Personal Experience Motivates Tian Zhang’s Work With AML Patients

It would be enough for a young physician-scientist to tackle the challenge of an extremely aggressive disease like acute myeloid leukemia (AML) while setting up a translational research program, but Tian Zhang, MD, PhD, is doing all that and more.

The new assistant professor of hematology has a young child with an exceptionally rare genetic disorder, but she has found a way for her son’s medical condition to motivate her in her work.

Zhang’s story begins after extensive basic science training, which led to a doctorate in cellular and molecular immunology. A desire to become a physician-scientist prompted her to attend medical school after earning her PhD. During a clinical rotation in year three she became aware of AML, which she says is “the most aggressive and most common kind of acute leukemia in the elderly.”

Zhang’s work with an AML patient showed her firsthand how dramatically the disease presents, as well as its very poor prognosis in most patients, with few treatment options. As part of a huge medical team following a complicated care plan for the AML patient, she was drawn to the disease both intellectually and emotionally, and she chose it for her clinical focus.

She didn’t know it at the time, but the bedside observations she made during both medical school and internal medicine residency would be of great value after she came to Stanford in 2014 for a hematology/oncology fellowship. As a fellow, she witnessed the work that hematology division chief Ravi Majeti, MD, PhD, was doing in the molecular characterization and therapeutic targeting of leukemia stem cells in AML.

“As a translational physician-scientist, I picked Dr. Majeti’s lab to do my postdoc work, and that’s where I took my bedside observations and created a preclinical model so we could study how an experimental treatment would affect human AML cells that were injected into mice,” she says.

Tian Zhang, MD, PhD, with her family

Motivated by Firsthand Experience

While in the midst of her postdoctoral work in Majeti’s lab, Zhang’s life took a dramatic turn when she learned that Isaac, her 4-month-old son, had spinal muscular atrophy (SMA) type 1 (also called Werdnig-Hoffmann disease). Children with SMA type 1, which is characterized by muscle weakness, are not expected to survive past early childhood.

“Obviously that was devastating,” Zhang says after a heavy sigh.

“People with the best of intentions gave me a lot of advice. Most said I should stop working and take care of my 2-year-old daughter and my sick baby, but I took a different track and immersed myself in my work.”

Zhang questioned whether that was a coping mechanism, but she believes it was more likely something else.

“I wasn’t much of a drug developer, to be

honest, before all of this happened to Isaac, but

when I personally witnessed what could come from

the type of research I was performing, I recommitted

myself to working on a rare disease”

“I wasn’t much of a drug developer, to be

honest, before all of this happened to Isaac, but

when I personally witnessed what could come from

the type of research I was performing, I recommitted

myself to working on a rare disease”

Groundbreaking Drugs

What happened—and what would have made a lifesaving difference to so many other babies before Isaac—was that he received three first-in-human drugs from the time he was 4 months old.

Just a year before Isaac’s birth, there was no treatment at all for SMA type 1. Then, the drug Spinraza was approved, and specialists prescribed it for Isaac to keep the disease from progressing.

The following year, Isaac received another breakthrough treatment—the first gene-replacement therapy to correct a genetic deficiency that was lethal in babies—which improved his condition.

And in August 2020, he received a third FDA-approved treatment, risdiplam, for SMA type 1, which furthered his improvement.

“I am a scientist at heart, and I know all the details of how long it takes for a drug to become available. So when I saw firsthand the direct benefit that Isaac received from people like me who were working on rare diseases and invested in drug development, it actually motivated me.

“I wasn’t much of a drug developer, to be honest, before all of this happened to Isaac, but when I personally witnessed what could come from the type of research I was performing, I recommitted myself to working on a rare disease,” Zhang says.

Investigator-Initiated Trial

Success from her preliminary research led her to suggest repurposing the drug enasidenib for use in a variety of blood disorders. For more than a year, she offered her concept to pharmaceutical companies before she reached an agreement with Celgene for the Bristol-Myers Squibb subsidiary to fund her investigator-initiated trial.

Typically a pharmaceutical company develops its own drugs, and the company will approach an institution like Stanford to perform a study because of the drug’s promise for patients with a particular disease. This is known as a sponsored trial.

“We have many sponsored trials in the division of hematology, but we didn’t have many of these home-grown or home-investigated projects like mine that clearly could have clinical benefit,” she explains.

AML Translational Research Program

Zhang, who was appointed assistant professor of hematology in March 2020, is now working to establish an independent research program focused on translational research in AML. She’s collaborating closely with Majeti and Gabriel Mannis, MD, another AML physician and assistant professor of hematology, to link the lab and the clinic.

“The goal of this translational program in AML is to bridge the gap between basic laboratory scientific research and clinical trials, but equally importantly to take observations from the clinic back to the lab. A major focus will be on developing investigator-initiated trials at Stanford,” Majeti says.

Leaders of the translational program see the chance to create a better pathway for scientists who work on the bench, allowing them to engage with clinicians who are on the front lines of patient care. The program should allow them to exchange ideas for new research projects that can be developed with the eventual aim of translating them back into the clinic.

As a physician-scientist who’s been working in the Majeti lab as well as taking care of patients both in the clinic and on the inpatient side, Zhang is uniquely positioned to help both sides.

“Tian is the perfect person to head up our AML translational research program, as she is accomplished in both laboratory research and clinical care of AML patients,” says Majeti. “She knows exactly how basic investigation can be applied in the clinic and equally how clinical observations can be explored in the lab.”

While Zhang is building her program for translational science with an initial focus on AML, the broader goal is to expand into other diseases. “In fact, as we develop the AML program, we are building infrastructure that can be applied to research for other kinds of blood disorders,” she says.

“I’ve become a huge advocate for drug development because I now realize the benefit that patients can derive from new treatments that are coming up through translational research,” she adds.

How is Isaac today?

“Now he is 3 and doing things that I never imagined he would do,” she says.