Molecular predictors of therapeutic response to specific anti-cancer agents
Herein is described the use of a collection of 50 breast cancer cell lines to match responses to 77 conventional and experimental therapeutic agents with transcriptional, proteomic and genomic subtypes found in primary tumors. Almost all compounds produced strong differential responses across the cell lines produced responses that were associated with transcriptional and proteomic subtypes and produced responses that were associated with recurrent genome copy number abnormalities. These associations can now be incorporated into clinical trials that test subtype markers and clinical responses simultaneously.
1. A method for identifying a breast cancer patient suitable for treatment with an anti-cancer agent, wherein said anti-cancer agent is vorinostat, trichostatin A, erlotinib, fluoruracil and/or GSK1070916, said method comprising:
(a) obtaining a cell from a breast tissue biopsy sample of said cancer patient;
(b) measuring (i) the genomic copy number or expression level of a set of target genes in said cell from said sample from the patient to identify the molecular or cellular subtype of the cells in said sample, wherein the set of target genes selected comprising at least ER and PR (ii) the genomic copy numbers or expression level of said genes from the patient with normal copy number or the expression level of the gene in a normal tissue sample or a reference expression level, and (iii) the HER2, Claudin and/or K167 protein levels in said cell from said sample from the patient;
(c) determining the subtype of said cell subtype, wherein (i) a positive level or an increase in the expression level of the target genes ER and PR indicates the cellular subtype of the cells from said cancer patient is luminal, (ii) a decrease in the expression level of the target genes ER and PR, a decrease in HER2 protein levels, and an increase in Claudin protein levels indicates the cellular subtype of the cells is a basal subtype (ER-/PR-/HER2-Claudin+); (iii) a decrease in Claudin protein levels indicates the cellular subtype of the cells is a Claudin low subtype; and (iv) an increase in K167 protein levels indicates the cellular subtype of the cells is K167+ subtype; and
(d) assigning the patient as suitable for treatment with one of the selected anti-cancer agents based upon the molecular or cellular subtype identified, wherein if the subtype is (i) ER+/PR+, then the patient is assigned as suitable for treatment with Vorinostat and/or Trichostatin A; (ii) luminal, then the patient is assigned as suitable for treatment with Vorinostat and/or Trichostatin A; (iii) basal, then the patient is assigned as suitable for treatment with Erlotinib and/or Fluoruracil, (iv) Claudin-low, then the patient is assigned as suitable for treatment with GSK1070916 and/or Fluoruracil; (v) K167+, then the patient is suitable for treatment with Fluorouracil and wherein negative or low levels or a decrease in the protein levels of ER, PR, and HER2 and positive levels or an increase in protein levels of Claudin indicates the patient has a basal subtype and is ER-/PR-/HER2-Claudin+, then the patient is assigned as suitable for treatment with Erlotinib and/or Fluoruracil; and
(e) administering to said patient a therapeutically effective amount of one of the anti-cancer agents, Vorinostat, Trichostatin A, Erlotinib, Fluoruracil or GSK1070916.
2. The method of claim 1 , wherein step b) further comprises measuring 20q13 amplification levels in said cell from said sample of the patient, and wherein if the subtype is low or no 20q13 amplification is measured, then the patient is assigned as suitable for treatment with GSK1070916.