FGF9 mutant as an antagonist for FGF9 signaling and the treatment of cancer

Abstract

The present disclosure relates a mutant FGF9 polypeptide, an isolated nucleic acid encoding the mutant FGF9 polypeptide, a vector comprising the isolated nucleic acid, and the methods of use thereof in treating cancer.

Description

FGF9 MUTANT AS AN ANTAGONIST FOR FGF9 SIGNALING AND THE TREATMENT OF CANCERI. CROSS REFERENCE TO RELATED APPLICATIONSThis application claims priority to, and the benefit of, U.S. Provisional Patent Application No. 63 / 604,451, filed November 30, 2023, which is incorporated by reference herein in its entirety.IL STATEMENT REGARDING FEDERALLY SPONSORED RESEARCHThis invention was made with government support under Grant No. P30CA093373 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.III. REFERENCE TO SEQUENCE LISTINGThe sequence listing submitted on December 2, 2024, as an .XML file entitled “11716- 007W01_ST26.xml” created on November 26, 2024, and having a file size of 7,651 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).IV. FIELDThe present disclosure relates to compositions and methods of using an FGF9 mutant polypeptide to treat cancer.V. BACKGROUNDThe fibroblast growth factor (FGF) family is comprised of 22 members that can be divided into seven subfamilies in mammals. FGF9 (FGF9 subfamily) is a secretory protein that was first isolated from human glioma cells. Four isoforms of FGF receptors mediate FGF9’s biological effects. FGF9 is a potent mitogen and survival factor, but FGF9 protein level is generally low and restricted to a few adult organs. FGF9 is involved in a variety of complex responses in human or animal development. Mice lacking Fgf9 have hypoplastic lungs, sex reversal, impaired germ cells, impaired skeletal growth, defective cardiomyocyte growth, and impaired inner ear development. Aberrant expression of FGF9 usually results in cancer. And aberrant activation of FGF9 / FGFR signaling is associated with cancers including lung cancer, stomach cancer, and ovarian cancer. FGF9 promotes epithelium and mesenchyme proliferation inlung. Also, FGF9 enhances cell proliferation and invasive ability of prostate cancer cells and ovarian cancer. Overexpression of FGF9 can promote tumor growth and liver metastasis of mouse Lewis lung carcinoma via EMT induction. In addition, elevated FGF9 expression is associated with poor prognosis in non-small cell lung cancer (NSCLC). FGF9 binding to its receptor causes receptor dimerization and activates different signal transduction cascades but there are no specific high affinity antagonists for FGF9.What is needed are compositions and methods to inhibit FGF9-induced cancer progression and to treat FGF9-associated cancers.VI. SUMMARYThe present disclosure relates to compositions and methods of using an FGF9 mutant polypeptide to treat, prevent, reduce or inhibit cancer such as, for example, colon cancer, prostate cancer, breast cancer, gliomas, renal cancer, testicular cancer, uterine cancer, skin cancer, lung cancer, stomach cancer, and ovarian cancer.In one aspect, disclosed herein are mutant FGF9 polypeptides comprising an amino acid substitution at residue 108 (such as for example, a substitution of an arginine (R) at residue 108 for a glutamic acid (E) (R108E) including, but not limited to SEQ ID NO: 2), 129 (such as for example, a substitution of an lysine (K) at residue 129 for a glutamic acid (E) (K129E)), 154 (such as for example, a substitution of an lysine (K) at residue 154 for a glutamic acid (E) (KI 54E)) or any combination thereof, wherein the amino acid substitution is relative to SEQ ID NO: 1.Also disclosed herein are isolated nucleic acids encoding the mutant FGF9 polypeptide of any preceding aspect (such as, for example, SEQE ID NO: 3).In one aspect, disclosed herein are vectors comprising the isolated nucleic acid of any preceding aspect.Also disclosed herein are pharmaceutical compositions comprising the mutant FGF9 polypeptide of any of claims of any preceding aspect, the isolated nucleic acid of claims of any preceding aspect, or the vector of claim of any preceding aspect and a pharmaceutically acceptable carrier.In one aspect, disclosed herein are methods of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing a cancer and / or metastasis (such as for example colon cancer) in a subject comprising administering to the subject the mutant FGF9 polypeptide of any preceding aspect or the pharmaceutical composition of any preceding aspect. For example, disclosedherein are method of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing a cancer and / or metastasis (such as for example colon cancer) in a subject comprising administering to the subject a mutant FGF9 polypeptide; wherein the mutant FGF9 polypeptide comprises an amino acid substitution at residue 108 (such as for example, a substitution of an arginine (R) at residue 108 for a glutamic acid (E) (R108E) including, but not limited to SEQ ID NO: 2), 129 (such as for example, a substitution of an lysine (K) at residue 129 for a glutamic acid (E) (K129E)), 154 (such as for example, a substitution of an lysine (K) at residue 154 for a glutamic acid (E) (K154E)) or any combination thereof, wherein the amino acid substitution is relative to SEQ ID NO: 1. In some aspects, the mutant FGF9 polypeptide is encoded by a nucleic acid (such as, for example, SEQ ID NO: 3).Also disclosed herein are methods of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing a cancer and / or metastasis of any preceding aspect, wherein the nucleic acid is encoded on a vector.In one aspect are disclosed herein are methods of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing a cancer and / or metastasis of any preceding aspect, wherein the mutant FGF9 polypeptide, isolated nucleic acid, or vector is a component of a pharmaceutical composition.Also disclosed herein are methods of treating, inhibiting, decreasing, reducing, ameliorating, and / or preventing a cancer and / or metastasis of any preceding aspect, wherein the cancer is selected from the group consisting of colon cancer, prostate cancer, breast cancer, gliomas, renal cancer, testicular cancer, uterine cancer, skin cancer, lung cancer, stomach cancer, and ovarian cancer.VII. BRIEF DESCRIPTION OF THE DRAWINGSThe accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description illustrate the disclosed compositions and methods.Figures 1 A, IB, and 1C show binding of soluble integrin avP3 to FGF9. Figure 1 A shows binding of FGF9 mutant to avP3 in ELISA binding assay. Wells of 96-well microtiter plate were coated with FGF9 and remaining protein binding sites were blocked with BSA. Soluble avP3 (1 pg / ml) was added to wells and incubated for 1 hour in Tyrode-HEPzxES buffer containing 1 mM Mn2+. Bound avP3 was quantified using anti-P3 and HRP-conjugated anti-mouse IgG. Figure IB shows binding of soluble av 3 in the presence of cyclic RGDfV, a specific inhibitor for av 3.Data are expressed as means ± S.D of triplicate experiments. Figure 1C shows the effect of cations and heat treatment on the binding of soluble integrin avf>3 to FGF9. Cations (1 mM) was included in Tyrode-HEPES buffer. Data are expressed as means ± S.D of triplicate experiments.Figures 2A and 2B show docking simulation of FGF9-integrin interaction. Docking simulation of interaction between FGF9 and integrin avP3 predicted that FGF9 binds to av 3 at high affinity (docking energy -23 Kcal / mol). Figure 2A shows the FGF9-avP3 docking model. Figure 2B shows that the FGF9-FGFR1 complex was superposed to the FGF9- avP3 docking model. The simulation predicted that FGF9 binds to the classical ligand-binding site of avP3.Figures 3 A, 3B, and 3C show identification of FGF9 mutants defective in integrin binding. Figure 3A shows that FGF9 mutants are defective in integrin binding. Several amino acid residues of FGF9 were chosen for mutagenesis studies. Argl08, Lysl29, and Lysl54 of FGF9 in the predicted integrin-binding site as shown in Figure 2 were mutated to Glutamate. The ability of FGF9 mutants (the R108E, K129E, and K154E mutants) to integrin was measured in binding assays using soluble avP3. Data are shown as means + / - SD of triplicate experiments. Figure 3B shows the binding of FGF9 mutants at 20 pg / ml is shown. Data are shown as means + / - SD of triplicate experiments. Figure 3C shows the effect of FGF9 mutations on DNA synthesis. NIH3T3 cells were starved for 24 hours and stimulated with FGF9 (WT and mutants at 100 ng / ml) and BrdU was added to the medium for the last two hours of the incubation.Figures 4A, 4B, 4C, 4D, 4E, and 4F show that an FGF9 mutant defective in integrin binding (R108E) is defective in inducing cell migration and invasion. Figure 4A shows expression of FGFRs in DLD1 and Colon26 colon cancer cells. Cell lysates were analyzed by western blotting with antibodies specific to FGFR1, FGFR-2, and FGFR3. Figure 4B shows FGF9-induced ERK1 / 2 activation in DLD1 and Colon26 colon cancer cells. DLD1 and Colon26 cells were serum starved for 24 hours and stimulated with WT FGF9 (50 ng / ml) or R108E (50ng / ml). Cell lysates were analyzed by western blotting. Figures 4C and 4D show migration of DLD1 and Colon26 colon cancer cells to FGF9, measured using Chemotaxicell chamber as described in the method section. Data are shown as means + / - SD of triplicate experiments. Figure 4E and 4F show the invasion of DLD1 and Colon26 colon cancer cells, respectively, induced by FGF9 was measured using Chemotaxicell chamber coated with growth factor- depleted Matrigel as described in the method section. Data are shown as means + / - SD of triplicate experiments.Figures 5A, 5B, 5C, and 5D show that R108E suppresses FRS2 and ERK1 / 2 activated by WT FGF9 in NIH3T3 cells. Figure 5A shows that NIH3T3 cells were starved for 24 hours and stimulated with WT FGF9 (20 ng / ml) and / or R108E (400 ng / ml). Cell lysates were analyzed by Western blotting using anti-phospho-FRS2a, anti-FRS2a, anti-phospho-ERKl / 2 and anti-total ERK1 / 2. [3-actin was used as an internal control. Density of the bands were quantified using ImageJ software and phospho-ERKl / 2 / |3-actin, as shown in Figure 5B, or phospho-FRS2a / p- actin, as shown in Figure 5C, was calculated. Data are shown as means + / - SD of triplicate experiments. Figure 5D shows that NIH3T3 cells were starved for 24 hours and stimulated with WT FGF9 (20 ng / ml) and / or R108E (400 ng / ml) and BrdU was added to the medium for the last two hours of the incubation. Data are shown as means + / - SD of triplicate experiments.Figures 6A, 6B. 6C, and 6D shows microscopic images of migration and invasion in colon cancer cells. Figures 6A and 6B show migration to FGF9 and invasion induced by FGF9, respectively, in DLD 1 colon cancer cells. Figures 6C and 6D show migration to FGF9 and invasion induced by FGF9, respectively, in Colon26 colon cancer cells.VIII. DETAILED DESCRIPTIONBefore the present compounds, compositions, articles, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods or specific recombinant biotechnology methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.A. DefinitionsAs used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. Itis also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10”as well as “greater than or equal to 10” is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.An "increase" can refer to any change that results in a greater amount of a symptom, disease, composition, condition or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant amount. Thus, the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% increase so long as the increase is statistically significant.A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant."Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control.By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed.The term “subject” refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. In one aspect, the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline. The subject can also be a guinea pig, rat, hamster, rabbit, mouse, or mole. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician.The term “therapeutically effective” refers to the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination.The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatmentdirected toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder."Comprising" is intended to mean that the compositions, methods, etc. include the recited elements, but do not exclude others. "Consisting essentially of’ when used to define compositions and methods, shall mean including the recited elements, but excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. "Consisting of" shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions provided and / or claimed in this disclosure. Embodiments defined by each of these transition terms are within the scope of this disclosure.A “control” is an alternative subject or sample used in an experiment for comparison purposes. A control can be "positive" or "negative."“Effective amount” of an agent refers to a sufficient amount of an agent to provide a desired effect. The amount of agent that is “effective” will vary from subject to subject, depending on many factors such as the age and general condition of the subject, the particular agent or agents, and the like. Thus, it is not always possible to specify a quantified “effective amount.” However, an appropriate “effective amount” in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of an agent can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts. An “effective amount” of an agent necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.A "pharmaceutically acceptable" component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation provided by the disclosure and administered to a subject as described herein without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When used in reference to administration to a human, the term generally implies the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration."Pharmaceutically acceptable carrier" (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil / water or water / oil emulsion) and / or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein.“Pharmacologically active” (or simply “active”), as in a “pharmacologically active” derivative or analog, can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.“Therapeutic agent” refers to any composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition (e.g., a non-immunogenic cancer). The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the terms “therapeutic agent” is used, then, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc.“Therapeutically effective amount” or “therapeutically effective dose” of a composition (e.g., a composition comprising an agent) refers to an amount that is effective to achieve a desired therapeutic result. In some embodiments, a desired therapeutic result is the control of type I diabetes. In some embodiments, a desired therapeutic result is the control of obesity. Therapeutically effective amounts of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject. The term can also refer to an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect, such as pain relief. The precise desired therapeutic effect will vary according to the condition to be treated, the tolerance of the subject, the agent and / or agent formulation to be administered (e.g., the potency of the therapeutic agent, the concentration of agent in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary skill in the art. In some instances, a desired biological or medical response is achieved following administration of multiple dosages of the composition to the subject over a period of days, weeks, or years. A “protein”, "polypeptide", or “peptide” each refer to a polymer of amino acids and does not imply a specific length of a polymer of amino acids. Thus, for example, the terms peptide, oligopeptide, protein, antibody, and enzyme are included within the definition of polypeptide. This term also includes polypeptides with postexpression modification, such as glycosylation (e.g., the addition of a saccharide), acetylation, phosphorylation, and the like.The term “amino acid,” includes but is not limited to amino acids contained in the group consisting of alanine (Ala or A), cysteine (Cys or C), aspartic acid (Asp or D), glutamic acid (Glu or E), phenylalanine (Phe or F), glycine (Gly or G), histidine (His or H), isoleucine (He or I), lysine (Lys or K), leucine (Leu or L), methionine (Met or M), asparagine (Asn or N), proline (Pro or P), glutamine (Gin or Q), arginine (Arg or R), serine (Ser or S), threonine (Thr or T), valine (Vai or V), tryptophan (Trp or W), and tyrosine (Tyr or Y) residues. The term “amino acid residue” also may include amino acid residues contained in the group consisting of homocysteine, 2-Aminoadipic acid, N-Ethylasparagine, 3-Aminoadipic acid, Hydroxylysine, P- alanine, - Amino-propionic acid, allo-Hydroxylysine acid, 2-Aminobutyric acid, 3- Hydroxyproline, 4-Aminobutyric acid, 4-Hydroxyproline, piperidinic acid, 6-Aminocaproic acid, Isodesmosine, 2-Aminoheptanoic acid, allo-Isoleucine, 2-Aminoisobutyric acid, N- Methylglycine, sarcosine, 3-Aminoisobutyric acid, N-Methylisoleucine, 2-Aminopimelic acid, 6- N-Methyllysine, 2,4-Diaminobutyric acid, N-Methylvaline, Desmosine, Norvaline, 2,2'-Diaminopimelic acid, Norleucine, 2,3-Diaminopropionic acid, Ornithine, and N-Ethylglycine. Typically, the amide linkages of the peptides are formed from an amino group of the backbone of one amino acid and a carboxyl group of the backbone of another amino acid.It should also be noted that amino acids, and derivatives (with exception of glycine) occurs in two isomeric forms: L-forms or D-forms. The L- and D- forms represent the same atoms of an amino acid, however the atoms can have different arrangements, which can impact the amino acid properties and functions. The two forms are similar in that they both occur naturally and comprise a central carbon atom, at least one hydrogen atom, a carboxylic group, an amine group, and a variable group. The two forms differ in that they are usually mirrored images of each other, wherein the location of the amine group varies. L-amino acids are used in protein synthesis, while D-amino acid are less common in protein synthesis. L-amino acids rotate counterclockwise or to the left in a process known as levorotation. D-amino acids rotate clockwise or to the right in a process known as dextrorotation. L-amino acids are used to synthesize proteins, while D-amino acids are found in the cell walls of bacteria.B. Mutant genes and proteinsDisclosed herein is a mutant FGF9 polypeptide comprising an amino acid substitution at residue 52, 53, 55, 56, 57, 78, 79, 80, 81, 108, 110, 111, 112, 113, 114, 115, 119, 120, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 151, 152, 154, 203, 204, 205, 206, 207, 208, or any combination thereof, wherein the amino acid substitution (such as, for example, substitution of an arginine (R) at residue 108 for a glutamic acid (E) (R108E) (including, but not limited to SEQ ID NO: 2), substitution of a lysine (K) at residue 129 for a glutamic acid (E) (K129E) or substitution of a lysine (K) at residue 154 for a glutamic acid (E) (K154E)) is relative to SEQ ID NO: 1. As disclosed herein SEQ ID NO: 1 comprises the wild-type human FGF9 protein starting at residue 4 of the FGF9 amino acid sequence. Thus, in some aspects, the amino acid substitution is a substitution of the threonine (T) at residue 52; substitution of the aspartate (D) at residue 53 (D53); a substitution of the aspartate (D) at residue 55 (D55); a substitution of the histidine (H) at residue 56 (H56; a substitution of the leucine (L) at residue 57 (L57); a substitution of the proline (P) at residue 78 (P78: a substitution of the asparagine (N) at residue 79 (N79) ; a substitution of the glycine (G) at residue 80 (G80) ; a substitution of the threonine (T) at residue 81 (T81) ; a substitution of the arginine (R) at residue 108 (R108); a substitution of the valine (V) at residue 110 (VI 10); a substitution of the aspartate (D) at residue 111 (Dill); a substitution of the serine (S) at residue 112 (SI 12); a substitution of the glycine (G) at residue 113 (G113) ; a substitution of the leucine (L) at residue 114 (LI 14); a substitution of the tyrosine(Y) at residue 115 (Y 115) ; a substitution of the asparagine (N) at residue 119 (Nil 9; a substitution of the glutamate (E) at residue 120 (El 20) ; a substitution of the tyrosine (Y) at residue 125 (Y125; a substitution of the glycine (G) at residue 126 (G126) ; a substitution of the serine (S) at residue 127 (S127) ; a substitution of the glutamate (E) at residue 128 (E128) ; a substitution of the lysine (K) at residue 129 (K129); a substitution of the leucine (L) at residue 130 (L130); a substitution of the threonine (T) at residue 131 (T131) ; a substitution of the glutamine (Q) at residue 132 (Q132) ; a substitution of the glutamate (E) at residue 133 (E133) ; a substitution of the cysteine (C) at residue 134 (C134); a substitution of the asparagine (N) at residue 151 (N151); a substitution of the leucine (L) at residue 152 (LI 52); a substitution of the lysine (K) at residue 154 (K154); a substitution of the aspartate (D) at residue 203 (D203); a substitution of the leucine (L) at residue 204 (L204); a substitution of the leucine (L) at residue 205 (L205); a substitution of the serine (S) at residue 206 (S206) ; a substitution of the glutamate (E) at residue 207 (E207); and / or a substitution of the serine (S) at residue 208 (S208).In one aspect disclosed herein, is an isolated nucleic acid encoding any of the mutant FGF9 polypeptide disclosed herein (such as, for example, SEQ ID NO: 3).It is understood that one way to define any known mutants and derivatives or those that might arise, of the disclosed genes and proteins herein is through defining the mutants and derivatives in terms of homology to specific known sequences. For example, SEQ ID NO: 1, disclosed herein sets forth a particular sequence of a wild-type human FGF9 gene, and SEQ ID NO: 2 sets forth a particular sequence of the FGF9 mutant protein encoded by SEQ ID NO: 3. Specifically disclosed are variants of these and other genes and proteins herein disclosed which have an amino acid substitution at residue 108, 129, 154 or any combination thereof, wherein the amino acid substitution (such as, for example, substitution of an arginine (R) at residue 108 for a glutamic acid (E) (R108E), substitution of a lysine (K) at residue 129 for a glutamic acid (E) (K129E) or substitution of a lysine (K) at residue 154 for a glutamic acid (E) (K154E)) is relative to SEQ ID NO: 1.There are a variety of molecules disclosed herein that are nucleic acid based, including for example the nucleic acids that encode, for example an FGF9 mutant polypeptide, or any of the nucleic acids disclosed herein for making an FGF9 knockouts, or fragments thereof, as well as various functional nucleic acids. The disclosed nucleic acids are made up of, for example, nucleotides, nucleotide analogs, or nucleotide substitutes. Non-limiting examples of these and other molecules are discussed herein. It is understood that for example, when a vector is expressed in a cell, the expressed mRNA will typically be made up of A, C, G, and U. Likewise,it is understood that if, for example, an antisense molecule is introduced into a cell or cell environment through for example exogenous delivery, it is advantageous that the antisense molecule be made up of nucleotide analogs that reduce the degradation of the antisense molecule in the cellular environment.Nucleotides and related moleculesAs disclosed herein, is an isolated nucleic acid encoding any of the mutant FGF9 polypeptide disclosed herein (such as, for example, SEQ ID NO: 3).A nucleotide is a molecule that contains a base moiety, a sugar moiety and a phosphate moiety. Nucleotides can be linked together through their phosphate moieties and sugar moieties creating an intemucleoside linkage. The base moiety of a nucleotide can be adenin-9-yl (A), cytosin-l-yl (C), guanin-9-yl (G), uracil-l-yl (U), and thymin-l-yl (T). The sugar moiety of a nucleotide is a ribose or a deoxyribose. The phosphate moiety of a nucleotide is pentavalent phosphate. An non-limiting example of a nucleotide would be 3'-AMP (3'-adenosine monophosphate) or 5'-GMP (5'-guanosine monophosphate). There are many varieties of these types of molecules available in the art and available herein.A nucleotide analog is a nucleotide which contains some type of modification to either the base, sugar, or phosphate moieties. Modifications to nucleotides are well known in the art and would include for example, 5 -methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, and 2-aminoadenine as well as modifications at the sugar or phosphate moieties. There are many varieties of these types of molecules available in the art and available herein.Nucleotide substitutes are molecules having similar functional properties to nucleotides, but which do not contain a phosphate moiety, such as peptide nucleic acid (PNA). Nucleotide substitutes are molecules that will recognize nucleic acids in a Watson-Crick or Hoogsteen manner, but which are linked together through a moiety other than a phosphate moiety. Nucleotide substitutes are able to conform to a double helix type structure when interacting with the appropriate target nucleic acid. There are many varieties of these types of molecules available in the art and available herein.It is also possible to link other types of molecules (conjugates) to nucleotides or nucleotide analogs to enhance, for example, cellular uptake. Conjugates can be chemically linked to the nucleotide or nucleotide analogs. Such conjugates include but are not limited to lipid moieties such as a cholesterol moiety. (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989,86, 6553-6556). There are many varieties of these types of molecules available in the art and available herein.A Watson-Crick interaction is at least one interaction with the Watson-Crick face of a nucleotide, nucleotide analog, or nucleotide substitute. The Watson-Crick face of a nucleotide, nucleotide analog, or nucleotide substitute includes the C2, Nl, and C6 positions of a purine based nucleotide, nucleotide analog, or nucleotide substitute and the C2, N3, C4 positions of a pyrimidine based nucleotide, nucleotide analog, or nucleotide substitute.A Hoogsteen interaction is the interaction that takes place on the Hoogsteen face of a nucleotide or nucleotide analog, which is exposed in the major groove of duplex DNA. The Hoogsteen face includes the N7 position and reactive groups (NH2 or O) at the C6 position of purine nucleotides.SequencesThere are a variety of sequences related to the protein molecules involved in inhibiting the FGF9 signaling pathways disclosed herein, for example FGF9 mutant polypeptide with an amino acid substitution at residue 108, 129, 154 or any combination thereof, wherein the amino acid substitution (such as, for example, substitution of an arginine (R) at residue 108 for a glutamic acid (E) (R108E), substitution of a lysine (K) at residue 129 for a glutamic acid (E) (K129E) or substitution of a lysine (K) at residue 154 for a glutamic acid (E) (K154E)) is relative to SEQ ID NO: 1 , or any of the nucleic acids disclosed herein for making an FGF9 mutant polypeptide, all of which are encoded by nucleic acids or are nucleic acids. The sequences for the human analogs of these genes, as well as other analogs, and alleles of these genes, and splice variants and other types of variants, are available in a variety of protein and gene databases, including GenBank. Those of skill in the art understand how to resolve sequence discrepancies and differences and to adjust the compositions and methods relating to a particular sequence to other related sequences. Primers and / or probes can be designed for any given sequence given the information disclosed herein and known in the art.Nucleic Acid DeliveryIn some aspects the isolated nucleic acid can be encoded in a vector.In the compositions and methods described above which include the administration and uptake of exogenous DNA into the cells of a subject (i.e., gene transduction or transfection), the disclosed nucleic acids can be in the form of naked DNA or RNA, or the nucleic acids can be in a vector for delivering the nucleic acids to the cells, whereby the antibody-encoding DNA fragment is under the transcriptional regulation of a promoter, as would be well understood byone of ordinary skill in the art. The vector can be a commercially available preparation, such as an adenovirus vector (Quantum Biotechnologies, Inc. (Laval, Quebec, Canada). Delivery of the nucleic acid or vector to cells can be via a variety of mechanisms. As one example, delivery can be via a liposome, using commercially available liposome preparations such as LIPOFECTIN, LIPOFECT AMINE (GIBCO-BRL, Inc., Gaithersburg, MD), SUPERFECT (Qiagen, Inc. Hilden, Germany) and TRANSFECT AM (Promega Biotec, Inc., Madison, WI), as well as other liposomes developed according to procedures standard in the art. In addition, the disclosed nucleic acid or vector can be delivered in vivo by electroporation, the technology for which is available from Genetronics, Inc. (San Diego, CA) as well as by means of a SONOPORATION machine (ImaRx Pharmaceutical Corp., Tucson, AZ).As one example, vector delivery can be via a viral system, such as a retroviral vector system which can package a recombinant retroviral genome (see e.g., Pastan et al., Proc. Natl. Acad. Sci. U.S.A. 85:4486, 1988; Miller et al., Mol. Cell. Biol. 6:2895, 1986). The recombinant retrovirus can then be used to infect and thereby deliver to the infected cells nucleic acid encoding a broadly neutralizing antibody (or active fragment thereof). The exact method of introducing the altered nucleic acid into mammalian cells is, of course, not limited to the use of retroviral vectors. Other techniques are widely available for this procedure including the use of adenoviral vectors (Mitani et al., Hum. Gene Ther. 5:941-948, 1994), adeno-associated viral (AAV) vectors (Goodman et al., Blood 84:1492-1500, 1994), lentiviral vectors (Naidini et al., Science 272:263-267, 1996), pseudotyped retroviral vectors (Agrawal et al., Exper. Hematol. 24:738-747, 1996). Physical transduction techniques can also be used, such as liposome delivery and receptor-mediated and other endocytosis mechanisms (see, for example, Schwartzenberger et al., Blood TA72 7 , 1996). This disclosed compositions and methods can be used in conjunction with any of these or other commonly used gene transfer methods.As one example, if the antibody-encoding nucleic acid is delivered to the cells of a subject in an adenovirus vector, the dosage for administration of adenovirus to humans can range from about 107to 109plaque forming units (pfu) per injection but can be as high as 1012pfu per injection (Crystal, Hum. Gene Ther. 8:985-1001 , 1997; Alvarez and Curiel, Hum. Gene Ther. 8:597-613, 1997). A subject can receive a single injection, or, if additional injections are necessary, they can be repeated at six month intervals (or other appropriate time intervals, as determined by the skilled practitioner) for an indefinite period and / or until the efficacy of the treatment has been established.Parenteral administration of the nucleic acid or vector, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. For additional discussion of suitable formulations and various routes of administration of therapeutic compounds, see, e.g., Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995.Delivery of the compositions to cellsThere are a number of compositions and methods which can be used to deliver nucleic acids to cells, either in vitro or in vivo. These methods and compositions can largely be broken down into two classes: viral based delivery systems and non-viral based delivery systems. For example, the nucleic acids can be delivered through a number of direct delivery systems such as, electroporation, lipofection, calcium phosphate precipitation, plasmids, viral vectors, viral nucleic acids, phage nucleic acids, phages, cosmids, or via transfer of genetic material in cells or carriers such as cationic liposomes. Appropriate means for transfection, including viral vectors, chemical transfectants, or physico-mechanical methods such as electroporation and direct diffusion of DNA, are described by, for example, Wolff, J. A., et al., Science, 247, 1465-1468, (1990); and Wolff, J. A. Nature, 352, 815-818, ( 1991). Such methods are well known in the art and readily adaptable for use with the compositions and methods described herein. In certain cases, the methods will be modified to specifically function with large DNA molecules. Further, these methods can be used to target certain diseases and cell populations by using the targeting characteristics of the carrier.Nucleic acid based delivery systemsTransfer vectors can be any nucleotide construction used to deliver genes into cells (e.g., a plasmid), or as part of a general strategy to deliver genes, e.g., as part of recombinant retrovirus or adenovirus (Ram et al. Cancer Res. 53:83-88, (1993)).As used herein, plasmid or viral vectors are agents that transport the disclosed nucleic acids into the cell without degradation and include a promoter yielding expression of the gene in the cells into which it is delivered. In some embodiments the vectors are derived from either a virus or a retrovirus. Viral vectors are , for example, Adenovirus, Adeno-associated virus, Herpes virus, Vaccinia virus, Polio virus, AIDS virus, neuronal trophic virus, Sindbis and other RNA viruses, including these viruses with the HIV backbone. Also preferred are any viralfamilies which share the properties of these viruses which make them suitable for use as vectors. Retroviruses include Murine Maloney Leukemia virus, MMLV, and retroviruses that express the desirable properties of MMLV as a vector. Retroviral vectors are able to carry a larger genetic payload, i.e., a transgene or marker gene, than other viral vectors, and for this reason are a commonly used vector. However, they are not as useful in non-proliferating cells. Adenovirus vectors are relatively stable and easy to work with, have high titers, and can be delivered in aerosol formulation, and can transfect non-dividing cells. Pox viral vectors are large and have several sites for inserting genes, they are thermostable and can be stored at room temperature. A preferred embodiment is a viral vector which has been engineered so as to suppress the immune response of the host organism, elicited by the viral antigens. Preferred vectors of this type will carry coding regions for Interleukin 8 or 10.Viral vectors can have higher transaction (ability to introduce genes) abilities than chemical or physical methods to introduce genes into cells. Typically, viral vectors contain, nonstructural early genes, structural late genes, an RNA polymerase III transcript, inverted terminal repeats necessary for replication and encapsidation, and promoters to control the transcription and replication of the viral genome. When engineered as vectors, viruses typically have one or more of the early genes removed and a gene or gene / promotor cassette is inserted into the viral genome in place of the removed viral DNA. Constructs of this type can carry up to about 8 kb of foreign genetic material. The necessary functions of the removed early genes are typically supplied by cell lines which have been engineered to express the gene products of the early genes in trans.Retroviral VectorsA retrovirus is an animal virus belonging to the virus family of Retroviridae, including any types, subfamilies, genus, or tropisms. Retroviral vectors, in general, are described by Verma, I.M., Retroviral vectors for gene transfer.A retrovirus is essentially a package which has packed into it nucleic acid cargo. The nucleic acid cargo carries with it a packaging signal, which ensures that the replicated daughter molecules will be efficiently packaged within the package coat. In addition to the package signal, there are a number of molecules which are needed in cis, for the replication, and packaging of the replicated virus. Typically, a retroviral genome, contains the gag, pol, and env genes which are involved in the making of the protein coat. It is the gag, pol, and env genes which are typically replaced by the foreign DNA that it is to be transferred to the target cell. Retrovirus vectors typically contain a packaging signal for incorporation into the package coat, asequence which signals the start of the gag transcription unit, elements necessary for reverse transcription, including a primer binding site to bind the tRNA primer of reverse transcription, terminal repeat sequences that guide the switch of RNA strands during DNA synthesis, a purine rich sequence 5' to the 3’ LTR that serve as the priming site for the synthesis of the second strand of DNA synthesis, and specific sequences near the ends of the LTRs that enable the insertion of the DNA state of the retrovirus to insert into the host genome. The removal of the gag, pol, and env genes allows for about 8 kb of foreign sequence to be inserted into the viral genome, become reverse transcribed, and upon replication be packaged into a new retroviral particle. This amount of nucleic acid is sufficient for the delivery of a one to many genes depending on the size of each transcript. It is preferable to include either positive or negative selectable markers along with other genes in the insert.Since the replication machinery and packaging proteins in most retroviral vectors have been removed (gag, pol, and env), the vectors are typically generated by placing them into a packaging cell line. A packaging cell line is a cell line which has been transfected or transformed with a retrovirus that contains the replication and packaging machinery, but lacks any packaging signal. When the vector carrying the DNA of choice is transfected into these cell lines, the vector containing the gene of interest is replicated and packaged into new retroviral particles, by the machinery provided in cis by the helper cell. The genomes for the machinery are not packaged because they lack the necessary signals.Adenoviral VectorsThe construction of replication-defective adenoviruses has been described (Berkner et al., J. Virology 61 :1213-1220 (1987); Massie et al., Mol. Cell. Biol. 6:2872-2883 (1986); Haj- Ahmad et al., J. WroZog 57:267-274 (1986); Davidson et al., J. Virology 61:1226-1239 (1987); Zhang "Generation and identification of recombinant adenovirus by liposome-mediated transfection and PCR analysis" BioTechniques 15:868-872 (1993)). The benefit of the use of these viruses as vectors is that they are limited in the extent to which they can spread to other cell types, since they can replicate within an initial infected cell, but are unable to form new infectious viral particles. Recombinant adenoviruses have been shown to achieve high efficiency gene transfer after direct, in vivo delivery to airway epithelium, hepatocytes, vascular endothelium, CNS parenchyma and a number of other tissue sites (Morsy, J. Clin. Invest. 92:1580-1586 (1993); Kirshenbaum, J. Clin. Invest. 92:381-387 (1993); Roessler, J. Clin. Invest. 92: 1085-1092 (1993); Moullier, Nature Genetics 4: 154-159 (1993); La Salle, Science 259:988-990 (1993); Gomez-Foix, J. Biol. Chem. 267:25129-25134 (1992); Rich, Human GeneTherapy 4:461-476 (1993); Zabner, Nature Genetics 6:75-83 (1994); Guzman, Circulation Research 73:1201-1207 (1993); Bout, Human Gene Therapy 5:3-10 (1994); Zabner, Cell 75:207-216 (1993); Caillaud, Eur. J. Neuroscience 5:1287-1291 (1993); and Ragot, J. Gen. Virology 74:501-507 (1993)). Recombinant adenoviruses achieve gene transduction by binding to specific cell surface receptors, after which the virus is internalized by receptor-mediated endocytosis, in the same manner as wild type or replication-defective adenovirus (Chardonnet and Dales, Virology 40:462-477 (1970); Brown and Burlingham, J. Virology 12:386-396 (1973); Svensson and Persson, J. Virology 55:442-449 (1985); Seth, et al., J. Virol. 51:650-655 (1984); Seth, et al., Mol. Cell. Biol. 4: 1528-1533 (1984); Varga et al., J. Virology 65:6061-6070 (1991); Wickham et al., Cell 73:309-319 (1993)).A viral vector can be one based on an adenovirus which has had the El gene removed and these virions are generated in a cell line such as the human 293 cell line. In another preferred embodiment both the El and E3 genes are removed from the adenovirus genome.Adeno-associated viral vectorsAnother type of viral vector is based on an adeno-associated virus (AAV). This defective parvovirus is a preferred vector because it can infect many cell types and is nonpathogenic to humans. AAV type vectors can transport about 4 to 5 kb and wild type AAV is known to stably insert into chromosome 19. Vectors which contain this site specific integration property are preferred. An especially preferred embodiment of this type of vector is the P4.1 C vector produced by Avigen, San Francisco, CA, which can contain the herpes simplex virus thymidine kinase gene, HSV-tk, and / or a marker gene, such as the gene encoding the green fluorescent protein, GFP.In another type of AAV virus, the AAV contains a pair of inverted terminal repeats (ITRs) which flank at least one cassette containing a promoter which directs cell-specific expression operably linked to a heterologous gene. Heterologous in this context refers to any nucleotide sequence or gene which is not native to the AAV or B19 parvovirus.Typically, the AAV and B19 coding regions have been deleted, resulting in a safe, noncytotoxic vector. The AAV ITRs, or modifications thereof, confer infectivity and sitespecific integration, but not cytotoxicity, and the promoter directs cell-specific expression. United states Patent No. 6,261,834 is herein incorporated by reference for material related to the AAV vector.The disclosed vectors thus provide DNA molecules which are capable of integration into a mammalian chromosome without substantial toxicity.The inserted genes in viral and retroviral usually contain promoters, and / or enhancers to help control the expression of the desired gene product. A promoter is generally a sequence or sequences of DNA that function when in a relatively fixed location in regard to the transcription start site. A promoter contains core elements required for basic interaction of RNA polymerase and transcription factors, and may contain upstream elements and response elements.Large payload viral vectorsMolecular genetic experiments with large human herpesviruses have provided a means whereby large heterologous DNA fragments can be cloned, propagated and established in cells permissive for infection with herpesviruses (Sun et al., Nature genetics 8: 33-41, 1994; Cotter and Robertson,. Curr Opin Mol Ther 5: 633-644, 1999). These large DNA viruses (herpes simplex virus (HSV) and Epstein-Barr virus (EBV), have the potential to deliver fragments of human heterologous DNA > 150 kb to specific cells. EBV recombinants can maintain large pieces of DNA in the infected B-cells as episomal DNA. Individual clones carried human genomic inserts up to 330 kb and appeared genetically stable. The maintenance of these episomes requires a specific EBV nuclear protein, EBNA1, constitutively expressed during infection with EBV. Additionally, these vectors can be used for transfection, where large amounts of protein can be generated transiently in vitro. Herpesvirus amplicon systems are also being used to package pieces of DNA > 220 kb and to infect cells that can stably maintain DNA as episomes.Other useful systems include, for example, replicating and host-restricted non-replicating vaccinia virus vectors.Non-nucleic acid based systemsThe disclosed compositions can be delivered to the target cells in a variety of ways. For example, the compositions can be delivered through electroporation, or through lipofection, or through calcium phosphate precipitation. The delivery mechanism chosen will depend in part on the type of cell targeted and whether the delivery is occurring for example in vivo or in vitro.Thus, the compositions can comprise, in addition to the disclosed FGF9 mutant polypeptide or vectors for example, lipids such as liposomes, such as cationic liposomes (e.g., DOTMA, DOPE, DC-cholesterol) or anionic liposomes. Liposomes can further comprise proteins to facilitate targeting a particular cell, if desired. Administration of a composition comprising a compound and a cationic liposome can be administered to the blood afferent to a target organ or inhaled into the respiratory tract to target cells of the respiratory tract. Regarding liposomes, see, e.g., Brigham et al. Am. J. Resp. Cell. Mol. Biol. 1:95-100 (1989); Feigner et al.Proc. Natl. Acad. Sci USA 84:7413-7417 (1987); U.S. Pat. No.4,897,355. Furthermore, the compound can be administered as a component of a microcapsule that can be targeted to specific cell types, such as macrophages, or where the diffusion of the compound or delivery of the compound from the microcapsule is designed for a specific rate or dosage.In the methods described above which include the administration and uptake of exogenous DNA into the cells of a subject (i.e., gene transduction or transfection), delivery of the compositions to cells can be via a variety of mechanisms. As one example, delivery can be via a liposome, using commercially available liposome preparations such as LIPOFECTIN, LIPOFECT AMINE (GIBCO-BRL, Inc., Gaithersburg, MD), SUPERFECT (Qiagen, Inc. Hilden, Germany) and TRANSFECT AM (Promega Biotec, Inc., Madison, WI), as well as other liposomes developed according to procedures standard in the art. In addition, the disclosed nucleic acid or vector can be delivered in vivo by electroporation, the technology for which is available from Genetronics, Inc. (San Diego, CA) as well as by means of a SONOPORATION machine (ImaRx Pharmaceutical Corp., Tucson, AZ).The materials may be in solution, suspension (for example, incorporated into microparticles, liposomes, or cells). These may be targeted to a particular cell type via antibodies, receptors, or receptor ligands. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Senter, et al., Bioconjugate Chem., 2:447-451 , (1991 ); Bagshawe, K.D., Br. J. Cancer, 60:275-281 , (1989); Bagshawe, et al., Br. J. Cancer, 58:700-703, (1988); Senter, et al., Bioconjugate Chem., 4:3-9, (1993); Battelli, et al., Cancer Immunol. Immunother., 35:421-425, (1992); Pietersz and McKenzie, Immunolog. Reviews, 129:57-80, (1992); and Roffler, et al., Biochem. Pharmacol, 42:2062-2065, (1991)). These techniques can be used for a variety of other specific cell types. Vehicles such as "stealth" and other antibody conjugated liposomes (including lipid mediated drug targeting to colonic carcinoma), receptor mediated targeting of DNA through cell specific ligands, lymphocyte directed tumor targeting, and highly specific therapeutic retroviral targeting of murine glioma cells in vivo. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Hughes et al., Cancer Research, 49:6214-6220, (1989); and Litzinger and Huang, Biochimica et Biophysica Acta, 1104: 179-187, (1992)). In general, receptors are involved in pathways of endocytosis, either constitutive or ligand induced. These receptors cluster in clathrin-coated pits, enter the cell via clathrin-coated vesicles, pass through an acidified endosome in which the receptors are sorted, and then either recycle to the cell surface, become stored intracellularly, or are degraded in lysosomes. The internalizationpathways serve a variety of functions, such as nutrient uptake, removal of activated proteins, clearance of macromolecules, opportunistic entry of viruses and toxins, dissociation and degradation of ligand, and receptor- level regulation. Many receptors follow more than one intracellular pathway, depending on the cell type, receptor concentration, type of ligand, ligand valency, and ligand concentration. Molecular and cellular mechanisms of receptor-mediated endocytosis has been reviewed (Brown and Greene, DNA and Cell Biology 10:6, 399-409 (1991)).Nucleic acids that are delivered to cells which are to be integrated into the host cell genome, typically contain integration sequences. These sequences are often viral related sequences, particularly when viral based systems are used. These viral integration systems can also be incorporated into nucleic acids which are to be delivered using a non-nucleic acid based system of deliver, such as a liposome, so that the nucleic acid contained in the delivery system can be come integrated into the host genome.Other general techniques for integration into the host genome include, for example, systems designed to promote homologous recombination with the host genome. These systems typically rely on sequence flanking the nucleic acid to be expressed that has enough homology with a target sequence within the host cell genome that recombination between the vector nucleic acid and the target nucleic acid takes place, causing the delivered nucleic acid to be integrated into the host genome. These systems and the methods necessary to promote homologous recombination are known to those of skill in the art.In vivo / ex vivoAs described above, the compositions can be administered in a pharmaceutically acceptable carrier and can be delivered to the subject’s cells in vivo and / or ex vivo by a variety of mechanisms well known in the art (e.g., uptake of naked DNA, liposome fusion, intramuscular injection of DNA via a gene gun, endocytosis and the like).If ex vivo methods are employed, cells or tissues can be removed and maintained outside the body according to standard protocols well known in the art. The compositions can be introduced into the cells via any gene transfer mechanism, such as, for example, calcium phosphate mediated gene delivery, electroporation, microinjection or proteoliposomes. The transduced cells can then be infused (e.g., in a pharmaceutically acceptable carrier) or homotopically transplanted back into the subject per standard methods for the cell or tissue type. Standard methods are known for transplantation or infusion of various cells into a subject.PeptidesProtein variantsAs discussed herein there are numerous variants of the FGF9 mutant protein that are not known previously and are herein contemplated. In addition, there are mutants of the FGF9 protein which also function in the disclosed methods and compositions. Protein variants and derivatives are well understood to those of skill in the art and in can involve amino acid sequence modifications. For example, amino acid sequence modifications typically fall into one or more of three classes: substitutional, insertional or deletional variants. Insertions include amino and / or carboxyl terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Insertions ordinarily will be smaller insertions than those of amino or carboxyl terminal fusions, for example, on the order of one to four residues. Immunogenic fusion protein derivatives, such as those described in the examples, are made by fusing a polypeptide sufficiently large to confer immunogenicity to the target sequence by cross-linking in vitro or by recombinant cell culture transformed with DNA encoding the fusion. Deletions are characterized by the removal of one or more amino acid residues from the protein sequence. Typically, no more than about from 2 to 6 residues are deleted at any one site within the protein molecule. These variants ordinarily are prepared by site specific mutagenesis of nucleotides in the DNA encoding the protein, thereby producing DNA encoding the variant, and thereafter expressing the DNA in recombinant cell culture. Techniques for making substitution mutations at predetermined sites in DNA having a known sequence are well known, for example M 13 primer mutagenesis and PCR mutagenesis. Amino acid substitutions are typically of single residues, but can occur at a number of different locations at once; insertions usually will be on the order of about from 1 to 10 amino acid residues; and deletions will range about from 1 to 30 residues. Deletions or insertions preferably are made in adjacent pairs, i.e., a deletion of 2 residues or insertion of 2 residues. Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final construct. The mutations must not place the sequence out of reading frame and preferably will not create complementary regions that could produce secondary mRNA structure. Substitutional variants are those in which at least one residue has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with the following Tables 1 and 2 and are referred to as conservative substitutions.TABLE l:Amino Acid AbbreviationsAmino Acid AbbreviationsAlanine Ala A allosoleucine AlleArginine Arg R asparagine Asn N aspartic acid Asp DCysteine Cys C glutamic acid Glu EGlutamine Gin QGlycine Gly GHistidine His HIsolelucine lie ILeucine Leu LLysine Lys K phenylalanine Phe F proline Pro P pyroglutamic acid pGluSerine Ser SThreonine Thr TTyrosine Tyr YTryptophan Trp WValine Vai VTABLE 2: Amino Acid SubstitutionsOriginal Residue Exemplary Conservative Substitutions, others are known in the art.Ala Ser Arg Lys; Gin Asn Gin; His Asp Glu Cys Ser Gin Asn, LysGlu Asp Gly Pro His Asn; Gin He Leu; VaiLeu lie; VaiLys Arg; Gin Met Leu; He Phe Met; Leu; Tyr Ser Thr Thr Ser Trp TyrTyr Trp; PheVai lie; LeuSubstantial changes in function or immunological identity are made by selecting substitutions that are less conservative than those in Table 2, i.e., selecting residues that differ more significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site or (c) the bulk of the side chain. The substitutions which in general are expected to produce the greatest changes in the protein properties will be those in which (a) a hydrophilic residue, e.g. seryl or threonyl, is substituted for (or by) a hydrophobic residue, e.g. leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (b) a cysteine or proline is substituted for (or by) any other residue; (c) a residue having an electropositive side chain, e.g., lysyl, arginyl, or histidyl, is substituted for (or by) an electronegative residue, e.g., glutamyl or aspartyl; or (d) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine, in this case, (e) by increasing the number of sites for sulfation and / or glycosylation.For example, the replacement of one amino acid residue with another that is biologically and / or chemically similar is known to those skilled in the art as a conservative substitution. For example, a conservative substitution would be replacing one hydrophobic residue for another, or one polar residue for another. The substitutions include combinations such as, for example, Gly, Ala; Vai, He, Leu; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe, Tyr. Such conservatively substituted variations of each explicitly disclosed sequence are included within the mosaic polypeptides provided herein.Substitutional or deletional mutagenesis can be employed to insert sites for N- glycosylation (Asn-X-Thr / Ser) or O-glycosylation (Ser or Thr). Deletions of cysteine or other labile residues also may be desirable. Deletions or substitutions of potential proteolysis sites, e.g., Arg, is accomplished for example by deleting one of the basic residues or substituting one by glutaminyl or histidyl residues.Certain post-translational derivatizations are the result of the action of recombinant host cells on the expressed polypeptide. Glutaminyl and asparaginyl residues are frequently post- translationally deamidated to the corresponding glutamyl and aspartyl residues. Alternatively, these residues are deamidated under mildly acidic conditions. Other post-translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the o-amino groups of lysine, arginine, and histidineside chains (T.E. Creighton, Proteins: Structure and Molecular Properties, W. H. Freeman & Co., San Francisco pp 79-86

[1983] ), acetylation of the N-terminal amine and, in some instances, amidation of the C-terminal carboxyl.It is understood that the description of conservative mutations and homology can be combined together in any combination, such as embodiments that have at least 70% homology to a particular sequence wherein the variants are conservative mutations.As this specification discusses various proteins and protein sequences it is understood that the nucleic acids that can encode those protein sequences are also disclosed. This would include all degenerate sequences related to a specific protein sequence, i.e., all nucleic acids having a sequence that encodes one particular protein sequence as well as all nucleic acids, including degenerate nucleic acids, encoding the disclosed variants and derivatives of the protein sequences. Thus, while each particular nucleic acid sequence may not be written out herein, it is understood that each and every sequence is in fact disclosed and described herein through the disclosed protein sequence. For example, one of the many nucleic acid sequences that can encode the protein sequence set forth in SEQ ID NO: 4 is set forth in SEQ ID NO: 1 [human FGF9 protein]. In addition, for example, a disclosed conservative derivative of SEQ ID NO: 4 is shown in SEQ ID NO: 3, where the Arginine (R) at position 108 is changed to a glutamic acid (G). It is understood that while no amino acid sequence indicates what particular DNA sequence encodes that protein within an organism, where particular variants of a disclosed protein are disclosed herein, the known nucleic acid sequence that encodes that protein in the particular cancer cell from which that protein arises is also known and herein disclosed and described.It is understood that there are numerous amino acid and peptide analogs which can be incorporated into the disclosed compositions. For example, there are numerous D amino acids or amino acids which have a different functional substituent then the amino acids shown in Table 1 and Table 2. The opposite stereo isomers of naturally occurring peptides are disclosed, as well as the stereo isomers of peptide analogs. These amino acids can readily be incorporated into polypeptide chains by charging tRNA molecules with the amino acid of choice and engineering genetic constructs that utilize, for example, amber codons, to insert the analog amino acid into a peptide chain in a site specific way.Molecules can be produced that resemble peptides, but which are not connected via a natural peptide linkage. For example, linkages for amino acids or amino acid analogs can include CH2NH-, -CH2S-, -CH2-CH2-, -CH=CH- (cis and trans), -COCH2-, - CH(OH)CH2-, and -CHH2SO — (These and others can be found in Spatola, A. F. in Chemistry’and Biochemistry of Amino Acids, Peptides, and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Spatola, A. F., Vega Data (March 1983), Vol. 1, Issue 3, Peptide Backbone Modifications (general review); Morley, Trends Pharm Sci (1980) pp. 463-468; Hudson, D. et al., Int J Pept Prot Res 14:177-185 (1979) (-CH2NH-, CH2CH2-); Spatola et al. Life Sci 38: 1243-1249 (1986) (-CH H2-S); Hann J. Chem. Soc Perkin Trans. I 307-314 (1982) (-CH-CH-, cis and trans); Almquist et al. J. Med. Chem. 23:1392-1398 (1980) (-COCH2-); Jennings-White et al. Tetrahedron Lett 23:2533 (1982) (-- COCH2— ); Szelke et al. European Appln, EP 45665 CA (1982): 97:39405 (1982) (-CH(OH)CH2-); Holladay et al. Tetrahedron. Lett 24:4401-4404 (1983) (-C(OH)CH2-); and Hruby Life Sci 31 : 189-199 (1982) (-CH2-S-); each of which is incorporated herein by reference. A particularly preferred non-peptide linkage is — CH2NH— . It is understood that peptide analogs can have more than one atom between the bond atoms, such as b-alanine, g- aminobutyric acid, and the like.Amino acid analogs and analogs and peptide analogs often have enhanced or desirable properties, such as, more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum of biological activities), reduced antigenicity, and others.D-amino acids can be used to generate more stable peptides, because D amino acids are not recognized by peptidases and such. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) can be used to generate more stable peptides. Cysteine residues can be used to cyclize or attach two or more peptides together. This can be beneficial to constrain peptides into particular conformations.Pharmaceutical carriers / Delivery of pharmaceutical productsIn one aspect it is disclosed and herein contemplated that the mutant FGF9 polypeptides, nucleic acids, and vectors disclosed herein can be formulated as a pharmaceutical composition. Thus, disclosed herein is a pharmaceutical composition comprising the mutant FGF9 polypeptide, the isolated nucleic acid, the vector and a pharmaceutically acceptable carrier. Some exemplary pharmaceutically acceptable carriers can be an oil-in-water emulsion, a nano-emulsion, a nanoparticle, an excipient, a diluent, a salt, a buffer, a stabilizer, a lipid, or combinations thereof. One or more active agents (e.g., FGF9 mutant polypeptide) can be administered in the “native” form or, if desired in the form of salts, esters, amides, prodrugs, or a derivative that is pharmacologically suitable. Salts, esters, amides, prodrugs, and other derivatives of the active agents can be prepared using standards procedures known to those skilled in the art of syntheticorganic chemistry and described, for example, by March (1992) Advanced Organic Chemistry; Reactions, Mechanisms, and Structure, 4thEd. N.Y. Wiley-Interscience.As described above, the compositions can also be administered in vivo in a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject, along with the nucleic acid or vector, without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.The compositions may be administered orally, parenterally (e.g., intravenously), by intramuscular injection, by intraperitoneal injection, transdermally, extracorporeally, topically or the like, including topical intranasal administration or administration by inhalant. As used herein, "topical intranasal administration" means delivery of the compositions into the nose and nasal passages through one or both of the nares and can comprise delivery by a spraying mechanism or droplet mechanism, or through aerosolization of the nucleic acid or vector. Administration of the compositions by inhalant can be through the nose or mouth via delivery by a spraying or droplet mechanism. Delivery can also be directly to any area of the respiratory system (e.g., lungs) via intubation. The exact amount of the compositions required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the severity of the allergic disorder being treated, the particular nucleic acid or vector used, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every composition. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein.Parenteral administration of the composition, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. See, e.g., U.S. Patent No. 3,610,795, which is incorporated by reference herein.The materials may be in solution, suspension (for example, incorporated into microparticles, liposomes, or cells). These may be targeted to a particular cell type via antibodies, receptors, or receptor ligands. The following references are examples of the use ofthis technology to target specific proteins to tumor tissue (Senter, et al., Bioconjugate Chem., 2:447-451, (1991); Bagshawe, K.D., Br. J. Cancer, 60:275-281, (1989); Bagshawe, et al., Br. J. Cancer, 58:700-703, (1988); Senter, et al., Bioconjugate Chem., 4:3-9, (1993); Battelli, et al., Cancer Immunol. Immunother., 35:421-425, (1992); Pietersz and McKenzie, Immunolog. Reviews, 129:57-80, (1992); and Roffler, et al., Biochem. Pharmacol, 42:2062-2065, (1991)). Vehicles such as "stealth" and other antibody conjugated liposomes (including lipid mediated drug targeting to colonic carcinoma), receptor mediated targeting of DNA through cell specific ligands, lymphocyte directed tumor targeting, and highly specific therapeutic retroviral targeting of murine glioma cells in vivo. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Hughes et al., Cancer Research, 49:6214- 6220, (1989); and Litzinger and Huang, Biochimica et Biophysica Acta, 1104:179-187, (1992)). In general, receptors are involved in pathways of endocytosis, either constitutive or ligand induced. These receptors cluster in clathrin-coated pits, enter the cell via clathrin-coated vesicles, pass through an acidified endosome in which the receptors are sorted, and then either recycle to the cell surface, become stored intracellularly, or are degraded in lysosomes. The internalization pathways serve a variety of functions, such as nutrient uptake, removal of activated proteins, clearance of macromolecules, opportunistic entry of viruses and toxins, dissociation and degradation of ligand, and receptor-level regulation. Many receptors follow more than one intracellular pathway, depending on the cell type, receptor concentration, type of ligand, ligand valency, and ligand concentration. Molecular and cellular mechanisms of receptor-mediated endocytosis has been reviewed (Brown and Greene, DNA and Cell Biology 10:6, 399-409 (1991)).Pharmaceutically Acceptable CarriersThe compositions, including antibodies, can be used therapeutically in combination with a pharmaceutically acceptable carrier.Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles,e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered.Pharmaceutical carriers are known to those skilled in the art. These most typically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. The compositions can be administered intramuscularly or subcutaneously. Other compounds will be administered according to standard procedures used by those skilled in the art.Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.The pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthalmically, vaginally, rectally, intranasally), orally, by inhalation, or parenterally, for example by intravenous drip, subcutaneous, intraperitoneal or intramuscular injection. The disclosed antibodies can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, inert gases and the like.Formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders may be desirable.Some of the compositions may potentially be administered as a pharmaceutically acceptable acid- or base- addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines and substituted ethanolamines.Therapeutic UsesEffective dosages and schedules for administering the compositions may be determined empirically, and making such determinations is within the skill in the art. The dosage ranges for the administration of the compositions are those that are large enough to produce the desired effect in which the symptoms of the disorder are effected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. For example, guidance in selecting appropriate doses for antibodies can be found in the literature on therapeutic uses of antibodies, e.g., Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, N.J., (1985) ch. 22 and pp. 303-357; Smith et al., Antibodies in Human Diagnosis and Therapy, Haber et al., eds., Raven Press, New York (1977) pp. 365-389. A typical daily dosage of the antibody used alone might range from about 1 pg / kg to up to 100 mg / kg of body weight or more per day, depending on the factors mentioned above.Following administration of a disclosed composition, of an FGF9 mutant polypeptide, for treating, inhibiting, or preventing a cancer, the efficacy of the therapeutic antibody can be assessed in various ways well known to the skilled practitioner. For instance, one of ordinary skill in the art will understand that a composition, of an FGF9 mutant polypeptide, disclosed herein is efficacious in treating or inhibiting a cancer in a subject by observing that the composition reduces cancer cell / tumor load or prevents a further increase in cancer cell / tumor load. Cancer cell / tumor loads can be measured by methods that are known in the art, forexample, using clinical techniques (such as, for example, scanning or histology to detect the presence of cancer markers in a sample (e.g., but not limited to, blood) from a subject or patient, or by measuring the level of circulating cancer marker levels in the patient. Efficacy of the administration of the disclosed composition may also be determined by measuring the number of NK cells and / or T cells in the cancer-bearing subject. The FGF9 mutant polypeptide treatment that inhibits an initial or further decrease in NK cells and / or T cells in a cancer-bearing subject or patient is an efficacious antibody treatment.The compositions that inhibit FGF9 signaling induced by integrin and FGF9 interactions disclosed herein may be administered prophylactically to patients or subjects who are at risk for cancer.Other molecules that interact with integrins as antagonists to inhibit FGF9 signaling induced by integrin and FGF9 interactions which do not have a specific pharmaceutical function, but which may be used for tracking changes within cellular chromosomes or for the delivery of diagnostic tools for example can be delivered in ways similar to those described for the pharmaceutical products.The disclosed compositions and methods can also be used for example as tools to isolate and test new drug candidates for a variety of cell proliferation-related diseases.Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.C. Methods of treating cancerIn one aspect, disclosed herein is a method of treating a cancer (such as, for example, colon cancer, prostate cancer, breast cancer, gliomas, renal cancer, testicular cancer, uterine cancer, skin cancer, lung cancer, stomach cancer, and ovarian cancer) in a subject. As disclosed herein, the cancer is colon cancer.In certain aspects, the cancer is a proliferative disorder and, in certain embodiments, the composition further includes an anti-cancer agent. Exemplary proliferative diseases include, but are not limited to, tumors, benign neoplasms, pre-malignant neoplasms (carcinoma in situ), and malignant neoplasms (cancers).Exemplary cancers include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa- associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenstrom's macroglobulinemia”), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or moreleukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's disease of the vulva).As disclosed herein the method comprises administering to the subject a mutant FGF9 polypeptide or a pharmaceutical composition, wherein the mutant FGF9 polypeptide comprises an amino acid substitution at residue 108, 129, 154 or any combination thereof, wherein the amino acid substitution (such as, for example, substitution of an arginine (R) at residue 108 for a glutamic acid (E) (R108E), substitution of a lysine (K) at residue 129 for a glutamic acid (E) (K129E) or substitution of a lysine (K) at residue 154 for a glutamic acid (E) (K154E)) is relative to SEQ ID NO: 1. As disclosed herein, the pharmaceutical composition can comprise any of theFGF9 mutant polypeptides , isolated nucleic acids encoding said mutant FGF9 polypeptides, and / or a vectors disclosed herein and a pharmaceutically acceptable carrier.The FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the cancer, the particular FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, its mode of administration, its mode of activity, and the like. The FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the cancer being treated and the severity of the cancer; the activity of the pharmaceutical composition, disclosed herein, employed; the specific pharmaceutical composition, disclosed herein, employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, employed; the duration of the treatment; drugs used in combination or coincidental with the FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, employed; and like factors well known in the medical arts.The FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, may be administered by any route. In some embodiments, the FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, is administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc.The exact amount of FGF9 mutant polypeptide or pharmaceutical composition, disclosed herein, required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.The concentration of active agent(s) can vary widely and will be selected primarily based on activity of the active ingredient(s), body weight and the like in accordance with the particular mode of administration selected and the patient's needs. Concentrations, however, will typically be selected to provide dosages ranging from about 0.1 or 1 mg / kg / day to about 50 mg / kg / day and sometimes higher. Typical dosages range from about 0.1 mg / kg / day to about 1 mg / kg / day, about 0.5 mg / kg / day to about 1.5 mg / kg / day, about 1 mg / kg / day to about 2 mg / kg / day, about 1.5 mg / kg / day to about 2.5 mg / kg / day, about 2 mg / kg / day to about 3 mg / kg / day, about 2.5 mg / kg / day to about 3.5 mg / kg / day, about 3 mg / kg / day to about 3.5 mg / kg / day, about 3 mg / kg / day to about 3.5 mg / kg / day, preferably from about 3.5 mg / kg / day to about 7.2 mg / kg / day, preferably from about 5 mg / kg / day to about 7.2 mg / kg / day, more preferably from about 7.2 mg / kg / day to about 11.0 mg / kg / day, and most preferably from about 11.0 mg / kg / day to about 15.0 mg / kg / day. In certain preferred embodiments, dosages range from about 10 mg / kg / day to about 50 mg / kg / day. In certain embodiments, dosages range from about 20 mg to about 50 mg given orally twice daily. It will be appreciated that such dosages may be varied to optimize a therapeutic and / or prophylactic regimen in a particular subject or group of subjects.In some aspects, the FGF9 mutant polypeptide or pharmaceutical composition can be prepared as a “concentrate”, e.g., in a storage container of a premeasure volume and / or a predetermined amount ready for dilution, or in a soluble capsule ready for addition to a specified volume of water, saline, alcohol, hydrogen peroxide, or other diluent.In some aspects, the FGF9 mutant polypeptide or pharmaceutical composition is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or more times. In some embodiments, the FGF9 mutant polypeptide or pharmaceutical composition is administered daily. In some embodiments, the FGF9 mutant polypeptide or pharmaceuticalcomposition is administered every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, or more. In some embodiments, the FGF9 mutant polypeptide or pharmaceutical composition is administered every week, every 2 weeks, every 3 weeks, every 4 weeks, or more. In some embodiments, the FGF9 mutant polypeptide or pharmaceutical composition is administered every month, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, every 12 months, or more. In some embodiments, the FGF9 mutant polypeptide or pharmaceutical composition is administered every year, every 2 years, every 3 years, every 4 years, every 5 years, or more.D. ExamplesThe following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.Example 1: FGF9, a Potent Mitogen, is a New Ligand for Integrin avp3, and the FGF9 Mutant Defective in Integrin Binding Acts as an AntagonistIntegrins are a superfamily of cell adhesion receptors and recognize extracellular matrix (ECM) ligands, cell surface ligands, and small soluble ligands (e.g., growth factors). It has been established that integrins are critically involved in growth factor signaling through integrin- growth factor crosstalk. The first indication of the role of integrins in growth factor signaling is that antagonists to integrin avp3 suppressed FGF2-induced angiogenesis. The specifics of this crosstalk are, however, unclear. Currently popular models of integrin and growth factor crosstalk suggest that integrins promote growth factor signals through interaction of integrins with the extracellular matrix.Previous studies showed that FGF1 and FGF2 directly bind to integrin avp3, and this interaction is critical for signaling functions (FGF-integrin crosstalk). FGF1 and FGF2 mutants defective in integrin binding were defective in signaling, whereas the mutants still bound to FGFR, and suppressed angiogenesis and tumor growth, indicating that they act as antagonists.Although FGF9 messenger RNA (mRNA) is ubiquitously expressed in embryos, FGF9 protein expression is generally low and restricted to a few adult organs. Previous studies showed that FGF1 signaling requires direct integrin binding and subsequent integrin-FGFl-FGFRl ternary complex formation is required for signaling functions and an FGF1 mutant defective in integrin binding (R50E) was defective in signaling functions and suppressed FGF1 signaling induced by WT FGF1 act as an antagonist of FGFR. FGF1 mutants defective in integrin binding strongly blocked angiogenesis in vitro and tumor growth in vivo. Similar results were obtained in FGF2. It is unclear if FGF9 requires crosstalk with integrins for signaling. It was hypothesized that FGF9 directly binds to integrins and that FGF9 mutants defective in integrin binding acts as antagonists for FGF9 signaling.In the present study, it is shown that FGF9 directly binds to integrin avf>3. Docking simulation predicted that FGF9 bound to the classical ligand-binding site of integrin avP3. Point mutations were introduced in the predicted integrin binding interface of FGF9. An FGF9 mutant R108E was defective in integrin binding and in signaling functions. It was found that the R108E suppressed signaling induced by WT FGF9, indicating that R108E is a dominant-negative antagonist of FGF9. Thus, it is shown that R108 has therapeutic potential and the integrin-FGF9 interaction is a novel therapeutic target.Materials and MethodsMaterials: DLD 1 human colorectal cancer and Colon26 mouse colon cancer cells were cultured in Dulbecco's Modified Eagle Medium (DMEM)(Gibco, USA) containing 10% fetal bovine serum, 100 U / ml penicillin and 100 pg / ml streptomycin. NIH3T3 mouse embryonic fibroblasts, which were obtained from Bioresource Collection and Research Center, Taiwan, were cultured in DMEM containing 10% bovine serum (Gibco, USA) and MycoZap (LONZA, Switzerland) in an atmosphere of 95% air, 5% CO2- The antibodies were purchased from the following sources: rabbit anti-FRS2a (ProteinTech, USA), rabbit anti-phospho-FRS2a (Tyr-196) (Cell Signaling Technology, USA), rabbit anti-p44 / 42 MAPK (ERK1 / 2) (Cell Signaling Technology, USA), anti-phospho-p44 / 42 MAPK (p-ERKl / 2) (Thr-202 / Tyr204) (Cell Signaling Technology, USA), rabbit anti-FGFRl (Cell Signaling Technology, USA), rabbit anti-FGFR2 (Sigma Aldrich, USA), and rabbit anti-FGFR3 (Novus Biologicals, USA). cRGDfV was obtained from Enzo Life Sciences Inc. (Lausen, Switzerland).Synthesis of FGF9: The cDNA fragment encoding human FGF9 (LGEVGNYFGVQDAVPFGNVPVLPVDSPVLLSDHLGQSEAGGLPRGPAVTDLDHLKGILR RRQLYCRTGFHLEIFPNGTIQGTRKDHSRFGILEFISIAVGLVSIRGVDSGLYLGMNEKGELYGSEKLTQECVFREQFEENWYNTYSSNLYKHVDTGRRYYVALNKDGTPREGTRTKRHQ KFTHFLPRPVDPDKVPELYKDILSQS) was amplified by PCR using full length human FGF9 cDNA as a template and subcloned into BamHl / EcoRl site of pET28aAmp vector, in which the kanamycin resistant gene was replaced with ampicillin resistant gene. Site-directed mutagenesis was performed using the QuickChange method. The existenceof FGF9 mutations was checked by DNA sequencing. The WT FGF9, R108E, K129E and K154E mutants were expressed in E. coli strain BL21(DE3) by isopropyl P-d- thiogalactoside (IPTG) induction and synthesized as insoluble proteins. The His-tag of proteins were used to purified proteins using Ni-NTA affinity chromatography in denaturing conditions (8 M urea). The Ni-NTA resin was washed with 0.5% Triton X-114 (Sigma, USA) to eliminate endotoxin before eluting the bound protein. The purified proteins were eluted in 250 mM imidazole / 8 M urea. Purified proteins were diluted into refolding buffer (100 mM Tris-HCl, pH 8.0, 400 mM Arg, 2 mM EDTA, 0.5 mM oxidized glutathione, 5 mM reduced glutathione and PMSF) on ice. The dilution was kept for 16 hours at 4°C with a slow stirring movement. Then the proteins were concentrated by ultrafiltration. Around 4 to 5 milligrams of purified proteins were obtained from one liter of bacterial culture. Purified proteins concentration was determined by measuring A280 and Bio-Rad protein Assay.Docking Simulation: Docking simulation of interaction between FGF9 (PDB code 1IHK) and integrin av 3 (PDB code 1L5G) was performed using Autodock 3.05. In the present study, the headpiece (residues 1-438 of av and residues 55-432 of 3) of avP3 (open-headpiece form, lL5G.pdb) were used. Cations were not present in avP3 during docking simulation.Binding of Soluble Integrin avp3 to FGF9: ELISA-type binding assays were performed as previously described. Briefly, wells of 96-well microtiter plates were coated with FGF9 by incubating for 30 min at room temperature and the remaining protein binding sites were blocked with BSA (heat-treated). Wells were incubated with soluble av03 (1 pg / ml) in Tyrode- HEPES buffer in 1 mM Mn2+and incubated for 1 hour at room temperature. After washing the wells with the same buffer, bound avP3 was quantified using anti-P3 (mAb AV10) and HRP- conjugated anti-mouse IgG and peroxidase substrate.FGF9 binding to the FGFR1 D2D3 fragment and heparin: The ligand-binding site of FGFR1 (the immunoglobulin-like D2 and D3 domains, amino acid residues 140-365) was synthesized as described. Briefly, pET21a encoding the cDNA fragment in the BamHI / XhoI sites of the vector was used to transform BL21 (DE3). The protein was expressed as an insoluble protein and refolded. The refolded protein was purified by affinity chromatography on heparin- Sepharose to enrich the properly folded protein. Bound protein was eluted with 1 m NaCl.Binding of R108E to heparin-Sepharose. Purified WT and mutant FGF9 were incubated with heparin-Sepharose and eluted with 1.5 M NaCl. Bound and unbound proteins were analyzed by SDS-PAGE and proteins stained with Coomassie Brilliant Blue.Cell Migration Assay: A polycarbonate filter of 8 pm pore size of the Chemotaxicell chamber (Kurabo, Osaka, Japan) was used to test cell migration. Lower side of the filter was coated with 10 pg / ml fibronectin (Asahi Glass, Tokyo, Japan) for Ih at room temperature. After washing, the chamber was placed into a 24-well cell culture plate, and the lower portion of the plate was filled with serum-free DMEM containing 50 ng / ml WT FGF9-or R108E FGF9. Cells were plated on the upper side of chamber and incubated at 37 °C for 6 h. Cells were fixed and visualized by crystal violet staining. The uncoated upper side of each filter was wiped with a cotton swab to remove cells that had not migrated through the filter. Migrated cells were counted from the digital images of the stained cells, determining the mean number of cells counted per field. Results were expressed as means ± S.D. of the cell number.Invasion Assay: Invasion assays were done in 8 pm pore size of the Chemotaxicell chamber coated with 100 pg / ml Growth factor reduced Matrigel (BD Biosciences, San Jose CA) for 3 hour at 37°C and blocked with 0.1% bovine serum albumin in PBS. Cells were suspended in serum- free DMEM containing 0.1% BS A and plated in the upper chamber. The lower chamber was filled with DMEM containing 0.1% BSA and 50 ng / ml recombinant human WT FGF9 or R108E FGF9. Then, cells were allowed to migrate for 24 h. The top side of the filters was wiped with cotton swabs, fixed, and stained with 0.1% crystal violet. Images were taken by digital camera and counted using cell counting function of Image J software.BrdU Incorporation Assay: DNA synthesis or replication was monitored by measuring the Cell Proliferation ELISA BrdU kit (Roche). Cells were cultured on a Nunc 96-well plate (Thermo Scientific) at the density of 2xl03cells / well. After 24 hours, cells were rendered quiescent by incubation in serum free medium for 16 to 18 hours and then stimulated with either WT FGF9 or FGF9 mutations for 16 hours. BrdU labeling solution was added to each well concomitantly and those cells were incubated for 2 hours in a CO2 incubator at 37°C in the presence of BrdU. Incorporated BrdU was detected using monoclonal mouse anti-BrdU antibody conjugated with HRP and tetramethylbenzidine (TMB).Statistical Analysis: Data processing was performed using Prism 7 software (GraphPad, USA). All results were expre sed as mean ± standard deviation . The stati stical analy si s of difference between two groups was analyzed by unpaired Student’s t test and differencebetween multiple groups was performed by one-way analysis of variance (ANOVA).P< 0.05 was considered to indicate statistically significant.ResultsFGF9 Directly Binds to Integrin avp3: The ability of FGF9 to bind to integrin avP3 was investigated in ELISA-type binding assays. Wells of 96-well microtiter plate were coated with FGF9, and the remaining protein binding sites were blocked with BSA. It was found that soluble integrin av03 (extracellular domains) bound to immobilized FGF9 in a dose-dependent manner in 1 mM Mn2+(FIG. 1 A), as predicted by docking simulation. Soluble integrin avP3 did not bind to wells that are coated only with BSA (which serves as a negative control), and therefore FGF9 binding to avp3 is specific. Cyclic RGDfV, an inhibitor specific to avp3, suppressed the binding of av'PS to FGF9, indicating that avP3 specifically bound to FGF9 (FIG. IB). The binding of FGF9 to integrin avP3 required Mn2+, but Ca2+, Mg2+or EDTA (all 1 mM) did not support FGF9 binding to integrin avP3 (FIG. 1C). Also, heat treatment reduced FGF9 binding to avP3, indicating that FGF9 should be properly folded. These findings indicate that FGF9 is a ligand for integrin avP3.To study how FGF9 binds to integrin avP3, docking simulation of interaction was performed between avP3 (PDB code 1L5G) and FGF9 (PDB code 1IHK) using AutoDock 3. 50 independent dockings were performed, and the obtained poses were clustered (RMSD<2.0). The pose in the first cluster (docking energy -23 Kcal / mol, the first cluster) was selected for further analysis. The simulation predicted that FGF9 binds to the classical ligand binding site of avP3 at high affinity (FIG. 2A). When the 3D structure of the FGF9-FGFR1 complex (5W59.pdb) was superposed with the avp3-FGF9 docking model, there was little or no steric hindrance (FIG. 2B). This predicts that the FGFR1 -binding site and the integrin-binding site are distinct, and that FGF9-binding site overlaps with that of FGF1, indicating that FGF9 binds to the classical ligandbinding site (site 1) of integrins. Amino acid residues that are predicted to be involved in FGF9- integrin avP3 interaction are shown in Table 3.Generation of Integrin-Binding Defective FGF9 Mutants: Argl08, Lysl29 andLys 154 were chosen in the predicted integrin-binding interface of FGF9 for mutagenesis studies (FIG. 3A, Table 1). The Argl08 to Glu (the R108E mutation) and the K154E mutations and much less the K129E mutation reduced the binding of soluble avP3 to FGF9 in ELISA-type binding assays (FIG. 3B). This result indicated that the R108E and K154E mutations effectively suppressed the binding of FGF9 to avf)3. FGF9 has been shown to induce strong dose-dependent mitogenic activity in NIH3T3 cells. This justifies to perform studies if FGF9 mutations affectDNA synthesis in NIH3T3 cells. (FIG. 3C). R108E completely lost the ability to induce BrdU incorporation, but K129E and K154E mutants were partly defective, indicating that direct binding to integrin avP3 is critical for signaling functions of FGF9. R108E was selected for further analysis.It was further studied if the R108E mutation affect FGFR1 binding using FGFR1 D2D3 fragment in EEISA-type binding assays. FGF9 WT and FGF9 R108E bound to immobilized FGFRD2D3 at a comparable level (FIG. 3D), indicating that the R108E mutation did not detectably affect FGFR1 binding.Since the R108E mutation is close to the heparin binding site of FGF9, it is possible that it affects heparin binding.R108E Is Defective in Inducing Migration and Invasion of Colon Cancer Cells: DLD1 human colon cancer cells express FGFR2 and FGFR3, and Colon26 mouse colon cancer cells express FGFR3 (FIG. 4A). The ability of WT FGF9 and R108E to induce pERKl / 2 was studied. Fetal bovine serum (FBS, 10%) was used as a positive control. WT FGF9 induced ERK1 / 2 activation, but R108E was defective in inducing ERK1 / 2 activation (FIG. 4B).-FGF9 is a potent chemoattractant. It was found that R108E was defective in inducing cell migration (FIGS. 4C and 4D) and invasion of DEDI and Colon26 cells (FIGS. 4E and 4F).R108E Suppresses Activation of FRS2 and ERK1 / 2 and DNA Synthesis Induced by WT FGF9 (Dominant-Negative Effect) in NIH3T3 Cells: If integrin binding to FGF9 and integrin-FGF9-FGFR ternary complex formation is required for FGF9 signaling, FGF9 R108E mutant defective in integrin binding is expected to be dominant-negative, as in the case of FGF1 and FGF2. It was studied if R108E suppresses FRS2a and ERK1 / 2 phosphorylation induced by WT FGF9 in NIH3T3 cells. NIH3T3 cells were incubated with WT FGF9 and / or R108E for 30 min. It was found that 20-fold excess R108E blocked FRS2a, and ERK1 / 2 activation induced by WT FGF9 (FIGS. 5 A, 5B, and 5C). It was examined whether R108E suppresses DNA synthesis induced by WT FGF9 in NIH3T3 cells in BrdU incorporation assays. R108E did not induce DNA synthesis. It was found that excess (20x) R108E suppressed DNA synthesis induced by WT FGF9 (FIG. 5D). These findings suggest that R108E is a dominant-negative mutant of FGF9.FGF9 R108 mutant suppressed proliferation of cancer cells: The results so far suggests that FGF9 R108E suppresses proliferative signals induced by WT FGF9. Since FGF9 is over expressed in cancer and plays a role in cancer proliferation, it was studied if FGF9 R108E suppresses cancer cell proliferation.DiscussionR108E (FGF9 Antagonist) Has Potential as Therapeutic in Cancer: FGF9 has been implicated in the pathogenesis of cancer through its high affinity receptor FGFR3c. FGF9 is over-expressed in cancer-associated fibroblasts (CAFs) and mediates communication with cancer cells. This indicates that FGF9 is a major therapeutic target in cancer, and antagonists to FGF9 must be developed. In previous studies, docking simulation predicted that FGF1 and FGF2 directly bind to integrins and dominant-negative FGF1 and FGF2 mutants, which have therapeutic potential, were developed. The present study for the first time showed that FGF9 requires direct integrin binding for signaling functions. Docking simulation predicted that FGF9 binds to the classical ligand-binding site of av[33. An FGF9 mutant defective in integrin binding (the R108E mutant) was generated. The position of R108E mutation cannot be deduced from comparison of primary structure of FGF9 and FGF1 / FGF2, probably because FGF1, 2 and 9 interact with integrins differently.The R108E mutant was defective in signaling functions, including DNA synthesis, activation of ERK1 / 2 and FRS2a, cell migration, and invasion. This indicates that binding of FGF9 to integrin is required for FGF9 signaling. Notably, R108E is a dominant-negative mutant, and effectively suppressed DNA synthesis, FRS2 phosphorylation and ERK1 / 2 activation induced by WT FGF9. This suggests that R108E has potential as a therapeutic in diseases in which FGF9 is involved. Previous studies showed that dominant- negative FGF 1 mutant R50E bound to FGFR1 with an affinity comparable to that of WT FGF1. It was predicted that FGF9 induces integrin-FGF9-FGFR ternary complex on the cell surface, which is critical for FGF9 signaling. FGF9 binds to FGFR (high affinity receptor), and to integrins (low affinity receptor). The loss of integrin binding is assumed to result in the loss of signaling functions but still binds to FGFR, which makes potent a dominant-negative antagonist to FGF9 signaling. Since FGF9 has oncogenic activity and overexpressed in many cancers (see Introduction), FGF9 R108E should be useful as a potential therapeutic. It is highly likely that binding of FGF9 to FGFR is not sufficient for FGF9 signaling. It would be interesting to study if the R108E mutant of FGF9 suppress cancer proliferation by inhibiting FGF9 signaling (e.g., through FGFR3) in future studies.It is possible that FGF9 binds to integrins other than avP3. If this is the case, blocking avP3 using antagonists to avP3 may not be effective in blocking FGF9 signaling, since other integrins may replace the position of avP3. However, the integrin-binding defective FGF9 R108E mutant can block FGF9-integrin interaction regardless of integrin species.Previous studies showed that several growth factors (e.g., FGF1 , IGF1, fractalkine, and CD40L) require direct integrin binding and subsequent integrin-growth factor-cognate receptor ternary complex formation for signaling functions (ternary complex model) and growth factor mutants defective in integrin binding were defective in signaling functions, whereas they still bind to cognate receptors, and act as antagonists of growth factor signaling (growth factor decoys). Integrins are common co-receptors of growth factors and the ternary complex model can be applied to many growth factor signaling and growth factor antagonists can be designed by screening growth factor mutants defective in integrin binding.Basic fibroblast growth factor (bFGF, FGF2) and integrin a601 are important for maintaining the pluripotency of human pluripotent stem cells (hPSCs). It has previously been shown that FGF2 binds to integrins and the FGF2 K125E mutant is defective in integrin binding and in inducing signals. It has recently been reported that integrin a6pi-FGF2-FGFR ternary complex formation is critical for maintaining the pluripotency of hPSCs. The FGF2 K125E was incapable of inducing the hPSC properties, such as proliferation, ERK activity, and large focal adhesions at the edges of human induced pluripotent stem cells (hiPSCs) colonies. These findings suggest that the integrin-FGF interaction and resulting ternary complex formation is a target for drug discovery. Dominant negative FGF9 R108E mutant is a therapeutic for cancer.E. References1. Takada, Y., X. Ye, and S. Simon, The integrins. Genome Biol, 2007. 8(5): p. 215. 10.1186 / gb-2007-8-5-215 PMC19291362. Eliceiri, B.P., Integrin and growth factor receptor crosstalk. Circ Res, 2001. 89(12): p. 1104-10.3. Brooks, P.C., R.A. Clark, and D.A. Cheresh, Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science, 1994. 264(5158): p. 569-71.4. Kim, S.H., J. Turnbull, and S. Guimond, Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J Endocrinol, 2011. 209(2): p. 139-51. 10.1530 / JOE-10-03775. Omitz, D.M. and N. Itoh, The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol, 2015. 4(3): p. 215-66. 10.1002 / wdev.l76 PMC43933586. Naruo, K., C. Seko, K. Kuroshima, E. Matsutani, R. Sasada, T. Kondo, and T. Kurokawa, Novel secretory heparin-binding factors from human glioma cells (glia-activating factors) involved in glial cell growth. Purification and biological properties. J Biol Chem, 1993. 268(4): p. 2857-64.7. Klint, P. and L. Claesson- Welsh, Signal transduction by fibroblast growth factor receptors. Front Biosci, 1999. 4: p. D165-77.8. Powers, C.J., S.W. McLeskey, and A. Wellstein, Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer, 2000. 7(3): p. 165-97.9. Colvin, J.S., A.C. White, S.J. Pratt, and D.M. Ornitz, Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development, 2001. 128(11): p. 2095-106. 10.1242 / dev.l28.11.209510. Colvin, J.S., R.P. Green, J. Schmahl, B. Capel, and D.M. Omitz, Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell, 2001. 104(6): p. 875-89.10.1016 / s0092- 8674(01 )00284-711. DiNapoli, L., J. Batchvarov, and B. Capel, FGF9 promotes survival of germ cells in the fetal testis. Development, 2006. 133(8): p. 1519-27. 10. 1242 / dev.0230312. Hung, I.H., K. Yu, K.J. Lavine, and D.M. Ornitz, FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol, 2007. 307(2): p. 300-13. 10.1016 / j.ydbio.2007.04.048 PMC226792213. Lavine, K.J., K. Yu, A.C. White, X. Zhang, C. Smith, J. Partanen, and D.M. Omitz, Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo. Dev Cell, 2005. 8(1): p. 85-95. 10.1016 / j.devcel.2004.12.00214. Pirvola, U., X. Zhang, J. Mantela, D.M. Omitz, and J. Ylikoski, Fgf9 signaling regulates inner ear morphogenesis through epithelial-mesenchymal interactions. Dev Biol, 2004. 273(2): p. 350-60. 10.1016 / j.ydbio.2004.06.01015. Chang, M.M., H.Y Weng, M.S. Lai, L.W. Wang, S.H. Yang, C.C. Wu, C.Y Wang, and B.M. Huang, FGF9 promotes cell proliferation and tumorigenesis in TM3 mouse Leydig progenitor cells. Am J Cancer Res, 2022. 12(12): p. 5613-5630. PMC982708416. Chang, M.M., M.S. Lai, S.Y. Hong, B.S. Pan, H. Huang, S.H. Yang, C.C. Wu, H.S. Sun, J. I. Chuang, C.Y. Wang, and B.M. Huang, FGF9 / FGFR2 increase cell proliferation by activating ERK1 / 2, Rb / E2F1, and cell cycle pathways in mouse Leydig tumor cells. Cancer Sci, 2018. 109(11): p. 3503-3518. 10.1111 / cas.l3793 PMC621587917. Arai, D., A.E. Hegab, K. Soejima, A. Kuroda, K. Ishioka, H. Yasuda, K. Naoki, K. Shizuko, J. Hamamoto, Y. Yin, D.M. Ornitz, and T. Betsuyaku, Characterization of the cell of origin and propagation poten tial of the fibroblast growth factor 9-induced mouse model of lung adenocarcinoma. J Pathol, 2015. 235(4): p. 593-605. 10.1002 / path.4486 PMC432909718. Huang, Y, C. Jin, T. Hamana, J. Liu, C. Wang, L. An, W.L. McKeehan, and F. Wang, Overexpression of FGF9 in prostate epithelial cells augments reactive stroma formation and promotes prostate cancer progression. Int J Biol Sci, 2015. 11(8): p. 948-60.10.7150 / ijbs.12468 PMC449541219. Chen, T.M., YH. Shih, J.T. Tseng, M.C. Lai, C.H. Wu, YH. Li, S.J. Tsai, and H.S. Sun, Overexpression ofFGF9 in colon cancer cells is mediated by hypoxia-induced translational activation. Nucleic Acids Res, 2014. 42(5): p. 2932-44. 10.1093 / nar / gktl286 PMC395068520. Ren, C., H. Chen, C. Han, D. Fu, F. Wang, D. Wang, L. Ma, L. Zhou, and D. Han, The anti-apoptotic and prognostic value of fibroblast growth factor 9 in gastric cancer. Oncotarget, 2016. 7(24): p. 36655-36665. 10.18632 / oncotarget.9131 PMC509502921. Bhattacharya, R., S. Ray Chaudhuri, and S.S. Roy, FGF9-induced ovarian cancer cell invasion involves VEGF- A / VEGFR2 augmentation by virtue of ETS 1 upregulation and metabolic reprogramming. J Cell Biochem, 2018. 119(10): p. 8174-8189. 10.1002 / jcb.2682022. Yin, Y, F. Wang, and D.M. Ornitz, Mesothelial- and epithelial-derived FGF9 have distinct functions in the regulation of lung development. Development, 2011. 138(15): p.3169-77. 10.1242 / dev.065110 PMC318860723. Teishima, J., K. Shoji, T. Hayashi, K. Miyamoto, S. Ohara, and A. Matsubara, Relationship between the localization of fibroblast growth factor 9 in prostate cancer cells and postoperative recurrence. Prostate Cancer Prostatic Dis, 2012. 15(1): p. 8-14.10.1038 / pcan.2011.4824. Chang, M.M., S.Z. Wu, S.H. Yang, C.C. Wu, C.Y. Wang, and B.M. Huang, FGF9 / FGFR1 promotes cell proliferation, epithelial-mesenchymal transition, M2 macrophage infiltration and liver metastasis of lung cancer. Transl Oncol, 2021. 14(11): p. 101208. 10.1016 / j.tranon.2021.101208 PMC839052925. Ohgino, K., K. Soejima, H. Yasuda, Y. Hayashi, J. Hamamoto, K. Naoki, D. Arai, K. Ishioka, T. Sato, H. Terai, S. Ikemura, S. Yoda, T. Tani, A. Kuroda, and T. Betsuyaku, Expression of fibroblast growth factor 9 is associated with poor prognosis in patients with resected non-small cell lung cancer. Lung Cancer, 2014. 83(1): p. 90-6. 10.1016 / j.lungcan.2013.10.01626. Mori, S., C.Y. Wu, S. Yamaji, J. Saegusa, B. Shi, Z. Ma, Y. Kuwahara, K.S. Lam,R.R. Isseroff, YK. Takada, and Y. Takada, Direct binding ofintegrin alphavbeta3 to FGF1 plays a role in FGF1 signaling. J Biol Chem, 2008. 283(26): p. 18066-75. 10.1074 / jbc.M801213200 PMC244059327. Mori, S., V. Tran, K. Nishikawa, T. Kaneda, Y. Hamada, N. Kawaguchi, M. Fujita, J. Saegusa, YK. Takada, N. Matsuura, M. Zhao, and Y. Takada, A dominant-negative FGF1 mutant (the R50E mutant) suppresses tumorigenesis and angiogenesis. PLoS One, 2013. 8(2): p. e57927. 10.1371 / joumal.pone.0057927 PMC358525028. Mori, S., N. Hatori, N. Kawaguchi, Y. Hamada, T.C. Shih, C.Y. Wu, K.S. Lam, N. Matsuura, H. Yamamoto, YK. Takada, and Y. Takada, The integrin-binding defective FGF2 mutants potently suppress FGF2 signaling and angiogenesis. Biosci Rep, 2017. 37(2). 10.1042 / BSR20170173 PMC548219729. Sun, C., H. Fukui, K. Hara, X. Zhang, Y. Kitayama, H. Eda, T. Tomita, T. Oshima,S. Kikuchi, J. Watari, M. Sasako, and H. Miwa, FGF9 from cancer-associated fibroblasts is a possible mediator of invasion and anti-apoptosis of gastric cancer cells. BMC Cancer, 2015. 15: p. 333. 10.1186 / S12885-015-1353-3 PMC442458030. Fujita, M., YK. Takada, and Y. Takada, Integrins alphavbeta3 and alpha4betal act as coreceptors for fractalkine, and the integrin-binding defective mutant of fractalkine is an antagonist of CX3CR1. J Immunol, 2012. 189(12): p. 5809-19. 10.4049 / jimmunol.1200889 PMC351866031. Fujita, M., K. leguchi, D.M. Cedano-Prieto, A. Fong, C. Wilkerson, J.Q. Chen, M. Wu, S.H. Lo, A.T. Cheung, M.D. Wilson, R.D. Cardiff, A.D. Borowsky, Y.K. Takada, and Y. Takada, An integrin binding-defective mutant of insulin-like growth factor- 1 (R36E / R37E IGF1 ) acts as a dominant-negative antagonist of the IGF1 receptor (IGF1R) and suppresses tumorigenesis but still binds to IGF1R. J Biol Chem, 2013. 288(27): p. 19593-603. 10.1074 / jbc.Ml 13.470872 PMC370766032. Takada, Y.K., J. Yu, M. Shimoda, and Y. Takada, Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40 / CD40L Signaling. J Immunol, 2019. 203(5): p. 1383-1391. 10.4049 / jimmunol. 180163033. Wang, W. and B.A. Malcolm, Two-stage PCR protocol allowing introduction of multiple mutations, deletions and insertions using QuikChange Site-Directed Mutagenesis. Biotechniques, 1999. 26(4): p. 680-2.34. Saegusa, J., N. Akakura, C.Y Wu, C. Hoogland, Z. Ma, K.S. Lam, FT. Liu, Y.K. Takada, and Y. Takada, Pro-inflammatory secretory phospholipase A2 type IIA binds to integrins alphavbeta3 and alpha4betal and induces proliferation of monocytic cells in an integrin- dependent manner. J Biol Chem, 2008. 283(38): p. 26107-15. 10.1074 / jbc.M804835200 PMC253379535. Wang, S., H. Lin, T. Zhao, S. Huang, D.G. Fernig, N. Xu, F. Wu, M. Zhou, C. Jiang, and H. Tian, Expression and purification of an FGF9 fusion protein in E. coli, and the effects of the FGF9 subfamily on human hepatocellular carcinoma cell proliferation and migration. Appl Microbiol Biotechnol, 2017. 101(21): p. 7823-7835.10.1007 / IX. TABLESTable 3. Amino acid residues that are predicted to be involved in integrin avP3 and FGF9 interaction (site 1).X. SEQUENCESSEQ ID NO: 1 - P31371 • FGF9 HUMAN (WT, 4-208)LGEVGNYFGVQDAVPFGNVPVLPVDSPVLLSDHLGQSEAGGLPRGPAVTDLDHLKGILR RRQLYCRTGFHLEIFPNGTIQGTRKDHSRFGILEFISIAVGLVSIRGVDSGLYLGMNEKGEL YGSEKLTQECVFREQFEENWYNTYSSNLYKHVDTGRRYYVALNKDGTPREGTRTKRHQ KFTHFLPRPVDPDKVPELYKDILSQSSEQ ID NO: 2 - P31371 • FGF9 HUMAN Mutant R108ELGEVGNYFGVQDAVPFGNVPVLPVDSPVLLSDHLGQSEAGGLPRGPAVTDLDHL KGILRRRQLYCRTGFHLEIFPNGTIQGTRKDHSRFGILEFISIAVGLVSIEGVDSGLYLGMN EKGELYGSEKLTQECVFREQFEENWYNTYSSNLYKHVDTGRRYYVALNKDGTPREGTRT KRHQKFTHFLPRPVDPDKVPELYKDILSQSSEQ ID NO: 3 - FGF9_HUMAN Mutant R108ECTGGGCGAAGTGGGCAACTATTTTGGCGTGCAGGATGCGGTGCCGTTTGGCAACGTGCCGGTGCTGCCGGTGGATAGCCCGGTGCTGCTGAGCGATCATCTGGGCCAGAG CGAAGCGGGCGGCCTGCCGCGCGGCCCGGCGGTGACCGATCTGGATCATCTGAAAG GCATTCTGCGCCGCCGCCAGCTGTATTGCCGCACCGGCTTTCATCTGGAAATTTTTCC GAACGGCACCATTCAGGGCACCCGCAAAGATCATAGCCGCTTTGGCATTCTGGAATTTATTAGCATTGCGGTGGGCCTGGTGAGCATTGAAGGCGTGGATAGCGGCCTGTATCTGG GCATGAACGAAAAAGGCGAACTGTATGGCAGCGAAAAACTGACCCAGGAATGCGTG TTTCGCGAACAGTTTGAAGAAAACTGGTATAACACCTATAGCAGCAACCTGTATAAAC ATGTGGATACCGGCCGCCGCTATTATGTGGCGCTGAACAAAGATGGCACCCCGCGCG AAGGCACCCGCACCAAACGCCATCAGAAATTTACCCATTTTCTGCCGCGCCCGGTGGATCCGGATAAAGTGCCGGAACTGTATAAAGATATTCTGAGCCAGAGCSEQ ID NO: 4 - FGF9_HUMANCTGGGCGAAGTGGGCAACTATTTTGGCGTGCAGGATGCGGTGCCGTTTGGCAACGTGCCGGTGCTGCCGGTGGATAGCCCGGTGCTGCTGAGCGATCATCTGGGCCAGAG CGAAGCGGGCGGCCTGCCGCGCGGCCCGGCGGTGACCGATCTGGATCATCTGAAAG GCATTCTGCGCCGCCGCCAGCTGTATTGCCGCACCGGCTTTCATCTGGAAATTTTTCC GAACGGCACCATTCAGGGCACCCGCAAAGATCATAGCCGCTTTGGCATTCTGGAATTTGCATGAACGAAAAAGGCGAACTGTATGGCAGCGAAAAACTGACCCAGGAATGCGTGTTTCGCGAACAGTTTGAAGAAAACTGGTATAACACCTATAGCAGCAACCTGTATAAACATGTGGATACCGGCCGCCGCTATTATGTGGCGCTGAACAAAGATGGCACCCCGCGCGAAGGCACCCGCACCAAACGCCATCAGAAATTTACCCATTTTCTGCCGCGCCCGGTGG ATCCGGATAAAGTGCCGGAACTGTATAAAGATATTCTGAGCCAGAGC

Claims

CLAIMSWhat is claimed is:

1. A mutant FGF9 polypeptide comprising an amino acid substitution at residue 108, 129, 154 or any combination thereof, wherein the amino acid substitution is relative to SEQ ID NO: 1.

2. The mutant FGF9 polypeptide of claim 1 , wherein the amino acid substitution at residue 108 comprises a substitution of an arginine (R) at residue 108 for a glutamic acid (E) (R108E).

3. The mutant FGF9 polypeptide of any one of claims 1-2, wherein the amino acid substitution at residue 129 comprises a substitution of a lysine (K) at residue 129 for a glutamic acid (E) (K129E).

4. The mutant FGF9 polypeptide of any one of claims 1-3, wherein the amino acid substitution at residue 154 comprises a substitution of a lysine (K) at residue 154 for a glutamic acid (E) (K154E).

5. The mutant FGF9 polypeptide of claim 1 or 2, wherein the mutant FGF9 polypeptide comprising the amino acid substitution of an arginine (R) at residue 108 for a glutamic acid (E) (R108E) comprises SEQ ID NO: 2.

6. An isolated nucleic acid encoding the mutant FGF9 polypeptide of any of claims 1-5.

7. The isolated nucleic acid of claim 6, wherein the isolated nucleic acid comprises SEQ ID NO: 3.

8. A vector comprising the isolated nucleic acid of claim 6 or 7.

9. A pharmaceutical composition comprising the mutant FGF9 polypeptide of any of claims 1-5, the isolated nucleic acid of claims 6 or 7, or the vector of claim 8 and a pharmaceutically acceptable carrier.

10. A method of treating a cancer in a subject comprising administering to the subject the mutant FGF9 polypeptide of any one of claims 1-5 or the pharmaceutical composition of claim 9.

11. A method of treating a cancer in a subject comprising administering to the subject a mutant FGF9 polypeptide; wherein the mutant FGF9 polypeptide comprises an amino acid substitution at residue 108, 129, 154 or any combination thereof, wherein the amino acid substitution is relative to SEQ ID NO: 1.

12. The method of treating a cancer of claim 11, wherein the amino acid substitution at residue 108 comprises a substitution of an arginine (R) at residue 108 for a glutamic acid (E) (R108E).

13. The method of treating a cancer of claim 11 or 12, wherein the amino acid substitution at residue 129 comprises a substitution of a lysine (K) at residue 129 for a glutamic acid (E) (K129E).

14. The method of treating a cancer of any one of claims 11-13, wherein the amino acid substitution at residue 154 comprises a substitution of a lysine (K) at residue 154 for a glutamic acid (E) (K154E).

15. The method of treating a cancer of any claim 11 or 12, wherein the mutant FGF9 polypeptide comprising the amino acid substitution of an arginine (R) at residue 108 for a glutamic acid (E) (R108E) comprises SEQ ID NO: 2.

16. The method of treating a cancer of any one of claims 11-15, wherein mutant FGF9 polypeptide is encoded by a nucleic acid.

17. The method of treating a cancer of claim 16, wherein the nucleic acid comprises SEQ ID NO: 3.

18. The method of treating a cancer of claim 16 or 17, wherein the nucleic acid is encoded on a vector.

19. The method of treating a cancer of any one of claims 11-18, wherein the mutant FGF9 polypeptide, isolated nucleic acid, or vector is a component of a pharmaceutical composition.

20. The method of any one of claims 10-19, wherein the cancer is selected from the group consisting of colon cancer, prostate cancer, breast cancer, gliomas, renal cancer, testicular cancer, uterine cancer, skin cancer, lung cancer, stomach cancer, and ovarian cancer.

21. The method of claim 20, wherein the cancer is colon cancer.

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