“Our previous research had shown that 84% of pancreatic cancer patients have high levels of αvβ6 on their cancers,” John Marshall, the study’s senior author, explained in a statement. “Foot-and-mouth-disease virus uses αvβ6 as a route to infect cattle, as the virus binds to this protein on a cow's tongue. By testing pieces of the protein in the virus that attaches to αvβ6, we've developed a route to deliver a drug specifically to pancreatic cancers.”
Researchers linked the αvβ6-specific peptide to the payload tesirine, a drug developed by Spirogen, which was bought by AstraZeneca in 2013 in a $440 million deal.
Marshall and colleagues tested their peptide-drug conjugate, now dubbed SG3299, in cancer cells grown in lab dishes and in mouse models of pancreatic cancer. The drug killed off cancer cell lines, while a non-αvβ6-targeting tesirine combo failed to bind to them, the team reported.
Cancer cells can form little spheres in lab dishes that are believed to help enrich the stem cell-like properties in pancreatic cells, which have been linked to tumor metastasis and development of treatment resistance. In patient-derived xenografts, the researchers found that SG3299 significantly reduced the number of spheres.
In mice, the drug also showed promising results. When used at a small dosage given three times a week, SG3299 significantly reduced the size of tumors. At an increased strength given bi-weekly, the drug eliminated tumors in four out of five mice and left just one small tumor in the other animal. The tumor reduction also translated into survival benefits. Mice that got SG3299 were all alive after 130 days, whereas those given avb6-specific peptide alone or a non-αvβ6-targeting drug only posted median survival 62.5 days and 95 days respectively.
The idea of delivering highly potent drug right to the cancer target resembles that of antibody-drug conjugates (ADCs), a technology that’s already been applied in FDA-approved anticancer therapies such as Roche’s Kadcyla and Daiichi Sankyo and AstraZeneca’s Enhertu. Tesirine has also been used to design ADCs, perhaps most notably in AbbVie’s failed small-cell lung cancer med Rova-T (ravalpituzumab tesirine).
Swiss biotech ADC Therapeutics is backed by AstraZeneca and recently withdrew a potential $200 million initial public offering. The company’s lead candidates, ADCT-402 and ADCT-301, also use tesirine in their constructs and they’re under clinical testing in blood cancers.
Marshall’s team hopes targeting αvβ6 with their peptide-drug conjugate could become a new weapon against pancreatic cancer.
“One advantage of targeting αvβ6 is that it is very specific to the cancer because most normal human tissues have little or none of this protein,” he said. “So we're hopeful that, if we can develop this into an effective treatment for pancreatic cancer, it would have limited side effects.”
Moving forward, the team plans to further test SG3299 in more complex mice models to explore the drug’s ability to stop cancer metastases before starting clinical trials.