by ecancer reporter Janet Fricker

A drug targeting a novel molecular pathway involved in angiogenesis could provide a new treatment option in advanced cancer, reports an abstract at the 22^nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (16 to 19 November,  Berlin, Germany).

The new drug ACE-041 was designed specially to inhibit the activin receptor-like kinase (ALK-1) receptor that is transiently expressed on arterial endothelial cells during development. ALK-1 signalling plays a pivotal role in the maturation phase of angiogenesis and is therefore critical to vasculature development.

 The connection of ALK-1 molecular pathway with angiogenesis was made following the discovery that mutations in the gene for the  ALK-1 receptor  caused a condition known as hereditary haemorrhagic telangiectasia 2 (HHT2),  characterised by impaired formation of capillary beds and results in red markings on the skin. Acceleron Pharma, a biotechnology company in Cambridge, Massachusetts (USA) designed ACE-041 to inhibit ALK-1 signalling. In preclinical studies, ACE-041 inhibited blood vessel formation induced by multiple angiogenesis factors, including VEGF and FGF, even though ACE-041 does not bind to these molecules.

“Since ALK-1 is only transiently expressed on proliferating endothelial cells, in contrast to the VEGF receptors which are constitutively expressed on endothelial and other cells, it may be a more selective target for the inhibition of angiogenesis,” suggested Sunil Sharma, from the University of Utah, Salt Lake City (USA) who led the study.

In the phase 1 study, 25 patients with a range of  advanced solid tumours (such as multiple, myeloma, non-small cell lung cancer (NSCLC), head and neck cancers and carcinoid tumours) that had spread to other parts of the body were given ACE-041 via subcutaneous injection, at a starting dose was 0.1 mg/kg escalating to 4.8 mg/kg subcutaneously.

Results show that one patient with head and neck cancer had a partial response, three patients who had previously progressed on chemotherapy and/or  anti-VEGF therapy had stable disease and several other patients have had strongly positive response, shown by FDG-PET scans. Preliminary adverse effects, which were generally of low grade toxicity,  included nausea, fatigue, anorexia, headache, fever and vomiting,

Commenting on the results Sharma said that it had been encouraging to see so many signals of efficacy, particularly in the study population of end-stage cancer patients, who had already been treated with and become refractory to multiple lines of standard therapy. “It’s also important to note that while we have demonstrated significant activity with ACE-041 monotherapy in this study, we might expect to see even more efficacy in future studies with ACE-041 used in combination with other therapies,” he said, adding that since ACE-041 inhibits angiogenesis in a completely different way it may have synergistic efficacy with VEGF-inhibitors and be effective in patients who have developed resistance to VEGF-inhibitors.

Reference

S Sharma, JC Bendell, H Hurtitz et al. Angiogenesis, metastasis and inhibitors. A Phase 1 dose escalating study of ACE-041, a novel inhibitor of ALK-1 mediated angiogenesis in patients with advanced solid tumors. Abstract  no 465. EORTC-NCI-AACR Symposium.