Efficacy of Ganitumab (AMG 479), Alone and in Combination with Rapamycin, in Ewing's and Osteogenic Sarcoma Models

Abstract

Ewing's and osteogenic sarcoma are two of the leading causes of cancer deaths in children and adolescents. Recent data suggest that sarcomas may depend on the insulin-like growth factor type 1 (IGF-1) receptor (IGF1R) and/or the insulin receptor (INSR) to drive tumor growth, survival, and resistance to mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We evaluated the therapeutic value of ganitumab (AMG 479; C 6472 H 10028 N 1728 O 2020 S 42 ), an anti-IGF1R, fully human monoclonal antibody, alone and in combination with rapamycin (mTORC1 inhibitor) in Ewing's (SK-ES-1 and A673) and osteogenic (SJSA-1) sarcoma models. IGF1R was activated by IGF-1 but not by insulin in each sarcoma model. INSR was also activated by IGF-1 in the SJSA-1 and SK-ES-1 models, but not in the A673 model where insulin was the preferred INSR ligand. Ganitumab significantly inhibited the growth of SJSA-1 and SK-ES-1 xenografts; inhibition was associated with decreased IGF1R and Akt phosphorylation, reduced total IGF1R and bromodeoxyuridine detection, and increased caspase-3 expression. Ganitumab inhibited rapamycin-induced IGF1R, Akt, and glycogen synthase kinase-3␤ hyperphosphorylation in each sarcoma model. However, ganitumab in combination with rapamycin also resulted in a marked increase in INSR expression and activity in the SJSA-1 and A673 models. The in vivo efficacy of ganitumab in the two ganitumab-sensitive models (SJSA-1 and SK-ES-1) was significantly enhanced in combination with rapamycin. Our results support studying ganitumab in combination with mTORC1 inhibitors for the treatment of sarcomas and suggest that INSR signaling is an important mechanism of resistance to IGF1R blockade.

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

“…Decreased production of IGF-1 by inhibition of GHRH-R by GHRH antagonists occurs in vivo (33). Notably, the IGF-1 signaling axis is dysregulated in various cancers, including prostate cancer (34)(35)(36)(37).…”

Safety and Pharmacokinetics of Ganitumab (AMG 479) Combined with Sorafenib, Panitumumab, Erlotinib, or Gemcitabine in Patients with Advanced Solid Tumors

“…Ganitumab (AMG 479) is a fully human immunoglobulin G1 monoclonal antibody against IGF1R that inhibits tumor cell proliferation, promotes tumor cell death, and causes regression of established tumor xenografts (23,24). In a phase 1, first-in-human study, ganitumab as monotherapy had acceptable toxicity up to the maximum tested dose (20 mg/kg i.v.…”

Pharmacodynamic Modeling of Sequence-Dependent Antitumor Activity of Insulin-like Growth Factor Blockade and Gemcitabine

“…Consequently, several small molecule inhibitors and antibodies targeting IGF system are being developed with clinical responses seen in phase I and II trials (1)(2)(3). The IGF system is composed of the circulating ligands, insulin-like growth factor-I (IGF-I), IGF-II, and insulin; multiple receptors, IGF-IR, IGF-IIR, insulin receptors (IR), and hybrid receptors composed of IGF-IR and IR; and binding proteins (4).…”