Methods and compositions for the treatment of Bcr-abl positive lymphoblastic leukemias
Patent Number: US20150133462​

Executive Summary:
  • Invention Type: Therapeutic
  • Patent Status: US Grant
  • Patent Link: https://patents.google.com/patent/US20150133462/
  • Research Institute: St. Jude Children's Research Hospital
  • Disease Focus: Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL)
  • Basis of Invention: Drug combination of a BCR-ABL kinase inhibitor (BCR-ABL-KI), including imatinib, dasatinib or nilotinib, with at least one artemisinin analogue
  • How it works: the cotreatment circumvents the intrinsic resistance to BCR-ABL-KIs in Ph+ ALL
  • Lead Challenge Inventor: R. Kiplin Guy
  • Inventors: Richard T. Williams, R. Kiplin Guy, Harpreet Singh
  • Development Stage: Preclinical (murine model of Ph+ ALL)
  • Novelty: Novel combination therapy
  • Clinical Applications: Treatment of adult and pediatric Ph+ ALL

General Description:
BCR-ABL-KIs induce only transient remissions in patients with Ph+ ALL and relapses remain common. The combination of a BCR-ABL-KI with an antimalarial agent enhances the depth of remission induction and achieves near-complete long-term survival in a robust murine model of human Ph+ ALL.

Scientific Progress:
A repurposing screen of FDA-approved drugs identified the antimalarial drug dihydroartemisinin (DHA) as an inhibitor of Ph+ positive cells proliferation. In vitro, DHA provides strong synergy with BCR-ABL-KIs against Ph+ ALL cells. DHA-dasatinib combination therapy eradicates dasatinib-refractory leukemia in vivo, providing near-complete long-term survival.

Future Directions:
  • Clinical trial

Strengths:
  • Those drugs are FDA-approved, therefore the PK/PD and the side effects are known in human
  • DHA is orally bioavailable and well tolerated
  • New clinical indication for DHA

Weaknesses:
  • Combination therapy of commercially available drugs
 
Patent Status:
Legal Status: Pending
  • Priority date: 2012.05.23
  • Filing date: 2013.05.23
  • Publication date: 2015.05.14

Publication PMID: 23989453

Publications:
Singh H, Shelat AA, Singh A, Boulos N, Williams RT, Guy RK. A screening-based approach to circumvent tumor microenvironment-driven intrinsic resistance to BCR-ABL+ inhibitors in Ph+ acute lymphoblastic leukemia. J Biomol Screen. 2014 Jan;19(1):158-67. doi: 10.1177/1087057113501081. Epub 2013 Aug 29.

Inventor Bio: R. Kiplin Guy
https://uknow.uky.edu/uk-healthcare/kentucky-childrens-hospital/uk-college-pharmacy-names-new-dean