Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers. Our group previously developed a series of orally bioavailable small molecule activators of PP2A, termed SMAPs. We now report that SMAP treatment inhibited the growth of KRAS-mutant lung cancers in mouse xenografts and transgenic models. Mechanistically, we found that SMAPs act by binding to the PP2A Aα scaffold subunit to drive conformational changes in PP2A. These results show that PP2A can be activated in cancer cells to inhibit proliferation. Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other diseases and represents an advancement toward the development of small molecule activators of tumor suppressor proteins

Medial swivel dislocation of the talonavicular joint

Medial swivel dislocation, a variant of subtalar dislocation is uncommon. A 35 years old male presented after 6 weeks old injury to left ankle following motor cycle accident. He had pain, swelling around ankle and was unable to bear weight on left foot. Clinical examination revealed diffuse swelling and tenderness in mid foot region. His plain X rays and CT scan showed talonavicular dislocation with compression defect of the head of the talus. He was treated by open reduction and K-wire fixation. At 32 months follow up foot was painless, stable with normal range of ankle and subtalar motion