LDLR-targeted peptides: a new hope for diagnosis and therapy of PDAC

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, due to a delayed onset of clinical symptoms, an early metastatic dissemination, and a lack of effective diagnostic tools and treatments. To tackle the unmet diagnostic needs, we designed novel PDAC-targeted delivery systems.

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Pancreatic ductal adenocarcinoma (PDAC) is currently one of the deadliest cancers worldwide. The overall 5-year survival rate of PDAC patients is about 8% and their median survival time of 6 months (Huang et al., 2021). The reasons why this cancer is so devastating are a delayed onset of clinical symptoms, an early metastatic dissemination, and a lack of effective diagnostic tools and treatments. Regarding imaging modalities currently used for distinction of mass-forming chronic pancreatitis from PDAC, detection and staging of primary and metastatic PDAC, such as computed tomography (CT), endoscopic ultrasonography and magnetic resonance imaging (MRI)), their performances are fairly poor (Scialpi et al., 2016).

To tackle the unmet diagnostic needs, in collaboration with the Vect-Horus company, we designed novel PDAC-targeted delivery systems (Acier et al., 2021). We produced cyclic VH4127 peptides which specifically bind with high affinity to extracellular domain of the low-density lipoprotein receptor (LDLR) and have an improved serum half-life provided by their conjugation to a human IgG Fc fragment. As LDLR is essential to satisfy cholesterol requirements for PDAC growth (Guillaumond et al., 2015), it is highly represented at the cell-surface of human pancreatic cancer cells at the primary and metastatic sites (Acier et al., 2021). Once labelled with Alexa Fluor 680 dyes, this conjugate, namely Fc(A680)-VH4127, specifically targets LDLR in murine PDAC cells as the natural ligand (i.e. LDL), and is properly internalized through LDLR-mediated endocytosis, before trafficking to the late endosome/lysosome pathway (Acier et al., 2021) (Figure 1). These remarkable properties make LDLR-targeting peptides promising theranostic tools to diagnose and treat PDAC and other cholesterol addictive cancers, such as glioblastoma and breast tumors (Riscal et al., 2019).

In immunodeficient mice inoculated subcutaneously with wild-type or knock-out Ldlr pancreatic cancer cells, we demonstrated the specific addressing of the Fc(A680)-VH4127 to LDLR positive tumours by near-infrared fluorescence (NIRF) imaging (Acier et al., 2021). Moreover, the conjugate accumulation is significantly higher in PDAC than in healthy organs, including pancreas. We validated the PDAC targeting using the Fc(A680)-VH4127 in spontaneous pancreatic cancer mouse model (KIC mice: LSL-KrasG12D; Ink4a/Arffl/fl; Pdx1-Cre) (Aguirre et al., 2017), in which this LDLR-targeting conjugate is able to bypass the PDAC-stromal barrier that makes tumor cells extremely hard-to-reach until now (Figure 1). Furthermore, we showed its diagnostic ability in discriminating spontaneous PDAC from induced-chronic pancreatitis (CP) with a sensitivity and specificity of 100% (Acier et al., 2021). Hence, combined to a radioisotope, this conjugate may be particularly useful in positron emission tomography/computed tomography (PET/CT) or magnetic resonance imaging (MRI) to discern these two pathologies that share very similar clinical symptoms and imaging features. Finally, we showed that fluorescent LDLR-targeting conjugate allows detection of pancreatic metastases in liver (Acier et al., 2021) (Figure 1), which account for most PDAC-associated deaths. A property that could be exploited to reduce the rate of unnecessary explorative laparoscopy in PDAC’s patients and adapt the treatment according to the status of the disease.

To conclude, this proof-of-concept study highlights the powerful potential of LDLR-targeting peptides in preclinical models and offers new useful perspectives in clinic, notably in molecular imaging to improve PDAC diagnosis (PET/CT, MRI) and surgical tumour resection margins (NIRF guided-surgery), and in anti-cancer therapy.

Acier, A. et al. LDL receptor-peptide conjugate as in vivo tool for specific targeting of pancreatic ductal adenocarcinoma. Commun Biol 4, 987 (2021).

Aguirre, A. J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).

Guillaumond, F. et al. Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proc. Natl Acad. Sci. USA 112, 2473–2478 (2015).

Huang J. et al. Worldwide burden of, risk factors for, and trends in pancreatic cancer. Gastroenterology 160, 744–754 (2021).

Riscal, R. et al. Even Cancer Cells Watch Their Cholesterol! Mol. Cell 76, 220-231 (2019).

Scialpi, M. et al. Pancreatic tumors imaging: an update. Int. J. Surg. 28, S142–S155 (2016).

Angélina ACIER

Researcher, INSERM