Abstract 4059: KPC34: a co-drug that combines a DNA damaging agent with a targeted therapy for the treatment of AML
Authors: Gregory L. Kucera, Peter Alexander, Kristin Pladna, Timothy S. Pardee
Journal: Cancer Research (2017)

Abstract AML occurs in the elderly with ~18,000 new US cases in 2014. Mortality is an estimated 10,050 US deaths in 2014. Elderly patient prognosis is a dismal 6.6%, 5 year survival rate. AML treatment involves induction chemotherapy with Ara-C followed by consolidation therapy or stem cell transplant. The major obstacle to long-term disease-free survival is relapse after treatment due to chemoresistance. Chemoresistance occurs by several mechanisms including reduced activation of Ara-C via down-regulated deoxycytidine kinase (dCK) levels or decreased uptake via lowered Equilibrative Nucleoside Transporter 1 (ENT-1) levels. The low expression of both dCK and ENT-1 correlates with a poor prognosis in patients with acute leukemias. Recurrent disease is more difficult to treat successfully. Elderly patients often have trouble tolerating repeated chemotherapy treatments. Activation of NF-κβ by protein kinase C (PKC) promotes proliferation and inhibits apoptosis in AML. Increased expression of PKC isoforms has been detected in AML. The activity of these isoforms promotes leukemic proliferation and survival by ERK activation and BCL-2. KPC34 is a novel synthetic phospholipid/deoxycytidine analog conjugate. KPC34's novel properties result in improved pharmacokinetics. It overcomes chemoresistance to Ara-C by bypassing ENT-1 uptake and dCK activation. KPC34 is administered orally. It crosses the blood-brain barrier, targeting CNS-infiltrating leukemias. Finally, KPC34’s lipid moiety inhibits PKC activity. The study’s hypothesis is that KPC34 is active against AML in vivo. KPC34 is highly cytotoxic to a variety of leukemic cell lines in vitro, with IC50s in the nM range. The mean IC50 was 45.92 nM (range from 7.39-175.6 nM). In order to assess the activity of KPC34 in vivo, we injected NSG mice with OCI-AML-3 cells expressing luciferase. Following engraftment, mice were treated with KPC34, Ara-C, or water on days 1, 4 and 7. A significant prolongation of survival was observed in the KCP34-treated mice (median survival 44.5 days vs. 25 days for Ara-C-treated mice, p=0.0033, by log-rank test). Retreatment of the mice with additional KPC34 resulted in a median survival time of 78.5 days (p=0.0028, single KPC34 course vs. 2 additional treatment courses). KPC34 + doxorubicin is superior to the treatment of mice with Ara-C + doxorubicin. In a PDX murine model, KPC 34 showed a reduction in leukemic burden in the liver and spleen. KPC34 is well tolerated in vivo. KPC34 is effective against multiple models of naïve and chemoresistant leukemia. It has two distinct anti-neoplastic mechanisms. Oral administration improves efficacy over i.v. dosing. These data demonstrate KPC34 efficacy in multiple preclinical models of leukemia, and support its continued translation to the clinic. This co-drug has the potential to replace Ara-C-based therapies as a single agent/combo in naïve AML, a single agent in relapsed leukemia, and it reduces the CNS leukemic burden. Citation Format: Gregory L. Kucera, Peter Alexander, Kristin Pladna, Timothy S. Pardee. KPC34: a co-drug that combines a DNA damaging agent with a targeted therapy for the treatment of AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4059. doi:10.1158/1538-7445.AM2017-4059