiple tumor models. Moreover, [177Lu]Lu-P4 substantially suppressed subcutaneous melanoma tumor growth with an acceptable safety profile. Additionally, [177Lu]Lu-P4 combined with IMM-H012 showed synergistic antitumor effects. The mechanistic study suggested a novel radiosensitization mechanism of 177Lu to PI3K inhibitors by downregulating fatty acid oxidase expression. These findings reposition PI3K as a versatile theranostic target while providing an effective repurposing strategy for PI3K inhibitors.
Insights
New radiopharmaceuticals targeting phosphoinositide 3-kinase (PI3K) offer a safer cancer therapy. A novel agent, [177Lu]Lu-P4, effectively reduced melanoma growth and showed synergistic effects with existing PI3K inhibitors.
Area of Science:
- Oncology
- Radiochemistry
- Pharmacology
Background:
- Dysregulated phosphoinositide 3-kinase (PI3K) signaling is a key driver of cancer, promoting cell proliferation and survival.
- Approved PI3K inhibitors often cause severe off-tumor toxicity, limiting their clinical utility.
- Radiopharmaceuticals present a promising strategy to reduce systemic toxicity by delivering therapeutic radionuclides directly to tumors.
Purpose of the Study:
- To design and synthesize novel bifunctional radiolabeled small-molecule chimeras targeting PI3K.
- To evaluate the therapeutic efficacy and safety of these agents in preclinical cancer models.
- To elucidate the underlying mechanisms of action, including potential radiosensitization effects.
Main Methods:
- Synthesis and characterization of four novel PI3K inhibitor-based radiolabeled compounds ([68Ga]Ga/[177Lu]Lu-P(1-4)).
- Pharmacodynamic and pharmacokinetic profiling of the lead candidate ([177Lu]Lu-P4) in various tumor models.
- Assessment of antitumor efficacy and safety of [177Lu]Lu-P4 in subcutaneous melanoma models.
- Combination therapy studies with the parent PI3K inhibitor IMM-H012.
- Mechanistic investigations into radiosensitization.
Main Results:
- Radiolabeled P4 ([177Lu]Lu-P4) exhibited favorable pharmacodynamic and pharmacokinetic properties.
- [177Lu]Lu-P4 demonstrated significant suppression of subcutaneous melanoma tumor growth with a good safety profile.
- Combination therapy of [177Lu]Lu-P4 and IMM-H012 resulted in synergistic antitumor effects.
- A novel radiosensitization mechanism involving downregulation of fatty acid oxidase by 177Lu was identified.
Conclusions:
- [177Lu]Lu-P4 is a potent and safe radiopharmaceutical for targeting PI3K-driven tumors.
- This approach offers an effective strategy for repurposing PI3K inhibitors and reducing their associated toxicities.
- PI3K inhibitors show potential as versatile theranostic agents in oncology.
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