Antibody may present new way to treat AML

What researchers at the UC San Diego School of Medicine and Moores Cancer Center found was that cell surface molecule known as CD98 promotes AML. In general, CD98 controls how cells stick to one another, the university explains, and CD98 is known to play a role in the proliferation and activation of certain immune cells—importantly, CD98 levels are also known to be elevated in some solid tumors as well as being linked to poor prognosis.

Naturally, this knowledge led the UC San Diego researchers down the path of inhibiting CD98—IGN523, as it happens, is an anti-CD98 antibody—and using the antibody for this purpose showed a blocking of AML growth both in patient-derived cells and in mouse models. These results were published Oct. 27 in Cancer Cell.

Dr. Tannishtha Reya, a professor of pharmacology at the UC San Diego School of Medicine and Moores Cancer Center, led the study along with Dr. Mark Ginsberg, a professor of medicine at UC San Diego School of Medicine and Moores Cancer Center. Co-author Dr. Edward van der Horst, senior director at Igenica Biotherapeutics Inc., provided the anti-CD98 antibody IGN523.

“To improve therapeutic strategies for this disease, we need to look not just at the cancer cells themselves, but also at their interactions with surrounding cells, tissues, molecules and blood vessels in the body,” said Reya. “In this study, we identified CD98 as a critical molecule driving AML growth. We showed that blocking CD98 can effectively reduce leukemia burden and improve survival by preventing cancer cells from receiving support from the surrounding environment.”

Reya’s team and others have previously shown that leukemia cells interact with their surroundings in the body via molecules on their cell surfaces, and that these interactions can help the cancer cells divide, replicate and metastasize.

To determine CD98’s role in AML as part of this most recent study, Reya and her team engineered mouse models that lack the molecule. They found that the loss of CD98 blocked AML growth and improved survival. CD98 loss mostly seemed to spare normal blood cells, which the researchers said indicates a potential therapeutic window. Further experiments revealed that leukemia cells lacking CD98 had fewer stable interactions with the lining of blood vessels.

With that work established, the team moved on to actively delivering an inhibitor. As it happens, the Moores Cancer Center had been part of a Phase 1 clinical trial of Igenica’s humanized antibody IGN523, and so with that familiarity and access already in place, Reya and her colleagues tested the CD98 inhibitor in their own AML models.

The researchers found that IGN523 blocks CD98’s AML-promoting activity in both mouse models of AML and human cells in the laboratory. They also transplanted human patient-derived AML cells into mice and treated the recipients soon after with either IGN523 or with a control antibody. In the IGN523 group, treatment effectively eliminated AML cells, the researchers say, while among the mice in the control group saw AML expand more than a hundredfold.

“This study suggests that human AML can’t get established without CD98, and that blocking the molecule with anti-CD98 antibodies could be beneficial for the treatment of AML in both adults and children,” Reya said.

Moving forward, Reya and team are working to further define whether CD98 could be targeted to treat pediatric AML.

“Many of the models we used in this work were based on mutations found in childhood AML,” she said. “While many childhood cancers have become very treatable, childhood AML continues to have a high rate of relapse and death. We plan to work with pediatric oncologists to test if anti-CD98 agents can be effective against pediatric AML, and whether it can improve responses to current treatments. I think this is particularly important to pursue since the anti-CD98 antibody has already been through Phase 1 trials, and could be more easily positioned to test in drug-resistant pediatric AML.”

In other recent cancer news from UC San Diego, researchers at the UC San Diego School of Medicine and at the Mayo Clinic say they have provided the first evidence that the Hedgehog signaling pathway is central to the formation of gastrointestinal stromal tumors (GIST), which are frequently driven by the KIT oncogene. Results of the human study were recently published online in Oncotarget.

“Our new finding is a step forward in overcoming tyrosine kinase inhibitor resistance, a clinically significant problem in the management of GIST,” said Dr. Jason Sicklick, an associate professor of surgery at the UC San Diego School of Medicine and a surgical oncologist at Moores Cancer Center. “By knowing that Hedgehog signaling is altered in human GIST, and that it controls KIT expression, we may have found a way to turn the cancer off.”