Cathepsin L inactivation leads to multimodal inhibition of prostate cancer cell dissemination in a preclinical bone metastasis model

• Published in: International journal of cancer Vol. 138; no. 11; pp. 2665 - 2677
• Main Authors: Sudhan, Dhivya R., Pampo, Christine, Rice, Lori, Siemann, Dietmar W.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-06-2016
• Subjects: Angiogenesis; Animals; Bone Neoplasms - genetics; Bone Neoplasms - pathology; Bone Neoplasms - secondary; bone resorption; Bone Resorption - genetics; Bone Resorption - pathology; Cancer; cathepsin L; Cathepsin L - antagonists & inhibitors; Cathepsin L - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Humans; KGP94; Male; Medical prognosis; Medical research; Metastasis; Mice; Morbidity; Neoplasm Metastasis; Osteoclasts - metabolism; Osteoclasts - pathology; Pharmaceutical industry; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Thiosemicarbazones - administration & dosage; Thiourea - administration & dosage; Thiourea - analogs & derivatives; Tumor Burden - genetics; Xenograft Model Antitumor Assays; prostate cancer; cathepsin L; metastasis; KGP94; bone resorption
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29992

It is estimated that approximately 90% of patients with advanced prostate cancer develop bone metastases; an occurrence that results in a substantial reduction in the quality of life and a drastic worsening of prognosis. The development of novel therapeutic strategies that impair the metastatic process and associated skeletal adversities is therefore critical to improving prostate cancer patient survival. Recognition of the importance of Cathepsin L (CTSL) to metastatic dissemination of cancer cells has led to the development of several CTSL inhibition strategies. The present investigation employed intra‐cardiac injection of human PC‐3ML prostate cancer cells into nude mice to examine tumor cell dissemination in a preclinical bone metastasis model. CTSL knockdown confirmed the validity of targeting this protease and subsequent intervention studies with the small molecule CTSL inhibitor KGP94 resulted in a significant reduction in metastatic tumor burden in the bone and an improvement in overall survival. CTSL inhibition by KGP94 also led to a significant impairment of tumor initiated angiogenesis. Furthermore, KGP94 treatment decreased osteoclast formation and bone resorptive function, thus, perturbing the reciprocal interactions between tumor cells and osteoclasts within the bone microenvironment which typically result in bone loss and aggressive growth of metastases. These functional effects were accompanied by a significant downregulation of NFκB signaling activity and expression of osteoclastogenesis related NFκB target genes. Collectively, these data indicate that the CTSL inhibitor KGP94 has the potential to alleviate metastatic disease progression and associated skeletal morbidities and hence may have utility in the treatment of advanced prostate cancer patients.
What's new?
A majority of advanced prostate cancer patients suffer from bone metastases and related skeletal morbidities, with no known cure. Cathepsin L (CTSL), a tumor secreted protease, has been clinically associated with metastatic disease incidence and progression in prostate cancer. The present study demonstrates that treatment with KGP94, a small‐molecule inhibitor of CTSL, impairs various aspects of metastatic progression including incidence, disease burden, tumor‐induced angiogenesis, and osteolysis in a pre‐clinical prostate cancer model. The CTSL inhibitor KGP94, thus, has the potential to alleviate metastatic disease progression and associated skeletal morbidities and have utility in the treatment of advanced prostate cancer patients.