This study systematically reveals the critical role of AXL protein in bone-metastatic prostate cancer and demonstrates that monotherapy with the soluble AXL receptor batiraxcept or its combination with chemotherapy drugs docetaxel/carboplatin effectively suppresses tumor growth and metastasis, showing significant clinical translational potential.
Literature Overview
This article, 'Targeting AXL Inhibits Prostate Cancer Bone Metastasis', published in Clinical Cancer Research, reviews the functional role of the AXL signaling pathway in bone-metastatic prostate cancer and evaluates the antitumor and antimetastatic effects of batiraxcept (a soluble AXL receptor) alone or in combination with docetaxel/carboplatin. The study further confirms AXL's critical role in tumor stem cell maintenance, chemoresistance, and bone metastasis through patient-derived xenograft (PDX) models and molecular mechanism analyses.
Background Knowledge
Prostate cancer (PCa) is one of the most common malignant tumors in men, with bone metastasis in advanced stages being a leading cause of mortality. Although androgen deprivation therapy (ADT) and novel chemotherapeutic agents like docetaxel/carboplatin provide short-term disease control, most patients progress to castration-resistant metastatic disease (mCRPC) or neuroendocrine prostate cancer (NEPC), with poor prognosis. AXL, a member of the TAM (TYRO3, AXL, MER) receptor family, interacts with its ligand GAS6, which is highly expressed in the bone marrow microenvironment and promotes tumor growth, invasion, and drug resistance. Current AXL inhibition strategies, such as small-molecule kinase inhibitors, face clinical limitations due to off-target effects and toxicity. Batiraxcept, a high-affinity soluble AXL receptor, effectively blocks the GAS6-AXL signaling axis to inhibit tumor progression. This study systematically evaluates the antitumor efficacy of batiraxcept and its synergistic effects with chemotherapy through multi-model and multi-omics analyses, providing new molecular targets and therapeutic strategies for bone-metastatic prostate cancer.
Research Methods and Experiments
The research team analyzed phosphorylated AXL (p-AXL) expression in biopsy samples from 31 patients with bone-metastatic mCRPC and assessed its correlation with overall survival (OS) using Kaplan-Meier analysis. Subsequently, LuCaP 147, 147CR, 35, 35CR, and 49 PDX models were employed. Tumor cells were injected into mouse tibias to evaluate the effects of batiraxcept monotherapy or combination therapy with docetaxel/carboplatin on tumor growth and lung metastasis. Key methodologies included serum PSA detection, bioluminescence imaging (BLI), qRT-PCR, immunohistochemistry (IHC), and Western blot to assess tumor burden, metastasis, and signaling pathway alterations.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides robust preclinical evidence for AXL-targeted therapeutic strategies in bone-metastatic prostate cancer and reveals the potential for synergistic enhancement of antitumor activity through combination with chemotherapy. Future clinical trials should validate batiraxcept's efficacy in patients with high AXL expression and explore its applications in other cancers.
Conclusion
This study systematically evaluates AXL's critical role in bone-metastatic prostate cancer and confirms batiraxcept's antitumor efficacy as monotherapy or combined with docetaxel/carboplatin. The research demonstrates that batiraxcept effectively suppresses intraosseous tumor growth and lung metastasis through multi-mechanistic regulation of stemness genes and signaling pathways. Additionally, batiraxcept exhibits favorable safety profiles in preclinical models, strongly supporting subsequent clinical trials. This work identifies AXL as a novel therapeutic target and provides a promising strategy to improve clinical outcomes for patients with bone-metastatic prostate cancer.
