Polymerase q as a target in hr-deficient cancers
AssigneeDana-Farber Cancer Institute, Inc.
InventorsAlan D. D'Andrea, Raphael Ceccaldi
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Abstract
The disclosure relates, in some aspects, to methods of treating homologous recombination (HR)-deficient cancers. In some embodiments, the disclosure provides method for treating HR-deficient cancer by administering a polymerase Q (PolQ) inhibitor.
Claims44
A method for treating homologous recombination (HR)-deficient cancer in a subject, the method comprising:
- administering to the subject in need thereof a DNA polymerase θ (Polθ) inhibitor in an amount effective to treat the HR-deficient cancer.
A method for treating a cancer that is resistant to PARP inhibitor therapy in a subject, the method comprising:
- administering to the subject in need thereof a Polθ inhibitor in an amount effective to treat the PARP inhibitor-resistant cancer.
A method for treating a cancer that is characterized by overexpression of Polθ in a subject, the method comprising
- administering to the subject in need thereof a Polθ inhibitor in an amount effective to treat the Polθ-overexpressing cancer.
A method for treating a cancer that is characterized by one or more BRCA mutations and/or reduced expression of Fanconi (Fanc) proteins in a subject, the method comprising
- administering to the subject in need thereof a Polθ inhibitor in an amount effective to treat the cancer.
A high-throughput screening method for identifying an inhibitor of ATPase activity of Polθ, the method comprising:
- (i) contacting Polθ or a fragment thereof with adenosine triphosphate (ATP) and single-stranded DNA (ssDNA) substrate in the presence and absence of a candidate compound;
- (ii) quantifying amount of adenosine diphosphate (ADP) produced in the presence and absence of the candidate compound;
- and
- (iii) identifying the candidate compound as an inhibitor of the ATPase activity of Polθ if the amount of ADP produced in the presence of the candidate compound is less than the amount produced in the absence of candidate compound.
Dependencies are inferred from the claim text.