Targets for Peritoneum Cancer

Peritoneum cancer, most commonly manifesting as primary peritoneal carcinoma or peritoneal metastases (notably from ovarian origin), is a malignancy characterized by complex molecular alterations promoting tumor growth, immune evasion, angiogenesis, and chemoresistance. The molecular targets identified here represent key nodes in these pathogenic networks. Understanding these targets provides insight into mechanisms of tumor progression—such as dysregulated cell survival (inhibitor of apoptosis proteins), uncontrolled proliferation (receptor tyrosine kinases), immune escape (immune checkpoint molecules), neovascularization (angiopoietins), and drug resistance (ABC transporters). Collectively, these targets inform the development of targeted therapeutics, immunotherapies, and predictive biomarkers. By dissecting their mechanistic roles, researchers can prioritize druggable vulnerabilities, improve patient stratification, and design rational combination therapies to overcome resistance and enhance clinical outcomes in peritoneum cancer.

Apoptosis And Cell Survival Regulation

This category includes targets that regulate apoptosis and cell survival, which are central to peritoneum cancer pathogenesis. Inhibitor of apoptosis proteins (IAPs) such as BIRC2, BIRC3, and BIRC5 are frequently upregulated in peritoneal and ovarian cancers, contributing to therapy resistance and tumor persistence by blocking caspase activation and promoting cell survival. Their overexpression is associated with poor prognosis and chemoresistance, making them critical contributors to disease progression and attractive targets for therapeutic intervention.

Baculoviral IAP Repeat Containing 2 (BIRC2)

BIRC2 (cIAP1) is a member of the inhibitor of apoptosis (IAP) family, characterized by three baculoviral IAP repeat (BIR) domains and a RING finger domain. It regulates apoptosis by directly inhibiting caspases 3 and 7 and modulating NF-κB signaling. In peritoneum and ovarian cancers, BIRC2 overexpression has been linked to resistance to apoptosis and chemotherapy, as well as enhanced tumor cell survival. BIRC2 also interacts with TNF receptor-associated factors and is regulated by proteasomal degradation. Therapeutically, small-molecule IAP antagonists (e.g., SMAC mimetics) are under investigation to sensitize tumors to apoptosis. BIRC2 is a potential predictive biomarker for poor response to therapy and disease recurrence.

Baculoviral IAP Repeat Containing 3 (BIRC3)

BIRC3 (cIAP2) shares structural and functional similarities with BIRC2, containing BIR and RING domains. It inhibits apoptosis by binding and inhibiting caspases and modulates NF-κB signaling, contributing to inflammation and survival of malignant cells. BIRC3 is upregulated in peritoneal and ovarian cancer tissues, correlating with chemoresistance and aggressive tumor behavior. Targeting BIRC3 with SMAC mimetics or siRNA restores apoptosis and reduces tumor growth in preclinical models, supporting its role as a therapeutic target and biomarker.

Baculoviral IAP Repeat Containing 5 (BIRC5)

BIRC5 (Survivin) is a unique IAP with a single BIR domain, predominantly expressed in embryonic tissues and cancers, but low in normal adult tissues. It inhibits apoptosis by blocking caspase activation and is essential for cell division. BIRC5 is overexpressed in peritoneal and ovarian cancers, where its levels correlate with advanced stage, high-grade tumors, and poor prognosis. Mechanistically, BIRC5 is regulated by the PI3K/AKT and Wnt/β-catenin pathways. Therapeutic approaches include antisense oligonucleotides, small-molecule inhibitors, and immunotherapeutic vaccines targeting BIRC5, some of which are in clinical trials.

Angiogenesis And Vascular Remodeling

This category encompasses targets that mediate angiogenesis and vascular remodeling, critical for tumor growth, peritoneal dissemination, and ascites formation in peritoneum cancer. ANGPT1 and ANGPT2, acting via the TIE2 receptor, orchestrate the balance between vascular stability and neovascularization. Dysregulation of these factors promotes abnormal vessel formation, increased vascular permeability, and metastatic spread within the peritoneal cavity.

Angiopoietin 1 (ANGPT1)

ANGPT1 is a secreted glycoprotein that binds and activates the TIE2 receptor tyrosine kinase on endothelial cells, promoting vessel maturation, stability, and quiescence. Structurally, it contains a coiled-coil domain and a fibrinogen-like domain. In peritoneum and ovarian cancers, ANGPT1 expression is often reduced relative to ANGPT2, leading to destabilized vasculature. ANGPT1 acts as a counterbalance to ANGPT2-driven angiogenesis. Modulation of ANGPT1/TIE2 signaling is being explored therapeutically to normalize tumor vasculature and enhance drug delivery.

Angiopoietin 2 (ANGPT2)

ANGPT2 is a context-dependent antagonist or partial agonist of TIE2, destabilizing blood vessels and promoting angiogenesis in the presence of VEGF. It shares structural domains with ANGPT1. ANGPT2 is upregulated in peritoneal and ovarian cancers, correlating with increased microvessel density, ascites, and poor prognosis. ANGPT2 facilitates tumor dissemination within the peritoneal cavity. Therapeutic agents targeting ANGPT2, including monoclonal antibodies and peptibodies, are in clinical development for solid tumors.

Drug Resistance Mechanisms

This category includes targets that mediate multidrug resistance, a major barrier to effective chemotherapy in peritoneum cancer. ABCB1 encodes P-glycoprotein, an ATP-dependent efflux pump that expels chemotherapeutic agents from cancer cells, reducing intracellular drug accumulation and efficacy. Overexpression of ABCB1 is a hallmark of chemoresistant peritoneal and ovarian cancers.

ATP Binding Cassette Subfamily B Member 1 (ABCB1)

ABCB1 (P-glycoprotein, MDR1) is a transmembrane ATP-binding cassette transporter with two nucleotide-binding domains and two transmembrane domains. It actively effluxes a broad range of chemotherapeutic drugs, including paclitaxel and doxorubicin. In peritoneum cancer, upregulation of ABCB1 is associated with acquired and intrinsic chemoresistance, leading to treatment failure. ABCB1 expression is regulated by transcription factors (e.g., NF-κB) and microRNAs. Inhibitors of ABCB1 (e.g., tariquidar, elacridar) have been tested in clinical trials with variable success. ABCB1 is a validated biomarker for predicting chemoresistance.

Immune Evasion And Checkpoint Regulation

This category covers targets involved in immune evasion, a key feature of peritoneum cancer progression. Tumor cells exploit immune checkpoint molecules such as CD274 (PD-L1) to inhibit cytotoxic T cell responses and escape immune surveillance. High PD-L1 expression in peritoneal and ovarian cancers is linked to poor prognosis and reduced response to immunotherapy.

CD274 Molecule (CD274)

CD274 (Programmed Death-Ligand 1, PD-L1) is a type I transmembrane protein with IgV- and IgC-like domains, expressed on tumor and immune cells. It binds to PD-1 on T cells, delivering inhibitory signals that suppress T cell activation and promote immune escape. In peritoneum cancer, overexpression of CD274 correlates with advanced disease and poor prognosis. PD-L1 expression is induced by oncogenic and inflammatory pathways (e.g., IFN-γ/JAK/STAT). Immune checkpoint inhibitors targeting PD-1/PD-L1 (e.g., pembrolizumab, nivolumab) are approved for several cancers and under investigation in peritoneal malignancies.

Receptor Tyrosine Kinase Signaling And Tumor Progression

This category includes receptor tyrosine kinases that drive tumor cell proliferation, survival, migration, and invasion. AXL is frequently overexpressed in peritoneal and ovarian cancers, contributing to epithelial-mesenchymal transition (EMT), metastasis, and resistance to therapy. Targeting AXL signaling represents a promising strategy to inhibit tumor progression and overcome drug resistance.

AXL Receptor Tyrosine Kinase (AXL)

AXL is a member of the TAM (Tyro3, AXL, Mer) family of receptor tyrosine kinases, featuring two Ig-like and two fibronectin type III extracellular domains, a transmembrane region, and an intracellular tyrosine kinase domain. Ligand binding (e.g., GAS6) activates AXL, triggering downstream PI3K/AKT, MAPK, and NF-κB pathways. In peritoneum cancer, AXL overexpression promotes EMT, invasion, and metastasis, and is associated with poor prognosis and chemoresistance. AXL inhibitors (e.g., bemcentinib, cabozantinib) are in clinical trials for solid tumors, including ovarian cancer.