Methods and systems for predicting response of cells to a therapeutic agent
The invention provides methods for treating patients which methods comprise methods for predicting responses of cells, such as tumor cells, to treatment with therapeutic agents. These methods involve measuring, in a sample of the cells, levels of one or more components of a cellular network and then computing a Network Activation State (NAS) or a Network Inhibition State (NIS) for the cells using a computational model of the cellular network. The response of the cells to treatment is then predicted124 based on the NAS or NIS value that has been computed. The invention also comprises predictive methods for cellular responsiveness in which computation of a NAS or NIS value for the cells (e.g., tumor cells) is combined with use of a statistical classification algorithm. Biomarkers for predicting responsiveness to treatment with a therapeutic agent that targets a component within the ErbB signaling pathway are also provided.
1. A method of selecting anti-ErbB3 therapy for a patient having a neoplastic tumor, said method comprising:
(a) obtaining a sample of the tumor,
(b) determining a level of pErbB3 in the sample by indirect measurement that includes: measuring total protein in the sample and levels of (i) at least one receptor selected from ErbB1, ErbB2, and ErbB3 and (ii) at least one of heregulin and betacellulin,
(c) comparing the level of pErbB3 in the sample to a level of pErbB3 directly measured in a culture of ACHN cells following culture for 20-24 hours in serum-free medium, and subsequently administering an anti-ErbB3 therapeutic agent to the patient only when the level of pErbB3 determined in the sample is no lower than 50% of the level of pErbB3 measured in the culture of ACHN cells following culture for 20-24 hours in serum-free medium.
2. The method of claim 1 , wherein the at least one receptor is ErbB3.
3. The method of claim 1 , wherein the at least one receptor is ErbB3 and the at least one of heregulin and betacelulin is heregulin.
4. A method according to claim 1 , wherein the anti-ErbB3 therapeutic agent is an anti-ErbB3 antibody.
5. A method according to claim 4 , wherein the anti-ErbB3 antibody comprises at least one of:
(i) an antibody comprising heavy chain variable region (V H ) and light chain variable region (V L ) sequences as shown in SEQ ID NOs: 1 and 2, respectively, or an antibody comprising V H and V L CDR sequences as shown in SEQ ID NOs: 7-9 and 10-12, respectively;
(ii) an antibody comprising V H and V L sequences as shown in SEQ ID NOs: 3 and 4, respectively, or an antibody comprising V H and V L CDR sequences shown in SEQ ID NOs: 13-15 and 16-18, respectively;
(iii) an antibody comprising V H and V L sequences as shown in SEQ ID NOs: 5 and 6, respectively, or an antibody comprising V H and V L CDR sequences shown in SEQ ID NOs: 19-21 and 22-24, respectively;
(iv) an antibody comprising V H and V L sequences as shown in SEQ ID NOs: 25 and 26, respectively, or an antibody comprising V H and V L CDR sequences shown in SEQ ID NOs: 27-29 and 30-32, respectively; and
(v) an antibody comprising V H and V L sequences as shown in SEQ ID NOs: 33 and 34, respectively, or an antibody comprising V H and V L CDR sequences shown in SEQ ID NOs: 35-37 and 38-40, respectively.
6. A method according to claim 4 , wherein the anti-ErbB3 antibody comprises MM-121.
7. A method according to claim 1 , wherein at least one of the at least one receptor selected from ErbB1, ErbB2, and ErbB3 and the at least one of ligands heregulin and betacellulin for which a level is measured is at least one protein and wherein the level of the at least one protein is measured by quantitative fluorescence activated cell sorting, enzyme linked immunosorbent assay, immunohistochemistry, quantitative immunohistochemistry, fluorescence resonance energy transfer, Forster resonance energy transfer, biomolecular fluorescence complementation, mass spectrometry, immunoblot assay or coimmunoprecipitation assay.
8. A method according to claim 1 , wherein at least one of the at least one receptor selected from ErbB1, ErbB2, and ErbB3 and the at least one of heregulin and betacellulin for which a level is measured is an mRNA.
9. A method according to claim 1 , wherein the tumor is a breast cancer tumor.
10. A method according to claim 1 , wherein the tumor is a tumor of a tissue selected from of lung, rectum, gall bladder, brain, spinal cord, breast, kidney, pancreas, stomach, colon, liver, bone, skin, spleen, ovary, testis, prostate and muscle.
11. A method according to claim 1 , wherein the sample of the tumor is selected from tumor tissue, fine needle aspirate, nipple aspirate, circulating tumor cells isolated from a blood sample, whole blood, serum, plasma, lymph, saliva and urine, or shed or circulating tumor cells isolated therefrom.