Diagnostic and therapeutic implications of novel peptides in hepatocellular carcinoma
Authors: Jordan M Cloyd, Timothy M Pawlik
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. See article on page 1391 Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancers in the world and a leading cause of cancer‐related mortality.1 Furthermore, the incidence of HCC appears to be increasing across most demographic groups.2 HCC is closely related to chronic liver disease (CLD) and therefore is endemic among populations with high rates of chronic hepatitis B and hepatitis C infections, and also those with alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD). Despite intensive screening programs in high risk patients, most cases of HCC are diagnosed at late stages when treatment options are limited. Even among patients with early stage disease who undergo potentially curative resection, intrahepatic recurrence is common due to the infiltrative nature of HCC and the underlying liver dysfunction.3 For these reasons and others, the development of novel molecular imaging tools could have significant implications for the early detection and improved therapeutic targeting of HCC. In this issue of Hepatology, Jing et al.4 describe the systematic identification and evaluation of a novel HCC‐binding peptide and demonstrate its sensitivity and specificity for detecting micronodules in a murine model. The authors use phage display to screen for peptides that preferentially bind to HCC, using in vitro selection on human HCC tissue samples and high throughput sequencing to increase the resolution of the selection. The candidate peptide, known as P47, was shown to have high binding affinity for large and small HCCs in both in vitro and in vivo orthotopic murine models. Next, they show that P47 is specific to HCC, not preferential for other cancer types or normal liver tissue, with a sensitivity for detecting micronodules as small as 0.03 cm. P47 was also effective at differentiating HCC from peritumoral tissue even in the setting of liver fibrosis. Finally, the authors demonstrated the potential for fluorescence guided surgical navigation in both orthotopic and ectopic murine models, using polymerase chain reaction techniques to demonstrate complete microscopic resection of HCC tumors. These exciting results raise the potential for a novel molecular imaging modality that can be used for the early detection and staging of HCC. For example, the incorporation of this technology into screening protocols may improve diagnostic capabilities since screening ultrasound is limited in its sensitivity and specificity for HCC.5 Even high‐resolution magnetic resonance imaging (MRI) is limited in its determination of small subcentimeter lesions, unable to differentiate from shunts, regenerative nodules, or other benign lesions. To that end, the use of molecular imaging techniques may provide earlier determination of small at‐risk lesions, avoiding the need for short‐term follow‐up imaging or biopsy. In addition, since current imaging modalities, including PET (positron emission tomography), CT (computed tomography), and bone scans, are suboptimal for the diagnosis of metastatic disease, the ability to detect micronodules using HCC‐specific peptides could enable more accurate staging and better clarification of the most appropriate stage‐based treatment strategy. The results of the current study also preview its potential for real‐time surgical navigation. HCC is an infiltrative malignancy that invades along the segmental portal pedicles. For this reason, anatomically oriented resections are often recommended in an attempt to facilitate complete microscopically negative resection and prevent local recurrence.6 However, anatomic resection typically requires a removal of a greater volume of uninvolved liver than nonanatomic parenchymal sparing hepatectomy, which is important in patients with CLD. The ability of P47 peptide to sharply differentiate normal peritumoral liver from HCC raises the possibility that fluorescence‐guided parenchymal sparing resections could be as effective as nonguided anatomic resections. Furthermore, the detection of satellite micronodules either prior to or at the time of surgery may improve the opportunities for complete margin‐negative resection and prevention of HCC recurrence (Fig. 1). Finally, ablative techniques are increasingly used, especially for small HCCs, in patients who are not surgical candidates.7 Peptide fluorescent navigation could be used to facilitate a more complete ablation and/or allow for the effective ablation of larger lesions.Figure 1: Intraoperative detection of satellite tumor nodules in a murine model: (A) The implanted liver tumor tissue exhibited obvious contrast in color and texture from normal liver tissues. (B) Molecular targeting using indocyanine green confirmed the position and margin of the tumor tissue and showed the presence of several microtumor foci (yellow arrow) separate from the major tumor with remarkable optical contrast. (C) The major tumor tissue was resected. (D) The microtumor foci that were again identified by fluorescence imaging. (E,F) With proper magnification, these satellite foci were even more clearly and sharply defined. (G,H) Hematoxylin and eosin staining and fluorescence imaging of the specimen. Used with permission from: Zeng et al., Sci Rep 2016;29:21959.Perhaps most importantly, the development of HCC‐specific peptides may allow for the introduction of novel targeted therapeutic options. Radioembolization with yytrium‐90 (Y‐90) tagged microspheres is now a standard therapeutic option for patients who are not surgery or transplant candidates. Theoretically, HCC‐specific peptides could be tagged with a radionuclide that delivers targeted internal radiation, a process similar to peptide receptor radionuclide therapy for neuroendocrine tumors or radioactive iodine for thyroid cancer. Similarly, these peptides could be tagged with novel chemotherapies and then delivered in a targeted fashion. Recently, Yan et al. reported a thermally sensitive liposomal doxorubicin tagged to HCC‐specific peptide for delivery during radiofrequency ablation.8 Such combination regimens of novel multimodal therapies may hold the most promise for this aggressive cancer. The results of the study by Jing et al. are clearly exciting, though only the first step to groundbreaking advances in the diagnosis and treatment of HCC. Future translational studies will be needed to bring this novel peptide to the clinical arena. Clearly, human in vivo studies are needed to clarify its sensitivity, specificity, and stability. Can this peptide be incorporated into traditional scintigraphy or single‐photon emission computed tomography (SPECT) for 3D reformations? What is the optimal intraoperative navigation platform for use of this fluorescent peptide? Finally, how can this technology be harnessed to create opportunities for novel therapies? Further research into the specific receptor that P47 binds to may also elucidate novel mechanistic pathways which can then be targeted. In summary, Jing et al. report the identification of a novel HCC‐specific peptide. This fluorescent‐labeled peptide was sensitive and specific for detecting HCC micronodules as small as 0.03 cm and its ability to facilitate surgical navigation was demonstrated in vivo using an orthotopic mouse model. Hopefully, these exciting results will create new opportunities that can lead to significant breakthroughs in the early detection of, precision surgery for, and development of novel targeted therapies for HCC.