Identification of Mechanisms of Resistance to Trametinib Monotherapy in PAX-fusion Negative Rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and can be divided into two main subtypes: embryonal and alveolar. The prognosis of patients with metastatic RMS at diagnosis is dismal and novel treatment approaches, such as the use of targeted agents, are needed. Genetic studies of RMS tumors showed that the key event in embryonal RMS development is a cancer-causing mutation in one of the RAS genes. While drugs that inhibit RAS directly are unavailable, targeted agents designed to inhibit the enzymes that are activated by RAS are in clinical use. Previously, we have shown that trametinib, an inhibitor of a RAS-dependent enzyme, MEK, is effective in cell culture and animal models of embryonal RMS. The anti-tumor response to trametinib is short-lived, however, because the RMS cells are able to circumvent the action of the single targeted agent.
The goal of the experiments is to identify the ways in which the RMS cells evade the action of trametinib so that we might design more effective therapies. We propose the use of several complementary unbiased approaches that employ newly designed technologies to identify mechanisms of trametinib resistance in embryonal RMS.
"The clinical efficacy of using targeted therapy for cancers driven by the Ras oncogene, like Pax-fusion negative rhabdomyosarcoma, is limited by the cancer's ability to become resistant to the targeted agent. Thanks to this award from Alex's Lemonade Stand Foundation, I will be able to investigate how Pax-fusion negative rhabdomyosarcoma becomes resistant to a targeted therapeutic agent, the MEK inhibitor, trametinib. Results of these experiments will enable us to evolve trametinib therapy to provide meaningful clinical benefit for patients with Pax-fusion negative rhabdomyosarcoma." - Marielle Yohe, MD/PhD