50th Annual Meeting of the American Society of Clinical Oncology (ASCO):

Medullary Thyroid Cancer—Personalized Approach to Treatment

Researchers at the Icahn School of Medicine at Mount Sinai are evaluating a model in which fruit flies (Drosophila) are used to develop personalized cancer therapy for patients with metastatic medullary thyroid cancer.

Krzysztof Misiukiewicz, MD, and his colleagues from Mount Sinai, New York City, presented an overview of their work-in-progress on May 31, 2014, at the Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois.

The researchers explained that standard methods used to develop cancer therapies are beneficial to an average population of patients, yet responses to therapy can vary substantially between individual patients. Thus, the responses observed in a group of patients may not accurately predict a drug’s efficacy in an individual patient.

Another limitation of the current approach to therapy, the researchers added, is that targeted therapies often fail to account for the genomic complexity of individual tumors. Ideally, they noted, cancer therapy would be tailored to an individual’s specific tumor characteristics and would account for its complexity.

The personalized approach to cancer therapy being evaluated by Dr. Misiukiewicz and his colleagues involves three phases:

  1. Conducting a tumor genome analysis to identify relevant mutations
  2. Developing a personalized Drosophila model and screening for the most promising drugs for an individual patient
  3. Validating the findings in a mouse model

In the first phase, individual tumors will be genetically analyzed to screen for “tumor drivers”—alterations that promote tumor development.  These genetic alterations will then be incorporated into a Drosophila model. Up to 10 of a patient’s driver mutations can be incorporated into the flies, the researchers explained. By incorporating multiple alterations, this technique is able to capture the complexity of individual tumors.

After the personalized fly model is developed, a library of FDA-approved drugs will be tested in the genetically altered flies and researchers will observe the effects of the drugs to gauge their efficacy and toxicity. “This allows rapid and parallel screening of more than 800 drugs and subsequent drug combinations,” the researchers explained. Fly mortality will be used as a surrogate for drug toxicity and increased survival and improvements in eye or wing abnormalities caused by the tumor mutation will be used to assess efficacy. Outcomes from these studies may reveal a specific drug or drug combination that could best target a specific patient’s tumor characteristics.

An integral part of the approach involves a Multidisciplinary Tumor Board of Experts (MTBE) consisting of medical oncologists, pharmacologists, scientists, and other specialists. Based on the results from the fly studies, the MTBE will select one of five single agents or a combination of two or three drugs that show improved survival in the fly model. The researchers added that the MTBE will not intend to exceed the FDA label for any treatment plan, and will use synergy between drugs when possible to allow the use of lower doses. Based on various factors, including the pharmacology, toxicity, and cost of the regimen, and the patient’s individual circumstances, the best treatment option for that patient is selected.  Patients would then consent to receive personalized treatment on the study.

If possible, candidate drug combinations are tested in mouse xenograft tumor models. Moreover, if deemed necessary for patient safety reasons, novel combinations would first be evaluated in an animal model.

The researchers plan to evaluate the technique in 50 patients with metastatic medullary thyroid cancer, comparing the approach against the current standard treatment, cabozantinib, which demonstrated a 27% response rate in this patient population in a phase III trial, but also had substantial toxicity, the researchers noted.  They plan to evaluate whether their technique for personalized cancer therapy yields improved efficacy or, at least, less toxicity compared with cabozantinib.

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