Cancer

Patient sample, cell culture and mouse studies suggest inhibiting activin signaling could enhance the efficacy of platinum-based chemotherapy in KRAS-mutant lung cancer. In 59 patients with stage IV non-small cell lung cancer (NSCLC) lacking activating mutations in EGFR or anaplastic lymphoma kinase (ALK) and receiving platinum-based chemotherapy, high tumor levels of three activin signaling components -- activin A, MSTN and GDF11 -- were associated with poor progression-free survival. In four KRAS-mutant human platinum-resistant NSCLC cell lines, a tool compound dual inhibitor of the GDF11 receptors ACVR1B and TGFBR1 plus carboplatin decreased viability compared with carboplatin alone. In a xenograft mouse model of KRAS-mutant NSCLC, the ACVR1B/TGFBR1 inhibitor plus carboplatin decreased tumor volume and increased survival compared with either agent alone. Also in the model, FST -- an inhibitor of activin A, MSTN and GDF11 -- plus carboplatin reduced tumor sizes to undetectable levels in 7 of 10 treated mice and increased survival. In another xenograft mouse model of KRAS-mutant NSCLC, a patient-derived xenograft (PDX) mouse model of KRAS-mutant NSCLC and a syngeneic mouse model of Lewis lung adenocarcinoma (LLC), FST plus carboplatin increased survival. Next steps include starting Phase I testing of FST in NSCLC and testing FST in animal models of other head and neck, bladder and other cisplatin-treated tumors.

Roche has the MSTN inhibitor RG6206 in Phase III testing for Duchenne muscular dystrophy (DMD)...