Summary
Acute myeloid leukemia (AML) is one of the most common cancers, accounting for about 30,000 new cases each year in the US and EU. Despite recent advances in leukemia research, AML patients are still receiving the same treatment utilised over past few decades, and have a relatively poor prognosis, with 5 year overall survival rate of only about 25%. There is, an urgent need to design better therapeutic strategies to AML patients who are resistant to current therapies.
Recent research has shown that synthetic-lethality using poly-(ADP-ribose)-polymerase (PARP) inhibitors can be a safe and efficacious treatment for breast and ovarian cancers with mutations of BRCA1/BRCA2, two well-known mediators of Homologous Recombination (HR)-DNA damage repair (DDR). This highly selective and effective PARPi treatment is a result of the compromised DDR in cancer cells with defective HR machinery, which remains largely intact in normal cells. Given the encouraging PARPi phase III trial data on various solid tumors which carry mutations affecting DDR genes, it is generally believed that similar successes can also be translated into other cancers including AML. A major hurdle to this end is the identification of AML patients whose leukemic cells will be sensitive to PARPi treatment.
The current invention is the identification of novel markers for PARPi sensitivity in AML, and the underlying mechanisms accounting for sensitivity to PARPi. In mouse models of primary cell transformation and human leukemia cell xenograft studies, PARPi treatment results in leukemic suppression in vitro and significantly extended disease latency. These markers found in about 10-15% of all AML cases are highly stable and required for disease progression.
Picture: Bone marrow aspirate showing acute myeloid leukemia. Several blasts have Auer rods.
(Licensed under the GNU Free Documentation License (source))
Applications
The current invention proposes the selective use of PARPi treatment in targeted AML subgroups accounting for about 10-15% of all AML cases. This could have important implications on the design and execution of effective clinical trials using PARPi on targeted AML patients.
Benefits
The current invention will significantly benefit those patients carrying highly specific genetic markers that make the leukemic cells sensitive to PARPi treatment. In so doing, stratification will spare PARPi-refractory AML patients an otherwise ineffective treatment.
Opportunity
KCL is seeking a partner for further development and commercialization of this technology. A patent is available for licensing.
Keywords:
Acute myeloid leukaemia
PARP inhibitor
Patient stratificatio