Researcher develops cancer drug in memory of girl who died of neuroblastoma

Linda H. Malkas, PhD, remembers the day a photograph for a newspaper changed her life.

“I was the Vera Bradley chair for oncology at Indianapolis University School of Medicine, and I was doing breast cancer work,” Malkas, who now serves as dean of translational science and M.T. and B.A. Ahmadinia professor in molecular oncology at City of Hope, told Healio. “I had started out as a biochemist and molecular biologist and was interested in DNA replication and repair. I probably would have kept doing that for the rest of my life. Then I met Steve Healey, who showed up to take my photo for a newspaper article.”

Running a bit late for the photo assignment, Healey explained to Malkas that his daughter, Anna, was at Riley Hospital for Children. At age 8 years, Anna had been living with neuroblastoma for almost half of her life.

“Steve took a beautiful photo of me, and as he packed up his camera and equipment, he said, ‘Dr. Malkas, what is it you do?’ I looked at him and said, ‘Come here,’” Malkas said. “We sat in front of my computer, and for 2 hours, I gave him the only thing I could: my data.”

The two wished each other luck, and that might have been the end of the story. However, Malkas kept tabs on Healey and his family. She learned that Anna died of her disease not long after she and Steve met.

When Healey contacted her sometime later asking to visit Malkas at her laboratory, he wasn’t sure she would remember him.

“I said, ‘Oh, I remember you,’” Malkas said.

From inspiration to execution

Malkas hosted Healey at her laboratory for an afternoon, introducing him to each of her young employees and discussing the group’s work.

“It was a wonderful afternoon,” Malkas recalled. “Each of my employees got up and talked for 5 to 10 minutes about what they do. Then we went down to my lab, and he did something that changed the course of my life.”

Healey handed Malkas a check for $25,000 from himself and his wife, Barbara.

“He said, ‘Dr. Malkas, we know you do all this great work on breast cancer, but if you could do something for neuroblastoma, it would mean the world to Barbara and me,’” she said. “This set the whole thing in motion.”

Malkas spoke with her husband and collaborator, Robert Hickey, PhD, associate professor in City of Hope’s department of cancer and molecular medicine, about what they had learned about DNA replication in cancer cells. The two had identified a protein that is altered in cancer cells and correlates with a change in replication fidelity.

“I asked him, ‘Do you think we could make a drug against this protein, and possibly provide a less toxic treatment to these patients?’ I was completely starry-eyed; I had no training in this. And he said, ‘Sure.’”

Malkas’ next challenge: Find a medicinal chemist to help her make this idea a reality.

She spoke with several laboratories, but none could commit the necessary time and resources. Then she received a phone call from City of Hope, asking to meet with her and discuss the possibility of bringing her to their institution.

“We talked about everything they had done during the prior 8 years,” she said. — “They had set up everything I was looking for — current good manufacturing practices facilities and the people for the regulatory process and drug discovery. They had developed the talent. Everything was there.”

When City of Hope offered Malkas a position as director of translational research, she didn’t hesitate.

“I said yes, and the first people I told were Steve and Barbara Healey,” she said. “When I told Barbara, she started to cry. She said, ‘I know if you go, something wonderful is going to happen.’”

‘I came with a target’

When Malkas began her work at City of Hope in 2011, she did so with a mandate: to develop a molecule that would shut down the protein she and Hickey had identified, proliferating cell nuclear antigen (PCNA).

“I came with a target, one that had never been drugged before,” she said. “This protein interacts with at least 200 partners in the human cell, and those are not just DNA replication repair but apoptosis, transcription and cell cycle regulation. I thought if I could shut down the form of this protein that is expressed in cancer cells, I could block not just one pathway, but a variety of pathways.”

Malkas likened this to an airport hub with multiple planes coming into terminals.

“In Indianapolis, the one way you could shut down U.S. air traffic would be with a good snowstorm,” she said. “I thought if I could make a molecule that was like a snowstorm, I’d be able to block those planes from getting into those terminals.”

Malkas and Hickey developed one molecule that came close but was not successful when put into human serum. All the while, the Healey family was never far from Malkas’ mind.

“All I could think of was that I had made a promise to this family,” she said. “I kept thinking of Anna. I needed to do something.”

When Malkas and Hickey created the molecule, she named it AOH1996, which stands for Anna Olivia Healey, the child’s full name, and 1996, her birth year.

“We sent the molecule to the NIH and when they tested it in their NCI-60 cell line panel, it had activity across the board,” she said. “If I hadn’t come to City of Hope, I don’t think I would have been able to create this drug.”

Anna’s legacy

City of Hope has initiated the phase 1 clinical trial of AOH1996, and the institution has announced that the first patient to receive the drug is doing well.

The trial, which will test the safety of AOH1996 in people with recurring solid tumors, is expected to continue for the next 2 years. Although originally studied for neuroblastoma, the pill has shown efficacy in preclinical studies treating cells from breast, prostate, brain, ovarian, cervical, skin and lung cancers.

Malkas said she and her colleagues are investigating other potential indications for AOH1996, including as a combination treatment for patients who may have difficulty tolerating cisplatin or other chemotherapy drugs.

“A lot of the time, you have to cut back on some of these drugs, because the patients’ systems just can’t take it,” she said. “So, I am thinking that this is probably where the home for this molecule will be — in combination treatment.”

Malkas praised her colleagues at City of Hope, including the trial’s principal investigator, Vincent Chung, MD, who she said brings a “quiet strength” to his role of leading the phase 1 trial, and Daniel Von Hoff, MD, who is serving as an advisor on the trial.

“The day I got the [FDA] approval, which was maybe 2 days before Christmas, I emailed Dr. Von Hoff about it. I thought of it as my Christmas present,” she said. “He emailed me back, saying, ‘I want you to know what you’ve done,’ and he sent me a chart with 350 steps on it, from the naming of the compound to getting the first patient. I was on something like step 348. I said, ‘Dan, I’m so glad I didn’t see this before.’”

Perhaps even more meaningful — the email response Malkas received from the Healey family when she notified them of the approval.

“They sent the most beautiful comments back, “she said. “I was so moved by this family who has suffered such a loss. They said, ‘Now Anna has a legacy.’”

For more information :

Linda H. Malkas, PhD, can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010.