1.Identification of Bone-Derived Factors Conferring De Novo Therapeutic Resistance in Metastatic Prostate Cancer.
Lee YC1, Lin SC1, Yu G1, Cheng CJ2, Liu B3, Liu HC1, Hawke DH1, Parikh NU4, Varkaris A4, Corn P4, Logothetis C4, Satcher RL5, Yu-Lee LY6, Gallick GE7, Lin SH8. Cancer Res. 2015 Nov 15;75(22):4949-59. doi: 10.1158/0008-5472.CAN-15-1215. Epub 2015 Nov 3.
Resistance to currently available targeted therapies significantly hampers the survival of patients with prostate cancer with bone metastasis. Here we demonstrate an important resistance mechanism initiated from tumor-induced bone. Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed that tumor cells resistant to cabozantinib, a Met and VEGFR-2 inhibitor, reside in a "resistance niche" adjacent to prostate cancer-induced bone. We performed secretome analysis of the conditioned medium from tumor-induced bone to identify proteins (termed "osteocrines") found within this resistance niche. In accordance with previous reports demonstrating that activation of integrin signaling pathways confers therapeutic resistance, 27 of the 90 osteocrines identified were integrin ligands. We found that following cabozantinib treatment, only tumor cells positioned adjacent to the newly formed woven bone remained viable and expressed high levels of pFAK-Y397 and pTalin-S425, mediators of integrin signaling.
2.A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.
Shimizu T1, Fukuoka K2, Takeda M2, Iwasa T2, Yoshida T2, Horobin J3, Keegan M3, Vaickus L3, Chavan A3, Padval M3, Nakagawa K2. Cancer Chemother Pharmacol. 2016 May;77(5):997-1003. doi: 10.1007/s00280-016-3010-1. Epub 2016 Mar 30.
PURPOSE: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting.
3.A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors.
Jones SF1, Siu LL2, Bendell JC3, Cleary JM4, Razak AR2, Infante JR3, Pandya SS5, Bedard PL2, Pierce KJ6, Houk B7, Roberts WG6, Shreeve SM7, Shapiro GI8. Invest New Drugs. 2015 Oct;33(5):1100-7. doi: 10.1007/s10637-015-0282-y. Epub 2015 Sep 4.
OBJECTIVE: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies.
