Abstract
Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance and relapse; signaling via insulin-like growth factor (IGF) has been implicated in castration-resistant prostate cancer. We evaluated the antitumor activity of xentuzumab (IGF ligand-neutralizing antibody), alone and in combination with enzalutamide, in prostate cancer cell lines (VCaP, DuCaP, MDA PCa 2b, LNCaP, and PC-3) using established in vitro assays, and in vivo, using LuCaP 96CR, a prostate cancer patient-derived xenograft (PDX) model. Xentuzumab + enzalutamide reduced the viability of phosphatase and tensin homolog (PTEN)-expressing VCaP, DuCaP, and MDA PCa 2b cells more than either single agent, and increased antiproliferative activity and apoptosis induction in VCaP. Xentuzumab or xentuzumab + enzalutamide inhibited IGF type 1 receptor and AKT serine/threonine kinase (AKT) phosphorylation in VCaP, DuCaP, and MDA PCa 2b cells; xentuzumab had no effect on AKT phosphorylation and proliferation in PTEN-null LNCaP or PC-3 cells. Knockdown of PTEN led to loss of antiproliferative activity of xentuzumab and reduced activity of xentuzumab + enzalutamide in VCaP cells. Xentuzumab + enzalutamide inhibited the growth of castration-resistant LuCaP 96CR PDX with acquired resistance to enzalutamide, and improved survival in vivo The data suggest that xentuzumab + enzalutamide combination therapy may overcome castration resistance and could be effective in patients who are resistant to enzalutamide alone. PTEN status as a biomarker of responsiveness to combination therapy needs further investigation.
Highlights
Worldwide, prostate cancer is the second most commonly diagnosed cancer and the fifth most common cause of cancer-related death among men, with 1,276,106 new cases and 358,989 deaths estimated in 2018 [1]
The notion that addition of xentuzumab enhanced the activity of enzalutamide in three phosphatase and tensin homolog (PTEN) wild-type cell lines but not in PTEN-null LNCaP cells prompted us to investigate the effect of PTEN knockdown in VCaP cells
Our in vitro data show that xentuzumab þ enzalutamide reduces proliferation more effectively than either treatment alone in PTENpositive prostate cancer cells
Summary
Prostate cancer is the second most commonly diagnosed cancer and the fifth most common cause of cancer-related death among men, with 1,276,106 new cases and 358,989 deaths estimated in 2018 [1]. The growth and survival of prostate cancer cells is androgen dependent, and androgen deprivation therapy is standard treatment for advanced and metastatic prostate cancer [2]. Most men relapse within 2–3 years despite achieving castrate serum androgen levels, and progress to a castration-resistant state that precedes lethality [3, 4]. The androgen receptor (AR) is an important mediator of castration resistance [3], as is the AR splice variant, AR variant 7 Liu: Mustang Bio, Inc. Worcester, Massachusetts; and current address for T.
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