Lasker Honors Discovery of Cell Adhesion Molecules

Three scientists who revealed how neighboring cells interact with each other and their surroundings have received this year's Albert Lasker Basic Medical Research Award. The trio will share the award's $250,000 prize.

The adhesion molecules these researchers discovered, known as integrins, are now understood to play a central role in tumor cell migration and invasion. Drug companies have advanced integrin inhibitors for various cancer indications, albeit with limited success.

But cancer biologists who study these signaling receptors expect to see renewed interest in integrins as therapeutic targets—and they credit the seminal contributions of the three Lasker awardees for helping to make that happen.

“The role these three amazing gentlemen have had in the field of integrins has been second to none,” says John Marshall, PhD, of Barts Cancer Institute in London, UK. “They are superstars and still continue to be.”

Integrins comprise a large family of 24 heterodimeric receptors that mediate interactions between all cell types and the extracellular matrix.

But none of that was known back in 1973 when Richard Hynes, PhD, now at the Massachusetts Institute of Technology in Cambridge, MA, and Erkki Ruoslahti, MD, PhD, now at Sanford Burnham Prebys in La Jolla, CA, independently discovered the first known ligand of integrin receptors.

This protein, later named fibronectin, was lost in oncogenically transformed cells, and its absence helped explain why cancer cells, unlike normal cells, tend not to stick to the laboratory dishes in which they are cultured.

Hynes would go on to clone the first integrin-encoding gene in 1986 and help link integrin–matrix interactions to cancer growth. Ruoslahti in 1984 also identified the three-amino-acid sequence within integrins that underpins their attachment to cells.

Meanwhile, Timothy Springer, PhD, of Harvard Medical School in Boston, MA, was studying immune cell binding of target molecules when, in the early 1980s, he characterized some of the first integrins involved in adhesion reactions. His immunity-focused work also formed the basis of multiple approved therapeutics, including an α4β7 integrin antagonist now marketed for inflammatory bowel disease.

Although there are several integrin-targeting drugs available for inflammatory conditions, plus others prescribed for combatting thrombosis, none have yet garnered approval for treating cancer. The one-time oncology candidates were the αvβ3 inhibitors cilengitide (Merck KGaA) and etaracizumab (MEDI-522; Abergrin; MedImmune), but neither provided a survival benefit in mid- to late-stage trials.

Part of the problem with those early development efforts stemmed from an in­complete understanding of integrin function. Both cilengitide and etaracizumab were initially touted as antiangiogenesis agents. But as Hynes and others later showed, integrins often serve as negative regulators of tumor vascularization, so targeting them may have inadvertently promoted vessel growth rather than having the opposite effect as intended.

“There's a lot of biology that we just didn't appreciate at the time,” says David Cheresh, PhD, of the University of California, San Diego, who discovered the murine precursor to etaracizumab in the late 1980s. Emboldened by 30 years of additional research, Cheresh has since created a new αvβ3-targeted antibody designed to arm tumor-associated macrophages to eliminate αvβ3-positive tumor cells.

Integrins “remain as important as ever,” Cheresh says, “and if you deliver the appropriate inhibitors at the right time, it's certainly possible to interfere with the communication between cancer cells and their microenvironment, and thereby change the biological behavior of the cells in question.”

With a fuller picture of integrin activities—and with the added recognition of their importance, thanks to the Lasker nod—he and others expect more drug companies to revisit the therapeutic opportunities afforded by integrin inhibition. “I think we're going to see a resurgence of targeting integrins,” Marshall says. –Elie Dolgin

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