The protein kinase activity of phosphoglycerate kinase 1 as a target for cancer treatment and diagnosis
OwnerZhimin LUinventor
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Abstract
Compositions and methods for characterizing cancer cells by determining a marker of PGK1 activity. For example, methods are provided for predicting a patient response to a PGK1 inhibitor, a MEK/ERK inhibitor, an EGFR inhibitor, or a PIN1 inhibitor therapy. Methods for treating patients with such therapies are likewise provided.
Claims53
A composition for use in treating a patient having a cancer determined to comprise:
- an elevated level of PGK1 S203 phosphorylation;
- an elevated level of PGK1 Y324 phosphorylation;
- an elevated level of PDHK1 T338 phosphorylation;
- an elevated level of PDH S293 phosphorylation;
- an elevated level of CDC45 S386 phosphorylation;
- an elevated level of histone H3 S10 phosphorylation;
- or an elevated level of Beclin-1 S30 phosphorylation compared to a reference level, the composition comprising a PGK1 inhibitor, a MEK/ERK inhibitor, a EGFR inhibitor, or a PIN1 inhibitor.
A method for treating a patient having a cancer comprising:
- (a) selecting a patient whose cancer cells have been determined to comprise an elevated level of PGK1 S203 phosphorylation;
- an elevated level of PGK1 Y324 phosphorylation;
- an elevated level of PDHK1 T338 phosphorylation;
- an elevated level of PDH S293 phosphorylation;
- an elevated level of CDC45 S386 phosphorylation;
- an elevated level of histone H3 S10 phosphorylation;
- or an elevated level of Beclin-1 S30 phosphorylation compared to a reference level;
- and
- (b) treating the patient with a PGK1 inhibitor therapy, a MEK/ERK inhibitor therapy, a EGFR inhibitor therapy, or a PIN1 inhibitor therapy.
An in vitro method of selecting a patient having a cancer for a PGK1 inhibitor therapy, a MEK/ERK inhibitor therapy, a EGFR inhibitor therapy, or a PIN1 inhibitor therapy comprising determining whether cancer cell of the patient comprise an elevated level of PGK1 S203 phosphorylation;
- an elevated level of PGK1 Y324 phosphorylation;
- an elevated level of PDHK1 T338 phosphorylation;
- an elevated level of PDH S293 phosphorylation;
- an elevated level of CDC45 S386 phosphorylation;
- an elevated level of histone H3 S10 phosphorylation;
- or an elevated level of Beclin-1 S30 phosphorylation compared to a reference level, wherein if the patient comprises an elevated level then the patient is selected for a PGK1 inhibitor therapy, a MEK/ERK inhibitor therapy, a EGFR inhibitor therapy, or a PIN1 inhibitor therapy.
An in vitro method of selecting a patient having a cancer for a PGK1 inhibitor therapy, a MEK/ERK inhibitor therapy, a EGFR inhibitor therapy, or a PIN1 inhibitor therapy comprising (a) determining whether cancer cell of the patient comprise an elevated level of PGK1 S203 phosphorylation;
- an elevated level of PGK1 Y324 phosphorylation;
- an elevated level of PDHK1 T338 phosphorylation;
- an elevated level of PDH S293 phosphorylation;
- an elevated level of CDC45 S386 phosphorylation;
- an elevated level of histone H3 S10 phosphorylation;
- or an elevated level of Beclin-1 S30 phosphorylation compared to a reference level, and (b) selecting a patient for a PGK1 inhibitor therapy, a MEK/ERK inhibitor therapy, a EGFR inhibitor therapy, or a PIN1 inhibitor therapy if cancer cells of the patient comprise an elevated level.
A method of predicting a response to a PGK1 inhibitor therapy, a MEK/ERK inhibitor therapy, a EGFR inhibitor therapy, or a PIN1 inhibitor therapy in a patient having cancer comprising determining whether cancer cells of the patient comprise an elevated level of PGK1 S203 phosphorylation;
- an elevated level of PGK1 Y324 phosphorylation;
- an elevated level of PDHK1 T338 phosphorylation;
- an elevated level of PDH S293 phosphorylation;
- an elevated level of CDC45 S386 phosphorylation;
- an elevated level of histone H3 S10 phosphorylation;
- or an elevated level of Beclin-1 S30 phosphorylation compared to a reference level, wherein if the cancer cells comprise an elevated level, then the patient is predicted to have a favorable response to a PGK1 inhibitor therapy, a MEK/ERK inhibitor therapy, a EGFR inhibitor therapy, or a PIN1 inhibitor therapy.
A method of predicting a response to a PGK1 inhibitor therapy, a MEK/ERK inhibitor therapy, a EGFR inhibitor therapy, or a PIN1 inhibitor therapy in a patient having cancer comprising (a) determining whether cancer cells of the patient comprise:
- an elevated level of PGK1 S203 phosphorylation;
- an elevated level of PGK1 Y324 phosphorylation;
- an elevated level of PDHK1 T338 phosphorylation;
- an elevated level of PDH S293 phosphorylation;
- an elevated level of CDC45 S386 phosphorylation;
- an elevated level of histone H3 S10 phosphorylation;
- or an elevated level of Beclin-1 S30 phosphorylation compared to a reference level, and (b) identifying the patient as predicted to have a favorable response to a PGK1 inhibitor therapy, a MEK/ERK inhibitor therapy, a EGFR inhibitor therapy, or a PIN1 inhibitor therapy if cancer cells from the patient comprise an elevated level of PGK1 S203 phosphorylation;
- an elevated level of PGK1 Y324 phosphorylation;
- an elevated level of PDHK1 T338 phosphorylation;
- an elevated level of PDH S293 phosphorylation;
- an elevated level of CDC45 S386 phosphorylation;
- an elevated level of histone H3 S10 phosphorylation;
- or an elevated level of Beclin-1 S30 phosphorylation compared to a reference level;
- or identifying the patient as not predicted to have a favorable response to a PGK1 inhibitor therapy, a MEK/ERK inhibitor therapy, a EGFR inhibitor therapy, or a PIN1 inhibitor therapy if cancer cells from the patient do not comprise an elevated level of PGK1 S203 phosphorylation;
- an elevated level of PGK1 Y324 phosphorylation;
- an elevated level of PDHK1 T338 phosphorylation;
- an elevated level of PDH S293 phosphorylation;
- an elevated level of CDC45 S386 phosphorylation;
- an elevated level of histone H3 S10 phosphorylation;
- or an elevated level of Beclin-1 S30 phosphorylation compared to a reference level.
A method of determining a prognosis in a patient having a cancer comprising determining whether cancer cells of the patient comprise an elevated level of PGK1 S203 phosphorylation or an elevated level of PDHK1 T338 phosphorylation compared to a reference level, wherein if the cancer cells comprise an elevated level of PGK1 S203 phosphorylation or an elevated level of PDHK1 T338 phosphorylation, then the patient is predicted to have an aggressive cancer.
An in vitro method of determining a prognosis in a patient having a cancer comprising:
- (a) determining whether cancer cells of the patient comprise an elevated level of PGK1 S203 phosphorylation;
- an elevated level of PGK1 Y324 phosphorylation;
- an elevated level of PDHK1 T338 phosphorylation;
- an elevated level of PDH S293 phosphorylation;
- an elevated level of CDC45 S386 phosphorylation;
- an elevated level of histone H3 S10 phosphorylation compared to a reference level;
- and (b) identifying the patient as predicted to have an aggressive cancer, if cancer cells from the patient comprise the elevated level or identifying the patient as not predicted to have an aggressive cancer, if cancer cells from the patient do not comprise the elevated level.
A method for screening candidate PGK1 inhibitors or anti-cancer agents comprising determining the binding of PGK1 to PDHK1 and/or the phosphorylation of PDHK1 by PGK1 in the presence or absence of an agent, wherein an agent that disrupts binding of PGK1 to PDHK1 and/or disrupts phosphorylation of PDHK1 by PGK1 is a candidate PGK1 inhibitor or anti-cancer agent.
A method for screening candidate PGK1 inhibitors or anti-cancer agents comprising:
- (a) determining the binding of PGK1 to PDHK1 and/or the phosphorylation of PDHK1 by PGK1 in the presence or absence of an agent;
- and
- (b) selecting a candidate PGK1 inhibitor or anti-cancer agent based on the agent disrupting the binding of PGK1 to PDHK1 and/or the phosphorylation of PDHK1 by PGK1.
An in vitro method of predicting the severity of a cancer in a patient comprising:
- (a) determining a level of PGK1 activity, a level of PGK1 S203 phosphorylation, a level of PGK1 Y324 phosphorylation, or a level of PGK1 mitochondrial localization in a patient sample;
- and
- (b) predicting the severity of a cancer in the subject based on the level of PGK1 activity, a level of PGK1 S203 phosphorylation, a level of PGK1 Y324 phosphorylation, or a level of PGK1 mitochondrial localization, wherein an elevated level of PGK1 activity, PGK1 S203 phosphorylation, PGK1 Y324 phosphorylation, or PGK1 mitochondrial localization relative to a reference level indicates a more severe cancer.
Dependencies are inferred from the claim text.