Abstract
Philadelphia chromosome positive B cell acute lymphoblastic leukemia (Ph+ ALL) is an aggressive cancer of the bone marrow. The addition of tyrosine kinase inhibitors (TKIs) has improved outcomes but many patients still suffer relapse and novel therapeutic agents are needed. KPC34 is an orally available, novel phospholipid conjugate of gemcitabine, rationally designed to overcome multiple mechanisms of resistance, inhibit the classical and novel isoforms of protein kinase C, is able to cross the blood brain barrier and is orally bioavailable. KPC34 had an IC50 in the nanomolar range against multiple ALL cell lines tested but was lowest for Ph+ lines. In mice bearing either naïve or resistant Ph+ ALL, KPC34 treatment resulted in significantly improved survival compared to cytarabine and gemcitabine. Treatment with KPC34 and doxorubicin was more effective than doxorubicin and cytarabine. Mice with recurrence of their ALL after initial treatment with cytarabine and doxorubicin saw dramatic improvements in hind limb paralysis after treatment with KPC34 demonstrating activity against established CNS disease. Consistent with this KPC34 was better than gemcitabine at reducing CNS leukemic burden. These promising pre-clinical results justify the continued development of KPC34 for the treatment of Ph+ALL.
Highlights
Ph+ ALL is a cancer of the blood and bone marrow that causes an accumulation of immature lymphoblasts, leading to bone marrow failure and death [1]
The mouse leukemia line B6 ALL was maintained in 45% DMEM, 45% IMDM, and 10% FBS supplemented with L-glutamine, penicillin, and streptomycin
In order to determine the activity of KPC34 against acute lymphoblastic leukemia we determined the IC50 values of a panel of human and murine cell lines The IC50 values for all lines
Summary
Ph+ ALL is a cancer of the blood and bone marrow that causes an accumulation of immature lymphoblasts, leading to bone marrow failure and death [1]. When TKIs are used as single agents responses are shortlived with rapid development of resistance [4] This is likely a reflection of the intra-tumoral genetic heterogeneity contained within ALL patients (reviewed in [5]). Cytarabine is a prodrug that requires several cellular enzymes for leukemia cell uptake and metabolism before it becomes the active triphosphorylated metabolite, Ara-CTP It must enter the cell via an equilibrative nucleoside transporter (ENT-1), and needs to be phosphorylated by deoxycytidine kinase (dCK), the rate limiting step for its activation. It is rationally designed to simultaneously deliver a Protein Kinase C (PKC) inhibitor and a DNA damaging agent It is orally bio-available, able to cross the BBB, and taken up independently of cellular nucleoside transport proteins like ENT-1. In this study we sought to determine the activity of KPC34 against preclinical models of treatment naïve as well as resistant Ph+ ALL
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