How Patient Genetics is Shaping a New Class of Leukemia Inhibitors

8 November 2012 by Nathalia Holt, posted in Uncategorized

Rebecca was 8 months pregnant with their first child when her husband started acting strangely. He began to experience a debilitating stomach pain. He shrugged off the pain as the flu, intent on focusing on his wife and soon-to-be daughter. Conceiving a child had not been easy for the couple. Now, here they were, on the verge of becoming parents; about to get the family they wanted.

Rebecca, however, was becoming increasingly uneasy about her husband who, in all their years together, was rarely sick. George, 6’2”, 190 lbs. and a marine, never seemed to feel pain at all. To see him doubled over in agony, crying, made her afraid. She worried that he had appendicitis or perhaps gallbladder disease.  She wanted him to go to the hospital but he refused. George wanted to be there for his wife. He didn’t want to cave in to his own medical need.

As George fought his battle internally, Rebecca fought on the outside. After 11 hours in labor, without pain medication, their baby was born by emergency C-section. A little girl entered their lives. As Rebecca recovered from her labor and surgery, charged with not lifting anything, she found herself frustrated with her husband. “I need help,” she would tell him. Her husband’s mysterious illness was not going away as they had both hoped it would. When their newborn was 2 weeks old they would learn why: George had acute myeloid leukemia or AML. To make matters worse he also had markers for FLT3, a poor prognostic marker.

AML is a sneaky cancer. It begins in our bone marrow. The bone marrow is the cradle for developing blood cells, playing a key role in our response to infection. When the developing lymphocytes within the bone marrow are damaged, so is our ability to fight disease. This means the survival rate for AML is low: it dips below 17% at five years, although varies between subtypes and the age of the patient. Survival rates are lower for a subset of people who have specific mutations in the FLT3 gene.

FLT3, a protein, lies on the surface of hematopoietic stem cells. This special group of stem cells differentiates, forming all the cells of our immune system. FLT3 helps regulate that differentiation, playing a key role in how these stem cells expand and form our mature blood cells. Our thinking is that mutations in the FLT3 gene lead to higher amounts of the protein on stem cells. This, in turn, leads to wildly dividing cells. Like a horse without a bridle, the stem cell has lost its ability to control itself. Cells proliferate nonstop: the hallmark of cancer. But how can we use our understanding of mutations in this gene to develop new therapies? One researcher has put all her effort into figuring this out: Dr. Catherine Choy Smith.

Dr. Catherine Choy Smith and her family

Cathy graduated from medical school not knowing exactly what she wanted to do. In 2003 she was a second year internal medicine resident in Boston, working at the Dana Farber Cancer Institute. In the middle of the night, one patient would greatly influence her career: a young man with AML. A man who, like George a decade later, had a young daughter he loved. The complications were building. The patient had relapsed after receiving a stem cell transplant and now had tumor lysis, a condition where dying cells release electrolytes into the bloodstream, shutting down the kidneys. The attending doctor in charge was called, his advice, given over the phone was stark: “He just has really bad leukemia Cathy and there’s nothing else you can do.” Recalling that night Cathy remembers thinking “I don’t ever want to hear those words again.”

What came next was a transformative period in oncology. Imatinib was born: the first of a new class of drugs that inhibit a receptor characteristic of cancer cells, rather than all dividing cells. The receptor it targets is in the same group as FLT3. It was an exciting time for a young physician thinking about oncology. Cathy describes this time in her life as a “perfect storm” where her experiences with patients with AML lined up perfectly with the advent of a new class of inhibitors.

Cathy started her research career in Neil Shah’s lab at UCSF. In her own words she “became a doctor to be a doctor.” That is, to see patients. At the same time she was drawn to research. She saw working in the lab as “similar to taking vitamins, it would be good for me.” Her first 6 months in the lab were slow; she worked on a project that went nowhere. She then went on maternity leave with her daughter. When she came back opportunity was in the air. Her real interest, FLT3 inhibitors, was a potential new project.

FLT3 inhibitors had so far been a clinical failure. No one knew if the problem lay in the ability of the drugs to inhibit the gene or if the mutations themselves weren’t that important to the progressing cancer.  Cathy, with her mentor, uncovered the development of drug resistant mutations from patients who relapsed on the inhibitors. Their data, published this year in Nature, convinced the pharmaceutical company Plexxikon that specific mutations in FLT3 represent a viable clinical target. With their collaborators, they’re now conducting a Phase I/II clinical trial on a new type of FLT3 inhibitor, currently named PLX3397. While the clinical trial is still in early days, Cathy is hopeful. She relishes her role as physician scientist. She feels it lets her “offer something to people they can’t get anywhere else.” Not only do they get a lasting bond with a caring oncologist, they also get the latest medicine science has to offer. Cathy sees herself as “living the dream.” Although that dream sometimes means holding back tears as she talks to her patients.

Rebecca can relate to the importance of finding a caring oncologist. She’s had trouble finding someone who’s focused on her husband and his disease. Despite her education, she has a Master's degree in psychology, she finds it difficult to find information about FLT3 and what it ultimately means for AML. George has taken part in the FLT3 inhibitor clinical trial, no small feat as federal law makes it difficult for military personnel to participate in clinical trials. Rebecca is a powerful advocate for her husband, making sure he gets the best care he possibly can. When she looks at her 5-month-old daughter, who’s just starting to crawl, she becomes worried. She doesn’t want her husband to miss out on all her firsts.

George has been lucky enough to find a bone marrow donor, having needed a stem cell transplant, which he received just recently. Talking about the donor, a stranger, Rebecca gets emotional. When her husband walks their daughter down the aisle on her wedding day, Rebecca wants the “donor to be there, walking her down the aisle too.” Through the ups and downs of their medical journey Rebecca is particularly grateful to medical researchers. She worries that those that work at the bench “don’t get the accolades they need.” She knows that her husband’s therapies wouldn’t be possible without people like Cathy Smith and all the many scientists out there. She carries an important message to those researchers with little patient interaction: keep doing what you’re doing; work like someone’s life depends on it, because it does.


Patient/family names have been changed to protect their privacy. However, Rebecca is happy to speak with interested researchers/science communicators. Email me for contact info:

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