Biology subjects

Vargas, S. H.

Publications and source records attributed to Vargas, S. H..

3 recordsLinked to original sources

bioRxiv2025

Fibulin-4 is highly expressed in metastatic breast cancer and can serve as a target of peptide-based imaging probes and experimental therapeutics

We have previously reported a cyclic peptide CRAGVGRGC (termed BLMP6) that homes to disseminating tumor cells in mouse cancer models and could be used for metastasis detection and intervention. Here, based on BLMP6 similarity to latent transforming growth factor beta binding protein 4 (LTBP4), we discovered fibulin-4 as a BLMP6 target. We show that BLMP6 mimics the LTBP4 domain binding to fibulin-4 and selectively binds to fibulin-4 in vitro. Fibulin-4 knockout in mouse 4T1 cancer cells abrogated BLMP6 homing to lung metastases. Fibulin-4 expression was found to be increased in invasive and metastatic human breast cancer. AZDye555 fluorophore-labeled BLMP6 was developed as a reagent selectively binding to invasive and metastatic human breast cancer cells in tissue sections and homing to MDA-MB-231 metastases in mice. We show that radiolabeling BLMP6 with 68Ga can be used for the detection of MDA-MB-231 metastases. We designed a peptide-drug conjugate consisting of monomethyl auristatin E (MMAE) and BLMP6 that preferentially kills aggressive cancer cells. Cytotoxicity of MMAE-BLMP6 against MDA-MB-231 tumors was confirmed in vivo. In an immunocompetent mouse model of B16F10 experimental lung metastases, treatment with MMAE-BLMP6 suppressed metastasis growth and improved survival. There was also a trend for metastasis suppression and survival improvement in the MDA-MB-231 experimental metastasis model. Our results suggest that fibulin-4 and BLMP6 may be further developed for the detection and targeting of metastatic human cancers. Statement of significanceThis study identifies fibulin-4 as a protein highly expressed in breast cancer metastasis. It evaluates the application of peptide conjugates targeting fibulin-4 in mouse models as non-invasive probes for metastasis detection and cytotoxic drug delivery.

cancer biology↗

bioRxiv2025

Somatostatin Receptor 2 Overexpression in Hepatocellular Carcinoma: Implications for Cancer Biology and Theranostic Applications

(1) BackgroundSomatostatin receptor 2 (SSTR2) is overexpressed in various tumors, including hepatocellular carcinoma (HCC), yet its role in tumorigenesis remains unclear. This study examines the roles of SSTR2 in the molecular pathology of HCC and explores its potential as a target for SSTR2-directed radiopharmaceuticals in this malignancy. (2) MethodsSSTR2 expression was analyzed across 22 malignancies using TNMplot and specifically in HCC through The Human Protein Atlas. Transcriptomic data, protein expression, and copy number alterations in HCC patients with varying SSTR2 levels were compared using The Cancer Genome Atlas (TCGA). Gene Ontology (GO) enrichment analysis was performed using SRplot, while survival analysis was conducted with GEO datasets. (3) ResultsMost HCC patients exhibit moderate levels of SSTR2 expression. Elevated SSTR2 expression is associated with worse overall and disease-specific survival, as well as the activation of pathways involved in tumor growth and metastasis. Furthermore, SSTR2 expression is linked to key oncogenes and receptor tyrosine kinases. (4) ConclusionsSSTR2 in HCC signifies an oncogenic network and represents a promising therapeutic target to inhibit tumor invasion and serve as a theranostic biomarker. HCC patients with elevated SSTR2 expression could benefit from SSTR2-targeted theranostics, enabling enhanced tumor detection and more effective therapy.

cancer biology↗

bioRxiv2024

SSTR2-targeted theranostics in hepatocellular carcinoma

(1) BackgroundWhile the clinical use of radiolabeled somatostatin analogs is established in neuroendocrine tumors, there is significant interest in expanding their use for other somatostatin receptor 2 (SSTR2)-expressing cancers. This study investigates the utility of SSTR2-targeted theranostics in hepatocellular carcinoma (HCC); (2) MethodsWe measured SSTR2 expression in HCC cell lines and clinical samples using qRT-PCR, Western blot, and a public dataset. We evaluated [67Gallium]Ga-DOTATATE uptake, tested [177Lutetium]Lu-DOTATATE cytotoxicity, and assessed [68Gallium]Ga-DOTATATE tumor targeting in HCC animal models and a patient via PET/CT; (3) ResultsSSTR2 expression was confirmed in HCC cell lines and clinical samples. Radioligand uptake studies validated SSTR2-mediated [67Gallium]Ga-DOTATATE uptake, and [177Lutetium]Lu-DOTATATE treatment reduced cell proliferation. [68Gallium]Ga-DOTATATE PET/CT scans detected tumors in animal models and spinal metastases in a patient with HCC; (4) ConclusionThese findings suggest for the first time that SSTR2-based theranostics could have strong implications for detection and treatment of HCC. Simple SummaryThis study investigates the use of SSTR2-targeted theranostics, combining diagnostic and therapeutic approaches, in hepatocellular carcinoma (HCC). We confirmed significant SSTR2 expression in HCC cells and patient samples, showing that radiolabeled compounds such as [67Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE, commonly used in neuroendocrine tumors, could also target HCC. In preclinical models and a patient case, PET/CT imaging and treatments demonstrated effective tumor detection and shrinkage. These findings suggest that SSTR2-targeted theranostics could offer a novel, targeted method for diagnosing and treating HCC, potentially improving outcomes for patients with this challenging cancer.

cancer biology↗