Systems and methods for determining individualized medical interventions for disease conditions

Abstract

To provide a system and method for determining individualized medical intervention for a particular disease state, based on molecular profiling that is used to target specific genes and / or gene expressed proteins with specific drugs or agents that is independent of disease lineage diagnosis.SOLUTION: The present invention relates to the application of molecular profiling to provide a system and method for determining medical intervention for a particular disease state. The system and method can be conducted at any stage of the disease. In particular, the present invention relates to a system and method for determining medical intervention for a seriously diseased patient, for example, a patient with cancer that has progressed on at least two chemotherapeutic or hormonal regimens.SELECTED DRAWING: None

Description

Technical Field

[0001] (Field of the Invention) The present invention generally relates to the application of molecular profiling to provide systems and methods for determining medical interventions for specific disease states. Such systems and methods can be performed at any stage of the disease. In particular, the present invention relates to systems and methods for determining medical interventions for patients suffering from a serious disease, for example, a patient having cancer in which at least two chemotherapy regimens or hormonal regimens are in progress, the method comprising the steps of molecular profiling a biological sample derived from the patient, determining whether any molecular findings, including one or more genes, gene expression proteins, molecular mechanisms and / or combinations thereof, show a change in expression compared to a normal reference, and identifying a drug therapy that can interact with the gene, gene expression protein, molecular mechanism or combination of molecular findings that shows a change in expression.

Background Art

[0002] (Background of the Invention) A patient's disease state is typically treated with a treatment regimen or therapy selected based on underlying clinical criteria; that is, the treatment therapy or regimen is selected for the patient based on the determination that the patient has been diagnosed with a particular disease (the diagnosis being made from conventional diagnostic assays). Although the molecular mechanisms underlying various disease states have been the subject of research for many years, the specific application of the individual's molecular profile in determining treatment regimens and therapies for affected individuals has been disease-specific and not widely pursued.

[0003] Some treatment regimens are determined using molecular profiling in combination with the patient's clinical characteristics (e.g., findings made by the physician (e.g., International Classification of Diseases code and the date such code was determined)), laboratory test results, X-rays, biopsy results, patient accounts, and any other medical information that the physician generally relies on to diagnose a particular disease. However, since some treatment regimens may be effective for a variety of disease conditions, even though they are associated with treating specific types of disease conditions, using a combination of selection materials based on molecular profiling and clinical characteristics (e.g., diagnosis of a specific type of cancer) to determine a treatment regimen or treatment carries the risk of overlooking an effective treatment regimen for a particular individual.

[0004] Patients with metastatic cancer are of particular interest to treating physicians. The majority of patients with metastatic cancer eventually run out of treatment options for their tumors. After pursuing standard first-line and second-line (and occasionally third-line and beyond) therapies for their tumors, these patients have very limited options. These patients may be able to participate in Phase I and Phase II clinical trials of novel anticancer drugs, but typically they must meet very stringent eligibility criteria to participate. Studies have shown that when patients participate in these types of trials, the novel anticancer drug can yield response rates ranging from an average of 5-10% in Phase I to 12% in Phase II. These patients also have the option of choosing to receive the best possible symptomatic treatment to manage their symptoms.

[0005] In recent years, there has been a surge in interest in developing novel anticancer drugs that more effectively target cell surface receptors or upregulated or amplified gene products. This approach has yielded some successes (e.g., Herceptin for HER2 / neu in breast cancer cells, rituximab for CD20 in lymphoma cells, bevacizumab for VEGF, and cetuximab for EGFR). However, patients' tumors still ultimately progress to these therapies. When numerous targets or molecular insights (e.g., molecular mechanisms, genes, gene-expressed proteins, and / or combinations thereof) are measured in a patient's tumor, further targets or molecular insights that can be utilized by using specific therapeutic agents may be discovered. By identifying multiple drugs that can address multiple targets or underlying mechanisms, patients with metastatic cancer may be offered viable alternative therapies to existing treatment regimens. [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, there is a need for systems and methods to determine individualized medical interventions for disease states based on molecular profiling, independent of disease systemic diagnosis, which is used to target specific genes and / or gene-expressed proteins using specific drugs or agents. [Means for solving the problem]

[0007] (Summary of the invention) The present invention relates to a system and method for determining individualized medical interventions for a particular disease condition. One exemplary method of the present invention for determining medical interventions for a disease condition includes the steps of testing genes and / or gene expression proteins derived from a biological sample of the affected individual, determining which genes and / or gene expression proteins showed altered expression compared to a reference, and identifying drug therapies, not limited to a single disease, that are used to interact with the genes and / or gene expression proteins that showed altered expression. In one aspect of this exemplary embodiment of the present invention, the step of identifying drug therapies that are used to interact with the genes and / or gene expression proteins that showed altered expression may include identifying drug therapies from an automated scrutiny of data obtained from a large literature database and / or clinical trials.

[0008] In another aspect of the above exemplary embodiments of the present invention, the step of testing a gene and / or a gene-expressed protein may include the step of performing immunohistochemical (IHC) analysis and / or microarray analysis. Furthermore, the step of performing microarray analysis may include the step of performing analysis using expression microarrays, comparative genomic hybridization (CGH) microarrays, single nucleotide polymorphism (SNP) microarrays, fluorescence in situ hybridization (ISH), in situ hybridization (ISH), and proteomics arrays. Furthermore, the step of performing IHC analysis may include the step of performing IHC analysis on a gene-expressed protein containing at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF.

[0009] In another aspect of the present invention, the step of performing microarray analysis in the above exemplary method for determining medical intervention for a disease state is to include BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, RXRB, ADA, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS 2. The procedure may include a step of performing microarray analysis on genes including at least one of the following: POLA, CES2, EGFR, OGFR, ASNS, NFKB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin β receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1.

[0010] In yet another aspect of the above-described exemplary method of the present invention, the step of testing genes and / or gene-expressed proteins derived from a biological sample of an affected individual may include the step of performing immunohistochemical analysis on the tumor, and the step of determining which genes and / or gene-expressed proteins show altered expression compared to a reference may include the step of determining whether 30% or more of the tumor cells stained (standing) at +2 or higher for a particular gene-expressed protein. In yet another aspect of the above-described exemplary method of the present invention, the step of testing genes and / or gene-expressed proteins derived from a biological sample of an affected individual may include the step of performing microarray analysis on the tumor, and the step of determining which genes and / or gene-expressed proteins show altered expression compared to a reference may include the step of identifying which genes are upregulated or downregulated by determining whether the overall change in expression of a particular gene compared to normal tissue of reference origin is significant at p<0.001. Furthermore, the above exemplary method of the present invention for determining medical interventions for a disease state may also include a step of providing a patient profile report that identifies changes in the expression of genes and / or gene-expressing proteins, along with what may be pharmacotherapy for interactions with each of the genes and / or gene-expressing proteins that exhibit changes in expression.

[0011] Another exemplary embodiment of the present invention relates to a method for identifying a drug therapy that can interact with a molecular target, the method comprising the steps of: identifying a molecular target in a plurality of affected individuals that exhibits altered expression compared to a normal reference; administering the drug therapy to the affected individuals exhibiting altered expression of the molecular target; and measuring any changes in the molecular target in the affected individuals after the drug therapy. Furthermore, in one aspect of this exemplary embodiment of the method for identifying a drug therapy that can interact with a molecular target, the step of identifying a molecular target in a plurality of affected individuals exhibiting altered expression compared to a normal reference may include the step of testing genes derived from biological samples of the affected individuals and / or testing gene-expressed proteins, wherein the testing includes immunohistochemical (IHC) analysis and / or microarray analysis.

[0012] In yet another exemplary embodiment of the present invention, a system is provided for determining individualized medical interventions for a disease state, the system comprising a host server, a user interface for accessing the host server, accessing and inputting data, a processor for processing the input data, a memory connected to the processor for storing the processed data, as well as instructions for a) accessing molecular profiles obtained from a patient's biological specimen, b) determining whether at least one of genes, gene-expressing proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile shows altered expression compared to a normal reference, and c) accessing a drug therapy database to identify one or more drug therapies that interact with the genes, gene-expressing proteins, molecular mechanisms, and / or other molecular findings that show altered expression, and display means for displaying genes, gene-expressing proteins, molecular mechanisms, and other molecular findings that show altered expression, as well as drug therapies that interact with them. With regard to exemplary embodiments of the present invention relating to a system for determining individualized medical interventions for a disease state, the molecular profiles obtained from a biological specimen may include the same immunohistochemical (IHC) analysis and microarray analysis described above with reference to the first exemplary embodiment of the present invention. Furthermore, these analyses, along with the genes analyzed using these analyses, may be the same as those described above with reference to the first exemplary embodiment of the present invention regarding methods for determining medical interventions for disease conditions.

[0013] Another exemplary embodiment of the present invention relates to a method for determining a medical intervention for a disease state, the method comprising the steps of: performing at least one molecular test on at least one target derived from a biological sample of an affected individual; determining whether the target shows a change in expression compared to a reference; and identifying at least one non-disease-specific drug that interacts with the target showing a change in expression. The step of identifying at least one non-disease-specific drug that interacts with the target may include identifying pharmacotherapy from an automated review of a large literature base and / or an automated review of data obtained from clinical trials. Furthermore, exemplary embodiments of the present invention relating to a method for determining a medical intervention for a disease state may also include the step of providing a patient profile report including the patient's test results for various targets and any treatment proposed based on those results.

[0014] In an exemplary embodiment of the present invention relating to a method for determining medical intervention for a disease state, the step of performing at least one molecular test on at least one target derived from a biological sample of an affected individual may include the above-described analyses relating to immunohistochemical (IHC) analysis and microarray analysis, as well as all genes analyzed using those analyses. Therefore, the present invention provides, for example, the following items: (Item 1) A method for determining medical interventions for a disease state: A step of performing at least one of the following: testing genes derived from biological samples of affected individuals and testing gene-expressed proteins; A step of determining which genes and / or gene-expressing proteins show changes in expression compared to a reference; and A method comprising the step of identifying drug therapies, not limited to a single disease, that are used to interact with at least one of the genes and / or gene-expressing proteins that have shown altered expression. (Item 2) The method according to item 1, wherein the step of identifying a drug therapy used to interact with at least one of the genes and / or gene-expressing proteins that have shown altered expression includes the step of identifying a drug therapy from at least one of automated scrutiny of large literature databases and data obtained from clinical trials. (Item 3) The method according to item 1, wherein the step of performing at least one of a gene test and a gene expression protein test includes a step of performing at least one of immunohistochemical (IHC) analysis and microarray analysis. (Item 4) The method according to item 3, wherein the above step of performing microarray analysis includes a step of performing analysis using at least one of the following: expression microarrays, comparative genomic hybridization (CGH) microarrays, single nucleotide polymorphism (SNP) microarrays, fluorescence in situ hybridization (FISH), in situ hybridization (ISH), and proteomics arrays. (Item 5) The method according to item 3, wherein the above step of performing IHC analysis includes a step of performing IHC analysis on a gene expression protein including at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF. (Item 6) The above process for performing microarray analysis includes BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, RXRB, ADA, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, ASNS, The method according to item 3, comprising the step of performing microarray analysis on a gene comprising at least one of the following: NFKB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin β receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1. (Item 7) The method according to item 3, wherein the step of performing at least one of testing genes derived from a biological sample of an affected individual and testing gene-expressed proteins includes a step of performing immunohistochemical analysis on the tumor, and the step of determining which genes and / or gene-expressed proteins show altered expression compared to a reference includes a step of determining whether 30% or more of the tumor cells stained +2 or higher for a particular gene-expressed protein. (Item 8) The method according to item 3, wherein the step of performing at least one of testing genes derived from a biological sample of an affected individual and testing gene-expressed proteins includes performing microarray analysis on the tumor, and the step of determining which genes and / or gene-expressed proteins show altered expression compared to a reference includes identifying which genes are upregulated or downregulated by determining how many times the expression change for a particular gene compared to normal tissue of reference origin is significant at p<0.001. (Item 9) The method according to item 1, further comprising the step of providing a patient profile report that identifies changes in the expression of the above-mentioned genes and / or gene-expressing proteins, along with potential pharmacotherapy for interactions with each of the genes and / or gene-expressing proteins exhibiting changes in expression. (Item 10) A method for identifying drug therapies that can interact with molecular targets, A process for identifying molecular targets that show altered expression compared to a normal reference in multiple affected individuals; The process of administering drug therapy to an affected individual that shows a change in the expression of the molecular target; and A step of measuring any change in the molecular target of the affected individual after drug therapy. Methods that include... (Item 11) The method according to item 10, wherein the step of identifying molecular targets that show altered expression in multiple affected individuals compared to a normal reference includes performing at least one of testing genes derived from biological samples of the affected individuals and testing gene-expressed proteins, wherein the test includes at least one of immunohistochemical (IHC) analysis and microarray analysis. (Item 12) A system for determining individualized medical interventions for disease conditions, Host server and; A user interface for accessing the host server, accessing data, and inputting data; A processor for processing the input data; The processed data, as well as i) Instructions for accessing a molecular profile obtained from a biological specimen of a patient; ii) Instructions for determining whether at least one or more of a gene, gene expression protein, molecular mechanism, and other molecular findings obtained from the molecular profile exhibit a change in expression compared to a normal reference; and iii) Instructions for accessing a drug therapy database to identify one or more drug therapies that interact with the at least one gene, gene expression protein, molecular mechanism, and other molecular findings that exhibit a change in expression A memory connected to the processor for storing; Display means for displaying the at least one gene, gene expression protein, molecular mechanism, and other molecular findings that exhibit a change in expression and the drug therapies that interact with them A system comprising. (Item 13) The system according to item 12, wherein the molecular profile includes at least one of immunohistochemical (IHC) analysis and microarray analysis. (Item 14) The system according to item 13, wherein the microarray analysis includes at least one of an expression microarray, a comparative genomic hybridization (CGH) microarray, a single nucleotide polymorphism (SNP) microarray, fluorescence in situ hybridization (FISH), in situ hybridization (ISH), and a proteomics array. (Item 15) The system described in item 13, wherein the above IHC analysis includes IHC analysis of gene expression proteins including at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF. (Item 16) The above microarray analysis shows BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, RXRB, AD A, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, ASNS, NF The system described in item 13, comprising microarray analysis of genes including at least one of the following: KB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin β receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1. (Item 17) The system according to item 13, wherein the above molecular profile includes immunohistochemical analysis of the tumor, and the instructions for determining whether at least one of the genes, gene-expressed proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile shows a change in expression compared to a reference, includes instructions for determining whether 30% or more of the tumor cells stained +2 or higher for a particular gene-expressed protein. (Item 18) The system according to item 13, wherein the molecular profile includes microarray analysis of a tumor, and the instructions for determining whether at least one of the genes, gene-expressed proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile shows altered expression compared to a normal reference, and the instructions for identifying which genes are upregulated or downregulated by determining how many times the expression change for a particular gene compared to normal tissue of the reference origin is significant at p<0.001. (Item 19) The system described in item 12, wherein the above-mentioned display means includes a printed patient profile report. (Item 20) The method of item 12, wherein the instructions for accessing a drug therapy database and identifying one or more drug therapies that interact with the at least one gene, gene-expressed protein, molecular mechanism and other molecular findings that have shown altered expression include instructions for performing an automated scrutiny of a large literature database containing literature that correlates genes and / or gene-expressed proteins with drug therapy interactions. (Item 21) A method for determining medical interventions for a disease state, A step of performing at least one molecular test on at least one target derived from a biological sample of an affected individual; A step of determining whether at least one target shows a change in expression compared to a reference; and A step to identify at least one non-disease-specific drug that interacts with the at least one target exhibiting altered expression. Methods that include... (Item 22) The method according to item 21, wherein the step of identifying at least one non-disease-specific drug that interacts with at least one of the above targets includes the step of identifying a drug therapy from at least one of automated scrutiny of a large literature database and data obtained from clinical trials. (Item 23) The method according to item 21, wherein the step of performing at least one molecular test on at least one target includes the step of performing at least one of immunohistochemical (IHC) analysis and microarray analysis. (Item 24) The method according to item 23, wherein the above step of performing microarray analysis includes a step of performing analysis using at least one of expression microarrays, comparative genomic hybridization (CGH) microarrays, single nucleotide polymorphism (SNP) microarrays, fluorescence in situ hybridization (FISH) and in situ hybridization (ISH), and proteomics arrays. (Item 25) The method according to item 23, wherein the step of performing at least one IHC analysis includes a step of performing an IHC analysis on a gene expression protein comprising at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF. (Item 26) The above steps, which involve performing at least one microarray analysis, include BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, RXRB, ADA, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, and AS. The method according to item 23, comprising the step of performing microarray analysis on a gene comprising at least one of the following: NS, NFKB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin β receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1. (Item 27) The method according to item 23, wherein the step of performing at least one molecular test on at least one target derived from a biological sample of an affected individual includes a step of performing an immunohistochemical analysis of the tumor, and the step of determining whether the at least one target shows a change in expression compared to a reference includes a step of determining whether 30% or more of the tumor cells stained +2 or higher for a specific gene expression protein. (Item 28) The method according to item 23, wherein the step of performing at least one molecular test on at least one target derived from a biological sample of an affected individual includes the step of performing microarray analysis on a tumor, and the step of determining whether the at least one target shows a change in expression compared to a reference includes the step of identifying which genes are upregulated or downregulated by determining how many times the change in expression of a particular gene compared to normal tissue of reference origin is significant at p<0.001. (Item 29) The method according to item 21, further comprising the step of providing a patient profile report that includes the patient's trial results for various targets and any treatments proposed based on those results. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 shows a block diagram of an exemplary embodiment of a system for determining individualized medical interventions for a specific disease state, utilizing molecular profiling of a patient's biological specimen, which is not disease-specific. [Figure 2] Figure 2 is a flowchart illustrating an exemplary embodiment of a method for determining individualized medical interventions for a specific disease state, utilizing molecular profiling of a patient's biological specimen, which is not disease-specific. [Figure 3A] Figures 3A–3D show exemplary patient profile reports as described in step 80 of Figure 2. [Figure 3B] Figures 3A–3D show exemplary patient profile reports as described in step 80 of Figure 2. [Figure 3C] Figures 3A–3D show exemplary patient profile reports as described in step 80 of Figure 2. [Figure 3D] Figures 3A–3D show exemplary patient profile reports as described in step 80 of Figure 2. [Figure 4]Figure 4 is a flowchart of an exemplary embodiment of a method for identifying drug therapies / agents that can interact with a target. [Figure 5] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. [Figure 6] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. [Figure 7] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. [Figure 8] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. [Figure 9] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. [Figure 10] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. [Figure 11] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. [Figure 12] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. [Figure 13] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. [Figure 14] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. [Figure 15]Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Figure 16] Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Figure 17] Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Figure 18] Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Figure 19] Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Figure 20] Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Figure 21] Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Figure 22] Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Figure 23] Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Figure 24] Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Figure 25] Figures 15-25 are printed computer screen outputs related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5-14. [Modes for carrying out the invention]

[0016] (Detailed explanation) The detailed descriptions of exemplary embodiments herein refer to the accompanying drawings and images, which illustrate exemplary embodiments and their best forms for illustrative purposes. While these exemplary embodiments are described in sufficient detail to enable those skilled in the art to carry out the invention, it should be understood that other embodiments may be realized, and that logical and mechanical modifications may be made without departing from the spirit and scope of the invention. Accordingly, the detailed descriptions herein are for illustrative purposes only, and not limiting purposes. For example, the steps listed in any description of a method or process may be performed in any order, and are not limited to the order shown. Furthermore, any function or step may be outsourced to or performed by one or more third parties. Furthermore, any reference to a singular form may include multiple embodiments, and any reference to more than one component may include a single embodiment. For the sake of brevity, conventional data networking, application development, and other functional aspects of the system (and components of the individual operating parts of the system) may not be described in detail herein. Furthermore, the connecting lines shown in the various diagrams contained herein are intended to illustrate exemplary functional relationships and / or physical connections between various elements. It should be noted that many alternative or further functional relationships or physical connections may exist in actual systems.

[0017] Various system components described herein may comprise one or more of the following: a host server or other computing system (including a processor for processing digital data; memory coupled to the processor for storing digital data; an input digitizer coupled to the processor for inputting digital data; application programs stored in memory and accessible to the processor for instructing the processor on how to process digital data; and a display device coupled to the processor and memory for displaying information derived from the digital data processed by the processor) and multiple databases. Various databases used herein may include patient data (e.g., family history, demographic and environmental data), biological sample data, pre-treatment and protocol data, clinical data of patients, molecular profiling data of biological samples, data on therapeutic and / or research drugs, gene libraries, disease libraries, drug libraries, patient tracking data, file management data, financial management data, billing data and / or similar data useful in the operation of the system. As those skilled in the art will understand, a user computer may be equipped with an operating system (e.g., Windows® NT, 95 / 98 / 2000, OS2, UNIX®, Linux®, Solaris, MacOS, etc.) as well as various conventional support software and drivers typically associated with a computer. The computer may be any suitable personal computer, network computer, workstation, minicomputer, mainframe, etc. The user computer may reside in a home or medical / business environment with network access. In exemplary embodiments, access is via a network or via the Internet through a commercially available web browser software package.

[0018] As used herein, the term “network” should include any electronic communication means incorporating both hardware and software components. Communication between parties may be achieved by any suitable communication channel (e.g., telephone networks, extranets, intranets, the Internet, points of interaction devices, personal digital assistants (e.g., Palm Pilot®, Blackberry®), mobile phones, kiosks, etc.), online communication, satellite communication, offline communication, wireless communication, transponder communication, local area networks (LANs), wide area networks (WANs), network-connected or associated devices, keyboards, mice, and / or any suitable communication modality or data input modality. Furthermore, although it is often stated herein that such a system runs on the TCP / IP communication protocol, it may also run on IPX, Appletalk, IP-6, NetBIOS, OSI, or a considerable number of existing or future protocols. If a network falls essentially into the category of a public network such as the Internet, it may be useful to assume that such a network is insecure and open to interceptors. The above protocols, standards, and specific information relating to application software used in connection with the Internet are generally known to those skilled in the art and therefore do not need to be detailed herein. For example, DlLIP NAIK, INTERNET STANDARDS AND PROTOCOLS (1998); JAVA 2 COMPLETE, various authors, (Sybex See DEBORAH RAY AND ERIC RAY, MASTERING HTML 4.0 (1999); and LOSHIN, TCP / IP CLEARLY EXPLAINED (1997); and DAVID GOURLEY AND BRIAN TOTTY, HTTP, THE DEFINITIVE GUIDE (2002) (these contents are incorporated herein by reference).

[0019] Various system components may be appropriately connected to a network via data links, independently, separately, or collectively, such network may include, for example, a connection to an Internet Service Provider (ISP) via a local loop, as is commonly used with standard modem communications, cable modems, dish networks, ISDN, digital subscriber lines (DSL), or various wireless communication methods. See, for example, Gilbert Held, Understanding Data Communications (1996), which is incorporated herein by reference. Note that the network may also operate as other types of networks, such as interactive television (ITV) networks. Furthermore, the system may intend to facilitate the use, sale, or distribution of any goods, services, or information through any network having similar functionality as described herein.

[0020] As used herein, “transmission” may include sending electronic data from one system component to another system component via a network connection. Furthermore, as used herein, “data” may include comprehensive information such as commands, queries, files, and storage data in digital or any other format.

[0021] This system is intended for use in web services, utility computing, broad and personalized computing, security and identity solutions, autonomous computing, commodity computing, mobility and wireless solutions, open source, biometrics, grid computing and / or mesh computing.

[0022] Any database described herein may include relational, hierarchical, graphical, or object-oriented structures and / or any other database configuration. Common database products that may be used to run a database include IBM (White Plains, NY) DB2, various database products available from Oracle Corporation (Redwood Shores, CA), Microsoft Access or Microsoft SQL Server from Microsoft Corporation (Redmond, Washington), or any other suitable database product. Furthermore, a database may be organized in any suitable format, for example, as a data table or a lookup table. Each record may be a single file, a set of files, an associated set of data fields, or any other suitable data structure. A particular data association may be achieved through any desired data association technique (e.g., one known or practiced in the art). For example, such association may be achieved manually or automatically. Examples of automated association techniques include database searches, database merges, GREP, AGREP, SQL, using key fields in tables to speed up searches, sequential searches across all tables and files, classification records in files according to known instructions to simplify searches, and / or similar methods. The association process can be achieved, for example, by a database merge function using "key fields" in a pre-selected database or data sector.

[0023] More specifically, a "key field" divides the database according to the high-level class of objects defined by that key field. For example, a particular type of data may be designated as a key field in several related data tables, and these data tables may be associated based on the type of data in that key field. The data corresponding to the key field in each of these associated data tables is preferably identical or of the same type. However, data tables that have similar but not identical data in that key field can also be associated, for example, by using AGREP. According to one embodiment, any suitable data storage technique may be used to store the data without a standard format. Datasets may be stored using any suitable technique, such as storing individual files using the ISO / IEC 7816-4 file structure; implementing a domain in which a dedicated file is selected to publish one or more base files containing one or more datasets; using datasets stored in individual files using a hierarchical filing system; storing datasets as records in a single file (including compressed, SQL-available, hashed via one or more keys, numbers, letters by a first tuple, etc.); as binary large objects (BLOBs); storing as ungrouped data elements encoded using ISO / IEC 7816-6 data elements; storing as ungrouped data elements encoded using ISO / IEC Abstract Syntax Notation (ASN.1) as found in ISO / IEC 8824 and 8825; and / or other proprietary techniques (which may include fractal compression, image compression, etc.).

[0024] In one exemplary embodiment, the ability to store diverse information in various formats is facilitated by storing the information as a BLOB. Thus, arbitrary binary information can be stored in the storage space associated with the dataset. The BLOB method can store a dataset as ungrouped data elements, formatted as blocks of binary data via a constant memory offset, using either fixed storage allocation, circular queue techniques, or the best of memory management (e.g., page memory that has not been used for the longest time). By using the BLOB method, the ability to store various datasets with different formats facilitates data storage by multiple and unrelated owners of the dataset. For example, a first dataset that can be stored may be provided by a first party, a second dataset that can be stored may be provided by an unrelated second party, and a third dataset that can be stored may be provided by a third party unrelated to both the first and second parties. Each of these three exemplary datasets may contain different information stored using various data storage formats and / or techniques. Furthermore, each dataset may contain a subset of data that may differ from other subsets.

[0025] As described above, in various embodiments, data may be stored in any format, regardless of its usual form. However, in one exemplary embodiment, when a dataset (e.g., a BLOB) is provided for data manipulation, that dataset may be annotated in a standard format. The annotation may include a short header, a postscript, or other appropriate indicators about each dataset, set to convey information useful for managing various datasets. For example, the annotation may be referred to herein as a “conditional header,” “header,” “postscript,” or “status,” and may include an indication of the status of the dataset or an identifier correlated with a particular issuer or owner of the data. Subsequent bytes of data may be used to indicate, for example, the identity of the issuer or owner of the data, a user, a transaction / membership account identifier, etc. Each of these conditional annotations is further described herein.

[0026] Data set annotations can also be used for other types of status information and various other purposes. For example, data set annotations may include security information that establishes access levels. Access levels may be set to allow only a specific unit, such as an employee, company, or other entity, to access a dataset, or to allow the data issuer or owner, user, etc., to access a particular dataset based on a transaction. Furthermore, security information may restrict / permit only certain actions (e.g., access to a dataset, modification of a dataset, and / or deletion of a dataset). In one example, data set annotations may indicate that only the dataset owner or user is allowed to delete the dataset, various verified users may be allowed to access the dataset for reading purposes, and all others are excluded from accessing the dataset. However, other access restriction parameters can also be used, when appropriate, to allow various entities to access a dataset at various permission levels. Data including headers or postscripts may be received by standalone interacting devices configured to add, delete, modify, or increment data according to the headers or postscripts.

[0027] Those skilled in the art will also recognize that, for security reasons, any database, system, device, server, or other component of a system may consist of any combination thereof in a single location or multiple locations. Here, each database or system may have any of the appropriate security features (e.g., firewall, access code, encryption, decryption, compression, decompression, etc.).

[0028] The web client's computing unit may further comprise an internet browser connected to the internet or intranet using standard dial-up, cable, DSL, or any other internet protocol known in the field. Transactions from the web client may pass through firewalls to prevent unauthorized access by users on other networks. Furthermore, additional firewalls may be deployed between the various components of the CMS for further security.

[0029] A firewall may include any hardware and / or software appropriately configured to protect CMS components and / or enterprise computing resources from users on other networks. Furthermore, a firewall may be configured to limit or restrict access to various systems and components beyond the firewall for web clients connecting via a web server. Firewalls can exist in various configurations, including, among others, stateful inspection, proxy-based and packet filtering. A firewall may be integrated within the web server or any other CMS component, or it may exist as a separate entity.

[0030] The computers described herein may provide appropriate websites or other internet-based graphical user interfaces accessible to users. In one embodiment, Microsoft Internet Information Server (IIS), Microsoft Transaction Server (MTS), and Microsoft SQL Server are used together with the Microsoft operating system, Microsoft NT web server software, the Microsoft SQL Server database system, and Microsoft Commerce Server. Furthermore, an Active Data Object (ADO) compliant database management system may be provided by using components such as Access or Microsoft SQL Server, Oracle, Sybase, Informix MySQL, Interbase, etc.

[0031] Any communication, input, storage, database, or display described herein may be facilitated through a website having web pages. The term “web page,” as used herein, is not intended to limit the types of documents and applications that may be used to interact with a user. For example, a typical website may include, in addition to standard HTML documents, various forms, Java® applets, Java® Script, Active Server Pages (ASP), Common Gateway Interface Script (CGI), Extended Markup Language (XML), Dynamic HTML, Cascading Style Sheets (CSS), helper applications, plugins, and so on. A server may include a web service that receives requests from a web server, such as a URL (http: / / yahoo.com / stockquotes / ge) and an IP address (123.56.789.234). The web server searches for a suitable web page and sends data or applications about that web page to the IP address. A web service is an application that can interact with other applications through means of communication such as the internet. Web services are typically based on standards or protocols such as XML, XSLT, SOAP, WSDL, and UDDI. Web service methods are well-known in the field and are covered in many standard textbooks. See, for example, Alex Nghiem, IT Web Services: A Roadmap for the Enterprise (2003), which is referenced herein.

[0032] The web-based clinical database of the system and method of the present invention preferably has the ability to upload and store clinical data files in native format and is searchable for any clinical parameter. The database is also extensible and can input clinical annotations from any study for easy integration with other studies by utilizing the EAV data model (metadata). Furthermore, the web-based clinical database may be XML and XSLT, which are adaptable and can dynamically add user-customized questions. The database also has exportability to CDISC ODM.

[0033] Those skilled in the art will also recognize that there are numerous ways to display data within browser-based documents. Data can be displayed as standard text, or within fixed lists, scrollable lists, dropdown lists, editable text fields, static text fields, popup windows, and so on. Similarly, there are numerous methods available for modifying data on web pages (e.g., freehand text input using a keyboard, selection of menu items, checkboxes, option boxes, etc.).

[0034] The above system and method may be described herein with respect to functional block components, screenshots, option selections, and various processing steps. It should be recognized that such functional blocks may be realized by several hardware and / or software components configured to perform specific functions. For example, the above system may use various integrated circuit components, such as memory elements, processing elements, logic elements, lookup tables, etc., which may perform various functions under the control of one or more microprocessors or other control devices. Similarly, the software elements of the above system may use any programming or scripting language (e.g., C, C++, Macromedia Cold Fusion, Microsoft Active Server Pages, Java®, COBOL, Assembler, Perl, Visual Basic, SQL). Stored Procedures can be executed using Extended Markup Language (XML), and various algorithms can be executed using any combination of data structures, objects, processes, routines, or other programming elements. Furthermore, it should be noted that the above system may utilize some prior art for data transmission, signaling, data processing, network control, etc. Moreover, the above system may use client-side scripting languages ​​(e.g., Java® Script, VBScript, etc.) to detect or circumvent security issues. For a basic introduction to cryptography and network security, see one of the following references: (1) “Applied Cryptography: Protocols, Algorithms, and Source Code in C” by Bruce Schneier, published by John Wiley & Sons (2nd edition, 1995); (2) “Java Cryptography” by Jonathan Knudson, published by O'Reilly & Associates (1998); (3) “Cryptography & Network Security: Principles & Practice” by William Stallings, published by Prentice Hall; all of these are incorporated herein by reference.

[0035] When used herein, the terms “end-user,” “consumer,” “customer,” “client,” “doctor,” “hospital,” or “establishment” may be used interchangeably, and each should mean any person, entity, machine, hardware, software, or establishment. Each of the persons concerned is equipped with a computing device for exchanging information with the above system and for facilitating online data access and data entry. The customer has a arithmetic unit in the form of a personal computer, but may use other types of arithmetic units, including laptops, notebooks, portable computers, set-top boxes, mobile phones, push-button telephones, etc. The owner / operator of the system and method of the present invention has a arithmetic unit that runs in the form of a computer server, but other executions by a system including a computing center, such as a mainframe computer, minicomputer, PC server, or a network of computers of the same type located in different geographical locations, are also contemplated. Furthermore, the system is contemplated for the use, sale, or distribution of any goods, services, or information through any network having similar functionality as described herein.

[0036] In one exemplary embodiment, each client customer may be given an “account” or “account number.” As used herein, an account or account number may include any device, code, number, character, symbol, digital certificate, smart chip, digital signal, analog signal, biometric or other identifier / sign (e.g., one or more of the following: authorization code / access code, personal identification number (PIN), internet code, other identification code, etc.) that is appropriately configured to allow a consumer to access, interact with, or communicate with the System. The account number may, as necessary, be a charge card, credit card, debit card, prepaid card, embossed card. A fob may be located on or associated with a card, smart card, magnetic stripe card, barcode card, transponder, radio frequency card, or related account. The system may comprise, or interface with, either a fob having the aforementioned card or device or transponder, or an RFID reader for RF communication with the fob. The system may comprise, but is not limited to, a fob embodiment. In fact, the system may comprise any device having a transponder configured to communicate with an RFID reader via RF communication. Typical devices include, for example, keyrings, tags, cards, mobile phones, watches, or any such form that can display information in response to an interrogation. Furthermore, the systems, arithmetic units, or devices described herein may comprise “pervasive computing devices,” which may comprise previously uncomputerized devices to which an arithmetic unit is attached. Account numbers may be distributed and stored in any form of plastic devices, electronic devices, magnetic devices, radio frequency devices, wireless devices, audio devices, and / or optical devices that are capable of transmitting or downloading data from themselves to a second device.

[0037] As will be recognized by those skilled in the art, the system can be embodied as a custom-made product of an existing system, an add-on product, upgraded software, a standalone system, a distributed system, a method, a data processing system, a device for data processing, and / or a computer program product. Accordingly, the system can take the form of a software-only embodiment, a hardware-only embodiment, or an embodiment that combines both software and hardware aspects. Furthermore, the system can take the form of a computer program product on a computer-readable recording medium having computer-readable program code means embodied on the recording medium. Any suitable computer-readable recording medium can be used, including hard disks, CD-ROMs, optical storage devices, magnetic storage devices, and the like.

[0038] This system and method are described herein with reference to screenshots, block diagrams, and flowcharts of methods, apparatus (e.g., systems), and computer program products of various embodiments. It is understood that each functional block in the block diagrams and flowcharts, as well as combinations of functional blocks in each block diagram and flowchart, can be executed by instructions in a computer program.

[0039] We will now refer to Figures 2-25, but the process flows and screenshots shown are merely embodiments and are not intended to limit the scope of the invention as described herein. For example, the steps listed in either the method or process description may be performed in any order and are not limited to the order shown. It will be recognized that the following description appropriately refers not only to the steps and user interface elements shown in Figures 2-25, but also to the various system components described above with reference to Figure 1.

[0040] These computer program instructions can be loaded into a general-purpose computer, a special-purpose computer, or other programmable data processing device to manufacture a machine, and the instructions executed in the computer or other programmable data processing device create means for performing the functions specified in the flowchart block. These computer program instructions can also be stored in computer-readable memory, which can instruct the computer or other programmable data processing device to function in a specific manner, and the instructions stored in that computer-readable memory manufacture a product that has instruction means for performing the functions specified in the flowchart block. The computer program instructions can also be loaded into a computer or other programmable data processing device, which can cause a series of operations to be performed in the computer or other programmable device, resulting in a process executed by the computer, and the instructions executed in the computer or other programmable device provide steps for performing the functions specified in the flowchart block.

[0041] Accordingly, functional blocks in block diagrams and flowcharts support combinations of means for performing a particular function, combinations of processes for performing a particular function, and program instruction means for performing a particular function. It will also be understood that each functional block in block diagrams and flowcharts, as well as combinations of functional blocks in block diagrams and flowcharts, may be executed by either a special-purpose hardware-based computer system for performing a particular function or process, or by an appropriate combination of special-purpose hardware and computer instructions. Furthermore, diagrams and descriptions of process flows may refer to user windows, web pages, websites, web forms, prompts, etc. Those skilled in the art will recognize that the illustrated processes described herein may be included in several settings, including the use of windows, web pages, web forms, pop-up windows, prompts, etc. It should be further recognized that multiple processes, as illustrated and described, may be integrated into a single web page and / or window, but are expanded for simplification. In other cases, a process illustrated and described as a single process step may be divided into multiple web pages and / or windows, but are integrated for simplification.

[0042] The advantages, other merits, and solutions to the problem are described herein in relation to specific embodiments. However, the advantages, merits, and solutions to the problem, and any elements that may result in or make more apparent any advantages, merits, or solutions, should not be construed as any very significant, necessary, or essential feature or element of any or all of the claims of the present invention. Accordingly, the scope of the present invention should not be limited by anything other than the appended claims, and in the claims, singular references to elements are intended to mean "one or more" and not "one and just one" unless explicitly stated as "one and just one". All structural, chemical, and functional equivalents to the elements of the above exemplary embodiments, which are known to those skilled in the art, are expressly incorporated herein by reference and are intended to be encompassed by the claims of the present invention. Furthermore, any device or method encompassed by the claims of the present invention does not need to address each or all of the problems that the present invention seeks to solve. Furthermore, no element, component, or process in this disclosure is intended to be made publicly available, regardless of whether such element, component, or process is expressly enumerated in the claims. Unless such element is expressly enumerated using the phrase “means for,” the elements in the claims herein are subject to the United States Patent Law (35 It should not be construed in accordance with the provisions of Section 112, paragraph 6 of the USC. When used herein, the terms “comprises,” “comprising,” or any other variation thereof are intended to be non-exclusive, and a process, method, article, or apparatus containing a list of elements does not necessarily encompass only those elements, but may encompass other elements not expressly enumerated or other elements not specific to such process, method, article, or apparatus. Furthermore, elements described herein are not necessary for the practice of the invention unless expressly stated as “essential” or “very important.”

[0043] Figure 1 is a block diagram of an exemplary embodiment of a system 10 for determining individualized medical interventions for a specific disease state using molecular profiling of a patient's biological specimen. The system 10 comprises a user interface 12, a host server 14 with a processor 16 for processing data, memory 18 connected to the processor, application programs 20 accessible to the processor 16 and stored in memory 18 for instructing the processor 16 on data processing, multiple internal databases 22 and external databases 24, and an interface 26 to a wired or wireless communication network (e.g., the Internet). The system 10 may also include an input digitizer 28 connected to the processor 16 for inputting digital data from data received from the user interface 12.

[0044] The user interface 12 includes an input device 30 for inputting data into the system 10 and a display 32 for displaying information obtained from the data processed by the processor 16. The user interface 12 may also include a printer 34 for printing information obtained from the data processed by the processor 16 (for example, a patient report which may include test results for a target and drug therapies proposed based on those test results).

[0045] Internal databases 22 may include, but are not limited to, patient biological sample information / specimen information and tracking, clinical data, patient data, patient tracking, file management, research protocols, patient molecular profiling test results, and billing information and tracking. External databases 24 may include, but are not limited to, drug libraries, gene libraries, disease libraries, and public and private databases (e.g., UniGene, OMIM, GO, TIGR, GenBank, KEGG, and Biocarta).

[0046] Various methods may be used according to System 10. Figure 2 shows a flowchart of an exemplary embodiment of Method 50 for determining a personalized medical intervention for a specific disease state, which is not disease-specific, by utilizing molecular profiling of a patient's biological specimen. In order to determine a medical intervention for a specific disease state using molecular profiling that is independent of disease-series diagnosis (i.e., not limited to a single disease), at least one test is performed on at least one target derived from the biological specimen of the affected patient in step 52. A target is defined as any molecular findings that can be obtained from a molecular test. For example, targets may be one or more genes, one or more gene-expressed proteins, one or more molecular mechanisms and / or combinations thereof. Tests for finding such targets may include, but are not limited to, immunohistochemical (IHC) analysis, microarray analysis (e.g., comparative genomic hybridization (CGH) microarrays, single nucleotide polymorphism (SNP) microarrays, fluorescence in situ hybridization (FISH), in situ hybridization (ISH), and proteomics arrays) and other molecular tests known to those skilled in the art. Therefore, one or more of the following may be performed: IHC analysis in step 54, trace analysis in step 56, and other molecular tests known to those skilled in the art in step 58.

[0047] Biological samples are obtained from affected patients by taking a tumor biopsy, performing minimally invasive surgery, or, if a recent tumor is unavailable, by obtaining a blood sample or any other biological fluid sample (cell extract, nuclear extract, cell solubilize, or biological product or substance of biological origin (e.g., excrement, blood, serum, plasma, urine, sputum, tears, feces, saliva, membrane extract, etc.)).

[0048] In step 60, a determination is made as to whether one or more of the targets tested in step 52 show altered expression compared to a normal reference for a particular target. In one exemplary method of the present invention, IHC analysis may be performed in step 54, and a determination is made in step 64 as to whether any target from the IHC analysis shows altered expression by determining whether 30% or more of the biological sample cells stained +2 or higher for a particular target. Since staining results can vary depending on the technician performing the test and the type of target being tested, those skilled in the art will understand that staining of +1 or higher may indicate altered expression. In another exemplary embodiment of the present invention, microarray analysis may be performed in step 56, and a determination is made in step 66 as to whether any target from the microarray analysis shows altered expression by identifying which targets are upregulated or downregulated by determining how many times the altered expression of a particular target compared to a normal reference tissue is significant at p<0.001. Altered expression can also be demonstrated by the absence of one or more genes, gene-expressed proteins, molecular mechanisms or other molecular findings.

[0049] After determining which targets show altered expression in step 60, step 70 identifies at least one non-disease-specific drug that interacts with each of the altered targets. The drug can be any drug or compound with therapeutic effects. A non-disease-specific drug is a therapeutic drug or compound that can interact with targets derived from the patient's biological sample that showed altered expression, and which has not been previously associated with the treatment of the disease the patient was diagnosed with. Table 1 below shows some non-disease-specific drugs found to interact with specific targets in various cancer patients.

[0050] [Table 1] Finally, in step 80, a patient profile report may be provided that includes the patient's test results for various targets and any proposed therapies based on those results. Exemplary patient profile reports 100 are shown in Figures 3A-3D. The patient profile report 100 shown in Figure 3A identifies the targets to be tested 102, those tested targets 104 that showed significant changes in expression, and non-disease-specific drugs 106 proposed to interact with those targets. The patient profile report 100 shown in Figure 3B identifies whether a gene expression protein is a molecular target 112 by determining the results of immunohistochemical analysis 108 for a particular gene expression protein 110 and whether 30% or more of tumor cells stained +2 or higher. Report 100 also identifies immunohistochemical tests 114 that were not performed. The patient profile report 100 shown in Figure 3C identifies genes 116 analyzed using microarray analysis and whether those genes were underexpressed or overexpressed compared to a reference 118. Finally, the patient profile report 100 shown in Figure 3D identifies the patient's medical history 120 and the patient's submitted specimens 122.

[0051] Figure 4 shows a flowchart of an exemplary embodiment of method 200 for identifying drug therapies / agents that can interact with a target. Step 202 identifies a molecular target that shows altered expression in many affected individuals. Next, in step 204, the drug therapy / agent is administered to the affected individuals. In step 206, any alteration of the molecular target identified in step 202 is identified after the administration of the drug therapy / agent to determine whether the drug therapy / agent administered in step 204 interacts with the molecular target identified in step 202. If the drug therapy / agent administered in step 204 is determined to interact with the molecular target identified in step 202, the drug therapy / agent may be approved to treat patients showing altered expression of the identified molecular target, rather than approving the drug therapy / agent for a specific disease.

[0052] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized drug discovery system and method of the present invention. Figure 5 is a diagram illustrating an exemplary clinical decision support system of the information-based personalized drug discovery system and method of the present invention. It collects data obtained through clinical research and clinical nursing (e.g., clinical trial data, biomedical data / molecular imaging data, genomics / proteomics / chemical libraries / literature / expert curation, biological specimen tracking / LIMS, family history / environmental records, and clinical data) and stores them as databases and data marts in a data warehouse. Figure 6 is a diagram illustrating the flow of information through the clinical decision support system of the information-based personalized drug discovery system and method of the present invention, using a web service. Users interact with the system by inputting data into the system via form-based input / upload of datasets, formulating queries, and executing data analysis jobs and obtaining and evaluating the display of output data. The data warehouse in the web-based system is where data is extracted, transformed, and loaded from various database systems. A data warehouse is also a place where common formats, mappings, and transformations exist. Its web-based system also includes data marts created based on the desired data view.

[0053] Figure 7 shows a flowchart of an exemplary clinical decision support system for an information-based personalized drug discovery system and method of the present invention. The clinical information management system includes a laboratory information management system, and the medical information contained in the data warehouse and database includes medical information libraries (e.g., drug libraries, gene libraries, and disease libraries) in addition to literature text mining. The information management system for a specific patient, along with both the medical information database and the medical information data warehouse, are integrated in a data junction center from which diagnostic information and therapeutic options can be obtained. A financial management system may also be incorporated into the clinical decision support system for the information-based personalized drug discovery system and method of the present invention.

[0054] Figure 8 shows an exemplary biological specimen tracking and management system that may be used as part of a personalized drug discovery system and method based on the information of the present invention. Figure 8 shows two host medical centers that send specimens to tissue / blood banks. The specimens may undergo laboratory analysis before dispatch. Research may be performed on the samples via microarray, genotyping, and proteomics analysis. This information may be redistributed to tissue / blood banks. Figure 9 shows a flowchart of an exemplary biological specimen tracking and management system that may be used in conjunction with a personalized drug discovery system and method based on the information of the present invention. The host hospital obtains a sample from a patient and then dispatches the patient sample to a molecular profiling laboratory that can also perform RNA and DNA isolation and analysis.

[0055] Figure 10 shows a diagram illustrating a method for maintaining a clinically standardized vocabulary for use with the personalized drug discovery system and method based on the information of the present invention. Figure 10 illustrates how physician findings and patient information related to one physician's patient may be accessible to another physician so that the data can be used by that physician when making diagnostic and therapeutic decisions for that patient.

[0056] Figure 11 shows a schematic diagram of an exemplary microarray gene expression database that may be used as part of an information-based personalized drug discovery system and method of the present invention. This microarray gene expression database comprises both external and internal databases accessible via a web-based system. External databases may include, but are not limited to, UniGene, GO, TIGR, GenBank, and KEGG. Internal databases may include, but are not limited to, tissue tracking, LIMS, clinical data, and patient tracking. Figure 12 shows a diagram of an exemplary microarray gene expression database data warehouse that may be used as part of an information-based personalized drug discovery system and method of the present invention. Laboratory data, clinical data, and patient data may all be stored within the microarray gene expression database data warehouse, and the data may then be accessible through public / private release and utilized by data analysis tools.

[0057] Figure 13 shows another schematic diagram illustrating the flow of information through the information-based personalized drug discovery system and method of the present invention. Similar to Figure 7, this schematic diagram includes clinical information management, medical and literature information management, and financial management of the information-based personalized drug discovery system and method of the present invention. Figure 14 is a schematic diagram illustrating an exemplary network of the information-based personalized drug discovery system and method of the present invention. To provide patients with proposed treatments or drugs based on various identified targets, patients, practitioners, host hospitals, and laboratories all share and exchange various kinds of information.

[0058] Figures 15–25 are printouts of computer screens related to various parts of a personalized drug discovery system and method based on the information shown in Figures 5–14. Figures 15 and 16 show computer screens for entering physician and insurance company information on behalf of the client. Figures 17–19 show computer screens for entering information to order analysis and testing for patient samples.

[0059] Figure 20 is a computer screen showing the results of microarray analysis of a specific gene tested using a patient sample. This information and computer screen are similar to the information detailed in the patient profile report shown in Figure 3C. Figure 22 is a computer screen showing the results of immunohistochemical tests for a specific patient on various genes. This information is similar to the information included in the patient profile report shown in Figure 3B.

[0060] Figure 21 is a computer screen showing options for finding specific patients, ordering trials and / or trial results, publishing patient reports, and tracking current cases / patients.

[0061] Figure 23 is a computer screen outlining some of the steps for creating a patient profile report as shown in Figures 3A to 3D. Figure 24 shows a computer screen for ordering immunohistochemical testing on a patient sample, and Figure 25 shows a computer screen for inputting information about the primary tumor site for microarray analysis. It will be understood by those skilled in the art that any number and type of computer screens may be used to input the information necessary to utilize the information-based personalized drug discovery system and method of the present invention, and may be used to obtain information resulting from utilizing the information-based personalized drug discovery system and method of the present invention.

[0062] It will also be understood that the foregoing description is a preferred exemplary embodiment of the present invention, and that the present invention is not limited to any particular form shown or described herein. Various modifications can be made in the process of utilizing the present invention without departing from the scope of the present invention as expressed in the design, arrangement and type of elements disclosed herein and in the appended claims.

Claims

1. A method for providing data to determine medical interventions for metastatic cancer: A step of performing at least one test to obtain expression data for multiple molecular targets, including one or more genes and / or one or more gene expression proteins, derived from a biological sample of an individual affected with a specific type of cancer; A step of determining, by one or more processors, one or more molecular targets of genes and / or gene-expressing proteins that show altered expression compared to a reference, independently of the particular type of cancer, wherein the one or more molecular targets are determined using altered expression of the plurality of molecular targets; A step of using one or more processors to access one or more databases using one or more molecular targets unrelated to a particular type of cancer, wherein the one or more databases include drug therapies known to produce therapeutic effects for a particular target; and A step of identifying drug therapies that interact with at least one molecular target exhibiting the change in expression, based on one or more databases, using one or more processors. A method that includes this.

2. The method according to claim 1, wherein the step of identifying a drug therapy that interacts with the at least one molecular target exhibiting the change in expression includes identifying the drug therapy from at least one of automated scrutiny of a large literature database and data obtained from clinical trials.

3. The method according to claim 1, wherein the step of performing at least one test on the plurality of molecular targets includes the step of performing at least one of immunohistochemical (IHC) analysis and microarray analysis.

4. The method according to claim 3, wherein the step of performing the microarray analysis includes the step of performing the microarray analysis using at least one of an expression microarray, a comparative genome hybridization (CGH) microarray, a single nucleotide polymorphism (SNP) microarray, a fluorescence in situ hybridization (FISH), an in situ hybridization (ISH), and a proteomics array.

5. The method according to claim 3, wherein the step of performing the IHC analysis includes performing the IHC analysis on a gene expression protein comprising at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF.

6. The process of performing the aforementioned microarray analysis involves BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, and RXRB. , ADA, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, ASNS, N The method according to claim 3, comprising the step of performing microarray analysis on a gene comprising at least one of FKB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin β receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1.

7. The method according to claim 3, wherein the step of performing at least one test on the plurality of molecular targets derived from the biological sample of the affected individual includes the step of performing immunohistochemical analysis on the tumor, and the step of determining one or more molecular targets of genes and / or gene-expressed proteins that show a change in expression compared to the reference includes the step of determining whether 30% or more of the tumor cells stained +2 or higher for a specific gene-expressed protein.

8. The method according to claim 3, wherein the step of performing at least one test on the plurality of molecular targets derived from the biological sample of the affected individual includes the step of performing the microarray analysis on the tumor, and the step of determining one or more molecular targets of genes and / or gene-expressing proteins that show a change in expression compared to the reference includes the step of identifying which genes are upregulated or downregulated by determining whether the multiplier change in expression of a particular gene is significant at p < 0.001 compared to normal tissue of the reference origin.

9. The method according to claim 1, further comprising the step of providing a patient profile report that identifies the changes in the expression of the gene and / or gene-expressing protein, together with a pharmacotherapy that may be used for interactions with each of the gene and / or gene-expressing proteins exhibiting the changes in expression.

10. A system for determining individualized medical interventions for metastatic cancer. Host server and; A user interface configured to access data and to access the host server to input data; A processor configured to process the input data; The processed data, and the time it was executed, i) Accessing molecular profiles obtained from biological samples from patients with a specific type of cancer in order to obtain expression data for multiple molecular targets; ii) Determining whether at least one molecular target among genes, gene-expressed proteins, molecular mechanisms, and other molecular findings derived from the molecular profile shows altered expression compared to a normal reference, independently of a particular type of cancer, wherein the one or more molecular targets are determined using altered expression of the multiple molecular targets; and iii) Accessing drug therapy databases to identify one or more drug therapies known to interact with at least one molecular target among the genes, gene-expressed proteins, molecular mechanisms, and other molecular findings that exhibit the altered expression, regardless of the specific type of cancer. Memory attached to the processor that stores instructions that cause the processor to execute; Display means configured to display at least one molecular target among genes exhibiting the change in expression, gene-expressing proteins, molecular mechanisms, and other molecular findings, as well as the drug therapy that interacts with them. A system that includes these features.

11. The system according to claim 10, wherein the molecular profile includes at least one of immunohistochemical (IHC) analysis and microarray analysis.

12. The system according to claim 11, wherein the microarray analysis comprises at least one of an expression microarray, a comparative genome hybridization (CGH) microarray, a single nucleotide polymorphism (SNP) microarray, fluorescence in situ hybridization (FISH), in situ hybridization (ISH), and a proteomics array.

13. The system according to claim 11, wherein the IHC analysis comprises IHC analysis of a gene expression protein comprising at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF.

14. The aforementioned microarray analysis includes BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, RXRB, AD A, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DN MT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, ASNS, NF The system according to claim 11, comprising microarray analysis of a gene comprising at least one of KB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin β receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1.

15. The system according to claim 11, wherein the molecular profile comprises immunohistochemical analysis of a tumor, and the instructions for determining whether at least one of a gene, a gene-expressed protein, a molecular mechanism, and other molecular findings obtained from the molecular profile shows a change in expression compared to a normal reference, includes instructions for determining whether 30% or more of tumor cells stained +2 or higher for a particular gene-expressed protein.

16. The system according to claim 11, wherein the molecular profile comprises the microarray analysis of a tumor, and instructions for determining whether at least one of genes, gene-expressed proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile exhibits changes in expression compared to a normal reference, include instructions for identifying which genes are upregulated or downregulated by determining whether the multiplier change in expression of a particular gene is significant at p < 0.001 compared to normal tissue of the reference origin.

17. The system according to claim 10, wherein the display means includes a printed patient profile report.

18. The system according to claim 10, wherein the command to access the drug therapy database to identify one or more drug therapies known to interact with at least one molecular target among the genes, gene-expressed proteins, molecular mechanisms, and other molecular findings exhibiting the changes in expression includes a command to perform an automated scrutiny of a large literature database containing literature correlating genes and / or gene-expressed proteins with drug therapy interactions.

19. A method for providing data to determine medical interventions for metastatic cancer, A step of performing at least one molecular test on multiple molecular targets derived from biological samples of individuals with a specific type of cancer in order to obtain expression data for multiple molecular targets; A step of determining, by one or more processors, that at least one target exhibits altered expression compared to a reference, independently of the particular type of cancer, wherein the at least one target is determined using altered expression of a plurality of molecular targets; A step of using one or more processors to access one or more databases using at least one target unrelated to the particular type of cancer, wherein the one or more databases include drug therapies known to produce therapeutic effects for the particular target; and A step of identifying at least one non-disease-specific drug that interacts with the at least one target exhibiting the change in expression, using one or more databases and one or more processors. Methods that include...

20. The method according to claim 19, wherein the step of identifying the at least one non-disease-specific drug that interacts with the at least one target includes the step of identifying a pharmacotherapy from at least one of automated scrutiny of a large literature database and data obtained from clinical trials.

21. The method according to claim 19, wherein the step of performing the at least one molecular test on the plurality of molecular targets includes the step of performing at least one of immunohistochemical (IHC) analysis and microarray analysis.

22. The method according to claim 21, wherein the step of performing the microarray analysis includes the step of performing the microarray analysis using at least one of an expression microarray, a comparative genome hybridization (CGH) microarray, a single nucleotide polymorphism (SNP) microarray, fluorescence in situ hybridization (FISH) and in situ hybridization (ISH), and a proteomics array.

23. The method according to claim 21, wherein the step of performing at least one IHC analysis includes performing an IHC analysis on a gene expression protein comprising at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF.

24. The step of performing at least one of the microarray analyses is BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TY MS, RXRB, ADA, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, I L2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, AS The method according to claim 21, comprising the step of performing microarray analysis on a gene comprising at least one of NS, NFKB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin β receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1.

25. The method according to claim 21, wherein the step of performing the at least one molecular test on the plurality of molecular targets derived from the biological sample of the affected individual includes the step of performing an immunohistochemical analysis of the tumor, and the step of determining whether the at least one target shows the change in expression compared to the reference includes the step of determining whether 30% or more of the tumor cells stained +2 or higher for a specific gene expression protein.

26. The method according to claim 21, wherein the step of performing the at least one molecular test on the plurality of molecular targets derived from the biological sample of the affected individual includes the step of performing the microarray analysis on the tumor, and the step of determining whether the at least one target shows the change in expression compared to the reference includes the step of identifying which genes are upregulated or downregulated by determining whether the multiplier change in expression of a particular gene is significant at p < 0.001 compared to normal tissue of the reference origin.

27. The method according to claim 19, further comprising the step of providing a patient profile report including the patient's test results for various targets and any treatment proposed based on those results.

Images