Acute myeloid leukemia (AML) is associated with a poor prognosis. Despite progress made in implementing risk-adapted treatment strategies for AML and the design and clinical development of novel molecular-targeted therapeutics, the majority of patients will still die from this disease. Therefore, there is an urgent need to develo novel and potent anticancer drugs that have different mechanisms of action than traditional chemotherapeutics. The current application focuses on the clinical implementation of a novel halogenated ATP analog, 8-chloro-adenosine (8-Cl-Ado), which has a unique mode of action. In cells, 8-Cl-Ado is metabolized into the active, cytotoxic metabolite 8-Cl-ATP, which accumulates at high micromolar concentrations. 8-Cl-ATP incorporates predominantly into mRNA and inhibits ATP synthase activity, thus diminishing intracellular ATP pools. As a consequence, 8-Cl-Ado/8-Cl-ATP attacks cancer cells through multiple routes by interfering with transcription and translation, cellular bioenergy production, and signaling pathways critical for survival. Cancer cells, including AML cells, are more sensitive to growth and survival inhibition by 8-Cl-Ado than normal cells and frequently undergo apoptosis or autophagic cell death upon exposure to 8-Cl-Ado. 8-Cl-Ado may also help overcome another challenge in AML, that the disease is cytogenetically and molecularly very diverse, and so recurrent genetic or epigenetic aberrations have been used for risk-stratification, treatment guidance and prediction of outcome. For example, about 20 to 30% of AML patients carry an internal tandem duplication in the FLT3 gene (FLT3/ITD), which is associated with poor clinical outcome. 8-Cl-Ado has particularly high efficacy against AML cells that carry the FLT3 gene mutation, further suggesting it as an ideal drug candidate for AML. In addition, 8-Cl-Ado was extremely potent in vitro against a variety of solid and hematologic cancers and had favorable pharmacokinetic and pharmacodynamic properties in preclinical animal studies as well as in a phase I clinical trial in chronic lymphocyic leukemia (CLL). Moreover, in animal models, 8-Cl-Ado shows in vivo antitumor activity but minimal or non-detectable toxicity. Based on these previous studies, promising preliminary studies evaluating 8-Cl-Ado in AML, and encouraging results from the phase I clinical trial in CLL patients that support a favorable pharmacokinetic profile in humans, we now propose to advance 8-Cl-Ado to a phase I/II clinical trial in relapsed/refractory AML.
In Aim 1, we will determine the safety and efficacy of 8-Cl- Ado in a phase I/II clinical trial in relapsed/refractor adult AML.
In Aim 2, we will determine intracellular accumulation of 8-Cl-ATP and its effect on cellular ATP pools.
In Aim 3, we will determine the cytotoxicity of 8- Cl-Ado toward leukemic hematopoietic stem cells and generate a preliminary mRNA/miRNA signature associated with response to 8-Cl-Ado treatment. Successful completion of these studies could identify 8-Cl- Ado as a novel therapeutic drug with potential to substantially reduce or eliminate relapse of patients with AML.

Public Health Relevance

Acute myeloid leukemia (AML) is a devastating malignant disease of the hematopoietic system, and despite advances in treatment options, the majority of AML patients will die from this disease. The halogenated nucleoside analog 8-chloro-adenosine (8-Cl-Ado) is a novel, ribose sugar-containing drug candidate that has a unique mechanism of action and has shown preclinical antitumor activity and a favorable toxicity profile in a phase I clinical trial in patients with chronic lymphocytic leukemia. We propose to advance 8-Cl-Ado to a phase I/II clinical trial in AML to determine its safety and efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA201496-03
Application #
9458707
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010