Journal Article

The novel phospholipid mimetic KPC34 is highly active against preclinical models of Philadelphia chromosome positive acute lymphoblastic leukemia

Kucera, Gregory L., Pladna, Kristin M., Alexander, Peter M., Caudell, David L., Pardee, Timothy S.

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acute lymphoblastic leukemia / Acute lymphocytic leukemia / Adults / Animal models / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - toxicity / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - toxicity / Apoptosis - drug effects / Bearing / Bioavailability / Biology and Life Sciences / Biotechnology / Blood cancer / Blood-brain barrier / Bone cancer / Bone marrow / Brain / Cancer / Cancer therapies / Care and treatment / Cell Line, Tumor / Central nervous system / Chemical compounds / Chemotherapy / Chromosomes / Cytarabine / Cytarabine - pharmacology / Cytotoxicity / Deoxycytidine - analogs & derivatives / Deoxycytidine - pharmacology / Deoxycytidine - toxicity / DNA Damage - drug effects / Dose-Response Relationship, Drug / Doxorubicin / Doxorubicin - pharmacology / Drug Resistance, Neoplasm / Drug Screening Assays, Antitumor / Gemcitabine / Genetic aspects / Glycerophosphates - pharmacology / Glycerophosphates - toxicity / Health aspects / Health services / Hematology / Humans / Inhibitors / Internal medicine / Isoforms / Kinases / Leukemia / Lymphatic leukemia / Lymphocytes B / Medical prognosis / Medicine / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Mice, Transgenic / Neoplasm Transplantation / Nervous system / Oncology / Paralysis / Patients / Penicillin / Pharmacology / Philadelphia Chromosome / Phospholipids / Physiological aspects / Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy / Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism / Protein kinase / Protein kinase C / Protein Kinase C - antagonists & inhibitors / Protein Kinase C - metabolism / Protein-tyrosine kinase / Proteins / Random Allocation / Research and Analysis Methods / Signal transduction / Stem cells / Survival / Transplants & implants / Tumor Burden - drug effects / Tyrosine