Targeting the protein EphA3, which is found in the microenvironment of solid cancers, has been found to have antitumor effects by an international team of scientists. This antibody-based approach may be a suitable candidate treatment for solid tumors as EphA3 is only present in normal organs of the body during embryonic development but is expressed in blood cancers and solid tumors.
The team, led by the late Martin Lackmann, from the School of Biomedical Sciences at Monash University (Melbourne, Australia) and Andrew Scott from Ludwig Cancer Research, discovered that tumor cells can thrive even if they do not have this molecule by recruiting and taking advantage of supporting EphA3-containing cells in the tumor microenvironment.
First author, Mary Vail, Monash Department of Biochemistry and Molecular Biology commented: “The tumor cells send out signals to the surrounding area and say: ‘We need a blood supply and a foundation upon which to spread’.”
“We have shown that EphA3 expressing stromal stem cells, which are produced by the bone marrow, form cells that support and create blood vessels in tumors,” Vail continued.
Treatment with an antibody against EphA3 (chIIIA4) was demonstrated to significantly slow tumor growth. Blood vessels were damaged by the antibody, which disrupted the stromal microenvironment so compromising the cancer cells ‘life-support’ resulting in their death.
“In addition, we screened various tumors from patient biopsies — sarcomas, melanomas as well as prostate, colon, breast, brain and lung cancers — and confirmed EphA3 expression on stromal cells and newly forming blood vessels,” Scott explained.
“Our research findings indicate that the tumor microenvironment is important, and monoclonal antibodies against EphA3 are one way to target and kill a variety of solid tumors as well as blood cancers.”
The anti-EphA3 antibody KB004 is currently being tested in a multicenter Phase I/II clinical trial by KaloBios Pharmaceuticals (CA, USA). The trial is being carried out in Melbourne and the US in patients with acute myeloid leukemia, myelodysplastic syndromes and myelofibrosis; all of which are Eph3A-expressing blood malignancies.
It was said by Vali, who collaborated with Lackmann – her former mentor – on the project for 10 years, that this research presented his life’s work.
“Martin was dedicated to helping people, and believed that KB004 was a promising therapeutic approach. He rightly anticipated that it would be well-tolerated in cancer patients, and through this collaborative project, his pioneering research has progressed to clinical trials and potentially new treatments for cancer patients,” Vail said.
Source: M. E. Vail, C. Murone, A. Tan, L. Hii, D. Abebe, P et al. Targeting EphA3 Inhibits Cancer Growth by Disrupting the Tumor Stromal Microenvironment. Cancer Research, 74 (16): 4470 (2014); Monash University press release