“ Blockade of extracellular LRG1 by a mAb and targeted degradation of intracellular LRG1 together could provide a one-two punch to block its effects on cancer progression .”
BUFFALO, NY — August 26, 2026 — A new review was published in Volume 13 of Oncoscience on July 29, 2026, titled “ Targeting leucine-rich alpha-2-glycoprotein-1 (LRG1) and the LRG1-cytochrome c-Apaf-1 axis in cancer therapy .”
The review was authored by Ronald Jemmerson from the Department of Microbiology and Immunology at the University of Minnesota in Minneapolis, Minnesota, USA .
Leucine-rich alpha-2-glycoprotein-1 (LRG1) has emerged as both a prognostic indicator and a potential therapeutic target in cancer. Elevated LRG1 levels have been reported across multiple cancers and are generally associated with poorer outcomes. Beyond its role as a biomarker, accumulating evidence suggests that LRG1 can actively contribute to cancer progression by promoting abnormal blood-vessel formation, supporting tumor-cell survival and proliferation, and facilitating invasion and metastasis.
The review examines two complementary therapeutic strategies: neutralizing extracellular LRG1 with monoclonal antibodies and degrading intracellular LRG1 using proteolysis-targeting chimeras, or PROTACs. Together, these approaches could potentially interfere with several mechanisms that tumors use to survive and resist treatment.
One important role of extracellular LRG1 involves tumor angiogenesis. LRG1 interacts with endoglin and transforming growth factor-beta 1 (TGF-β1), promoting signaling that generates abnormally formed and leaky blood vessels. In mouse tumor models, an anti-LRG1 monoclonal antibody improved vascular function, slowed tumor growth, enhanced survival, and improved the effects of cisplatin. Antibody treatment also increased CD8+ T-cell infiltration and enhanced immune checkpoint blockade with anti-PD-1 therapy.
These effects distinguish LRG1 from vascular endothelial growth factor (VEGF), another major target of anti-angiogenic cancer therapy. Whereas anti-VEGF approaches inhibit blood-vessel formation, targeting LRG1 may help normalize the abnormal vasculature induced by LRG1, potentially allowing anticancer drugs to reach tumors more effectively. The review therefore suggests that LRG1 inhibition could complement established anti-angiogenic treatments rather than simply duplicate their effects.
LRG1 may also protect cancer cells from apoptosis, or programmed cell death. Extracellular LRG1 can signal through members of the epidermal growth factor receptor (EGFR) family, shifting the balance between apoptosis-regulating proteins by increasing anti-apoptotic Bcl-2 and decreasing pro-apoptotic Bax. This can restrict the release of cytochrome c (Cyt c) from mitochondria, an important step in activation of the apoptotic machinery.
The review extends this mechanism into what Jemmerson describes as the LRG1–Cyt c–Apaf-1 axis. Once released into the cytoplasm, Cyt c normally binds apoptotic protease activating factor-1 (Apaf-1), helping initiate caspase activation and apoptosis. However, intracellular LRG1 has been reported to bind Cyt c and compete with Apaf-1, potentially trapping Cyt c and preventing activation of the apoptotic pathway. In MCF-7 breast cancer cells overexpressing LRG1, cytoplasmic Cyt c was found associated with LRG1 rather than Apaf-1. Importantly, the author characterizes this intracellular interaction as putative because it has not yet been independently validated or demonstrated in other cancer cell types.
This intracellular mechanism presents a challenge for antibody therapy because monoclonal antibodies cannot readily enter cells to eliminate cytoplasmic LRG1. The review therefore discusses a second strategy based on targeted protein degradation. PROTACs recruit the cell’s ubiquitin-proteasome machinery to selectively degrade target proteins, potentially allowing intracellular LRG1 to be removed directly.
A recently developed ionizable nano-PROTAC was designed to overcome endosomal trapping and improve delivery into the cytoplasm. In a mouse mammary tumor model, the ionizable formulation decreased tumor weight by more than two-fold compared with the non-ionizable version and reduced intracellular LRG1 by more than half. This was accompanied by reduced Bcl-2, increased Bax, a two-fold increase in cleaved caspase-3, and reduced phosphorylated AKT, findings consistent with enhanced apoptotic signaling and reduced EGFR-associated survival signaling.
Combining extracellular and intracellular targeting could therefore address different components of LRG1 biology. An anti-LRG1 antibody could block extracellular signaling associated with abnormal angiogenesis, survival, proliferation, and metastasis, while a nano-PROTAC could degrade cytoplasmic LRG1 and potentially remove its competition with Apaf-1 for Cyt c. Intracellular degradation may also decrease LRG1 secretion, potentially reducing extracellular signaling at the same time.
“ LRG1 has both extracellular and putative intracellular effects promoting cell survival, proliferation, and metastasis, thus representing a unique target for cancer therapy .”
Despite the therapeutic potential, important uncertainties remain. Other intracellular mechanisms can also prevent Cyt c from activating Apaf-1, meaning that removing LRG1 alone may not necessarily restore apoptosis. In addition, although LRG1 has been implicated as a survival, proliferative, and metastatic factor in 18 cancer types, some studies have reported opposite, potentially anti-cancer effects in particular contexts. These apparently conflicting roles may depend on differences in receptor signaling and LRG1 expression between tumors.
Potential clinical limitations also include the relatively high concentration of circulating LRG1, which could interfere with delivery of LRG1-targeting agents to tumors. Because LRG1 is an acute-phase protein that may support cell survival during tissue injury or infection, reducing circulating LRG1 could theoretically have effects outside cancer treatment, although the antibody and nano-PROTAC approaches discussed in the review have not shown signs of off-target effects in mouse experiments.
Most importantly, these strategies remain preclinical. Neither monoclonal antibody targeting of extracellular LRG1 nor nano-PROTAC degradation of intracellular LRG1 has entered clinical trials. The humanized anti-LRG1 antibody magacizumab is undergoing preclinical testing in the United Kingdom, while the encouraging nano-PROTAC findings currently come from experimental models.
Overall, the review presents LRG1 as an unusual therapeutic target operating both outside and potentially inside cancer cells. By combining vascular normalization and inhibition of extracellular survival signaling with targeted degradation of intracellular LRG1, future strategies could potentially restore apoptotic susceptibility while improving the effectiveness of chemotherapy and immunotherapy. However, further mechanistic studies, independent validation of the intracellular LRG1–Cyt c interaction, and eventual clinical testing will be necessary to determine whether these approaches can translate into safe and effective cancer treatments.
DOI: https://doi.org/10.18632/oncoscience.667
Correspondence to: Ronald Jemmerson – jemme001@umn.edu
Keywords: cancer, leucine-rich alpha-2-glycoprotein-1, cytochrome c, apoptotic protease activating factor-1, targeted degradation, antibody therapy
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Targeting leucine-rich alpha-2-glycoprotein-1 (LRG1) and the LRG1-cytochrome c-Apaf-1 axis in cancer therapy
29-Jul-2026
The author is not involved in clinical applications regulating the functions of LRG1 and has no conflicts of interest to declare.