WO2016042114A1

WO2016042114A1 - Cxcl14 as a biomarker of hedgehog pathway activity for the diagnosis, prognosis and treatment of idiopathic pulmonary fibrosis

Info

Publication number: WO2016042114A1
Application number: PCT/EP2015/071395
Authority: WO
Inventors: Alexander R. Abbas; Joseph R. Arron; Daryle J. DEPIANTO; Jackson G. EGEN; Guiquan Jia
Original assignee: F. Hoffmann-La Roche Ag; Genentech, Inc.
Priority date: 2014-09-19
Filing date: 2015-09-18
Publication date: 2016-03-24

Abstract

Disclosed are methods using CXCL14 as a systemic biomarker for prognosing, diagnosing, and/or treating a condition mediated, in whole or in part, by the Hedgehog pathway including interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary and non-pulmonary fibrotic conditions, and cancer. Also disclosed are methods using CXCL14 as a systemic biomarker to monitor disease progression as well as the efficacy of Hedgehog and non-Hedgehog pathway therapies for treating a condition mediated, in whole or in part, by the Hedgehog pathway including interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary and non-pulmonary fibrotic conditions, and cancer.

Description

CXCL14 AS A BIOMARKER OF HEDGEHOG PATHWAY ACTIVITY FOR THE DIAGNOSIS, PROGNOSIS AND TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority under 35 USC 119(e) to U.S. provisional patent application number 62/052,872 filed September 19, 2014, the contents of which are incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present disclosure relates generally to CXCL14 as a biomarker to evaluate Hedgehog pathway activity in a subject. In particular, the present disclosure relates to the use of CXCL14 as a systemic biomarker for prognosing, diagnosing, and/or treating a condition mediated, in whole or in part, by the Hedgehog pathway including interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary and non-pulmonary fibrotic conditions, and cancer. The present disclosure is further directed to the use of CXCL14 as a systemic pharmacodynamic biomarker to monitor disease progression as well as the efficacy of Hedgehog pathway and non-Hedgehog pathway therapies for treating a condition mediated, in whole or in part, by the Hedgehog pathway including interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary and non-pulmonary fibrotic conditions, and cancer.

BACKGROUND OF THE INVENTION

[0003] Idiopathic pulmonary fibrosis ("IPF") is a chronic, progressive, and lethal fibrotic disease of unclear etiology leading to irreversible scarring of the lung parenchyma and loss of lung function. Multiple molecular pathways are aberrantly expressed in idiopathic pulmonary fibrosis tissue including directly pro-fibrotic mediators such as TGFp, IL13, and FGF. In addition, pathways implicated in embryonic development and patterning such as Wnt and Hedgehog appear to be reactivated in idiopathic pulmonary fibrosis and may contribute to fibrogenesis. [0004] Targeting the Hedgehog (Hh) pathway may be a potential therapeutic option for idiopathic pulmonary fibrosis. However, molecular, pathological, and clinical heterogeneity in idiopathic pulmonary fibrosis subjects makes it difficult to identify those most likely to benefit from therapy and monitor molecular responsiveness to treatment without directly sampling lung tissue, which poses risks to subjects and is logistically impractical in large multi-center clinical studies. Certain peripheral blood biomarkers measured at a single point in time have been reported to be prognostic for survival or disease progression, including MMP7, IL-8, ICAM1, VCAM1, and S100A12. Many of these biomarker studies, however, have been conducted in small cohorts without replication and have employed suboptimal, inconsistent, and/or unvalidated biomarker detection technologies. Given the limited understanding of targetable molecular mechanisms, the variability in disease trajectory, and time and expense of conducting survival studies in unselected populations of idiopathic pulmonary fibrosis subjects, designing appropriately powered clinical studies to assess the potential of a candidate therapeutic to prolong survival in idiopathic pulmonary fibrosis is challenging. Biomarkers that identify the activity of potentially targetable pathways and provide an accurate prognosis of subsequent disease progression would help to appropriately stratify enrollment in interventional trials to better assess the therapeutic value of investigational drug candidates.

[0005] Accordingly, there exists a need to identify candidate non-invasive biomarkers related to Hedgehog pathway activity that could be used as predictive and/or pharmacodynamic indicators of treatment effects. There also exists a need to have molecular-based diagnostic and prognostic markers associated with various clinical and/or pathophysiological and/or other biological indicators associated with pulmonary fibrotic conditions (such as idiopathic pulmonary fibrosis), non-pulmonary fibrotic conditions, and cancer. BRIEF DESCRIPTION OF THE INVENTION

[0006] In one aspect, the present disclosure is directed to a method of prognosing or of aiding in the prognosis of a condition selected from the group consisting of pulmonary fibrotic conditions (such as idiopathic pulmonary fibrosis), non-pulmonary fibrotic conditions, and cancer in a subject comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; wherein an elevated CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for shortened survival compared to median survival in a subject having the condition, and wherein a reduced CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for increased survival compared to median survival in a subject having the condition. In one embodiment, the method is directed to prognosing or of aiding prognosis of idiopathic pulmonary fibrosis in a subject. In another embodiment, the method is directed to prognosing or of aiding prognosis of a fibrotic disease in a subject. In another embodiment, the method is directed to prognosing or of aiding prognosis of cancer in a subject.

[0007] In one aspect, the present disclosure is directed to a method of prognosing or of aiding in the prognosis of idiopathic pulmonary fibrosis in a subject comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; wherein an elevated CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for shortened survival compared to median survival in a subject having idiopathic pulmonary fibrosis, and wherein a reduced CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for increased survival compared to median survival in a subject having idiopathic pulmonary fibrosis.

[0008] In another aspect, the present disclosure is directed to a method for diagnosing a condition selected from the group consisting of idiopathic pulmonary fibrosis, a fibrotic disease, and cancer in a subject at risk for idiopathic pulmonary fibrosis, fibrotic disease, and cancer comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent- CXCL14 complex, thereby determining the CXCL14 expression level; and providing a diagnosis of idiopathic pulmonary fibrosis when an elevated CXCL14 expression level is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control. In one embodiment, the method is directed to diagnosing idiopathic pulmonary fibrosis in a subject. In another embodiment, the method is directed to diagnosing a fibrotic disease in a subject. In another embodiment, the method is directed to diagnosing cancer in a subject.

[0009] In another aspect, the present disclosure is directed to a method for diagnosing idiopathic pulmonary fibrosis in a subject at risk for idiopathic pulmonary fibrosis comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and providing a diagnosis of idiopathic pulmonary fibrosis when an elevated CXCL14 expression level is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control.

[0010] In another aspect, the present disclosure is directed to a method for selecting a subject for treatment of a condition selected from interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary fibrotic conditions, non- pulmonary fibrotic conditions, and cancer, particularly a condition mediated, in whole or in part, by the Hedgehog pathway, the method comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and selecting the subject for treatment of the condition when an elevated expression level of CXCL14 is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control. In one embodiment, the method is directed to selecting a subject for treatment of idiopathic pulmonary fibrosis. In another embodiment, the method is directed to selecting a subject for treatment of a fibrotic disease. In another embodiment, the method is directed to selecting a subject for treatment of cancer.

[0011] In another aspect, the present disclosure is directed to a method for selecting a subject for idiopathic pulmonary fibrosis therapy comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and selecting the subject for idiopathic pulmonary fibrosis therapy when an elevated expression level of CXCL14 is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control. [0012] In another aspect, the present disclosure is directed to a method of treating a condition selected from the group consisting of idiopathic pulmonary fibrosis, a fibrotic disease, and cancer in a subject comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; detecting the specific binding agent-CXCL14 complex, thereby determining the CXCL14 expression level; and administering an effective amount of a Hedgehog pathway inhibitor to the subject to treat the idiopathic pulmonary fibrosis, provided that elevated expression of CXCL14 has been detected in a biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control. In one embodiment, the method is directed to treating idiopathic pulmonary fibrosis in a subject. In another embodiment, the method is directed to treating a fibrotic disease in a subject. In another embodiment, the method is directed to treating cancer in a subject.

[0013] In another aspect, the present disclosure is directed to a method of treating idiopathic pulmonary fibrosis in a subject comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; detecting the specific binding agent-CXCL14 complex, thereby determining the CXCL14 expression level; and administering an effective amount of a Hedgehog pathway inhibitor to the subject to treat the idiopathic pulmonary fibrosis, provided that elevated expression of CXCL14 has been detected in a biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control.

[0014] In another aspect, the present disclosure is directed to a method for identifying Hedgehog pathway activity in a subject having or diagnosed with a condition selected from the group consisting of interstitial lung disease , a pulmonary fibrotic condition, a non-pulmonary fibrotic condition and cancer comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and identifying a baseline Hedgehog pathway activity in the subject by the expression level of CXCL14 as compared to CXCL14 expression obtained from a biological sample obtained from a control.

[0015] In another aspect, the present disclosure is directed to a method for identifying Hedgehog pathway activity in a subject diagnosed with idiopathic pulmonary fibrosis comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and identifying Hedgehog pathway activity in the subject when an elevated expression level of CXCL14 is determined in the subject or a reduced expression level of CXCL14 is determined in the subject as compared to CXCL14 expression obtained from a biological sample obtained from a control.

[0016] In another aspect, the present disclosure is directed to a Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition for use in treating a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non- pulmonary fibrotic condition, and cancer in a subject comprising measuring in a biological sample obtained from the subject expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; detecting the specific binding agent-CXCL14 complex, thereby determining the CXCL14 expression level; and administering an effective amount of a therapy selected from the group consisting of a Hedgehog pathway inhibitor and a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition to the subject to treat the condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer, provided that elevated expression of CXCL14 has been detected in the biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control.

[0017] In another aspect, the present disclosure is directed to a Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition for use in selecting a subject for idiopathic pulmonary fibrosis therapy comprising measuring in a biological sample obtained from the subject expression of chemokine (C-X-C motif) ligand 14 (CXCL14), by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; selecting the subject for idiopathic pulmonary fibrosis therapy when an elevated expression level of CXCL14 is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control; and administering an effective amount of a therapy selected from the group consisting of a Hedgehog pathway inhibitor and a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

[0018] In another aspect, the present disclosure is directed to a Hedgehog pathway inhibitor for use in treating a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer in a subject with an elevated expression level of chemokine (C- X-C motif) ligand 14 (CXCL14). [0019] In another aspect, the present disclosure is directed to a Hedgehog pathway inhibitor for the manufacture of a medicament for use in treating a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer in a subject with an elevated expression level of chemokine (C-X-C motif) ligand 14 (CXCL14).

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1A-1F depict the expression of Hedgehog pathway genes in idiopathic pulmonary fibrosis and control lung biopsy tissue.

[0021] FIG. 2A depicts CXCL14 gene expression in idiopathic pulmonary fibrosis lung biopsies and in vitro induction by SHh and inhibition by vismodegib treatment in fibroblasts.

[0022] FIG. 2B depicts in vitro induction of GLI1, GLI2, PTCH1, PTCH2 and CXCL14 by varying concentrations of recombinant SHh.

[0023] FIG. 2C depicts vismodegib inhibition of GLI1, GLI2, PTCH1, PTCH2 and CXCL14.

[0024] FIG. 3A-3F depict adenovirus-mediated SHh overexpression in mouse lungs leads to transcriptional evidence of Hedgehog pathway activity of SHh (A), GLI1 (B), GLI2 (C), PTCH1 (D), PTCH2 (E) and elevated CXCL14 (F) expression.

[0025] FIG. 4A-4D depict immuno-localization of CXCL14 in idiopathic pulmonary fibrosis lung tissue.

[0026] FIG. 4E-4H depict CXCL14 gene expression by in situ hybridization in idiopathic pulmonary fibrosis lung tissue.

[0027] FIG. 5A depicts plasma CXCL14 levels in healthy control (N=10) and idiopathic pulmonary fibrosis subjects (N=80). [0028] FIG. 5B depicts plasma CXCL14 levels in a separate group of healthy control (N=18) and cancer subjects enrolled in the SHH4610g study at baseline (N=51).

[0029] FIG. 5C depicts plasma CXCL14 levels in "CXCL14-high" cancer subjects (N=15) over time after vismodegib treatment; subjects with baseline levels > 0.85 ng/ml shown.

[0030] FIG. 5D depicts plasma CXCL14 levels in "CXCL14-low" cancer subjects (N=15) over time after vismodegib treatment; subjects with baseline levels < 0.85 ng/ml; N=8.

[0031] FIG. 6A depicts plasma CCL18 levels in a separate group of healthy control (N=18) and cancer subjects enrolled in the SHH4610g study at baseline (N=51).

[0032] FIG. 6B depicts plasma CCL18 levels in "CCL18-high" cancer subjects (N=15) over time after vismodegib treatment.

[0033] FIG. 6C depicts plasma CXCL14 levels in "CCL18-low" cancer subjects (N=15) over time after vismodegib treatment.

DETAILED DESCRIPTION OF THE INVENTION

[0034] It has been discovered herein that CXCL14 can be employed as a biomarker evaluate Hedgehog pathway activity in a subject. In particular, the present disclosure relates to the use of CXCL14 as a systemic biomarker for prognosing, diagnosing, and/or treating a condition mediated, in whole or in part, by the Hedgehog pathway including pulmonary fibrotic conditions (such as idiopathic pulmonary fibrosis), non-pulmonary fibrotic conditions, and cancer. The present disclosure is further directed to the use of CXCL14 as a systemic biomarker to monitor disease progression as well as the efficacy of Hedgehog and non-Hedgehog pathway therapies for treating a condition mediated, in whole or in part, by the Hedgehog pathway including pulmonary fibrotic conditions (such as idiopathic pulmonary fibrosis), non- pulmonary fibrotic conditions, and cancer.

[0035] The present disclosure uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

[0036] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the ordinary meanings commonly understood by those of ordinary skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd. Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or parameters unless otherwise noted.

A. Definitions

[0037] As used herein, the term "targeted polypeptide" refers to "native sequence" polypeptides and variants (which are further defined herein). [0038] A "native sequence" polypeptide includes a polypeptide having the same amino acid sequence as the corresponding polypeptide derived from nature. Thus, the term "native sequence polypeptide" includes naturally-occurring truncated, augmented, and frame-shifted forms of a polypeptide, including alternatively spliced forms, isoforms and polymorphisms.

[0039] As used herein, the term "naturally occurring variant" refers to a polypeptide having at least about 60% amino acid sequence identity with a reference polypeptide and retains at least one biological activity of the naturally occurring reference polypeptide. Naturally occurring variants can include variant polypeptides having about 65 % amino acid sequence identity, about 70% amino acid sequence identity, about 75% amino acid sequence identity, about 80% amino acid sequence identity, about 80% amino acid sequence identity, about 85% amino acid sequence identity, about 90% amino acid sequence identity, about 95% amino acid sequence identity, about 98% amino acid sequence identity or about 99% amino acid sequence identity to a reference polypeptide.

[0040] As used interchangeably herein, the terms "polynucleotide" and "nucleic acid" refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. A polynucleotide can include modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure can be imparted before or after assembly of the polymer. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, "caps", substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars can be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid supports. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping groups moieties of from 1 to 20 carbon atoms. Other hydroxyls can also be derivatized to standard protecting groups.

[0041] Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2'-0- methyl-2'-0- allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, a-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages can be replaced by alternative linking groups. These alternative linking groups include embodiments wherein phosphate is replaced by P(0)S ("thioate"), P(S)S ("dithioate"), (O)NR 2 ("amidate"), P(0)R, P(0)OR, CO or CH 2 ("formacetal"), in which each R or R^* is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (~0~) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.

[0042] As used herein, the term "oligonucleotide" refers to short, single stranded polynucleotides that are at least about seven nucleotides in length and less than about 250 nucleotides in length. Oligonucleotides may be synthetic. The terms "oligonucleotide" and "polynucleotide" are not mutually exclusive. The description above for polynucleotides is equally and fully applicable to oligonucleotides. [0043] As used herein, the term "primer" refers to a single stranded polynucleotide that is capable of hybridizing to a nucleic acid and allowing the polymerization of a complementary nucleic acid, generally by providing a free 3'-OH group.

[0044] As used herein, the terms "array" and "microarray" refer to an ordered arrangement of hybridizable array elements, preferably polynucleotide probes (e.g., oligonucleotides), on a substrate. The substrate can be a solid substrate, such as a glass slide, or a semi-solid substrate, such as nitrocellulose membrane.

[0045] As used herein, the term "amplification" refers to the process of producing one or more copies of a reference nucleic acid sequence or its complement. Amplification may be linear or exponential (e.g., PCR). A "copy" does not necessarily mean perfect sequence complementarity or identity relative to the template sequence. For example, copies can include nucleotide analogs such as deoxyinosine, intentional sequence alterations (such as sequence alterations introduced through a primer comprising a sequence that is hybridizable, but not fully complementary, to the template), and/or sequence errors that occur during amplification.

[0046] As used herein, the term "detection" includes any methods of detecting, including direct and indirect detection.

[0047] The term "molecular subtype," is used interchangeably herein with "molecular phenotype," to refer to a subtype or phenotype of a condition (such as idiopathic pulmonary fibrosis) characterized by the expression of one or more particular genes or one or more particular proteins, or a particular pattern of expression of a combination of genes or a combination of proteins. The expression of particular genes, proteins or combinations of genes or proteins may be further associated with certain pathological, histological, and/or clinical features of the condition (such as idiopathic pulmonary fibrosis). [0048] As used herein, the term "multiplex-PCR" refers to a single PCR reaction carried out on nucleic acid obtained from a single source (e.g., a subject) using more than one primer set for the purpose of amplifying two or more DNA sequences in a single reaction.

[0049] As used herein, the term "biomarker" refers to an indicator of, for example, a pathological state of a subject, which can be detected in a biological sample of the subject. Biomarkers include DNA -based, RNA-based and protein-based molecular markers.

[0050] As used herein, the term "diagnosis" refers to the identification or classification of a molecular or pathological state, disease or condition. For example, "diagnosis" can refer to identification of a particular type of a condition (such as idiopathic pulmonary fibrosis or usual interstitial pneumonia ("UIP")). "Diagnosis" can also refer to the classification of a particular subtype of a condition (such as idiopathic pulmonary fibrosis), e.g., by histopathological or radiographic criteria or by molecular features (e.g., a subtype characterized by expression of one or a combination of particular genes or proteins encoded by the genes).

[0051] As used herein, the term "aiding diagnosis" refers to methods that assist in making a clinical determination regarding the presence, or nature, of a particular type of symptom or condition of a condition (such as idiopathic pulmonary fibrosis). For example, a method of aiding diagnosis of a condition (such as idiopathic pulmonary fibrosis) can include measuring the expression of certain genes in a biological sample from an individual.

[0052] As used herein, the term "prognosis" is used herein to refer to the prediction of the likelihood of survival over time as well as one or more disease symptoms attributable to a condition (such as idiopathic pulmonary fibrosis) worsening over time.

[0053] As used herein, "median survival" refers to the length of time from either the date of diagnosis or the start of treatment for a disease, such as idiopathic pulmonary fibrosis, that half of the subjects in a group of subjects diagnosed with the disease are still alive.

[0054] As used herein, the term "sample" refers to a composition that is obtained or derived from a subject of interest that contains a cellular and/or other molecular entity that is to be characterized and/or identified, for example based on physical, biochemical, chemical and/or physiological characteristics. For example, the phrase "disease sample" and variations thereof refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and/or molecular entity that is to be characterized. A "tissue" or "cell sample" refers to a collection of similar cells obtained from a tissue of a subject or patient. The source of the tissue or cell sample may be solid tissue as from a fresh, frozen and/or preserved organ or tissue sample or biopsy or aspirate; blood or any blood constituents; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject. The tissue sample can also be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a disease tissue/organ. The tissue sample can contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, and the like.

[0055] As used herein, the terms "control", "control cohort", "reference sample", "reference cell", "reference tissue", "control sample", "control cell", and "control tissue" refer to a sample, cell or tissue obtained from a source that is known, or believed, to not be afflicted with the disease or condition for which a method or composition of the invention is being used to identify. The control can include one control or multiple controls. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy part of the body of the same subject or patient in whom a disease or condition is being identified using a composition or method of the invention. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy part of the body of an individual who is not the subject or patient in whom a disease or condition is being identified using a composition or method of the invention.

[0056] As used herein, a "candidate therapeutic agent" refers to an agent that is being tested or will be tested in a clinical trial under conditions (e.g., a particular dose, dosing regimen, indication) for which the agent has not previously received market approval.

[0057] The term "antibody" is used in its broadest sense and specifically covers, for example, monoclonal antibodies, polyclonal antibodies, antibodies with polyepitopic specificity, single chain antibodies, multi-specific antibodies and fragments of antibodies. Such antibodies can be chimeric, humanized, human and synthetic.

[0058] "Percent (%) amino acid sequence identity" and "homology" with respect to the polypeptide and antibody sequences identified herein refers to the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the polypeptide being compared, after aligning the sequences considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, California. The ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0059] The "stringency" of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature that can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel et al, Current Protocols in Molecular Biology, Wiley Interscience Publishers, (1995). "Stringent conditions" and "high stringency conditions", as used herein, can be identified by those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50C; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/5 OmM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42°C; or (3) overnight hybridization in a solution that employs 50% formamide, 5 x SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1 % sodium pyrophosphate, 5 x Denhardt's solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10% dextran sulfate at 42°C, with a 10 minute wash at 42°C in 0.2 x SSC (sodium chloride/sodium citrate) followed by a 10 minute high-stringency wash consisting of 0.1 x SSC containing EDTA at 55°C. "Moderately stringent conditions" can be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and %SDS) less stringent that those described above. An example of moderately stringent conditions is overnight incubation at 37°C in a solution comprising: 20% formamide, 5 x SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5 x Denhardt's solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed by washing the filters in 1 x SSC at about 37°C-50°C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like.

[0060] The term "subject" is used interchangeably herein with "patient" to refer to an individual to be treated. The subject is a mammal (e.g., human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.). The subject can be a clinical patient, a clinical trial volunteer, an experimental animal, etc. The subject can be suspected of having or at risk for having a condition (such as idiopathic pulmonary fibrosis) or be diagnosed with a condition (such as idiopathic pulmonary fibrosis). The subject can also be suspected of having or at risk for having a lung disease or be diagnosed with a lung disease such as, for example, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease-associated interstitial lung disease. According to one embodiment, the subject to be treated according to this invention is a human.

[0061] As used herein, "treating", "treatment" and "alleviation" refer to measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder or relieve some of the symptoms of the disorder. Those in need of treatment can include those already with the disorder as well as those prone to have the disorder, those at risk for having the disorder and those in whom the disorder is to be prevented. For example, a subject is successfully "treated" for idiopathic pulmonary fibrosis or a lung disease such as, for example, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease- associated interstitial lung disease if, after receiving a therapeutic agent, the subject shows observable and/or measurable decrease or change from baseline in and/or measurable rate of change from baseline over time (e.g., over 3 months (12 weeks), or 6 months (24 weeks), or 9 months (36 weeks), or 12 months (1 year, 52 weeks) in one or more of the following: forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in idiopathic pulmonary fibrosis (ATAQ-IPF) or EuroQol 5- Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score, serum biomarkers including CXCL14, periostin, CCL18 (Chemokine (C-C motif) ligand 18), YKL40 (chitinase-3-like protein; CHI3L1), COMP (cartilage oligomeric matrix protein), OPN (osteopontin), CCL13 (Chemokine (C-C motif) ligand 13).

[0062] An "effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. The term "therapeutically effective amount" refers to an amount effective to "alleviate" or "treat" a disease or disorder in a subject. A therapeutically effective amount of a therapeutic agent can vary according to factors such as the disease state, age, gender, and weight of the individual, and the ability of the antibody to elicit a desired response in the subject. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agent are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount. "Chronic" administration refers to administration of the agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time. "Intermittent" administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.

[0063] As used herein, "Forced Vital Capacity" ("FVC") refers to which refers to a standard test that measures the change in lung air volume between a full inspiration and maximal expiration to residual volume (as opposed to the volume of air expelled in one second as in FEVl). It is a measure of the functional lung capacity. In patients with restrictive lung diseases such as interstitial lung disease including idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, sarcoidosis, and systemic sclerosis, the FVC is reduced typically due to scarring of the lung parenchyma.

[0064] As used herein, "Forced expiratory volume (FEVl)" refers to a standard test that measures the volume of air expelled in the first second of a forced expiration. FEVl is measured by a spirometer, which consists of a mouthpiece and disposable tubing connected to a machine that records the results and displays them on a graph. To perform spirometry, a person inhales deeply, closes the mouth tightly around the tube and then exhales through the tubing while measurements are taken. The volume of air exhaled, and the length of time each breath takes is recorded and analyzed. Spirometry results are expressed as a percentage. Examples of normal spirometry results include a FEVl of 75 percent of vital capacity after one second. An example of abnormal spirometry results include a reading of less than 80 percent of the normal predicted value. An abnormal result usually indicates the presence of some degree of obstructive lung disease such as asthma, emphysema or chronic bronchitis, or restrictive lung disease such as pulmonary fibrosis. For example, FEVl values (percentage of predicted) can be used to classify the obstruction that may occur with asthma and other obstructive lung diseases like emphysema or chronic bronchitis: FEVl 65 percent to 79 percent predicted = mild obstruction, FEVl 40 percent to 59 percent predicted = moderate obstruction, and FEVl less than 40 percent predicted = severe obstruction. In addition, obstructive and restrictive lung disease differ in at least the following way. In obstructive disease, the FEVl /FVC ratio may be lower than normal and the FVC may be normal, while in restrictive disease, the FEVl and FVC may both be lower than normal but the FEV1/FVC ratio may be normal. In such cases, FEV1 is reduced only because FVC is reduced.

[0065] "Elevated expression level" and "elevated levels" refer to an increased expression of a mRNA or a protein in a patient (e.g., a patient suspected of having or diagnosed as having idiopathic pulmonary fibrosis, a fibrotic disease, or cancer) relative to a control, such as subject or subjects who are not suffering from idiopathic pulmonary fibrosis, a fibrotic disease, or cancer.

[0066] "Bronchiolar gene signature," "Bronchiolar signature," and "Bronchiolar gene expression signature" are used interchangeably herein to refer to a combination or subcombination of genes including MUCL1 (Mucin-like protein 1), MUC4 (Mucin 4), MUC20 (Mucin-20), PRR7 (Proline rich 7), PRR15 (Proline rich 15), SPRR1B (small proline -rich protein IB), SPRR2D (small proline -rich protein 2D), KRT5 (keratin 5), KRT6B (keratin 5), KRT13 (keratin 13), KRT14 (keratin 14), KRT15 (keratin 14), KRT17 (keratin 17), SERPINB3 (serpin peptidase inhibitor, clade B, member 3), SERPINB4 (serpin peptidase inhibitor, clade B, member 4), SERPINB5 (serpin peptidase inhibitor, clade B, member 5), SERPINB13 (serpin peptidase inhibitor, clade B, member 13), CLCA2 (Calcium- activated chloride channel regulator 2), TRPV4 (Transient receptor potential cation channel subfamily V member 4), BBS5 (Bardet-Biedl syndrome 5 protein), MMP3 (matrix metalloproteinase-3; Stromelysin-1), SAA4 (serum amyloid A4 encoding constitutive serum amyloid A (SAA)), the gene expression pattern of which correlates with certain subsets of idiopathic pulmonary fibrosis patients. The polypeptides of the bronchiolar gene signature are "targeted polypeptides" as described herein.

[0067] "Lymphoid gene signature," "Lymphoid signature," and "Lymphoid gene expression signature," "Lymphoid follicle gene signature," "Lymphoid follicle signature," and "Lymphoid follicle gene expression signature" are used interchangeably herein to refer to a combination or subcombination of genes including CXCR3 (Chemokine (C-X-C Motif) Receptor 3), CXCR5 (Chemokine (C- X-C Motif) Receptor 5), CXCL13 (Chemokine (C-X-C Motif) Receptor 13), CCR6 (chemokine (C-C motif) receptor 6), CCR7 (chemokine (C-C motif) receptor 7), CD 19 (Cluster of Differentiation 19), MS4A1 (membrane-spanning 4-domains subfamily A member 1; CD20), TNFRSF17 (Tumor necrosis factor receptor superfamily member 17; BCMA), BLK (B Lymphoid Tyrosine Kinase), BLNK (B- cell linker), FCRLA (Fc receptor-like A), FCRL2 (Fc Receptor-Like 2), FCRL5 (Fc Receptor-Like 5), CD79A (Cluster of differentiation CD79A; B-cell antigen receptor complex-associated protein alpha chain; and MB-1 membrane glycoprotein), CD79B (Cluster of Differentiation 79B), CD27 (Tumor Necrosis Factor Receptor Superfamily, Member 7), CD28 (Cluster of Differentiation 28), CDIA (Cluster of Differentiation la), CDIB (T-cell surface glycoprotein CDlb), CDIC (T-Cell Surface Glycoprotein CDlc), CD IE (T-Cell Surface Glycoprotein CDle), IGHV1-69 (Immunoglobulin Heavy Variable 1-69), IGLJ3 (Immunoglobulin lambda joining 3), IGJ (Immunoglobulin J chain), IGHV3-48 (Immunoglobulin Heavy Variable 3-48), IGLV3-21 (Immunoglobulin Lambda Variable 3-21), IGKV1-5 (Immunoglobulin Kappa Variable 1-5), IGHG1 (Immunoglobulin Heavy Constant Gamma 1 (Glm Marker)), IGKC (Immunoglobulin Kappa Constant), IGLV6-57 (Immunoglobulin Lambda Variable 6-57), IGK@ (immunoglobulin kappa locus), IGHA1 (Immunoglobulin Heavy Constant Alpha 1), IGKV2-24 (Immunoglobulin Kappa Variable 2-24), IGKV1D-8 (Immunoglobulin Kappa Variable 1D-8), IGHM (Immunoglobulin Heavy Constant Mu), the gene expression pattern of which correlates with certain subsets of idiopathic pulmonary fibrosis patients. The polypeptides of the lymphoid follicle gene signature are "targeted polypeptides" as described herein.

[0068] "Myofibroblast gene signature," "Myofibroblast signature," "Myofibroblast gene expression signature," "Fibroblast gene signature," "Fibroblast signature," and "Fibroblast gene expression signature" are used interchangeably herein to refer to a combination or subcombination of genes including COL1A1 (collagen type 1 alpha 1), COL1A2 (collagen type 1 alpha 2), COL5A2 (collagen type V alpha 2), COL12A1 (collagen type XII alpha 1), COL14A1 (collagen type XIV alpha 1), COL15A1 (collagen type XV alpha 1), COL16A1 (collagen type XVI alpha 1), COL18A1 (collagen type XVIII alpha 1), CTHRC1 (collagen triple helix repeat containing 1), HGF (hepatocyte growth factor), IGFBP7 (insulin-like growth factor binding protein 7), SCGF (C-Type Lectin Domain Family 11, Member A; CLEC11A); LOXL1 (Lysyl oxidase-like 1), LOXL2 (Lysyl oxidase-like 2), GLI1 (Glioma-Associated Oncogene Family Zinc Finger 1), GLI2 (Glioma-Associated Oncogene Family Zinc Finger 2), SMO (Smoothened); SFRP2 (secreted frizzled- related protein 2), DI02 (Deiodinase 2), CDH11 (cadherin 11), POSTN (periostin), and TGFB3 (transforming growth factor beta 3), the gene expression pattern of which correlates with certain idiopathic pulmonary fibrosis patients. The polypeptides of the myofibroblast gene signature are "targeted polypeptides" as described herein.

[0069] Primers, oligonucleotides and polynucleotides employed in the present invention can be generated using standard techniques known in the art.

[0070] Gene expression signatures associated with idiopathic pulmonary fibrosis and certain subtypes of idiopathic pulmonary fibrosis are provided herein. These signatures constitute biomarkers for idiopathic pulmonary fibrosis and/or subtypes of idiopathic pulmonary fibrosis, and/or predispose or contribute to development, persistence and/or progression of idiopathic pulmonary fibrosis and also are prognostic of survival of idiopathic pulmonary fibrosis patients. Accordingly, the invention disclosed herein is useful in a variety of settings, e.g., in methods and compositions related to idiopathic pulmonary fibrosis prognosis, diagnosis and therapy.

[0071] Nucleic acid, according to any of the methods described herein may be RNA transcribed from genomic DNA or cDNA generated from RNA. Nucleic acid may be derived from a vertebrate, e.g., a mammal. A nucleic acid is said to be "derived from" a particular source if it is obtained directly from that source or if it is a copy of a nucleic acid found in that source. Nucleic acid includes copies of the nucleic acid, e.g., copies that result from amplification. Amplification may be desirable in certain instances, e.g., in order to obtain a desired amount of material for detecting variations. The amplicons may then be subjected to a variation detection method, such as those described below, to determine expression of certain genes.

[0072] A microarray is a multiplex technology that typically uses an arrayed series of thousands of nucleic acid probes to hybridize with, e.g., a cDNA or cRNA sample under high- stringency conditions. Probe-target hybridization is typically detected and quantified by detection of fluorophore-, silver-, or chemiluminescence- labeled targets to determine relative abundance of nucleic acid sequences in the target. In typical microarrays, the probes are attached to a solid surface by a covalent bond to a chemical matrix (via epoxy-silane, amino-silane, lysine, polyacrylamide or others). The solid surface is for example, glass, a silicon chip, or microscopic beads. Various microarrays are commercially available, including those manufactured, for example, by Affymetrix, Inc. and Illumina, Inc.

B. Methods of Prognosing

[0073] In one embodiment, the present disclosure is directed to a method of prognosing or of aiding in the prognosis of a condition selected from interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary fibrotic conditions, non- pulmonary fibrotic conditions, and cancer in a subject, particularly a condition mediated, in whole or in part, by the Hedgehog pathway. The method comprises: obtaining a biological sample from the subject;

measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and

detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level;

wherein an elevated CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for shortened survival compared to median survival in a subject having the condition, and wherein a reduced CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for increased survival compared to median survival in a subject having the condition.

[0074] In one embodiment, the method is directed to prognosing or of aiding in the prognosis of interstitial lung disease, particularly interstitial lung disease mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the interstitial lung disease is idiopathic pulmonary fibrosis, i.e., the method comprises: obtaining a biological sample from the subject;

wherein an elevated CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for shortened survival compared to median survival in a subject having idiopathic pulmonary fibrosis, and wherein a reduced CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for increased survival compared to median survival in a subject having idiopathic pulmonary fibrosis.

[0075] In another embodiment, the method is directed to a subset of idiopathic pulmonary fibrosis subjects. In one embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their bronchiolar gene signature. In another embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their lymphoid gene signature. In another embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their myofibroblast gene signature.

[0076] In one embodiment, the method is directed to prognosing or of aiding in the prognosis of a pulmonary fibrotic condition, particularly a pulmonary fibrotic condition mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the pulmonary fibrotic condition is selected from the group consisting of hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease- associated interstitial lung disease.

[0077] In one embodiment, the method is directed to prognosing or of aiding in the prognosis of a non-pulmonary fibrotic condition, particularly a non-pulmonary fibrotic condition mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the non-pulmonary fibrotic condition is selected from the group consisting of non-alcoholic steatohepatitis, systemic sclerosis, and renal fibrosis.

[0078] In one embodiment, the method is directed to prognosing or of aiding in the prognosis of a cancer, particularly a cancer mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is selected from the group consisting of, for example, basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma.

[0079] The specific binding agent can be selected from a nucleic acid, an antibody, a receptor, and a lectin.

[0080] The sample can be selected from lung tissue, whole blood, and plasma. In one embodiment, the plasma sample is ethylenediaminetetraacetic acid (EDTA)-anticoagulated plasma.

[0081] The method can further include measuring in the biological sample the expression of an additional biomarker selected from SMO, PTCH1, PTCH2, GLI1, GLI2, SHH (alternatively "SHh"; sonic hedgehog), CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof. The method can further include measuring at least 2 additional biomarkers, at least 3 additional biomarkers, at least 4 additional biomarkers, at least 5 additional biomarkers, at least 6 additional biomarkers, at least 7 additional biomarkers, at least 8 additional biomarkers, at least 9 additional biomarkers, at least 10 additional biomarkers, at least 11 additional biomarkers, at least 12 additional biomarkers, at least 13 additional biomarkers, at least 14 additional biomarkers, at least 15 additional biomarkers, at least 16 additional biomarkers, at least 17 additional biomarkers, at least 18 additional biomarkers, at least 19 additional biomarkers, at least 20 additional biomarkers, at least 21 additional biomarkers, at least 22 additional biomarkers, at least 23 additional biomarkers, at least 24 additional biomarkers, at least 25 additional biomarkers, at least 26 additional biomarkers, at least 27 additional biomarkers, at least 28 additional biomarkers, at least 29 additional biomarkers, at least 30 additional biomarkers, at least 31 additional biomarkers, at least 32 additional biomarkers, at least 33 additional biomarkers, at least 34 additional biomarkers, at least 35 additional biomarkers, at least 36 additional biomarkers, at least 37 additional biomarkers, at least 38 additional biomarkers, at least 39 additional biomarkers, at least 40 additional biomarkers, at least 41 additional biomarkers, at least 42 additional biomarkers, at least 43 additional biomarkers, at least 44 additional biomarkers, at least 45 additional biomarkers, at least 46 additional biomarkers, at least 47 additional biomarkers, at least 48 additional biomarkers, at least 49 additional biomarkers, at least 50 additional biomarkers, at least 51 additional biomarkers, at least 52 additional biomarkers, at least 53 additional biomarkers, at least 54 additional biomarkers, at least 55 additional biomarkers, at least 56 additional biomarkers, at least 57 additional biomarkers, at least 58 additional biomarkers, at least 59 additional biomarkers, at least 60 additional biomarkers, at least 62 additional biomarkers, and at least 62 additional biomarkers. [0082] The method can further include measuring one or more lung function parameters in the subject. Lung function parameters include, for example, vital capacity (VC); Forced vital capacity (FVC); Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEVl), 2.0 and 3.0 seconds; FEV/FEV ratio; forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco); a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D); St. George's Respiratory Questionnaire (SRGQ); 6-minute walk distance (6MWD); resting oxygen flow rate; radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score and combinations thereof. Lung function can be measured through any suitable means including high-resolution computed tomography (HRCT) imaging, spirometry, diffusing capacity and exercise tolerance.

[0083] The specific binding agent-CXCL14 complex can be detected using methods known to those skilled in the art such as, for example, nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry. Representative immunoassays include Western blot analysis, ELISA, and flow cytometry.

[0084] In one embodiment, the subject is receiving therapy comprising the administration of a Hedgehog pathway inhibitor. Hedgehog pathway inhibitors include, for example, vismodegib (GDC-0449), GANT61 (2,2 '-{ {dihydro-2-(4- pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine } ) ; sonidegib (N- [6- [(2S ,6R)-2,6-Dimethylmorpholin-4- yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide); itraconazole ((2R,4S)-rel-l-(Butan-2-yl)-4-{4-[4-(4-{ [(2R,4S)-2-(2,4-dichlorophenyl)-2-(lH- l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy}phenyl)piperazin-l-yl]phenyl}- 4,5-dihydro-lH-l,2,4-triazol-5-one)); saridegib (N-

((2S,3R,3aS,3'R,4a'R,6S,6a'R,6b'S,7aR,12a'S,12b'S)-3,6,i r,12b'-tetramethyl- 2',3a,3',4,4',4a',5,5',6,6',6a',6b',7,7a,7',8',10',12',12a',12b'-icosahydro-rH,3H- spko[furo[3,2-b]pyridine-2,9'-naphtho[2,l-a]azulen]-3'-yl)methanesulfonamide); BMS 833923 (N-(2-methyl-5-((methylamino)methyl)phenyl)-4-((4-phenylquinazolin- 2-yl)amino)benzamide,), LEQ 506; PF-04449913 (l-((2R,4R)-2-(lH- benzo[d]imidazol-2-yl)- l-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea); and TAK- 441 (6-Ethyl-N-[l-(hydroxyacetyl)piperidin-4-yl]-l-methyl-4-oxo-5-(2-oxo-2- phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2-c]pyridine-2- carboxamide). In one embodiment, the subject is receiving therapy comprising the administration of vismodegib (GDC-0449). In another embodiment, the subject is receiving therapy comprising the administration of sonidegib (LDE225, N-[6- [(2S,6R)-2,6-Dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4- (trifluoromethoxy)phenyl]benzamide).

[0085] In one embodiment, the subject is receiving therapy comprising the administration of therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition. Such compounds include, for example, pirfenidone (Esbriet), nintedanib (Vargatef), lebrikizumab, tralokinumab, dupilumab, SAR156597 (a bispecific mAb against interleukin-4 and interleukin-13), simtuzumab, FG3019 (a human monoclonal antibody to connective tissue growth factor (CTGF)), STX-vl00 (a humanized monoclonal antibody that targets integrin ανββ), fresolimumab (GC1008), BMS-986202 (Lysophosphatidic acid receptor 1 (LPAR1) (EDG2) antagonist), PRM151 (a recombinant form of Pentraxin-2 (PTX-2)), PXS4728 (inhibitor of semicarbazide-sensitive mono-amine oxidase (SSAO), also known as vascular adhesion protein- 1 (VAP-1)), PXS25 (a TGFb inhibitor), N-acetyl cysteine, and PC-SOD (lecithinized superoxide dismutase). Such therapeutic agents can be used to assess whether therapies directed at other molecular pathways have a secondary pharmacodynamic effect on Hedgehog pathway activity.

C. Methods of Diagnosing

[0086] In another embodiment, the present disclosure is directed to a method for diagnosing a condition selected from interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary fibrotic conditions, non-pulmonary fibrotic conditions, and cancer in a subject, particularly a condition mediated, in whole or in part, by the Hedgehog pathway. The method comprises:

obtaining a biological sample from the subject;

measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14;

detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and

providing a diagnosis of a condition selected from interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary fibrotic conditions, non- pulmonary fibrotic conditions, and cancer when an elevated expression level is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control.

[0087] In one embodiment, the method is directed to diagnosing interstitial lung disease, particularly interstitial lung disease mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the interstitial lung disease is idiopathic pulmonary fibrosis, i.e., the method comprises:

obtaining a biological sample from the subject;

providing a diagnosis of idiopathic pulmonary fibrosis when an elevated expression level is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control.

[0088] In another embodiment, the method is directed to a subset of idiopathic pulmonary fibrosis subjects. In one embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their bronchiolar gene signature. In another embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their lymphoid gene signature. In another embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their myofibroblast gene signature.

[0089] In one embodiment, the method is directed to diagnosing a pulmonary fibrotic condition, particularly a pulmonary fibrotic condition mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the pulmonary fibrotic condition is selected from the group consisting of hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease-associated interstitial lung disease.

[0090] In one embodiment, the method is directed to diagnosing a non- pulmonary fibrotic condition, particularly a non-pulmonary fibrotic condition mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the non-pulmonary fibrotic condition is selected from the group consisting of nonalcoholic steatohepatitis, systemic sclerosis, and renal fibrosis.

[0091] In one embodiment, the method is directed to diagnosing a cancer, particularly a cancer mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is selected from the group consisting of, for example, basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma.

[0092] The specific binding agent can be selected from a nucleic acid, an antibody, a receptor, and a lectin.

[0093] The sample can be selected from lung tissue, whole blood, and plasma. In one embodiment, the plasma sample is ethylenediaminetetraacetic acid (EDTA)-anticoagulated plasma. [0094] The method can further include measuring in the biological sample the expression of an additional biomarker selected from SMO, PTCH1, PTCH2, GLI1, GLI2, SHH (sonic hedgehog), CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof. The method can further include measuring at least 2 additional biomarkers, at least 3 additional biomarkers, at least 4 additional biomarkers, at least 5 additional biomarkers, at least 6 additional biomarkers, at least 7 additional biomarkers, at least 8 additional biomarkers, at least 9 additional biomarkers, at least 10 additional biomarkers, at least 11 additional biomarkers, at least 12 additional biomarkers, at least 13 additional biomarkers, at least 14 additional biomarkers, at least 15 additional biomarkers, at least 16 additional biomarkers, at least 17 additional biomarkers, at least 18 additional biomarkers, at least 19 additional biomarkers, at least 20 additional biomarkers, at least 21 additional biomarkers, at least 22 additional biomarkers, at least 23 additional biomarkers, at least 24 additional biomarkers, at least 25 additional biomarkers, at least 26 additional biomarkers, at least 27 additional biomarkers, at least 28 additional biomarkers, at least 29 additional biomarkers, at least 30 additional biomarkers, at least 31 additional biomarkers, at least 32 additional biomarkers, at least 33 additional biomarkers, at least 34 additional biomarkers, at least 35 additional biomarkers, at least 36 additional biomarkers, at least 37 additional biomarkers, at least 38 additional biomarkers, at least 39 additional biomarkers, at least 40 additional biomarkers, at least 41 additional biomarkers, at least 42 additional biomarkers, at least 43 additional biomarkers, at least 44 additional biomarkers, at least 45 additional biomarkers, at least 46 additional biomarkers, at least 47 additional biomarkers, at least 48 additional biomarkers, at least 49 additional biomarkers, at least 50 additional biomarkers, at least 51 additional biomarkers, at least 52 additional biomarkers, at least 53 additional biomarkers, at least 54 additional biomarkers, at least 55 additional biomarkers, at least 56 additional biomarkers, at least 57 additional biomarkers, at least 58 additional biomarkers, at least 59 additional biomarkers, at least 60 additional biomarkers, at least 62 additional biomarkers, and at least 62 additional biomarkers.

[0095] The method can further include measuring one or more lung function parameters in the subject. Lung function parameters include, for example, vital capacity (VC); Forced vital capacity (FVC); Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds; FEV/FEV ratio; forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco); a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D); St. George's Respiratory Questionnaire (SRGQ); St. George's Respiratory Questionnaire (SRGQ); St. George's Respiratory Questionnaire (SRGQ); 6-minute walk distance (6MWD); resting oxygen flow rate; radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score and combinations thereof. Lung function can be measured through any suitable means including high-resolution computed tomography (HRCT) imaging, spirometry, diffusing capacity and exercise tolerance.

[0096] The specific binding agent-CXCL14 complex can be detected using methods known to those skilled in the art such as, for example, nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry. Representative immunoassays include Western blot analysis, ELISA, and flow cytometry.

[0097] In one embodiment, the subject is receiving therapy comprising the administration of a Hedgehog pathway inhibitor. Hedgehog pathway inhibitors include, for example, vismodegib (GDC-0449), GANT61 (2,2 '-{ {dihydro-2-(4- pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine } ) ; sonidegib (N- [6- [(2S ,6R)-2,6-Dimethylmorpholin-4- yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide); itraconazole ((2R,4S)-rel-l-(Butan-2-yl)-4-{4-[4-(4-{ [(2R,4S)-2-(2,4-dichlorophenyl)-2-(lH- l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy}phenyl)piperazin-l-yl]phenyl}- 4,5-dihydro-lH-l,2,4-triazol-5-one)); saridegib (N-

((2S,3R,3aS,3'R,4a'R,6S,6a'R,6b'S,7aR,12a'S,12b'S)-3,6,i r,12b'-tetramethyl- 2',3a,3',4,4',4a',5,5',6,6',6a',6b',7,7a,7',8',10',12',12a',12b'-icosahydro-rH,3H- spiro[furo[3,2-b]pyridine-2,9'-naphtho[2,l-a]azulen]-3'-yl)methanesulfonamide); BMS 833923 (N-(2-methyl-5-((methylamino)methyl)phenyl)-4-((4-phenylquinazolin- 2-yl)amino)benzamide,), LEQ 506; PF-04449913 (l-((2R,4R)-2-(lH- benzo[d]imidazol-2-yl)- l-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea); and TAK- 441 (6-Ethyl-N-[l-(hydroxyacetyl)piperidin-4-yl]-l-methyl-4-oxo-5-(2-oxo-2- phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2-c]pyridine-2- carboxamide). In one embodiment, the subject is receiving therapy comprising the administration of vismodegib (GDC-0449). In another embodiment, the subject is receiving therapy comprising the administration of sonidegib (LDE225, N-[6- [(2S,6R)-2,6-Dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4- (trifluoromethoxy)phenyl]benzamide).

[0098] In one embodiment, the subject is receiving therapy comprising the administration of therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition. Such compounds include, for example, pirfenidone (Esbriet), nintedanib (Vargatef), lebrikizumab, tralokinumab, dupilumab, SAR156597 (a bispecific mAb against interleukin-4 and interleukin-13), simtuzumab, FG3019 (a human monoclonal antibody to connective tissue growth factor (CTGF)), STX-vl00 (a humanized monoclonal antibody that targets integrin ανββ), fresolimumab (GC1008), BMS-986202 (Lysophosphatidic acid receptor 1 (LPAR1) (EDG2) antagonist), PRM151 (a recombinant form of Pentraxin-2 (PTX-2)), PXS4728 (inhibitor of semicarbazide-sensitive mono-amine oxidase (SSAO), also known as vascular adhesion protein- 1 (VAP-1)), PXS25 (a TGFb inhibitor), N-acetyl cysteine, and PC-SOD (lecithinized superoxide dismutase). Such therapeutic agents can be used to assess whether therapies directed at other molecular pathways have a secondary pharmacodynamic effect on Hedgehog pathway activity. D. Methods of Selecting a Subject for Treatment

[0099] In another embodiment, the present disclosure is directed to a method for selecting a subject for treatment of a condition selected from interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary fibrotic conditions, non- pulmonary fibrotic conditions, and cancer, particularly a condition mediated, in whole or in part, by the Hedgehog pathway. The method comprises:

obtaining a biological sample from the subject;

selecting the subject for treatment of the condition when an elevated expression level of CXCL14 is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control.

[0100] In one embodiment, the method is directed to selecting a subject for treatment of an interstitial lung disease, particularly interstitial lung disease mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the interstitial lung disease is idiopathic pulmonary fibrosis, i.e., the method comprises:

obtaining a biological sample from the subject;

selecting the subject for treatment of idiopathic pulmonary fibrosis when an elevated expression level of CXCL14 is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control. [0101] In another embodiment, the method is directed to a subset of idiopathic pulmonary fibrosis subjects. In one embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their bronchiolar gene signature. In another embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their lymphoid gene signature. In another embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their myofibroblast gene signature.

[0102] In one embodiment, the method is directed to selecting a subject for treatment of a pulmonary fibrotic condition, particularly a pulmonary fibrotic condition mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the pulmonary fibrotic condition is selected from the group consisting of hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease- associated interstitial lung disease.

[0103] In one embodiment, the method is directed to selecting a subject for treatment of a non-pulmonary fibrotic condition, particularly a non-pulmonary fibrotic condition mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the non-pulmonary fibrotic condition is selected from the group consisting of non-alcoholic steatohepatitis, systemic sclerosis, and renal fibrosis.

[0104] In one embodiment, the method is directed to selecting a subject for treatment of a cancer, particularly a cancer mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is selected from the group consisting of, for example, basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma.

[0105] The specific binding agent can be selected from a nucleic acid, an antibody, a receptor, and a lectin. [0106] The sample can be selected from lung tissue, whole blood, and plasma. In one embodiment, the plasma sample is ethylenediaminetetraacetic acid (EDTA)-anticoagulated plasma.

[0107] The method can further include measuring in the biological sample the expression of an additional biomarker selected from SMO, PTCH1, PTCH2, GLI1, GLI2, SHH, CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@ , IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERP B4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof. The method can further include measuring at least 2 additional biomarkers, at least 3 additional biomarkers, at least 4 additional biomarkers, at least 5 additional biomarkers, at least 6 additional biomarkers, at least 7 additional biomarkers, at least 8 additional biomarkers, at least 9 additional biomarkers, at least 10 additional biomarkers, at least 11 additional biomarkers, at least 12 additional biomarkers, at least 13 additional biomarkers, at least 14 additional biomarkers, at least 15 additional biomarkers, at least 16 additional biomarkers, at least 17 additional biomarkers, at least 18 additional biomarkers, at least 19 additional biomarkers, at least 20 additional biomarkers, at least 21 additional biomarkers, at least 22 additional biomarkers, at least 23 additional biomarkers, at least 24 additional biomarkers, at least 25 additional biomarkers, at least 26 additional biomarkers, at least 27 additional biomarkers, at least 28 additional biomarkers, at least 29 additional biomarkers, at least 30 additional biomarkers, at least 31 additional biomarkers, at least 32 additional biomarkers, at least 33 additional biomarkers, at least 34 additional biomarkers, at least 35 additional biomarkers, at least 36 additional biomarkers, at least 37 additional biomarkers, at least 38 additional biomarkers, at least 39 additional biomarkers, at least 40 additional biomarkers, at least 41 additional biomarkers, at least 42 additional biomarkers, at least 43 additional biomarkers, at least 44 additional biomarkers, at least 45 additional biomarkers, at least 46 additional biomarkers, at least 47 additional biomarkers, at least 48 additional biomarkers, at least 49 additional biomarkers, at least 50 additional biomarkers, at least 51 additional biomarkers, at least 52 additional biomarkers, at least 53 additional biomarkers, at least 54 additional biomarkers, at least 55 additional biomarkers, at least 56 additional biomarkers, at least 57 additional biomarkers, at least 58 additional biomarkers, at least 59 additional biomarkers, at least 60 additional biomarkers, at least 62 additional biomarkers, and at least 62 additional biomarkers.

[0108] The method can further include measuring one or more lung function parameters in the subject. Lung function parameters include, for example, vital capacity (VC); Forced vital capacity (FVC); Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds; FEV/FEV ratio; forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco); a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D); St. George's Respiratory Questionnaire (SRGQ); 6-minute walk distance (6MWD); resting oxygen flow rate; radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score and combinations thereof. Lung function can be measured through any suitable means including high-resolution computed tomography (HRCT) imaging, spirometry, diffusing capacity and exercise tolerance.

[0109] The specific binding agent-CXCL14 complex can be detected using methods known to those skilled in the art such as, for example, nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry. Representative immunoassays include Western blot analysis, ELISA, and flow cytometry.

[0110] In one embodiment, the subject is receiving therapy comprising the administration of a Hedgehog pathway inhibitor. Hedgehog pathway inhibitors include, for example, vismodegib (GDC-0449), GANT61 (2,2 '-{ {dihydro-2-(4- pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ Ν,Ν- dimethylbenzenamine } ) ; sonidegib (N- [6- [(2S ,6R)-2,6-Dimethylmorpholin-4- yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide); itraconazole ((2R,4S)-rel-l-(Butan-2-yl)-4-{4-[4-(4-{ [(2R,4S)-2-(2,4-dichlorophenyl)-2-(lH- l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy}phenyl)piperazin-l-yl]phenyl}- 4,5-dihydro-lH-l,2,4-triazol-5-one)); saridegib (N-

[0111] In one embodiment, the subject is receiving therapy comprising the administration of therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition. Such compounds include, for example, pirfenidone (Esbriet), nintedanib (Vargatef), lebrikizumab, tralokinumab, dupilumab, SAR156597 (a bispecific mAb against interleukin-4 and interleukin-13), simtuzumab, FG3019 (a human monoclonal antibody to connective tissue growth factor (CTGF)), STX-vlOO (a humanized monoclonal antibody that targets integrin ανββ), fresolimumab (GC1008), BMS-986202 (Lysophosphatidic acid receptor 1 (LPAR1) (EDG2) antagonist), PRM151 (a recombinant form of Pentraxin-2 (PTX-2)), PXS4728 (inhibitor of semicarbazide-sensitive mono-amine oxidase (SSAO), also known as vascular adhesion protein- 1 (VAP-1)), PXS25 (a TGFb inhibitor), N-acetyl cysteine, and PC-SOD (lecithinized superoxide dismutase). Such therapeutic agents can be used to assess whether therapies directed at other molecular pathways have a secondary pharmacodynamic effect on Hedgehog pathway activity.

[0112] In another embodiment, the present disclosure is directed to a Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition for use in selecting a subject for idiopathic pulmonary fibrosis therapy comprising measuring in a biological sample obtained from the subject expression of chemokine (C-X-C motif) ligand 14 (CXCL14), by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; selecting the subject for idiopathic pulmonary fibrosis therapy when an elevated expression level of CXCL14 is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control; and administering an effective amount of a therapy selected from the group consisting of a Hedgehog pathway inhibitor and a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

[0113] The specific binding agent can be a nucleic acid, an antibody, a receptor, or a lectin.

[0114] The sample can be lung tissue, whole blood, or plasma. In one embodiment, the plasma is EDTA-anticoagulated plasma.

[0115] In another embodiment, the Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition for use in selecting a subject for idiopathic pulmonary fibrosis therapy may also include measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH, CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CDIA, CDIB, CDIC, CDIE, IGHVl-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@ , IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERP B4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

[0116] In another embodiment, the Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition for use in selecting a subject for idiopathic pulmonary fibrosis therapy may also include measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

[0117] In another embodiment, the detecting the specific binding agent- CXCL14 complex may be carried out by nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, or mass spectrometry.

[0118] In another embodiment, the immunoassay may be carried out using Western blot analysis, ELISA, or flow cytometry.

[0119] In another embodiment, the subject is administered a Hedgehog pathway inhibitor therapy. In some embodiments, the Hedgehog pathway inhibitor is selected from the group consisting of vismodegib; 2,2'-{ {dihydro-2-(4-pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis { Ν,Ν-dimethylbenzenamine } ; sonidegib; itraconazole; saridegib; N-(2-methyl-5-((methylamino)methyl)phenyl)-4- ((4-phenylquinazolin-2-yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH- benzo[d]imidazol-2-yl)- l-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea; and 6-Ethyl- N-[l-(hydroxyacetyl)piperidin-4-yl]-l-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3- (2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2-c]pyridine-2-carboxamide. In some embodiments, the Hedgehog pathway inhibitor is vismodegib. In some embodiments, the Hedgehog pathway inhibitor is sonidegib.

[0120] In another embodiment, the subject is administered a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition. The therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition may be pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vl00; fresolimumab; BMS- 986202; PRM151; PXS4728; PXS25; N-acetyl cysteine; or PC-SOD.

E. Methods of Treatment

[0121] In another aspect, the present disclosure is directed to a method of treating a condition selected from interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary fibrotic conditions, non-pulmonary fibrotic conditions, and cancer in a subject, particularly a condition mediated, in whole or in part, by the Hedgehog pathway. The method comprises:

obtaining a biological sample from the subject;

detecting the specific binding agent-CXCL14 complex, thereby determining the CXCL14 expression level; and

administering an effective amount of a Hedgehog pathway inhibitor to the subject to treat the condition provided that elevated expression of CXCL14 has been detected in a biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control.

[0122] In one embodiment, the method is directed to treating interstitial lung disease, particularly interstitial lung disease mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the interstitial lung disease is idiopathic pulmonary fibrosis, i.e., the method comprises:

obtaining a biological sample from the subject;

administering an effective amount of a Hedgehog pathway inhibitor to the subject to treat idiopathic pulmonary fibrosis provided that elevated expression of CXCL14 has been detected in a biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control.

[0123] In another embodiment, the method is directed to a subset of idiopathic pulmonary fibrosis subjects. In one embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their bronchiolar gene signature. In another embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their lymphoid gene signature. In another embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their myofibroblast gene signature.

[0124] In one embodiment, the method is directed to treating a pulmonary fibrotic condition, particularly a pulmonary fibrotic condition mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the pulmonary fibrotic condition is selected from the group consisting of hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease-associated interstitial lung disease.

[0125] In one embodiment, the method is directed to treating a non- pulmonary fibrotic condition, particularly a non-pulmonary fibrotic condition mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the non-pulmonary fibrotic condition is selected from the group consisting of nonalcoholic steatohepatitis, systemic sclerosis, and renal fibrosis.

[0126] In one embodiment, the method is directed to treating a cancer, particularly a cancer mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is selected from the group consisting of, for example, basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma.

[0127] The specific binding agent can be selected from a nucleic acid, an antibody, a receptor, and a lectin.

[0128] The sample can be selected from lung tissue, whole blood, and plasma. In one embodiment, the plasma sample is ethylenediaminetetraacetic acid (EDTA)-anticoagulated plasma.

[0129] The method can further include measuring in the biological sample the expression of an additional biomarker selected from SMO, PTCH1, PTCH2, GLI1, GLI2, SHH, CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CDIA, CDIB, CDIC, CDIE, IGHVl-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKVl-5, IGHGl, IGKC, IGLV6-57, IGK@ , IGHAl, IGKV2-24, IGKVlD-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERP B4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof. The method can further include measuring at least 2 additional biomarkers, at least 3 additional biomarkers, at least 4 additional biomarkers, at least 5 additional biomarkers, at least 6 additional biomarkers, at least 7 additional biomarkers, at least 8 additional biomarkers, at least 9 additional biomarkers, at least 10 additional biomarkers, at least 11 additional biomarkers, at least 12 additional biomarkers, at least 13 additional biomarkers, at least 14 additional biomarkers, at least 15 additional biomarkers, at least 16 additional biomarkers, at least 17 additional biomarkers, at least 18 additional biomarkers, at least 19 additional biomarkers, at least 20 additional biomarkers, at least 21 additional biomarkers, at least 22 additional biomarkers, at least 23 additional biomarkers, at least 24 additional biomarkers, at least 25 additional biomarkers, at least 26 additional biomarkers, at least 27 additional biomarkers, at least 28 additional biomarkers, at least 29 additional biomarkers, at least 30 additional biomarkers, at least 31 additional biomarkers, at least 32 additional biomarkers, at least 33 additional biomarkers, at least 34 additional biomarkers, at least 35 additional biomarkers, at least 36 additional biomarkers, at least 37 additional biomarkers, at least 38 additional biomarkers, at least 39 additional biomarkers, at least 40 additional biomarkers, at least 41 additional biomarkers, at least 42 additional biomarkers, at least 43 additional biomarkers, at least 44 additional biomarkers, at least 45 additional biomarkers, at least 46 additional biomarkers, at least 47 additional biomarkers, at least 48 additional biomarkers, at least 49 additional biomarkers, at least 50 additional biomarkers, at least 51 additional biomarkers, at least 52 additional biomarkers, at least 53 additional biomarkers, at least 54 additional biomarkers, at least 55 additional biomarkers, at least 56 additional biomarkers, at least 57 additional biomarkers, at least 58 additional biomarkers, at least 59 additional biomarkers, at least 60 additional biomarkers, at least 62 additional biomarkers, and at least 62 additional biomarkers.

[0130] The method can further include measuring one or more lung function parameters in the subject. Lung function parameters include, for example, vital capacity (VC); Forced vital capacity (FVC); Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds; FEV/FEV ratio; forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco); a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D); St. George's Respiratory Questionnaire (SRGQ); 6-minute walk distance (6MWD); resting oxygen flow rate; radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score and combinations thereof. Lung function can be measured through any suitable means including high-resolution computed tomography (HRCT) imaging, spirometry, diffusing capacity and exercise tolerance.

[0131] The specific binding agent-CXCL14 complex can be detected using methods known to those skilled in the art such as, for example, nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry. Representative immunoassays include Western blot analysis, ELISA, and flow cytometry.

[0132] In one embodiment, the hedgehog pathway inhibitor administered is selected from the group consisting of, for example, vismodegib (GDC-0449), GANT61 (2,2 ' - { { dihydro-2-(4-pyridinyl)- 1 ,3 (2H,4H)-pyrimidinediyl]bis-

(methylene)}bis{N,N-dimethylbenzenamine}); sonidegib (N-[6-[(2S,6R)-2,6- Dimethylmorpholin-4-yl] pyridin- 3 - yl] -2-methyl- 3 - [4-

(trifluoromethoxy)phenyl]benzamide); itraconazole ((2R,4S)-rel-l-(Butan-2-yl)-4-{4- [4-(4-{ [(2R,4S)-2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan- 4-yl]methoxy}phenyl)piperazin-l-yl]phenyl}-4,5-dihydro-lH-l,2,4-triazol-5-one)); saridegib (N-((2S,3R,3aS,3'R,4a'R,6S,6a'R,6b'S,7aR,12a'S,12b'S)-3,6,ir,12b'- tetramethyl-2',3a,3',4,4',4a',5,5',6,6',6a',6b',7,7a,7',8',10',12',12a',12b'-icosahydro- l'Fl,3H-spiro[furo[3,2-b]pyridine-2,9'-naphtho[2,l-a]azulen]-3'- yl)methanesulfonamide); BMS 833923 (N-(2-methyl-5-

((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide,), LEQ 506; PF-04449913 (l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4- yl)-3-(4-cyanophenyl)urea); and TAK-441 (6-Ethyl-N-[l-(hydroxyacetyl)piperidin-4- yl]-l-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro- lH-pyrrolo[3,2-c]pyridine-2-carboxamide). In one embodiment, the Hedgehog pathway inhibitor administered is vismodegib (GDC-0449). In another embodiment, the Hedgehog pathway inhibitor administered is sonidegib (LDE225, N-[6-[(2S,6R)-

2,6-Dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-

(trifluoromethoxy)phenyl]benzamide).

[0133] In one embodiment, the subject is receiving therapy comprising the administration of therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition. Such compounds include, for example, pirfenidone (Esbriet), nintedanib (Vargatef), lebrikizumab, tralokinumab, dupilumab, SAR156597 (a bispecific mAb against interleukin-4 and interleukin-13), simtuzumab, FG3019 (a human monoclonal antibody to connective tissue growth factor (CTGF)), STX-vlOO (a humanized monoclonal antibody that targets integrin ανββ), fresolimumab (GC1008), BMS-986202 (Lysophosphatidic acid receptor 1 (LPAR1) (EDG2) antagonist), PRM151 (a recombinant form of Pentraxin-2 (PTX-2)), PXS4728 (inhibitor of semicarbazide-sensitive mono-amine oxidase (SSAO), also known as vascular adhesion protein- 1 (VAP-1)), PXS25 (a TGFb inhibitor), N-acetyl cysteine, and PC-SOD (lecithinized superoxide dismutase). Such therapeutic agents can be used to assess whether therapies directed at other molecular pathways have a secondary pharmacodynamic effect on Hedgehog pathway activity.

[0134] The present disclosure is further directed to the corresponding use of the therapeutic agent in the preparation of a medicament.

[0135] In one embodiment, the present disclosure is directed to use of a Hedgehog pathway inhibitor to prepare a medicament for treating a condition in a subject, wherein the condition is selected from interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary fibrotic conditions, non-pulmonary fibrotic conditions, and cancer; and wherein an elevated expression of CXCL14 has been detected in a biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control. In one aspect, the condition is idiopathic pulmonary fibrosis.

[0136] In one embodiment, the present disclosure is directed to use of vismodegib to prepare a medicament for treating a condition in a subject, wherein the condition is selected from interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary fibrotic conditions, non-pulmonary fibrotic conditions, and cancer; and wherein an elevated expression of CXCL14 has been detected in a biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control. In one aspect, the condition is idiopathic pulmonary fibrosis.

[0137] In one embodiment, the present disclosure is directed to use of sonidegib to prepare a medicament for treating a condition in a subject, wherein the condition is selected from interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary fibrotic conditions, non-pulmonary fibrotic conditions, and cancer; and wherein an elevated expression of CXCL14 has been detected in a biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control. In one aspect, the condition is idiopathic pulmonary fibrosis.

[0138] In another embodiment the present disclosure is directed to a Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition for use in treating a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer in a subject comprising measuring in a biological sample obtained from the subject expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; detecting the specific binding agent-CXCL14 complex, thereby determining the CXCL14 expression level; and administering an effective amount of a therapy selected from the group consisting of a Hedgehog pathway inhibitor and a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition to the subject to treat the condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer, provided that elevated expression of CXCL14 has been detected in the biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control.

[0139] The specific binding agent may be a nucleic acid, an antibody, a receptor, or a lectin.

[0140] The may be lung tissue, whole blood, or plasma. In one embodiment, the plasma is EDTA-anticoagulated plasma.

[0141] In some embodiments, the expression of an additional biomarker may be measured in the biological sample such as SMO, PTCH1, PTCH2, GLI1, GLI2, SHH CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD 19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERP B13, CLCA2, TRPV4, BBS5, MMP3, SAA4 or combinations thereof.

[0142] In some embodiments, the lung function in the subject may be measured, wherein the lung function may be vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) or maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high- resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

[0143] In some embodiments, the detecting the specific binding agent- CXCL14 complex may be carried out by nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, or mass spectrometry.

[0144] In some embodiments, the immunoassay may be Western blot analysis, ELISA, or flow cytometry.

[0145] In some embodiments, the subject is administered a Hedgehog pathway inhibitor. In some embodiments, the Hedgehog pathway inhibitor may be vismodegib; 2,2'-{ {dihydro-2-(4-pyridinyl)-l,3(2H,4H)-pyrimidinediyl]bis-

(methylene)}bis{N,N-dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N- (2-methyl-5-((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2- yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l- methylpiperidin-4-yl)-3-(4-cyanophenyl)urea; and 6-Ethyl-N-[l-

(hydroxyacetyl)piperidin-4-yl]-l-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2- trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2-c]pyridine-2-carboxamide.

[0146] In some embodiments, the Hedgehog pathway inhibitor is vismodegib.

[0147] In some embodiments, the Hedgehog pathway inhibitor is sonidegib.

[0148] In some embodiments, the subject is administered a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

[0149] In some embodiments, the therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition may be pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vlOO; fresolimumab; BMS-986202; PRM151; PXS4728; PXS25; N- acetyl cysteine; or PC-SOD.

[0150] In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis. [0151] In some embodiments, the pulmonary fibrotic condition may be hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease- associated interstitial lung disease

[0152] In some embodiments, the non-pulmonary fibrotic condition may be non-alcoholic steatohepatitis, systemic sclerosis, or renal fibrosis.

[0153] In some embodiments, the cancer may be solid tumor.

[0154] In some embodiments, the cancer may be basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, or prostate adenocarcinoma.

[0155] In another embodiment, the present disclosure provides a Hedgehog pathway inhibitor for use in treating a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer in a subject with an elevated expression level of chemokine (C- X-C motif) ligand 14 (CXCL14). In another embodiment, the present disclosure provides a Hedgehog pathway inhibitor for the manufacture of a medicament for use in treating a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer in a subject with an elevated expression level of chemokine (C-X-C motif) ligand 14 (CXCL14). In some embodiments, the Hedgehog pathway inhibitor may be vismodegib; 2,2'-{ {dihydro-2-(4-pyridinyl)-l,3(2H,4H)-pyrimidinediyl]bis-

(hydroxyacetyl)piperidin-4-yl]-l-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2- trifluoroethoxy)-4,5-dihydro- lH-pyrrolo[3,2-c]pyridine-2-carboxamide. In one embodiment, the Hedgehog pathway inhibitor is vismodegib. In another embodiment, the Hedgehog pathway inhibitor is sonidegib.

F. Methods of Identifying Hedgehog Pathway Activity

[0156] In another aspect, the present disclosure is directed to a method for identifying Hedgehog pathway activity in a subject diagnosed with a condition selected from interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary fibrotic conditions, non-pulmonary fibrotic conditions, and cancer in a subject, particularly a condition mediated, in whole or in part, by the Hedgehog pathway. The method comprises:

obtaining a biological sample from the subject diagnosed with the condition; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14;

identifying a baseline Hedgehog pathway activity in the subject by the expression level of CXCL14 as compared to CXCL14 expression obtained from a biological sample obtained from a control.

[0157] This method for identifying Hedgehog pathway activity in a subject (which relies upon the use of CXCL14 as a systemic pharmacodynamic biomarker) can be employed to monitor disease progression as well as the efficacy of Hedgehog and therapeutic agents having a primary mechanism of action other than Hedgehog pathway inhibition for conditions mediated, in whole or in part, by the Hedgehog pathway including interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary and non-pulmonary fibrotic conditions, and cancer. A change in the Hedgehog pathway activity in the subject can then be monitored by determining CXCL14 expression level such as, for example, a first CXCL14 expression level, a second CXCL14 expression level, a third CXCL14 expression level, a fourth CXCL14 expression level, a fifth CXCL14 expression level, a sixth CXCL14 expression level, a seventh CXCL14 expression level, an eighth CXCL14 expression level, a ninth CXCL14 expression level, a tenth CXCL14 expression level, or additional CXCL14 expression levels and comparing the first CXCL14 expression level, the second CXCL14 expression level, the third CXCL14 expression level, the fourth CXCL14 expression level, the fifth CXCL14 expression level, the sixth CXCL14 expression level, the seventh CXCL14 expression level, the eighth CXCL14 expression level, the ninth CXCL14 expression level, the tenth CXCL14 expression level, and the additional CXCL14 expression levels.

[0158] In one embodiment, the method is directed to identifying Hedgehog pathway activity in a subject diagnosed with interstitial lung disease, particularly interstitial lung disease mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the interstitial lung disease is idiopathic pulmonary fibrosis, e.g., the method comprises:

obtaining a biological sample from the subject diagnosed with idiopathic pulmonary fibrosis;

[0159] The method can further comprise:

obtaining at least one additional biological sample from the subject;

measuring in the at least one additional biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the at least one additional biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14;

comparing the CXCL14 expression level obtained from the at least one additional biological sample to one or more CXCL14 expression levels obtained from the subject.

[0160] In another embodiment, the method is directed to a subset of idiopathic pulmonary fibrosis subjects. In one embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their bronchiolar gene signature. In another embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their lymphoid gene signature. In another embodiment, the subset of idiopathic pulmonary fibrosis subjects is identified by their myofibroblast gene signature.

[0161] In one embodiment, the method is directed to identifying Hedgehog pathway activity in a subject diagnosed with a pulmonary fibrotic condition, particularly a pulmonary fibrotic condition mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the pulmonary fibrotic condition is selected from the group consisting of hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease-associated interstitial lung disease.

[0162] In one embodiment, the method is directed to identifying Hedgehog pathway activity in a subject diagnosed with a non-pulmonary fibrotic condition, particularly a non-pulmonary fibrotic condition mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the non-pulmonary fibrotic condition is selected from the group consisting of non-alcoholic steatohepatitis, systemic sclerosis, and renal fibrosis. [0163] In one embodiment, the method is directed to identifying Hedgehog pathway activity in a subject diagnosed with a cancer, particularly a cancer mediated, in whole or in part, by the Hedgehog pathway. In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is selected from the group consisting of, for example, basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma.

[0164] The specific binding agent can be selected from a nucleic acid, an antibody, a receptor, and a lectin.

[0165] The sample can be selected from lung tissue, whole blood, and plasma. In one embodiment, the plasma sample is ethylenediaminetetraacetic acid (EDTA)-anticoagulated plasma.

[0166] The method can further include measuring in the biological sample the expression of an additional biomarker selected from SMO, PTCH1, PTCH2, GLI1, GLI2, SHH, CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@ , IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERP B4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof. The method can further include measuring at least 2 additional biomarkers, at least 3 additional biomarkers, at least 4 additional biomarkers, at least 5 additional biomarkers, at least 6 additional biomarkers, at least 7 additional biomarkers, at least 8 additional biomarkers, at least 9 additional biomarkers, at least 10 additional biomarkers, at least 11 additional biomarkers, at least 12 additional biomarkers, at least 13 additional biomarkers, at least 14 additional biomarkers, at least 15 additional biomarkers, at least 16 additional biomarkers, at least 17 additional biomarkers, at least 18 additional biomarkers, at least 19 additional biomarkers, at least 20 additional biomarkers, at least 21 additional biomarkers, at least 22 additional biomarkers, at least 23 additional biomarkers, at least 24 additional biomarkers, at least 25 additional biomarkers, at least 26 additional biomarkers, at least 27 additional biomarkers, at least 28 additional biomarkers, at least 29 additional biomarkers, at least 30 additional biomarkers, at least 31 additional biomarkers, at least 32 additional biomarkers, at least 33 additional biomarkers, at least 34 additional biomarkers, at least 35 additional biomarkers, at least 36 additional biomarkers, at least 37 additional biomarkers, at least 38 additional biomarkers, at least 39 additional biomarkers, at least 40 additional biomarkers, at least 41 additional biomarkers, at least 42 additional biomarkers, at least 43 additional biomarkers, at least 44 additional biomarkers, at least 45 additional biomarkers, at least 46 additional biomarkers, at least 47 additional biomarkers, at least 48 additional biomarkers, at least 49 additional biomarkers, at least 50 additional biomarkers, at least 51 additional biomarkers, at least 52 additional biomarkers, at least 53 additional biomarkers, at least 54 additional biomarkers, at least 55 additional biomarkers, at least 56 additional biomarkers, at least 57 additional biomarkers, at least 58 additional biomarkers, at least 59 additional biomarkers, at least 60 additional biomarkers, at least 62 additional biomarkers, and at least 62 additional biomarkers.

[0167] The method can further include measuring one or more lung function parameters in the subject. Lung function parameters include, for example, vital capacity (VC); Forced vital capacity (FVC); Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds; FEV/FEV ratio; forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco); a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D); St. George's Respiratory Questionnaire (SRGQ); 6-minute walk distance (6MWD); resting oxygen flow rate; radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score and combinations thereof. Lung function can be measured through any suitable means including high-resolution computed tomography (HRCT) imaging, spirometry, diffusing capacity and exercise tolerance. [0168] The specific binding agent-CXCL14 complex can be detected using methods known to those skilled in the art such as, for example, nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry. Representative immunoassays include Western blot analysis, ELISA, and flow cytometry.

[0169] In one embodiment, the subject is receiving therapy comprising the administration of a Hedgehog pathway inhibitor. Hedgehog pathway inhibitors include, for example, vismodegib (GDC-0449), GANT61 (2,2 '-{ {dihydro-2-(4- pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine } ) ; sonidegib (N- [6- [(2S ,6R)-2,6-Dimethylmorpholin-4- yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide); itraconazole ((2R,4S)-rel-l-(Butan-2-yl)-4-{4-[4-(4-{ [(2R,4S)-2-(2,4-dichlorophenyl)-2-(lH- l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy}phenyl)piperazin-l-yl]phenyl}- 4,5-dihydro-lH-l,2,4-triazol-5-one)); saridegib (N-

((2S,3R,3aS,3'R,4a'R,6S,6a'R,6b'S,7aR,12a'S,12b'S)-3,6,i r,12b'-tetramethyl- 2',3a,3',4,4',4a',5,5',6,6',6a',6b',7,7a,7',8',10',12',12a',12b'-icosahydro-rH,3H- spiro[furo[3,2-b]pyridine-2,9'-naphtho[2,l-a]azulen]-3'-yl)methanesulfonamide); BMS 833923 (N-(2-methyl-5-((methylamino)methyl)phenyl)-4-((4-phenylquinazolin- 2-yl)amino)benzamide,), LEQ 506; PF-04449913 (l-((2R,4R)-2-(lH- benzo[d]imidazol-2-yl)- l-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea); and TAK- 441 (6-Ethyl-N-[l-(hydroxyacetyl)piperidin-4-yl]-l-methyl-4-oxo-5-(2-oxo-2- phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2-c]pyridine-2- carboxamide). In one embodiment, the Hedgehog pathway inhibitor is vismodegib (GDC-0449). In another embodiment, the Hedgehog pathway inhibitor is sonidegib (LDE225, N-[6-[(2S,6R)-2,6-Dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4- (trifluoromethoxy)phenyl]benzamide).

[0170] In one embodiment, the subject is receiving therapy comprising the administration of therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition. Such compounds include, for example, pirfenidone (Esbriet), nintedanib (Vargatef), lebrikizumab, tralokinumab, dupilumab, SAR156597 (a bispecific mAb against interleukin-4 and interleukin-13), simtuzumab, FG3019 (a human monoclonal antibody to connective tissue growth factor (CTGF)), STX-vlOO (a humanized monoclonal antibody that targets integrin ανββ), fresolimumab (GC1008), BMS-986202 (Lysophosphatidic acid receptor 1 (LPAR1) (EDG2) antagonist), PRM151 (a recombinant form of Pentraxin-2 (PTX-2)), PXS4728 (inhibitor of semicarbazide-sensitive mono-amine oxidase (SSAO), also known as vascular adhesion protein- 1 (VAP-1)), PXS25 (a TGFb inhibitor), N-acetyl cysteine, and PC-SOD (lecithinized superoxide dismutase). Such therapeutic agents can be used to assess whether therapies directed at other molecular pathways have a secondary pharmacodynamic effect on Hedgehog pathway activity.

G. Biological Sample

[0171] The biological sample used in the methods of the present disclosure can be obtained using certain methods known to those skilled in the art. Biological samples may be obtained from vertebrate animals, and in particular, mammals. In certain instances, a biological sample is lung tissue, whole blood, plasma, serum or peripheral blood mononuclear cells (PBMC). By screening such body samples, a prognosis (e.g., of survival) or diagnosis (e.g., of a molecular subtype) can be achieved for conditions mediated, in whole or in part, by the Hedgehog pathway including interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary and non-pulmonary fibrotic conditions, and cancer. In addition, the progress of therapy can be monitored more easily by testing such body samples for variations in expression levels of target nucleic acids (or encoded polypeptides).

[0172] Subsequent to the determination that a subject, or the tissue or cell sample comprises a gene expression signature disclosed herein, it is contemplated that an effective amount of an appropriate therapeutic agent can be administered to the subject to treat the in the subject. Clinical diagnosis in a subject of the various pathological conditions described herein can be made by the skilled practitioner. Clinical diagnostic techniques are available in the art which allow, e.g., for the diagnosis or detection of Hedgehog pathway activity in a subject having or suspected of having a condition mediated, in whole or in part, by the Hedgehog pathway including interstitial lung disease (such as idiopathic pulmonary fibrosis), pulmonary and non-pulmonary fibrotic conditions, and cancer.

[0173] As used in the various methods of the present disclosure, the terms "control", "control value", "reference" and "reference value" refer to an expression level value obtained from control sample", "control cell", and "control tissue" "reference sample", "reference cell", and "reference tissue" obtained from a source that is known, or believed, to not be afflicted with the condition for which a method or composition is being used to identify. It is to be understood that the control need not be obtained at the same time as the biological sample of the subject is obtained. Thus, a control value for an expression level can be determined and used for comparison of the expression level for the biological sample of the subject or the biological samples of multiple subjects.

H. Detection of Biomarkers

[0174] Expression levels of nucleic acids (DNA and RNA) may be detected in samples of tissue, whole blood, plasma, or serum. Various methods are known in the art for detecting nucleic acid expression levels in such biological samples, including nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis.

[0175] Expression levels of proteins may be detected in samples of tissue, whole blood, plasma, or serum. Various methods are known in the art for detecting protein expression levels in such biological samples, including various immunoassay methods. A wide range of immunoassay techniques have been previously described, see, e.g., U.S. Pat. Nos. 4,016,043, 4,424,279 and 4,018,653. These include both single-site and two-site or "sandwich" assays of the non-competitive types, as well as in the traditional competitive binding assays. These assays also include direct binding of a labeled antibody to a target biomarker. [0176] Sandwich assays are among the most useful and commonly used assays. A number of variations of the sandwich assay technique exist, and all are intended to be encompassed by the present invention. Briefly, in a typical forward assay, an unlabeled antibody is immobilized on a solid substrate, and the sample to be tested brought into contact with the bound molecule. After a suitable period of incubation, for a period of time sufficient to allow formation of an antibody-antigen complex, a second antibody specific to the antigen, labeled with a reporter molecule capable of producing a detectable signal is then added and incubated, allowing time sufficient for the formation of another complex of antibody-antigen-labeled antibody. Any unreacted material is washed away, and the presence of the antigen is determined by observation of a signal produced by the reporter molecule. The results may either be qualitative, by simple observation of the visible signal, or may be quantitated by comparing with a control sample containing known amounts of biomarker.

[0177] Variations on the forward assay include a simultaneous assay, in which both sample and labeled antibody are added simultaneously to the bound antibody. These techniques are well known to those skilled in the art, including any minor variations as will be readily apparent. In a typical forward sandwich assay, a first antibody having specificity for the biomarker is either covalently or passively bound to a solid surface. The solid surface is typically glass or a polymer, the most commonly used polymers being cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene. The solid supports may be in the form of tubes, beads, discs of microplates, or any other surface suitable for conducting an immunoassay. The binding processes are well-known in the art and generally consist of cross-linking covalently binding or physically adsorbing, the polymer-antibody complex is washed in preparation for the test sample. An aliquot of the sample to be tested is then added to the solid phase complex and incubated for a period of time sufficient (e.g. 2-40 minutes or overnight if more convenient) and under suitable conditions (e.g. from room temperature to 40°C such as between 25° C and 32° C inclusive) to allow binding of any subunit present in the antibody. Following the incubation period, the antibody subunit solid phase is washed and dried and incubated with a second antibody specific for a portion of the biomarker. The second antibody is linked to a reporter molecule which is used to indicate the binding of the second antibody to the molecular marker.

[0178] An alternative method involves immobilizing the target biomarkers in the sample and then exposing the immobilized target to specific antibody which may or may not be labeled with a reporter molecule. Depending on the amount of target and the strength of the reporter molecule signal, a bound target may be detectable by direct labelling with the antibody. Alternatively, a second labeled antibody, specific to the first antibody is exposed to the target- first antibody complex to form a target-first antibody-second antibody tertiary complex. The complex is detected by the signal emitted by the reporter molecule. As used herein, "reporter molecule" refers to a molecule which, by its chemical nature, provides an analytically identifiable signal which allows the detection of antigen-bound antibody. The most commonly used reporter molecules in this type of assay are either enzymes, fluorophores, radionuclide containing molecules (i.e. radioisotopes) and chemiluminescent molecules.

[0179] In the case of an enzyme immunoassay, an enzyme is conjugated to the second antibody, generally by means of glutaraldehyde or periodate. As will be readily recognized, however, a wide variety of different conjugation techniques exist, which are readily available to the skilled artisan. Commonly used enzymes include horseradish peroxidase, glucose oxidase, galactosidase and alkaline phosphatase, amongst others. The substrates to be used with the specific enzymes are generally chosen for the production, upon hydrolysis by the corresponding enzyme, of a detectable color change. Examples of suitable enzymes include alkaline phosphatase and peroxidase. It is also possible to employ fluorogenic substrates, which yield a fluorescent product rather than the chromogenic substrates noted above. In all cases, the enzyme-labeled antibody is added to the first antibody-molecular marker complex, allowed to bind, and then the excess reagent is washed away. A solution containing the appropriate substrate is then added to the complex of antibody-antigen-antibody. The substrate will react with the enzyme linked to the second antibody, giving a qualitative visual signal, which may be further quantitated, usually spectrophotometrically, to give an indication of the amount of biomarker which was present in the sample. Alternately, fluorescent compounds, such as fluorescein and rhodamine, may be chemically coupled to antibodies without altering their binding capacity. When activated by illumination with light of a particular wavelength, the fluorochrome-labeled antibody adsorbs the light energy, inducing a state to excitability in the molecule, followed by emission of the light at a characteristic color visually detectable with a light microscope. As in the EIA, the fluorescent labeled antibody is allowed to bind to the first antibody- molecular marker complex. After washing off the unbound reagent, the remaining tertiary complex is then exposed to the light of the appropriate wavelength, the fluorescence observed indicates the presence of the molecular marker of interest. Immunofluorescence and EIA techniques are both very well established in the art. However, other reporter molecules, such as radioisotope, chemilumine scent or bioluminescent molecules, can also be employed.

I. Therapeutic Agents

[0180] The therapeutic agents used in the methods of the present disclosure can be administered in accordance with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes. Optionally, administration can be performed through mini-pump infusion using various commercially available devices. It should be noted with respect to the various embodiments disclosed in this application that any reference to a "therapeutic agent" generally and any reference to a specific compound that is a therapeutic agent should be construed to encompass all forms of the therapeutic agent or compound including, where applicable, the free form and pharmaceutically acceptable salts. For example, a reference to vismodegib should be construed to encompass all forms of vismodegib including, where applicable, the free form and pharmaceutically acceptable salts of vismodegib. [0181] As previously noted, the therapeutic agents for the treatment of idiopathic pulmonary fibrosis can include, for example, Hedgehog pathway inhibitors as well as therapeutic compounds having a primary mechanism of action other than Hedgehog pathway inhibition. In one embodiment, the therapeutic agent is a Hedgehog pathway inhibitor. Hedgehog pathway inhibitors for the treatment of idiopathic pulmonary fibrosis can include, for example, vismodegib (GDC-0449, a small molecule inhibitor of Smoothened (SMO)), GANT61 (2,2'-{ {dihydro-2-(4- pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine}, Merck Millipore, Billerica, MA); sonidegib (LDE225, N-[6- [(2S,6R)-2,6-Dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4- (trifluoromethoxy)phenyl]benzamide); itraconazole (Sporanox; (2R,4S)-rel-l-(Butan- 2-yl)-4-{4-[4-(4-{ [(2R,4S)-2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)- l,3-dioxolan-4-yl]methoxy}phenyl)piperazin-l-yl]phenyl}-4,5-dihydro-lH- 1,2,4- triazol-5-one)); saridegib (IPI-926; N-

((2S,3R,3aS,3'R,4a'R,6S,6a'R,6b'S,7aR,12a'S,12b'S)-3,6,i r,12b'-tetramethyl- 2',3a,3',4,4',4a',5,5',6,6',6a',6b',7,7a,7',8',10',12',12a',12b'-icosahydro-rH,3H- spiro[furo[3,2-b]pyridine-2,9'-naphtho[2,l-a]azulen]-3'-yl)methanesulfonamide); BMS 833923 (N-(2-methyl-5-((methylamino)methyl)phenyl)-4-((4-phenylquinazolin- 2-yl)amino)benzamide, Steve et al. Abstract B192 Mol Cancer Ther 2009; 8(123) Supplement), LEQ 506 (Peukert et al. Chem Med Chem 2013; 8:1261); PF-04449913 (Glasdegib; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4-yl)-3-(4- cyanophenyl)urea; Munchhof et al. ACS Med Chem Lett 2012; 3(2): 106); and TAK- 441 (6-Ethyl-N-[l-(hydroxyacetyl)piperidin-4-yl]-l-methyl-4-oxo-5-(2-oxo-2- phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2-c]pyridine-2- carboxamide; Ibuki et al. Int. J. Cancer 2013; 133: 1955). In one embodiment, the Hedgehog pathway inhibitor is vismodegib (GDC-0449). In another embodiment, the Hedgehog pathway inhibitor is sonidegib (LDE225, N-[6-[(2S,6R)-2,6- Dimethylmorpholin-4-yl] pyridin- 3 - yl] -2-methyl- 3 - [4- (trifluoromethoxy)phenyl]benzamide). J. Examples

[0182] The biological samples used to generate the data reported in Examples 1-4 were obtained in a multicenter, two-stage, open-label Phase lb study designed to describe the pharmacokinetics of daily (QD), three times weekly (ΤΓ\¥), and once weekly (QW) dosing of 150 mg vismodegib (GDC-0449, a small molecule, inhibitor of SMO) in 63 safety-evaluable subjects with advanced solid tumors that were refractory to treatment or for whom no standard therapy existed. Both total and unbound plasma concentrations of vismodegib were sustained through 72 hours after a single dose of vismodegib, and steady-state was achieved within 11 days of continuous once-daily dosing. The residual plasma samples from PK assays from the subjects on dose regimen of QD and ΤΓ\¥ were used for protein biomarker analysis due to low vismodegib plasma concentrations in the group of QW. Tissues were obtained from clinical samples from IPF subjects at the time of biopsy or lung transplantation, while plasma samples and clinical manifestation were obtained from a separate cohort of IPF subjects at the time of initial presentation to the interstitial lung disease clinic at University of California San Francisco (see, Chen W, et al. Proc Natl Acad Sci U S A 2011; 108:9589-94; DePianto et al, Thorax in press, 2014). Unless stated otherwise, the following methods were used to generate data presented in Examples 1-5.

1. Cell culture and gene expression quantitation

[0183] Human Colon Fibroblasts (CCD-I8C0) were cultured as recommended by ATCC and treated in medium with recombinant human SHh protein and/or two different Hedgehog pathway inhibitors, vismodegib (100 μιηοΙ/L) and GANT61 (2,2 ' - { { dihydro-2- (4-pyridinyl)- 1 ,3 (2H,4H)-pyrimidinediyl] bis-

(methylene)}bis{N,N-dimethylbenzenamine}; 5 μιηοΙ/L) (Merck Millipore, Billerica, MA), or dimethyl sulfoxide (DMSO) as equivalent control for inhibitors for 24 hours to 72 hours. The expression of genes of interest was analyzed using qPCR assays from Applied Biosystems Inc (ABI; Grand Island, NY). 2. Adenovirus mouse model

[0184] C56BL/6J mice were infected with 1x109 plaque forming units (pfu) of recombinant, replication-deficient adenovirus (Vector Biolabs) encoding murine SHh (Ad-mSHh) or luciferase (Ad-Luc) in 50 μΐ of phosphate buffered saline (PBS) by intratracheal (i.t.) administration or treated with PBS alone as a vehicle control. At 7 and 14 days post-treatment, mice were euthanized and lungs were removed and stored in RNALater (Qiagen). Lung tissue was disassociated in GentleMACS M Tubes (Miltenyi Biotec) and processed for total RNA using the RNeasy Mini Kit (Qiagen). Gene expression was analyzed using qPCR assays from Applied Biosystems Inc (ABI) and the Fluidigm platform. All animal experiments were approved by the Genentech Institutional Animal Care and Use Committee.

3. Measurement of plasma protein biomarkers

[0185] CXCL14 and CCL18 levels in plasma were determined using CXCL14 and CCL18 DuoSet assays from R&D systems (Minneapolis, MN) that have been further developed for human blood matrix, respectively. The quantitation assays were performed following the developed protocols with high and low controls on each assay plate for assay technical quality control. Briefly, plasma samples diluted in assay diluent were incubated in the plates pre-coated with capture antibody for two hours at room temperature with agitation. The biotinylated detection antibody was then incubated for 1 hour in the assay plates after thoroughly washing, and the signal quantitation was achieved with addition of conjugates and substrates subsequently. The plasma level of biomarker was interpreted against standard curve with 4-P fitting. The limit of detection (LOD) of the assay was 0.078 ng/niL and 15.6 pg/mL for CXCL14 and CCL18, respectively.

4. Immunohistochemistry and in situ hybridization

[0186] Formalin fixed paraffin embedded lung tissue sections from IPF patients, obtained at the time of lung transplantation, and control lung tissue from unused donor lungs were examined by immunohistochemistry (IHC) for localization of CXCL14 protein. IHC was performed with a polyclonal rabbit primary antibody to CXCL14, Abeam ab36622 (Abeam, Cambridge, MA). Immunoreactivity was detected using the VECTASTAIN elite ABC kit (for rabbit IgG) from Vector Labs (Burlingame, CA). Briefly, tissue sections were cleared and rehydrated, followed by overnight incubation with primary antibody at 4°C and detected following the manufacturer's protocol utilizing the VECTASTAIN ABC kit. Images were captured by brightfield microscopy on an Olympus 1X53 inverted microscope.

[0187] Nonisotopic RNA in situ hybridization (ISH) was performed on 4- μιη FFPE sections using the QuantiGene ViewRNA EZ tissue assay (Affymetrix/Panomics) following the manufacturer's protocol on a Tecan platform equipped to carry out nonisotopic ISH. Gene-specific probe sets for detection of human CXCL14 mRNA (VA1- 15998)— target region 157-1902, in GenBank accession NM_004887 was used on tissue samples. A probe set to Bacillus subtilis dihydropicolinate reductase (dapB) (VF1-11712)— target region 1363-2044 in GenBank accession L38424— was used as a negative control. De-paraffinization was carried out on a Leica stainer XL. After the boiling step in a Thermo Scientific PM module, the slides were briefly dipped in ethanol and dried before assembling the ISH chamber for the Tecan platform. Vulcan Fast Red substrate (Biocare) was used for chromogenic detection.

5. Statistical analysis

[0188] Statistical analyses were performed in R. Gene expression microarray data was analyzed from previously described datasets (Lorusso PM, et al. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2011; 17:5774-82; DePianto et al, Thorax in press, 2014) in R using LIMMA restricted to genes encoding soluble secreted proteins (GO:0005576 "extracellular space" in Bioconductor annotation) with thresholds of Benjamini- Hochberg adjusted p-value less than 0.05 and absolute value of fold change greater than 2. Relationships between gene expression and plasma protein concentration across patient groups was tested by the Wilcoxon rank-sum method. Mouse lung gene expression and plasma biomarker changes over time were analyzed by the Student paired T-test, with each time point compared to baseline pre-treatment levels. A nominal p-value < 0.05 was considered statistically significant.

EXAMPLE 1: Gene expression patterns in IPF implicate Hedgehog pathway activity

[0189] In this Example, Hedgehog pathway activity was assessed in lung biopsy tissue. Lung biopsies from subjects with IPF (N=40) and control unused donor lung tissue (N=8) were assessed for expression of GLI1, GLI2, SMO, SHH, PTCH1 and PTCH2 using qPCR A slightly decreased expression of SHH and PTCH1 was observed in IPF relative to control and significantly elevated expression of SMO, PTCH2, GLI1, and GLI2 was observed in IPF relative to control (FIG. 1).

EXAMPLE 2: CXCL14 is expressed at elevated levels in IPF lungs and is inducible by SHH in vitro

[0190] In this Example, candidate biomarkers of Hedgehog pathway activity were identified in IPF lung. Genes encoding soluble secreted proteins were identified by comparing transcriptome-wide expression patterns of genes encoding secreted proteins in CCD-I8C0 human colon myofibroblast cells stimulated in vitro with SHH (Chen W, et al. Proc Natl Acad Sci U S A 2011; 108:9589-94) and IPF vs. control lungs (DePianto et al, Thorax in press, 2014).

[0191] The most significantly differentially expressed gene common to both datasets was CXCL14, which encodes a soluble chemokine. CXCL14 had a mean expression level 16.8-fold higher in IPF than in control lung tissue and 7.3-fold higher in SHH stimulated vs. control CCD-I8C0 cells. Other genes encoding secreted proteins that were differentially expressed in both datasets included VCAN, IGFB7, and SLIT1; however VCAN and IGFB7 were only modestly upregulated to an average of 2-fold in IPF vs. control and SLIT1 was expressed at lower levels in IPF than in control lung (Table 1). Table 1. Genes encoding secreted proteins upregulated by SHH in CCD-I8C0 cells and overlap with genes upregulated in IPF vs. control.

[0192] Differential CXCL14 expression was confirmed by qPCR in IPF lung tissue (FIG. 2A) and in CCD-I8C0 cells upon SHH stimulation using recombinant SHH ("rSHh") (FIG. 2B). SHH-mediated CXCL14 induction in CCD-I8C0 cells was inhibited by vismodegib treatment (FIG. 2C). Taken together, these data show that CXCL14 expression is elevated in IPF lungs; CXCL14 is a Hedgehog-inducible gene whose expression can be inhibited by vismodegib in fibroblasts.

EXAMPLE 3: CXCL14 expression induced by lung overexpression of SHH in vivo [0193] In this Example, SHH was overexpressed in mice to determine whether Hh activity can regulate CXCL14 expression in vivo. Adenoviral vectors were used to enforce ectopic SHH expression in the lungs of wild-type mice following intratracheal infection with a replication-deficient adenoviral vector engineered to express murine SHH (Ad-mSHH). To account for potential effects of adenovirus itself, an adenoviral vector encoding luciferase (Ad-Luc) was used as a control and compared lung gene expression levels to mice infected with adenovirus encoding mouse SHH (Ad-mSHH) and controls without virus (PBS). At 7 and 14 days after adenovirus infection, mice infected with Ad-mSHH expressed significantly higher levels of SHH, GLIl, PTCH1, PTCH2, and CXCL14 compared to mice infected with Ad-Luc (FIG. 3A-3F. *, p<0.05 vs. Ad-Luc by Student's t-test). Increased SHH expression demonstrated sufficient viral infection and sustained Hedgehog ligand expression; increases in GLIl, PTCH1, and PTCH2 showed that the adenovirally-delivered SHH gene resulted in sufficient SHH protein expression to activate signaling; and induction of CXCL14 showed that CXCL14 is a transcriptional target of SHH activity in vivo in lung tissue.

EXAMPLE 4: In situ hybridization for SHH, GLIl, and CXCL14 in IPF lung biopsy tissue

[0194] In this Example, lung tissue was analyzed for SHH, GLIl and CXCL14 by immunohistochemistry and in situ hybridization. Lung tissue from IPF subjects exhibits substantial spatial heterogeneity, with areas of normal-appearing lung parenchyma interspersed with myofibroblastic foci typical of a usual interstitial pneumonia (UIP) pattern and dense scar tissue (Cavazza A, et al. Respiratory Medicine 2010; 104 Suppl l:Sl l-22; DePianto et al, Thorax in press, 2014). To characterize the spatial distribution of CXCL14 protein and CXCL14 gene expression, respectively, in IPF, immunohistochemistry (IHC) and in situ hybridization (ISH) were performed on explanted lung tissue from IPF subjects and control unused donor lung tissue. CXCL14 protein immunoreactivity was dramatically increased in IPF compared to control, with intense staining in bronchiolar epithelium and more diffuse staining in fibroblastic areas underlying relatively intact- appearing parenchymal tissue (FIG. 4A-D). CXCL14 gene expression was localized in epithelial cells and underlying fibroblasts in areas of dense fibrosis in IPF lung tissue but was virtually undetectable in control lung (FIG. 4E-H). Taken together, these data show that CXCL14 gene and protein expression are increased in fibrotic regions of IPF lung tissue.

EXAMPLE 5: CXCL14 protein levels in plasma from IPF and cancer subjects and pharmacodynamic effects of vismodegib on plasma CXCL14 levels in cancer subjects

[0195] In this Example, the use of CXCL14 as a systemic biomarker of IPF was investigated. CXCL14 levels were measured in plasma from IPF (N=80) and control (N=10) subjects using an immunoassay. Like many chemokines, CXCL14 interacts with heparin (Tanegashima K, et al. Experimental Cell Research 2010; 316: 1263-70) which could lead to assay interference in serum or heparinized plasma, therefore the CXCL14 assay utilized EDTA-anticoagulated plasma. Plasma CXCL14 levels were significantly higher in IPF subjects relative to controls, with approximately 70% of IPF subjects exhibiting levels greater than the upper limit observed in healthy controls (FIG. 5A).

[0196] Whether Hedgehog pathway inhibition with vismodegib exerted pharmacodynamic effects on circulating CXCL14 levels was then determined. As clinical samples from vismodegib-treated IPF subjects were not currently available, plasma samples were collected from solid tumor subjects enrolled in a phase IB dose- scheduling study of vismodegib (Lorusso PM, et al. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2011; 17:5774-82). At baseline, the cancer subjects in the vismodegib study (N=51) had elevated plasma CXCL14 levels relative to a separate cohort of healthy controls (N=18), exhibiting a similar distribution to that observed in IPF subjects (FIG. 5B).

[0197] Prior analyses suggested that weekly dosing of vismodegib in that study after an 11 -dose daily run-in period did not provide adequate systemic coverage to mediate biological effects, thus pharmacodynamic analyses were restricted to subjects in the daily (QD, N=17) or three times weekly (ΤΓ\¥, N=7) arms of the study (Lorusso PM, et al. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2011; 17:5774-82). Approximately 2/3 of the cancer subjects exhibited baseline elevation of plasma CXCL14 levels above the upper limit observed in controls (0.85 ng/ml). Thus, it was hypothesized that any pharmacodynamic effects of vismodegib treatment might only be detectable in those subjects. Consistent with that hypothesis, pharmacodynamic effect of vismodegib treatment was not observed on subjects with baseline CXCL14 levels in the normal range (less than 0.85 ng/ml). In subjects with elevated baseline levels of plasma CXCL14 (greater than 0.85 ng/ml, N=15), there was a significant decrease in plasma CXCL14 levels upon vismodegib treatment, with median decreases of 22 and 48% after 28 and 49 days of treatment, respectively (FIG. 5C. * p=0.05; **p<0.01). Four days after cessation of treatment, there appeared to be a slight rebound in plasma CXCL14 levels, with a median decrease of 15% compared to baseline at day 57. No significant pharmacodynamic effect of vismodegib treatment on subjects with baseline CXCL14 levels in the "normal" range (less than 0.85 ng/ml, N=8) was observed (FIG. 5D).

[0198] To assess whether this change over time reflected reversion to the mean or other unrelated effects, plasma levels of CCL18, a chemokine not known to be regulated by Hedgehog pathway activity, were assessed. No pharmacodynamic effects of vismodegib treatment on plasma CCL18 levels were observed despite systemically elevated levels in cancer subjects in the study relative to controls (FIG. 6). Taken together, these data show that blood levels of CXCL14 protein are elevated in IPF subjects compared to controls, and in solid tumor subjects with elevated baseline levels of CXCL14, there was a decrease in systemic CXCL14 upon Hedgehog pathway inhibition with vismodegib treatment.

[0199] As demonstrated herein, the CXCL14 gene and protein expression levels are elevated in IPF lung tissue, CXCL14 is the most highly upregulated gene encoding a secreted protein in SHH-treated fibroblasts, and peripheral blood concentrations of CXCL14 protein are elevated in both IPF and solid tumor subjects. Hedgehog pathway antagonism with vismodegib treatment in solid tumor subjects reduced circulating CXCL14 levels in the subset of subjects with elevated baseline levels. As IPF is a complex and heterogeneous disease, interpreting the outcomes of interventional clinical studies may be hampered by variable activity of the targeted pathway in the treated population. Thus, peripheral blood CXCL14 levels have utility as a noninvasive biomarker in IPF subjects in clinical studies. CXCL14 can be used as a predictive biomarker that identifies IPF subjects with high Hedgehog pathway activity and, hence, exhibit a biological response to Hedgehog pathway antagonism. CXCL14 can also serve as a pharmacodynamic biomarker to assess the extent of Hedgehog pathway inhibition mediated by treatment. Finally, as a specific biomarker of Hedgehog pathway activity in IPF, changes in CXCL14 levels upon inhibition of other molecular pathways known to be active in IPF (e.g., TGFp, IL13, PDGF, FGF, etc.) can indicate the degree of cross-talk between those pathways and the Hedgehog pathway.

[0200] The present disclosure establishes that measuring the levels of CXCL14 and determining whether the value of CXCL14 falls above or below the threshold level can be used to assess the degree of Hedgehog pathway activity in the lungs of IPF subjects at the time of diagnosis. As direct sampling of the lung is often impractical or infeasible in subjects with IPF, noninvasive assessments of disease activity and molecular pathology is of significant value. Blood-based biomarkers as described here have the potential to enable drug development for and clinical management of IPF on several levels: as predictive, prognostic, pharmacodynamic, and surrogate measures of disease activity.

[0201] Predictive biomarkers provide evidence of the activity of a particular molecular pathway prior to treatment and identify a subpopulation of subjects most likely to benefit from a targeted therapy. A given pathway may be heterogeneously expressed across a population of IPF subjects and the ability to identify clinical benefit from agents targeting that pathway may be compromised if only a subset of subjects that cannot otherwise be prospectively identified exhibits benefit. A predictive biomarker that identifies IPF subjects most likely to benefit from a targeted therapeutic could help stratify enrollment in clinical trials to more rigorously test the therapeutic hypothesis.

[0202] Prognostic biomarkers stratify the risk of future disease progression or death. Given the high mortality in IPF, a successful therapeutic intervention might be expected to significantly prolong lifespan relative to placebo. Given the variability in disease trajectory, however, it is challenging to assess survival benefits in early- stage clinical trials without treating large numbers of subjects for many years. A prognostic biomarker that identifies IPF subjects most likely to suffer significant disease progression or death within a 1-2 year period is useful to stratify enrollment in clinical trials to assess whether there is a short-term survival benefit in subjects most likely to progress during the trial. Furthermore, it is possible that a given therapeutic intervention benefits subjects with relatively good prognoses but is ineffective in subjects whose disease has progressed past a certain point of no return.

[0203] Pharmacodynamic biomarkers should reflect the proximal activity of a particular molecular pathway involved in the disease process and should change in response to a specific therapeutic intervention. Changes in pharmacodynamic markers upon treatment indicate whether and to what extent the molecular intervention is affecting its target; thus these markers may help enable appropriate dose selection in a dose-ranging study. In a disease with poorly defined short-term clinical outcome measures such as IPF, significant pharmacodynamic effects in the absence of any clinical benefit can help discriminate between inappropriate target selection and inappropriate dosing as the reason for failure of a trial. Surrogate biomarkers, like pharmacodynamic markers, should change in response to treatment but may be distal to the targeted pathway and are linked more closely to downstream manifestations of disease and clinical outcomes. Changes in surrogate biomarkers over the short term may indicate the likely long-term efficacy of continued treatment, e.g. on survival outcomes. A given biomarker may represent any, several, or all of the predictive, prognostic, pharmacodynamic, and surrogate categories.

Claims

WHAT IS CLAIMED IS:

1. A method of prognosing or of aiding prognosis of a condition selected from the group consisting of interstitial lung disease, a fibrotic disease and cancer in a subject comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; wherein an elevated CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for shortened survival compared to median survival in a subject having the condition, and wherein a reduced CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for increased survival compared to median survival in a subject having the condition.

2. The method of claim 1, wherein the specific binding agent is selected from the group consisting of a nucleic acid, an antibody, a receptor, and a lectin.

3. The method of claim 1, wherein the sample is selected from the group consisting of tissue, whole blood, and plasma.

4. The method of claim 3, wherein the plasma is EDTA-anticoagulated plasma.

5. The method according to claim 1 further comprising measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH, CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD 19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

6. The method of claim 1 further comprising measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

7. The method of claim 1, wherein detecting the specific binding agent- CXCL14 complex is selected from the group consisting of nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry.

8. The method of claim 7 wherein the immunoassay is selected from the group consisting of Western blot analysis, ELISA, and flow cytometry.

9. The method of claim 1, wherein the subject is receiving a Hedgehog pathway inhibitor therapy.

10. The method of claim 9, wherein the subject is receiving a Hedgehog pathway inhibitor therapy selected from the group consisting of vismodegib; 2,2'- { { dihydro-2-(4-pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N-(2-methyl-5- ((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4-yl)-3-(4- cyanophenyl)urea; and 6-Ethyl-N- [ 1 -(hydroxyacetyl)piperidin-4-yl] - 1 -methyl-4-oxo-

5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2- c]pyridine-2-carboxamide.

11. The method of claim 9, wherein the subject is receiving vismodegib.

12. The method of claim 9, wherein the subject is receiving sonidegib.

13. The method of claim 1, wherein the subject is receiving therapy comprising the administration of therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

14. The method of claim 13, wherein the subject is receiving a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition is selected from the group consisting of pirfenidone, nintedanib, lebrikizumab, tralokinumab, dupilumab, SAR156597, simtuzumab, FG3019, STX-vlOO, fresolimumab, BMS-986202, PRM151, PXS4728, PXS25, N-acetyl cysteine, and PC- SOD.

15. The method of claim 1, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

16. The method of claim 1, wherein the fibrotic condition is selected from the group consisting of a pulmonary fibrotic condition and a non-pulmonary fibrotic condition.

17. The method of claim 16, wherein the pulmonary fibrotic condition is selected from the group consisting of hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease-associated interstitial lung disease

18. The method of claim 16, wherein the non-pulmonary fibrotic condition is selected from the group consisting of non-alcoholic steatohepatitis, systemic sclerosis, and renal fibrosis.

19. The method of claim 1, wherein the cancer is a solid tumor.

20. The method of claim 1, wherein the cancer is selected from the group consisting of basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma.

21. A method of prognosing or of aiding prognosis of idiopathic pulmonary fibrosis in a subject comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent- CXCL14 complex, thereby determining the CXCL14 expression level; wherein an elevated CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for shortened survival compared to median survival in a subject having idiopathic pulmonary fibrosis, and wherein a reduced CXCL14 expression level compared to CXCL14 expression obtained from a biological sample obtained from a control is indicative of a prognosis for increased survival compared to median survival in a subject having idiopathic pulmonary fibrosis.

22. The method of claim 21, wherein the specific binding agent is selected from the group consisting of a nucleic acid, an antibody, a receptor, and a lectin.

23. The method of claim 21, wherein the sample is selected from the group consisting of lung tissue, whole blood, and plasma.

24. The method of claim 23, wherein the plasma is EDTA-anticoagulated plasma.

25. The method according to claim 21 further comprising measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH, CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

26. The method of claim 21 further comprising measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEVl), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

27. The method of claim 21, wherein detecting the specific binding agent - CXCL14 complex is selected from the group consisting of nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry.

28. The method of claim 21 wherein the immunoassay is selected from the group consisting of Western blot analysis, ELISA, and flow cytometry.

29. The method of claim 21, wherein the subject is receiving a Hedgehog pathway inhibitor therapy.

30. The method of claim 29, wherein the subject is receiving a Hedgehog pathway inhibitor therapy selected from the group consisting of vismodegib; 2,2'- { { dihydro-2-(4-pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N-(2-methyl-5- ((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4-yl)-3-(4- cyanophenyl)urea; and 6-Ethyl-N- [ 1 -(hydroxyacetyl)piperidin-4-yl] - 1 -methyl-4-oxo- 5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2- c]pyridine-2-carboxamide.

31. The method of claim 29, wherein the subject is receiving vismodegib.

32. The method of claim 29, wherein the subject is receiving sonidegib.

33. The method of claim 21, wherein the subject is receiving a therapy comprising the administration of therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

34. The method of claim 33, wherein the subject is receiving a therapy comprising the administration of therapeutic agent selected from the group consisting of pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vlOO; fresolimumab; BMS-986202; PRM151; PXS4728; PXS25; N-acetyl cysteine; and PC-SOD.

35. A method for diagnosing a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non- pulmonary fibrotic condition, and cancer in a subject at risk for interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and providing a diagnosis of a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer when an elevated expression level is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control.

36. The method of claim 35, wherein the specific binding agent is selected from the group consisting of a nucleic acid, an antibody, a receptor, and a lectin.

37. The method of claim 35, wherein the sample is selected from the group consisting of lung tissue, whole blood, and plasma.

38. The method of claim 37, wherein the plasma is EDTA-anticoagulated plasma.

39. The method according to claim 35 further comprising measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

40. The method of claim 35 further comprising measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEVl), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

41. The method of claim 35, wherein detecting the specific binding agent - CXCL14 complex is selected from the group consisting of nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry.

42. The method of claim 35 wherein the immunoassay is selected from the group consisting of Western blot analysis, ELISA, and flow cytometry.

43. The method of claim 35, wherein the subject is receiving a Hedgehog pathway inhibitor therapy.

44. The method of claim 43, wherein the subject is receiving a Hedgehog pathway inhibitor therapy selected from the group consisting of vismodegib; 2,2'- { { dihydro-2-(4-pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N-(2-methyl-5- ((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4-yl)-3-(4- cyanophenyl)urea; and 6-Ethyl-N- [ 1 -(hydroxyacetyl)piperidin-4-yl] - 1 -methyl-4-oxo- 5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2- c]pyridine-2-carboxamide.

45. The method of claim 43, the subject is receiving vismodegib.

46. The method of claim 43, the subject is receiving sonidegib.

47. The method of claim 35, wherein the subject is receiving a therapy comprising the administration of a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

48. The method of claim 47, wherein the subject is receiving a therapy comprising the administration of a therapeutic agent selected from the group consisting of pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vlOO; fresolimumab; BMS-986202; PRM151; PXS4728; PXS25; N-acetyl cysteine; and PC-SOD.

49. The method of claim 35, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

50. The method of claim 35, wherein the pulmonary fibrotic condition is selected from the group consisting of hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease-associated interstitial lung disease

51. The method of claim 35, wherein the non-pulmonary fibrotic condition is selected from the group consisting of non-alcoholic steatohepatitis, systemic sclerosis, and renal fibrosis.

52. The method of claim 35, wherein the cancer is a solid tumor.

53. The method of claim 35, wherein the cancer is selected from the group consisting of basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma.

54. A method for diagnosing idiopathic pulmonary fibrosis (IPF) in a subject at risk for IPF comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and providing a diagnosis of IPF when an elevated expression level is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control.

55. The method of claim 54, wherein the specific binding agent is selected from the group consisting of a nucleic acid, an antibody, a receptor, and a lectin.

56. The method of claim 54, wherein the sample is selected from the group consisting of lung tissue, whole blood, and plasma.

57. The method of claim 56, wherein the plasma is EDTA-anticoagulated plasma.

58. The method according to claim 54 further comprising measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

59. The method of claim 54 further comprising measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEVl), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

60. The method of claim 54, wherein detecting the specific binding agent - CXCL14 complex is selected from the group consisting of nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry.

61. The method of claim 60 wherein the immunoassay is selected from the group consisting of Western blot analysis, ELISA, and flow cytometry.

62. The method of claim 54, wherein the subject is receiving a Hedgehog pathway inhibitor therapy.

63. The method of claim 62, wherein the subject is receiving a Hedgehog pathway inhibitor therapy selected from the group consisting of vismodegib; 2,2'- { { dihydro-2-(4-pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N-(2-methyl-5- ((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4-yl)-3-(4- cyanophenyl)urea; and 6-Ethyl-N- [ 1 -(hydroxyacetyl)piperidin-4-yl] - 1 -methyl-4-oxo- 5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2- c]pyridine-2-carboxamide.

64. The method of claim 62, wherein the subject is receiving vismodegib.

65. The method of claim 62, wherein the subject is receiving sonidegib.

66. The method of claim 54, wherein the subject is receiving a therapy comprising the administration of a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

67. The method of claim 66, wherein the subject is receiving a therapy comprising the administration of a therapeutic agent selected from the group consisting of pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vlOO; fresolimumab; BMS-986202; PRM151; PXS4728; PXS25; N-acetyl cysteine; and PC-SOD.

68. A method of treating a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer in a subject comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; detecting the specific binding agent-CXCL14 complex, thereby determining the CXCL14 expression level; and administering an effective amount of a therapy selected from the group consisting of a Hedgehog pathway inhibitor and a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition to the subject to treat the condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer, provided that elevated expression of CXCL14 has been detected in a biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control.

69. The method of claim 68, wherein the specific binding agent is selected from the group consisting of a nucleic acid, an antibody, a receptor, and a lectin.

70. The method of claim 68, wherein the sample is selected from the group consisting of lung tissue, whole blood, and plasma.

71. The method of claim 70, wherein the plasma is EDTA-anticoagulated plasma.

72. The method according to claim 68 further comprising measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

73. The method of claim 68 further comprising measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

74. The method of claim 68, wherein detecting the specific binding agent- CXCL14 complex is selected from the group consisting of nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry.

75. The method of claim 68 wherein the immunoassay is selected from the group consisting of Western blot analysis, ELISA, and flow cytometry.

76. The method of claim 68, wherein the subject is administered a Hedgehog pathway inhibitor therapy.

77. The method of claim 76, wherein the subject is administered a Hedgehog pathway inhibitor therapy selected from the group consisting of vismodegib; 2,2'-{ {dihydro-2-(4-pyridinyl)-l,3(2H,4H)-pyrimidinediyl]bis-

78. The method of claim 76, wherein the subject is administered vismodegib.

79. The method of claim 76, wherein the subject is administered sonidegib.

80. The method of claim 68, wherein the subject is administered a therapy comprising the administration of a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

81. The method of claim 80, wherein the subject is administered a therapy comprising the administration of a therapeutic agent selected from the group consisting of pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vl00; fresolimumab; BMS-986202; PRM151; PXS4728; PXS25; N-acetyl cysteine; and PC-SOD.

82. The method of claim 68, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

83. The method of claim 68, wherein the pulmonary fibrotic condition is selected from the group consisting of hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease-associated interstitial lung disease

84. The method of claim 68, wherein the non-pulmonary fibrotic condition is selected from the group consisting of non-alcoholic steatohepatitis, systemic sclerosis, and renal fibrosis.

85. The method of claim 68, wherein the cancer is a solid tumor.

86. The method of claim 68, wherein the cancer is selected from the group consisting of basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma.

87. A method of treating idiopathic pulmonary fibrosis (IPF) in a subject comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and administering an effective amount of a therapy selected from the group consisting of a Hedgehog pathway inhibitor and a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition to the subject to treat the IPF, provided that elevated expression of CXCL14 has been detected in a biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control.

88. The method of claim 87, wherein the specific binding agent is selected from the group consisting of a nucleic acid, an antibody, a receptor, and a lectin.

89. The method of claim 87, wherein the sample is selected from the group consisting of lung tissue, whole blood, and plasma.

90. The method of claim 89, wherein the plasma is EDTA-anticoagulated plasma.

91. The method according to claim 87 further comprising measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

92. The method of claim 87 further comprising measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

93. The method of claim 87, wherein detecting the specific binding agent - CXCL14 complex is selected from the group consisting of nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry.

94. The method of claim 93 wherein the immunoassay is selected from the group consisting of Western blot analysis, ELISA, and flow cytometry.

95. The method of claim 87, wherein the subject is receiving a Hedgehog pathway inhibitor therapy.

96. The method of claim 95, wherein the subject is receiving a Hedgehog pathway inhibitor therapy selected from the group consisting of vismodegib; 2,2'- { { dihydro-2-(4-pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N-(2-methyl-5- ((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4-yl)-3-(4- cyanophenyl)urea; and 6-Ethyl-N- [ 1 -(hydroxyacetyl)piperidin-4-yl] - 1 -methyl-4-oxo- 5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2- c]pyridine-2-carboxamide.

97. The method of claim 95, wherein the subject is receiving vismodegib.

98. The method of claim 95, wherein the subject is receiving sonidegib.

99. The method of claim 87, wherein the subject is receiving a therapy comprising the administration of a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

100. The method of claim 99, wherein the subject is receiving a therapy comprising the administration of a therapeutic agent selected from the group consisting of pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vl00; fresolimumab; BMS-986202; PRM151; PXS4728; PXS25; N-acetyl cysteine; and PC-SOD.

101. A method for selecting a subject for idiopathic pulmonary fibrosis therapy comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and selecting the subject for idiopathic pulmonary fibrosis therapy when an elevated expression level of CXCL14 is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control.

102. The method of claim 101, wherein the specific binding agent is selected from the group consisting of a nucleic acid, an antibody, a receptor, and a lectin.

103. The method of claim 101, wherein the sample is selected from the group consisting of lung tissue, whole blood, and plasma.

104. The method of claim 103, wherein the plasma is EDTA-anticoagulated plasma.

105. The method according to claim 101 further comprising measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH, CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

106. The method of claim 101 further comprising measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

107. The method of claim 101, wherein detecting the specific binding agent-CXCL14 complex is selected from the group consisting of nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry.

108. The method of claim 107 wherein the immunoassay is selected from the group consisting of Western blot analysis, ELISA, and flow cytometry.

109. The method of claim 101, wherein the subject is administered a Hedgehog pathway inhibitor therapy.

110. The method of claim 109, wherein the subject is administered a Hedgehog pathway inhibitor therapy selected from the group consisting of vismodegib; 2,2'-{ {dihydro-2-(4-pyridinyl)-l,3(2H,4H)-pyrimidinediyl]bis- (methylene)}bis{N,N-dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N- (2-methyl-5-((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2- yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l- methylpiperidin-4-yl)-3-(4-cyanophenyl)urea; and 6-Ethyl-N-[l- (hydroxyacetyl)piperidin-4-yl]-l-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2- trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2-c]pyridine-2-carboxamide.

111. The method of claim 109, wherein the subject is administered vismodegib.

112. The method of claim 109, wherein the subject is administered sonidegib.

113. The method of claim 101, wherein the subject is administered a therapy comprising the administration of a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

114. The method of claim 113, wherein the subject is administered a therapy comprising the administration of a therapeutic agent selected from the group consisting of pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vlOO; fresolimumab; BMS-986202; PRM151; PXS4728; PXS25; N-acetyl cysteine; and PC-SOD.

115. A method for identifying Hedgehog pathway activity in a subject having or diagnosed with a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition and cancer comprising obtaining a biological sample from the subject; measuring in the biological sample the expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; and identifying a baseline Hedgehog pathway activity in the subject by the expression level of CXCL14 as compared to CXCL14 expression obtained from a biological sample obtained from a control.

116. The method of claim 115, wherein the specific binding agent is selected from the group consisting of a nucleic acid, an antibody, a receptor, and a lectin.

117. The method of claim 115, wherein the sample is selected from the group consisting of lung tissue, whole blood, and plasma.

118. The method of claim 117, wherein the plasma is EDTA-anticoagulated plasma.

119. The method according to claim 115 further comprising measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH, CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@, IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

120. The method of claim 115 further comprising measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5-Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

121. The method of claim 115, wherein detecting the specific binding agent-CXCL14 complex is selected from the group consisting of nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry.

122. The method of claim 121 wherein the immunoassay is selected from the group consisting of Western blot analysis, ELISA, and flow cytometry.

123. The method of claim 115, wherein the subject is receiving a Hedgehog pathway inhibitor therapy.

124. The method of claim 123, wherein the subject is receiving a Hedgehog pathway inhibitor therapy selected from the group consisting of vismodegib; 2,2'- { { dihydro-2-(4-pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N-(2-methyl-5- ((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4-yl)-3-(4- cyanophenyl)urea; and 6-Ethyl-N- [ 1 -(hydroxyacetyl)piperidin-4-yl] - 1 -methyl-4-oxo- 5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2- c]pyridine-2-carboxamide.

125. The method of claim 123, wherein the subject is receiving vismodegib.

126. The method of claim 123, wherein the subject is receiving sonidegib.

127. The method of claim 115, wherein the subject is receiving a therapy comprising the administration of a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

128. The method of claim 127, wherein the subject is receiving a therapy comprising the administration of a therapeutic agent selected from the group consisting of pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vlOO; fresolimumab; BMS-986202; PRM151; PXS4728; PXS25; N-acetyl cysteine; and PC-SOD.

129. The method of claim 115, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

130. The method of claim 115, wherein the pulmonary fibrotic condition is selected from the group consisting of hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease-associated interstitial lung disease

131. The method of claim 115, wherein the non-pulmonary fibrotic condition is selected from the group consisting of non-alcoholic steatohepatitis, systemic sclerosis, and renal fibrosis.

132. The method of claim 115, wherein the cancer is a solid tumor.

133. The method of claim 115, wherein the cancer is selected from the group consisting of basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma.

134. A Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition for use in treating a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer in a subject comprising measuring in a biological sample obtained from the subject expression of chemokine (C-X-C motif) ligand 14 (CXCL14) by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; detecting the specific binding agent-CXCL14 complex, thereby determining the CXCL14 expression level; and administering an effective amount of a therapy selected from the group consisting of a Hedgehog pathway inhibitor and a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition to the subject to treat the condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer, provided that elevated expression of CXCL14 has been detected in the biological sample obtained from the subject as compared to CXCL14 expression in a biological sample obtained from a control.

135. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134, wherein the specific binding agent is selected from the group consisting of a nucleic acid, an antibody, a receptor, and a lectin.

136. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134, wherein the sample is selected from the group consisting of lung tissue, whole blood, and plasma.

137. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 136, wherein the plasma is EDTA-anticoagulated plasma.

138. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition according to claim 134 further comprising measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@ , IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

139. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134 further comprising measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5- Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

140. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134, wherein detecting the specific binding agent-CXCL14 complex is selected from the group consisting of nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry.

141. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134 wherein the immunoassay is selected from the group consisting of Western blot analysis, ELISA, and flow cytometry.

142. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134, wherein the subject is administered a Hedgehog pathway inhibitor therapy.

143. The Hedgehog pathway inhibitor of claim 142, wherein the Hedgehog pathway inhibitor is selected from the group consisting of vismodegib; 2,2'- { { dihydro-2-(4-pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N-(2-methyl-5- ((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4-yl)-3-(4- cyanophenyl)urea; and 6-Ethyl-N- [ 1 -(hydroxyacetyl)piperidin-4-yl] - 1 -methyl-4-oxo- 5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2- c]pyridine-2-carboxamide.

144. The Hedgehog pathway inhibitor of claim 142, wherein the Hedgehog pathway inhibitor is vismodegib.

145. The Hedgehog pathway inhibitor of claim 142, wherein Hedgehog pathway inhibitor is sonidegib.

146. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134, wherein the subject is administered a therapy comprising the administration of a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

147. The therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 146, wherein the therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition is selected from the group consisting of pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vlOO; fresolimumab; BMS- 986202; PRM151; PXS4728; PXS25; N-acetyl cysteine; and PC-SOD.

148. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

149. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134, wherein the pulmonary fibrotic condition is selected from the group consisting of hypersensitivity pneumonitis, cryptogenic organizing pneumonia, diffuse alveolar damage, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, pulmonary arterial hypertension, nonspecific interstitial pneumonitis, systemic sclerosis associated interstitial lung disease, or collagen vascular disease- associated interstitial lung disease

150. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134, wherein the non-pulmonary fibrotic condition is selected from the group consisting of non-alcoholic steatohepatitis, systemic sclerosis, and renal fibrosis.

151. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134, wherein the cancer is a solid tumor.

152. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 134, wherein the cancer is selected from the group consisting of basal cell carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma.

153. A Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition for use in selecting a subject for idiopathic pulmonary fibrosis therapy comprising measuring in a biological sample obtained from the subject expression of chemokine (C-X-C motif) ligand 14 (CXCL14), by contacting the biological sample obtained from the subject with a specific binding agent that specifically binds to CXCL14, wherein the specific binding agent forms a complex with the CXCL14; and detecting the agent-CXCL14 complex, thereby determining the CXCL14 expression level; selecting the subject for idiopathic pulmonary fibrosis therapy when an elevated expression level of CXCL14 is determined in the subject compared to CXCL14 expression obtained from a biological sample obtained from a control; and administering an effective amount of a therapy selected from the group consisting of a Hedgehog pathway inhibitor and a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

154. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 153, wherein the specific binding agent is selected from the group consisting of a nucleic acid, an antibody, a receptor, and a lectin.

155. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 153, wherein the sample is selected from the group consisting of lung tissue, whole blood, and plasma.

156. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 155, wherein the plasma is EDTA-anticoagulated plasma.

157. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition according to claim 153 further comprising measuring in the biological sample the expression of an additional biomarker selected from the group consisting of SMO, PTCH1, PTCH2, GLI1, GLI2, SHH, CXCR3, CXCR5, CXCL13, CCR6, CCR7, CD19, MS4A1 (CD20), BLK, BLNK, FCRLA, FCRL2, FCRL5, CD79A, CD79B, CD27, CD28, CD1A, CD1B, CD1C, CD1E, IGHV1-69, IGLJ3, IGJ, IGHV3-48, IGLV3-21, IGKV1-5, IGHG1, IGKC, IGLV6-57, IGK@ , IGHA1, IGKV2-24, IGKV1D-8, IGHM, MUCL1, MUC4, MUC20, PRR7, PRR15, SPRRIB, SPRR2D, KRT5, KRT6B, KRT13, KRT14, KRT15, KRT17, SERPINB3, SERPINB4, SERPINB5, SERPINB13, CLCA2, TRPV4, BBS5, MMP3, SAA4 and combinations thereof.

158. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 153 further comprising measuring a lung function in the subject, wherein the lung function is selected from the group consisting of vital capacity (VC), Forced vital capacity (FVC), Forced expiratory volume (FEV) at timed intervals of 0.5, 1.0 (FEV1), 2.0 and 3.0 seconds, FEV/FEV ratio, forced expiratory flow 25-75% (FEF 25-75) and maximal voluntary ventilation (MVV or maximum breathing capacity) diffusion capacity of the lung for carbon monoxide (DLco), a subject reported outcome tool, such as A Tool to Assess Quality of Life in IPF (ATAQ-IPF) or EuroQol 5- Dimension Questionnaire (EQ-5D), St. George's Respiratory Questionnaire (SRGQ), 6-minute walk distance (6MWD), resting oxygen flow rate, radiographic findings on pulmonary high-resolution computed tomography (HRCT), including quantitative lung fibrosis (QLF) score.

159. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 153, wherein detecting the specific binding agent-CXCL14 complex is selected from the group consisting of nucleic acid hybridization, in situ hybridization, polymerase chain reaction, microarray analysis, immunoassay, immunohistochemistry, and mass spectrometry.

160. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 159 wherein the immunoassay is selected from the group consisting of Western blot analysis, ELISA, and flow cytometry.

161. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 153, wherein the subject is administered a Hedgehog pathway inhibitor therapy.

162. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 161, wherein the Hedgehog pathway inhibitor is selected from the group consisting of vismodegib; 2,2'-{ {dihydro-2-(4-pyridinyl)-l,3(2H,4H)-pyrimidinediyl]bis- (methylene)}bis{N,N-dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N- (2-methyl-5-((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2- yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l- methylpiperidin-4-yl)-3-(4-cyanophenyl)urea; and 6-Ethyl-N-[l- (hydroxyacetyl)piperidin-4-yl]-l-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2- trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2-c]pyridine-2-carboxamide.

163. The Hedgehog pathway inhibitor of claim 161, wherein the subject is administered vismodegib.

164. The Hedgehog pathway inhibitor of claim 161, wherein the subject is administered sonidegib.

165. The Hedgehog pathway inhibitor or a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 153, wherein the subject is administered a therapy comprising the administration of a therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition.

166. The therapeutic agent having a primary mechanism of action other than Hedgehog pathway inhibition of claim 165, wherein the therapeutic agent is selected from the group consisting of pirfenidone; nintedanib; lebrikizumab; tralokinumab; dupilumab; SAR156597; simtuzumab; FG3019; STX-vlOO; fresolimumab; BMS- 986202; PRM151; PXS4728; PXS25; N-acetyl cysteine; and PC-SOD.

167. A Hedgehog pathway inhibitor for use in treating a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer in a subject with an elevated expression level of chemokine (C-X-C motif) ligand 14 (CXCL14).

168. A Hedgehog pathway inhibitor for the manufacture of a medicament for use in treating a condition selected from the group consisting of interstitial lung disease, a pulmonary fibrotic condition, a non-pulmonary fibrotic condition, and cancer in a subject with an elevated expression level of chemokine (C-X-C motif) ligand 14 (CXCL14).

169. The Hedgehog pathway inhibitor of claim 167 or 168, wherein the Hedgehog pathway inhibitor is selected from the group consisting of vismodegib; 2,2'- { { dihydro-2-(4-pyridinyl)- 1 ,3(2H,4H)-pyrimidinediyl]bis-(methylene) }bis{ N,N- dimethylbenzenamine}; sonidegib; itraconazole; saridegib; N-(2-methyl-5- ((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide, LEQ 506; l-((2R,4R)-2-(lH-benzo[d]imidazol-2-yl)-l-methylpiperidin-4-yl)-3-(4- cyanophenyl)urea; and 6-Ethyl-N- [ 1 -(hydroxyacetyl)piperidin-4-yl] - 1 -methyl-4-oxo- 5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-lH-pyrrolo[3,2- c]pyridine-2-carboxamide.

170. The Hedgehog pathway inhibitor of claim 169, wherein the Hedgehog pathway inhibitor is vismodegib.

171. The Hedgehog pathway inhibitor of claim 169, wherein the Hedgehog pathway inhibitor is sonidegib.