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Screening for Cures

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  • Title: Pediatric Oncologist, Dana-Farber Cancer Institute
  • Education: MD, Harvard Medical School, 1996
  • Recommended by: Gary Gilliland

Kimberly Stegmaier is a pediatric oncologist who, frustrated with the still-elementary state of drug treatments for rare cancers affecting her patients, decided to take drug discovery efforts into her own hands.

Take acute myelogenous leukemia, for instance. AML cells are immature cells that spread like wildfire in bone marrow, incapable of becoming normal blood cells. “We actually know a lot about the molecular pathogenesis of AML, yet the treatment is still extremely primitive,” Stegmaier says. Currently, the only curative treatment available for AML is high-dose chemotherapy, which has terrible toxicity and an unimpressive cure rate. “We have treatments that haven't changed much since the 1980s, so I felt like we really needed to have more of a focus on this in [academia] and we need to try and develop new tools to find lead compounds.”

Stegmaier considers the methods for doing small molecule screening rather limited due to their focus on either target-based screening or phenotype-based screening. Target-based screening requires prior knowledge of the particular biological process and the target of the process that needs to be altered. Phenotype screening is also limited because it requires new screens and assays every time there's a new and complex biological question, she says.

Along with Todd Golub of Dana-Farber and the Broad, Stegmaier developed a way to work around these limitations using gene expression-based high-throughput screening. In this method, gene expression signatures serve as surrogates for various biological states. She and her colleagues were aware that a particular subtype of AML had good cure rates when treated with differentiation agents such as ATRA (all-trans retinoic acid) and cytotoxic drugs. It followed that other subtypes of AML might respond just as well. They started out using microarrays to define one signature for AML and another for mature white blood cells. Next, they looked for compounds that would trigger a change from the expression signature of leukemia to that of a mature white blood cell. After screening more than 1,500 chemicals, they arrived at eight compounds that reliably induced the gene signature of mature cells. Much to their delight, one of the most promising compounds they identified was gefitinib, an FDA-approved drug already in use for lung cancer patients.

Stegmaier is now applying this same approach to identify compounds that could be used to treat Ewing sarcoma. “We've been very excited about how this actually seems to be working — in that the platform is feasible and we can go from a screen concept to a candidate for clinical trial,” she says.

Looking ahead

Stegmaier hopes that in the next 10 years, cancer treatment modalities will be based on specific genetic information and not a one-size-fits-all mentality. She would like to see researchers and clinicians thinking more in terms of therapies that target genetic regions instead of being concerned with merely what type of tumor or cancer they're faced with.

Publications of note

Stegmaier published a paper in a clinical hematology journal earlier this year entitled “Genomic approaches in acute leukemia.” This study traced how expression-based approaches to research have been used, with particular attention paid to hematologic malignancy. A signature-based screening approach, which eliminates the need to have prior knowledge, is also discussed.

The Nobel goes to…

Stegmaier hopes her legacy will be having a significant impact on disease through genetically targeted treatments that result in higher cure rates, better quality of life, and a longer relapse-free time. “That would be amazing ... to really have a clinical impact on disease,” she says.

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