LRRC15 as a Novel Biomarker and Therapeutic Target for Triple-Negative Breast Cancer and Sarcomas

Abstract

Leucine-rich repeat-containing protein 15 (LRRC15) is recently discovered to be an intriguing biomarker and therapeutic target in malignant cancers, particularly triple-negative breast cancer (TNBC) and sarcomas. The aforementioned cancers are clinical challenges due to the lack of efficient targeted therapies and their unfavorable prognosis. LRRC15, which is a member of the leucine-rich repeat superfamily, is mostly expressed in tumor-associated fibroblasts and some populations of cancer cells. Its limited expression in normal tissues and increased presence in certain tumors render it a promising target for tumor-selective therapy. This paper examines the biological roles, expression patterns, and therapeutic potential of LRRC15, particularly its function in TNBC and sarcomas. It also reviews recent developments in antibody-drug conjugates (ADCs) against LRRC15 and points towards the potential of this protein in precision oncology.

Introduction: The Challenge of Treating TNBC and Sarcomas

Triple-negative breast cancer (TNBC) and sarcomas are of significant therapeutic concern. TNBC lacks estrogen receptor, progesterone receptor, and HER2 expression and is thus resistant to standard targeted therapy. Sarcomas, a heterogeneous group of mesenchymal tumors, also exhibit unpredictable response to standard chemotherapy, primarily in advanced or metastatic disease.

Detection of tumor-specific markers suitable for diagnosis as well as therapy is a significant goal in oncology. LRRC15 has also been identified as a tumor-selective marker with therapeutic potential in recent times. In TNBC and sarcomas, LRRC15 has been found to be overexpressed in the tumor microenvironment and in specific subsets of tumor cells, suggesting it may play a role in tumor proliferation as well as immune evasion.

What is LRRC15? Structural and Biological Features

LRRC15 belongs to the leucine-rich repeat (LRR) protein superfamily, which consists of tandem LRR motifs allowing for protein-protein interactions. LRRC15 is a type I transmembrane protein with an extracellular LRR-rich region and a short cytoplasmic tail.

Biologically, LRRC15 plays roles in cell adhesion, migration, and extracellular matrix (ECM) interactions. Although it is weakly expressed in the majority of healthy adult tissues, its expression may be induced during inflammation and is highly induced in disease states such as fibrosis and cancer[1].

LRRC15 is regulated by inflammatory cytokines—particularly TGF-β—and hypoxic signaling pathways, linking it to tumor stroma activation and cancer-associated fibroblast (CAF) biology.

LRRC15 is overexpressed in many solid tumors with strong enrichment in triple-negative breast cancer (particularly the mesenchymal-like and stroma-rich subtypes), other sarcomas such as osteosarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma, and in other cancers such as glioblastoma, head and neck squamous cell carcinoma, and non-small cell lung carcinoma.

Notably, LRRC15 expression is predominantly limited to tumor tissue, most notably the stroma, with low expression in the majority of normal organs. Low expression minimizes off-target toxicity and emphasizes LRRC15's potential as a therapeutic target[2].

LRRC15 and the Tumor Microenvironment

LRRC15 is predominantly secreted by cancer-associated fibroblasts (CAFs), which are critical components of tumor microenvironments. CAFs play a vital role in many functions in extracellular matrix remodeling, immune modulation, promotion of epithelial-to-mesenchymal transition (EMT), and resistance to chemotherapy and immunotherapy.

CAF-induced LRRC15 expression may create a tumor-supporting microenvironment and enable immune exclusion, hence diminishing tumor responsiveness to immune checkpoint blockade. LRRC15 targeting may have the ability to reconstruct the tumor stroma and enhance the efficacy of immunotherapy[3].

Figure 1. Current development in targeting the tumor-stromal interaction by ADCs is being pursued preclinically and in early clinical trials to discover novel therapeutic interventions. PDGFR, platelet-derived growth factor receptor; FRa, folate receptor a; CEACAM5/ 6, carcinoembryonic antigen-related cell adhesion molecules; Trop-2, trophoblast cell surface antigen 2; CTLA4, cytotoxic T-lymphocyte associated protein 4; TIGIT, T-cell immunoreceptor with immunoglobulin and ITIM domains; LAG3, lymphocyte activation gene-3; CD, cluster of differentiation; CCR-2/5, C-C chemokine receptor; SIRPa, signal regulatory protein a; VISTA, V-domain Ig suppressor of T-cell activation; FAP, fibroblast activation protein; MFAP5, microfibril associated protein 5[4].

Clinical Evidence for LRRC15 in TNBC and Sarcomas

In Triple-Negative Breast Cancer

LRRC15-positive tumor and fibroblasts of high-grade TNBC have been identified in research. Gene expression profiling shows enrichment of LRRC15 in poor-prognosis, low-immune-infiltrating stroma-rich subtypes of TNBC. Suppression of LRRC15 can hence be a method of both biomarker for poor disease and evasion of stromal resistance to treatment[5].

In Sarcomas

LRRC15 is highly expressed in several sarcoma subtypes, such as osteosarcoma and leiomyosarcoma. LTMs are well known to be highly refractory to treatment when metastasized. Preclinical data suggest that therapies against LRRC15 can potentially target and kill cancer cells directly or manipulate the tumor stroma for the purpose of immune cell invasion[6].

Therapeutic Targeting of LRRC15: Antibody-Drug Conjugates (ADCs)

The most advanced ABBV-085 is a drug-targeted therapy that is an antibody-drug conjugate (ADC) made of an anti-LRRC15 monoclonal antibody linked with monomethyl auristatin E (MMAE), a cytotoxic microtubule inhibitor[7].

Mechanism of Action

The mechanism of action of LRRC15-targeting antibody-drug conjugates (ADCs) includes specific binding of the antibody moiety to LRRC15 on tumor or stromal cells, followed by internalization and lysosomal targeting of the ADC. Following internalization within cells, the cytotoxic payload—typically monomethyl auristatin E (MMAE)—is released, inhibiting microtubules and inducing apoptosis. The released drug can also exhibit bystander killing, killing adjacent tumor cells regardless of LRRC15 expression[8].

Clinical Trials and Efficacy

ABBV-085 has shown encouraging activity in early-stage clinical trials, achieving durable responses and disease stabilization in sarcoma patients and substantial tumor growth inhibition in triple-negative breast cancer (TNBC) in vivo models. The side effects experienced were mild and in line with other MMAE-conjugates, favoring further exploration of LRRC15-targeting ADCs in larger, biomarker-selected clinical trials[9].

LRRC15 in Imaging and Diagnostics

In addition to its therapeutic potential, LRRC15 is also an effective biomarker for diagnostic and prognostic indicators. Anti-LRRC15 antibodies labeled with radionuclide would be employed in immunoPET imaging for visualizing LRRC15-positive tumors, and circulating exosomes or tumor-released vesicles carrying LRRC15 would be of interest as non-invasive liquid biopsy methods. Furthermore, LRRC15 overexpression might portend poor immunotherapy response and thus influence treatment regimens and patient stratification. These applications demonstrate the utility of LRRC15 as a multimodal biomarker with significant clinical implications[10].

At the same time, combination treatments against LRRC15 would be able to increase immune function and reverse resistance mechanisms within the tumor microenvironment. Co-administration with immune checkpoint drugs such as anti-PD-1/PD-L1 therapy could promote immune cell infiltration, while concurrent dual inhibition with TGF-β antagonists might reduce LRRC15 expression and block stromal resistance. Radiotherapy would also improve therapeutic gain by increasing antigen presentation in LRRC15-high tumors. Preclinical evidence supports these combinatorial approaches, and clinical trials evaluating such combinations are underway[11].

Conclusion

LRRC15 is a novel and promising biomarker and therapeutic target in TNBC and sarcomas—two cancers that urgently require new therapies. Its tumor-preponderant expression, biological role in the stroma, and ADC targetability present multiple therapeutic options. Emerging clinical data, most notably from ABBV-085 trials, promise an age when targeting LRRC15 will transform therapy regimens for those afflicted with these aggressive malignancies.

More studies, particularly in the context of combination therapy and diagnostic development, must be conducted to reveal the entire potential of LRRC15 in cancer treatment. On the path to personalized medicine, LRRC15 is a hope for better and targeted therapy of cancer.

Reference

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