Novel Neutralizing Hedgehog Antibody MEDI-5304 Exhibits Antitumor Activity by Inhibiting Paracrine Hedgehog Signaling

Abstract

The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays. The antibody inhibited transcription of hedgehog target genes and osteoblast differentiation of C3H10T1/2 cells. We evaluated the activity of MEDI-5304 in vivo in model systems that allowed us to evaluate two primary hypotheses of hedgehog function in human cancer, paracrine signaling between tumor and stromal cells and cancer stem cell (CSC) self-renewal. MEDI-5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models. These findings support the conclusion that hedgehog contributes to tumor biology via paracrine tumor-stromal signaling but not via CSC maintenance or propagation. Finally, the only safety study finding associated with MEDI-5304 was ondontodysplasia in rats. Thus, MEDI-5304 represents a potent dual hedgehog inhibitor suitable for continued development to evaluate efficacy and safety in human patients with tumors harboring elevated levels of SHH or IHH. Mol Cancer Ther; 13(2); 386-98. Ó2013 AACR.

Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy

“…Recently, a novel neutralising antibody acting on SHH and IHH with low picomolar affinity has been reported (Ref. 261 ). Moreover, two small molecules have been described; robotnikinin binds to and inhibits SHH protein (Ref.…”

Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment

“…Numerous studies reported the benefit of stromal modulation in enhancing chemo sensitivity in mouse models of PDA (19, 38–41), however the use of Hh inhibitor in combination with chemotherapy agents in clinical trials with human subjects failed to show benefit (20–23). The importance of Hh and c-Met pathways as potential PDA targets has been well documented (25, 42–44).…”

“…Though, targeting both the HGF/c-Met and Hh pathways have shown promising results in pre-clinical studies, the benefits were not readily translated into to clinical trials with PDA patients (20–23). Thus, we investigated the mechanisms of resistance to the single inhibitor of HGF/c-Met or Hh pathway and determined if targeting both the HGF/c-Met and Hh pathways simultaneously would overcome the resistance to single inhibitor treatment and lead to a more potent anti-tumor effect in combination with chemotherapy treatment.…”

Synthetic Small Molecule Inhibitors of Hh Signaling As Anti-Cancer Chemotherapeutics

“…In the report, two antibodies showed high affinity for SHh, 3H8 and 6D7 (MEDI-5304), with K d values of 36 pM and 5 pM, respectively; however, only MEDI-5304 had affinity for IHh with a K d of 34 pM, and neither had affinity for DHh [123]. Both antibodies were also shown to inhibit pathway signaling in Hh-dependent MEFs with IC 50 values of 3.4 and 5.3 nM respectively.…”

“…Both antibodies were also shown to inhibit pathway signaling in Hh-dependent MEFs with IC 50 values of 3.4 and 5.3 nM respectively. MEDI-5304 also decreased tumor volume in a compliant model of colorectal cancer, which mimics Hh-mediated paracrine cancer, in a dose-dependent manner with a modest overall growth reduction of 30–50% [123]. …”