Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression

Abstract

Metastasis is the cause of more than 90% of all cancer deaths. Despite this fact, most anticancer therapeutics currently in clinical use have limited efficacy in treating established metastases. Here, we identify the endoplasmic reticulum chaperone protein, glucose-regulated protein 78 (GRP78), as a metastatic dependency in several highly metastatic cancer cell models. We find that GRP78 is consistently upregulated when highly metastatic cancer cells colonize the lung microenvironment and that mitigation of GRP78 upregulation via short hairpin RNA or treatment with the small molecule IT-139, which is currently under clinical investigation for the treatment of primary tumors, inhibits metastatic growth in the lung microenvironment. Inhibition of GRP78 upregulation and an associated reduction in metastatic potential have been shown in four highly metastatic cell line models: three human osteosarcomas and one murine mammary adenocarcinoma. Lastly, we show that downmodulation of GRP78 in highly metastatic cancer cells significantly increases median survival times in our in vivo animal model of experimental metastasis. Collectively, our data indicate that GRP78 is an attractive target for the development of antimetastatic therapies.

Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-in-human, open-label, dose-escalation phase I study with expansion cohort

“…28 When treated in combination with gemcitabine, sensitivity to cytotoxic drugs was restored in drug-resistant PDAC cells and increased cell death over gemcitabine treatment alone. In another independent study of an ex vivo lung metastases model, IT-139 targeting GRP78 in metastatic osteosarcoma cells saw a decrease in tumour burden after treatment 29. Combination in vivo studies with cisplatin, 5-FU, oxaliplatin and vemurafenib all show increased anti-tumour efficacy in xenograft colorectal, lung23 and melanoma models (unpublished data).…”

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

“…We do know that in the early stages of metastatic lung colonization, disseminated cancer cells experience a variety of cellular stresses (eg, redox/ endoplasmic reticulum stress) that threaten their survival in the distant microenvironment. 49,[54][55][56][57][58][59] However, the clinical relevance of these potential vulnerabilities in patients has yet to be determined. [50][51][52] Animal studies using well-characterized xenograft models of metastatic OS 53 have identified a number of molecular pathways important for metastatic progression.…”

“…[50][51][52] Animal studies using well-characterized xenograft models of metastatic OS 53 have identified a number of molecular pathways important for metastatic progression. 49,[54][55][56][57][58][59] However, the clinical relevance of these potential vulnerabilities in patients has yet to be determined.…”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…[109][110][111] The combination of the two metal-based compounds exceeds the efficacy of each complex applied as monotherapy. [42] A phase I clinical trial www.advancedsciencenews.com www.advtherap.com including 46 patients with advanced solid tumors concluded (also based on related in vitro studies when combined, for example, with gemcitabine in endoplasmic reticulum chaperone glucose regulated protein 78 [GRP78] chemoresistant PDAC cells) [113][114][115] that (N)KP1339 could be beneficial in combination therapies with agents that cause hematological toxicity. A combination of NAMI-A and cisplatin was previously shown to result in additive interactions in an in vivo MCa mammary carcinoma model.…”

“…[118] One example of a terminated phase I clinical trial involved a study to evaluate the efficacy of vorinostat, a histone deacetylase inhibitor, in combination with fluorouracil and leucovorin. [114,115] Furthermore, patients diagnosed with metastatic colorectal carcinoma and previously treated with other medications were enrolled to the phase II clinical trial evaluating the activity of two drugs applied in combination, namely the chemotherapeutic 5azacitidine administered subcutaneously (day 1-5 and 8-10) and entinostat, which is a HDAC class 1 inhibitor in clinical evaluation specifically deactivating Treg cells, administered orally (day 3 and 10). [32] A secondary phase II trial evaluating differential treatment scheduling administering two doses of vorinostat in the same combination in pre-treated metastatic colorectal carcinoma patients failed as well.…”