Enhancing cytarabine efficacy in leukemia through CDK inhibition

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43CA213629-01
Agency Tracking Number: R43CA213629
Amount: $299,891.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: 102
Solicitation Number: PA15-269
Solicitation Year: 2015
Award Year: 2017
Award Start Date (Proposal Award Date): 2016-12-29
Award End Date (Contract End Date): 2018-11-30
Small Business Information
150 NEW SCOTLAND, Albany, NY, 12208-3423
DUNS: 170943240
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (803) 777-6161
Business Contact
Phone: (518) 727-5152
Email: roninson@senexbio.com
Research Institution
Acute myeloid leukemia AML is the most common acute leukemia in adults with new cases annually in the US A deoxycytidine nucleoside analog Cytarabine AraC is the principal chemotherapeutic agent used in AML AraC containing chemotherapeutic regimens induce complete remission in of newly diagnosed AML patients but a substantial minority of leukemias is intrinsically resistant to AraC Furthermore most of the initially responding patients relapse with resistant disease and poor response to subsequent therapies As a result the current overall survival rate for adult AML patients is less than The known mechanisms of AraC resistance involve changes in gene expression at least some of which can be induced epigenetically by treatment with AraC or other chemotherapeutic drugs A major cause of clinical resistance in AML is the presence of the leukemic stem cell population resistant to conventional therapies Novel therapies with the abilities to prevent the emergence of drug resistance or to target the leukemic stem cells are needed to improve patient outcomes This application proposes a potentially transformative approach to leukemia therapy based on combining AraC with a novel class of preclinical agents that target transcription regulating kinase CDK and its paralog CDK CDK inhibitors are characterized by a lack of toxicity chemopotentiating activity the ability to prevent transcriptional changes leading to drug resistance inhibition of stem cell differentiation and proliferation and direct suppression of a subset of leukemias We have found that the addition of CDK inhibitors to AraC drastically improves its long term efficacy in human AML cell lines that do not respond to CDK inhibitors alone and inhibits the development of AraC resistance A combination of CDK inhibitors with AraC also shows efficacy against AML lines with either acquired or intrinsic AraC resistance Senex Biotechnology has developed a highly selective inhibitor of CDK Senexin B and we now propose a program aimed at developing Senexin B AraC combinations for AML therapy In Phase I of this program we will investigate the long term in vitro efficacy of Senexin B AraC combinations against a panel of human AML cell lines and determine if the synergistic effect is associated with the impact of CDK inhibition on the stem cell like subpopulation of leukemic cells To establish the conditions for efficient and sustained suppression of AML growth in vivo by Senexin B AraC combination we will first carry out pharmacokinetics and toxicology studies of Senexin B combined with AraC in immunodeficient mice We will then test the efficacy of Senexin B alone in a mouse xenograft model of a Senexin B sensitive human leukemia and of Senexin B AraC combination in both Senexin B sensitive and Senexin B resistant mouse xenograft AML models In the future Phase II we will extend our studies to patient derived leukemia samples and generate an IND package to initiate clinical studies of a CDK inhibitor AraC combination for AML therapy Cytarabine AraC is the principal chemotherapeutic agent used for the treatment of acute myeloid leukemia AML the most common acute leukemia in adults but the overall survival rate for adult AML patients is less than due to the leukemia resistance to AraC containing chemotherapeutic regimens We propose to develop a new approach to AML therapy by combining AraC with a novel class of preclinical agents that target proteins CDK and greatly improve the efficacy of AraC by preventing the development of resistance

* Information listed above is at the time of submission. *

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