2013 OSU Molecular Life Sciences
Interdisciplinary Graduate Programs Symposium

 

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Poster number 74 submitted by Christopher Walker

KPT-330-mediated XPO1 inhibition displays preclinical and clinical efficacy in Ph+ leukemias through inhibition of XPO1 target trafficking.

Christopher J. Walker (CCC, Ohio State), Joshua J. Oaks, Ramasamy Santhanam, Paolo Neviani, Jason G. Harb, (CCC, Ohio State), Gregory Ferenchak, Justin J. Ellis, Guido Marcucci, Ramiro Garzon, (CCC, Ohio State), Yosef Landesman, Sharon Shacham, Michael Kauffmann (Karyopharm Therapeutics, Natick MA), Allistair Reid, Drogana Milojkovic, John M. Goldman, Jane Apperley (Haematology, Hammersmith Hospital, Imperial College London), Carrie L. Smith, Nash Gabrail (Garbrail Cancer Center, Canton OH)

Abstract:
As current treatments fail to induce long-term response in CML blast ciris (BC) and Philadelphia-chromosome positive (Ph+) ALL, novel therapies are necessary. We hypothesize that XPO1, which facilitates nuclear protein export, may contribute to Ph+ leukemogenesis, because it regulates cellular proliferation/survival, and many of the proteins it exports are tumor suppressors and leukemia-relevant proto-oncogenes (e.g. hnRNA A1, ABL1 and SET).
We found that compared to normal progenitors, XPO1 protein levels were elevated in CML and Ph+ ALL blasts. XPO1 inhibition by KPT-330 induced apoptosis and decreased clonogenic potential of CML and ALL blasts, but not normal progenitors, and treatment significantly increased survival of leukemic mice, 50% of which were alive after 16 weeks of treatment.
Mechanistically, KPT-330 treatment led to a nuclear accumulation of tumor suppressors (p53, p21, FOXO3A and IκB) and the proto-oncogene SET, which acts in the cytoplasm to inhibit the PP2A tumor suppressor. Accordingly, KPT-330 rescued PP2A activity and treatment of CML and Ph+ progenitors reduced BCR-ABL1 expression and activity. Finally, KPT-330 was administered (oral) to a CML-AP patient, as a run-in dose (12 mg/m2) for one week, then three therapeutic doses (16.5 mg/m2). After the first therapeutic dose there was a reduction in bone pain, immature myeloid, WBC count (>300,000 to 7000 cells/µL), splenomegaly (13cm to 4cm below costal margin), and serum lactate dehydrogenase (513 to 264 IU/L). One week after the last dose, WBC count increased to 37,000 cells/µL with reappearance of immature myeloid cells; however, the patient declined dose escalation. Therefore, XPO1 is necessary for the enhanced survival of Ph+ leukemic blasts, and KPT-330 may represent an effective treatment for TKI-refractory Ph+ leukemias.

Keywords: CML , XPO1