Insights into Doxorubicin and Liposomal Doxorubicin in Extra-Abdominal Desmoid-Type Fibromatosis

Abstract

Desmoid-type fibromatosis (DTF) is a rare, locally aggressive soft tissue tumor characterized by infiltrative growth and a high propensity for recurrence, though it lacks metastatic potential. While surgical resection remains the cornerstone of management, systemic cancer treatment options, particularly chemotherapy, have gained traction for unresectable or recurrent cases. Among chemotherapeutic agents, doxorubicin, a potent anthracycline, and its liposomal counterpart, liposomal doxorubicin, have demonstrated efficacy in controlling extra-abdominal DTF. This systematic review critically examines the molecular mechanisms through which these agents exert their anti-tumor effects, comparing their therapeutic profiles, safety, and impact on DTF pathogenesis. By synthesizing preclinical and clinical data, we explore how conventional doxorubicin disrupts Wnt/β-catenin signaling, induces DNA damage, and promotes apoptosis, while liposomal doxorubicin enhances drug delivery efficiency and mitigates systemic toxicity.

Introduction

Extra-abdominal desmoid-type fibromatosis (DTF) is a monoclonal fibroblastic neoplasm driven primarily by dysregulated Wnt/β-catenin signaling, frequently due to activating mutations in the CTNNB1 gene. The clinical behavior of DTF is highly unpredictable, ranging from spontaneous regression to aggressive local progression, necessitating tailored therapeutic strategies. For inoperable or recurrent cases, systemic cancer treatment becomes imperative, with chemotherapy emerging as a viable option. Conventional doxorubicin, a cornerstone of anthracycline-based chemotherapy, has been utilized with variable success, though its utility is often limited by dose-dependent cardiotoxicity. In contrast, liposomal doxorubicin, a nanoparticle-based formulation, offers a refined therapeutic approach by improving pharmacokinetics and reducing off-target effects. This review delves into the mechanistic underpinnings of these agents, evaluating their clinical applicability in DTF management.

Molecular Pathogenesis of Desmoid-Type Fibromatosis and Chemotherapeutic Targets

Wnt/β-Catenin Signaling Dysregulation in DTF

The pathogenesis of DTF is intimately linked to aberrant activation of the Wnt/β-catenin pathway, predominantly due to somatic mutations in CTNNB1, which encodes β-catenin. These mutations prevent β-catenin degradation, leading to its nuclear accumulation and subsequent transcriptional activation of proliferative genes such as cyclin D1 and c-Myc. This constitutive signaling drives uncontrolled fibroblast proliferation and tumor formation. Given the central role of Wnt/β-catenin dysregulation in DTF, effective cancer treatment strategies must either target β-catenin stabilization or induce selective apoptosis in neoplastic cells.

DNA Damage and Apoptosis Induction by Doxorubicin

Doxorubicin exerts its cytotoxic effects through multiple interconnected mechanisms, making it a potent agent against DTF. As a topoisomerase II inhibitor, doxorubicin intercalates into DNA, creating double-strand breaks and inhibiting DNA repair by preventing topoisomerase II-mediated religation. This results in replication stress and eventual apoptosis. Additionally, doxorubicin undergoes redox cycling within cells, generating reactive oxygen species (ROS) that cause oxidative DNA damage and mitochondrial dysfunction, further promoting cell death. Preclinical studies have also suggested that doxorubicin may modulate the Wnt/β-catenin pathway by downregulating β-catenin expression, thereby indirectly suppressing Wnt-driven proliferation in DTF cells.

Liposomal Doxorubicin: Enhanced Delivery and Reduced Toxicity

The development of liposomal doxorubicin represents a significant advancement in cancer treatment, addressing many limitations of conventional doxorubicin. Encapsulation within polyethylene glycol (PEG)-coated liposomes confers several pharmacokinetic advantages. PEGylation prolongs circulation time by reducing clearance by the reticuloendothelial system, while the enhanced permeability and retention (EPR) effect facilitates selective accumulation within tumor tissues. Liposomal encapsulation also minimizes free doxorubicin exposure to cardiomyocytes, significantly lowering the risk of dose-dependent cardiotoxicity. Furthermore, the sustained release of doxorubicin from liposomes within the tumor microenvironment ensures prolonged cytotoxic activity while sparing healthy tissues.

Clinical Efficacy of Doxorubicin and Liposomal Doxorubicin in DTF

Systemic Chemotherapy with Conventional Doxorubicin

Clinical studies evaluating doxorubicin-based chemotherapy in DTF have reported response rates ranging from 40% to 60%, with many regimens incorporating additional agents such as dacarbazine or ifosfamide. The therapeutic effect is attributed to direct cytotoxicity against fibroblastic cells, with some evidence suggesting secondary suppression of β-catenin signaling. However, the clinical utility of conventional doxorubicin is constrained by cumulative cardiotoxicity, myelosuppression, and other systemic adverse effects, prompting the exploration of safer alternatives.

Liposomal Doxorubicin: A Safer Alternative?

Emerging evidence supports the efficacy of liposomal doxorubicin in DTF, with retrospective studies indicating disease stabilization rates of approximately 50% in refractory cases. Notably, the incidence of severe cardiotoxicity is markedly reduced compared to conventional doxorubicin, making it a preferable option for long-term therapy. The preferential tumor uptake of liposomal doxorubicin, mediated by the EPR effect, is particularly advantageous in highly vascularized desmoid tumors, though its penetration into less vascularized lesions may be suboptimal.

Comparative Mechanistic Advantages and Limitations

Pharmacodynamic Differences

While both conventional and liposomal doxorubicin induce DNA damage and apoptosis, their pharmacodynamic profiles differ significantly. Liposomal doxorubicin achieves higher intratumoral concentrations due to sustained release and reduced systemic distribution, enhancing therapeutic efficacy while minimizing toxicity. This is particularly relevant for long-term cancer treatment in young DTF patients, where cumulative side effects are a major concern. However, conventional doxorubicin may offer superior tissue penetration in poorly vascularized tumors, highlighting the need for individualized treatment selection.

Future Directions: Optimizing Chemotherapy in DTF

Given the rarity of DTF, large-scale randomized trials are lacking, and future research should prioritize several key areas. Biomarker-driven therapy, including molecular profiling of Wnt/β-catenin mutations, could help predict chemosensitivity and guide treatment selection. Combination strategies, such as pairing liposomal doxorubicin with targeted agents like γ-secretase inhibitors, may enhance Wnt pathway suppression and improve outcomes. Additionally, advances in nanotechnology, including the development of tumor-specific ligand-conjugated liposomes, could further refine drug delivery and therapeutic precision.

Summary: Mechanistic Insights into Doxorubicin and Liposomal Doxorubicin for Extra-Abdominal Desmoid-Type Fibromatosis

Desmoid-type fibromatosis (DTF) is a rare, non-metastatic but locally aggressive soft tissue tumor that poses significant therapeutic challenges due to its unpredictable clinical behavior. While surgical resection remains primary for localized disease, systemic therapies including chemotherapy, have become increasingly important for unresectable or recurrent cases. Among chemotherapeutic options, doxorubicin and its liposomal formulation have emerged as potentially effective treatments for extra-abdominal DTF.

The molecular pathogenesis of DTF centers around dysregulated Wnt/β-catenin signaling, primarily due to CTNNB1 mutations that lead to β-catenin stabilization and nuclear accumulation. This results in uncontrolled transcription of proliferative genes, driving tumor growth. Conventional doxorubicin, a topoisomerase II inhibitor, combats this through multiple mechanisms: it intercalates into DNA causing double-strand breaks, generates reactive oxygen species that induce oxidative damage, and may indirectly modulate Wnt signaling by downregulating β-catenin expression. These actions collectively promote apoptosis in neoplastic fibroblasts.

Liposomal doxorubicin represents an advanced formulation that maintains the cytotoxic effects of doxorubicin while improving its therapeutic profile. The polyethylene glycol-coated liposomes prolong circulation time through reduced reticuloendothelial system clearance and exploit the enhanced permeability and retention effect to preferentially accumulate in tumor tissue. This targeted delivery system offers several advantages: sustained intratumoral drug release maintains effective concentrations while minimizing systemic exposure, and the liposomal encapsulation significantly reduces cardiotoxicity - a major limitation of conventional doxorubicin.

Clinical studies of conventional doxorubicin in DTF have demonstrated response rates of 40-60%, often in combination with other agents like dacarbazine. However, its utility is constrained by cumulative dose-dependent toxicities, particularly cardiomyopathy. Emerging data on liposomal doxorubicin show comparable efficacy with improved safety, with retrospective studies reporting disease stabilization in about 50% of refractory cases and markedly reduced cardiac complications.

The pharmacodynamic profiles of these two formulations differ meaningfully. While both induce DNA damage and apoptosis, liposomal doxorubicin achieves higher intratumoral concentrations through sustained release and shows reduced systemic distribution. This makes it particularly suitable for long-term treatment in younger patients. However, conventional doxorubicin may offer better penetration in less vascularized tumors, suggesting the need for individualized treatment selection based on tumor characteristics.

Future directions in DTF chemotherapy should focus on several key areas. Biomarker-driven approaches could optimize treatment selection by correlating CTNNB1 mutation status with drug sensitivity. Combination therapies pairing liposomal doxorubicin with targeted agents like γ-secretase inhibitors may enhance Wnt pathway suppression. Advances in nanomedicine, including tumor-specific ligand-conjugated liposomes, could further improve drug delivery precision. Additionally, standardized response criteria and larger clinical trials are needed to better establish treatment protocols for this rare disease.

In conclusion, both doxorubicin formulations represent valuable options for extra-abdominal DTF, each with distinct advantages. Conventional doxorubicin remains an effective but potentially toxic option, while liposomal doxorubicin offers improved safety at the potential cost of reduced penetration in some tumors. The choice between them should consider tumor characteristics, patient factors, and treatment duration. Ongoing research into Wnt pathway modulation and drug delivery optimization continues to refine the therapeutic landscape for this challenging condition, with the ultimate goal of achieving durable disease control while minimizing treatment-related morbidity.

Conclusion

Both conventional doxorubicin and liposomal doxorubicin represent valuable chemotherapy options for extra-abdominal DTF, each with distinct mechanistic and clinical advantages. While conventional doxorubicin remains effective, its toxicity profile limits its utility in prolonged regimens. Liposomal doxorubicin, with its improved safety profile and enhanced drug delivery, offers a promising alternative, though its efficacy in less vascularized tumors requires further investigation. A deeper understanding of Wnt pathway interactions and continued innovations in drug delivery systems will be crucial in refining cancer treatment paradigms for this challenging disease.