KR20170104114A

KR20170104114A - Compositions and methods for treating cancer

Info

Publication number: KR20170104114A
Application number: KR1020167010370A
Authority: KR
Inventors: 부옹 트리에우
Original assignee: 오토텔릭 엘엘씨
Priority date: 2016-02-09
Filing date: 2016-02-09
Publication date: 2017-09-14
Also published as: KR20180103817A; WO2017138925A1; KR101843985B1

Abstract

Compositions for sensitizing tumors to anti-tumor therapies are provided herein. The composition comprises an antisense oligonucleotide against TGF [beta] 2, wherein these compositions sensitize the tumor to anti-tumor therapy. Methods for treating cancer using the compositions described herein are also provided herein.

Description

&Lt; Desc / Clms Page number 1 > COMPOSITIONS AND METHODS FOR TREATING CANCER &

Field of invention

The present invention relates to medicine and oncology. Compositions and methods for treating cancer are provided herein.

background

All publications cited herein are incorporated by reference herein in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. Neither of the information provided herein is prior art or considered to be relevant to the presently claimed invention, nor is any publication referred to specifically or implicitly as prior art.

Melanoma, also known as malignant melanoma, is cancer of melanocytes. Although black pigment occurs primarily in skin, it can occur in the mouth, eyes and intestines. The primary cause of melanoma is exposure to ultraviolet light from skin with low levels of skin pigment. Treatment of melanoma includes, inter alia, surgery, chemotherapy, radiation, and immunotherapy. The need for more effective therapies in this area is still not met.

summary

The following embodiments and aspects thereof are illustrated and exemplified with compositions and methods that are exemplary and exemplary and are not meant to be limiting in scope.

Methods are provided herein for sensitizing tumors to antitumor therapy in individuals in need of treatment. These methods comprise, comprise, consist essentially of, or consist of administering to a subject an effective amount of the composition to provide a composition comprising an inhibitor of TGF [beta] signaling and to sensitize the tumor.

Also provided herein are methods for treating, inhibiting, reducing the severity of, and / or preventing the metastasis of cancer in a subject in need thereof. These methods include providing a composition comprising an inhibitor of TGF [beta] signaling and administering to the individual an effective amount of the composition to treat, inhibit, reduce the severity of, and / or prevent metastasis of the cancer in the subject Or consists essentially of, or consists of,

In one embodiment of the methods described herein, the cancer is a melanoma.

In various embodiments, the TGFβ signaling inhibitor includes, but is not limited to, small molecules, antibody or antigen-binding antibody fragments, intrude bodies, aptamers, antisense oligonucleotides, RNA interference agents, and ribozymes.

In some embodiments, antibodies that may be used in the methods described herein or in inhibiting TGF [beta] signal transduction for use in the compositions described herein include presoleimab (GC-1008), lerdedrimoodip (CAT-152 ), Mettelimimum (CAT-162), or a combination thereof. &Lt; RTI ID = 0.0 > In a further embodiment, the TGFβ signaling inhibitor for use in the methods described herein or for use in the compositions described herein includes a PF-03446962 antibody (a fully human monoclonal antibody to the transforming growth factor β (TGFβ) receptor ALK1) (Allogeneic tumor vaccine comprising a mixture of four allogeneic human non-small cell lung cancer cell lines transformed to express antisense oligonucleotides targeting TGFβ2) or But are not limited to, any one or more of TGF beta 2 antisense oligonucleotides in combination with GM-CSF, or combinations thereof. One of these TGF [beta] signal transduction inhibitors as described herein alone or in combination with a chemotherapeutic agent and / or radiotherapy as described herein may be used to treat a cancer (such as a melanoma) And the like.

In some embodiments, the inhibitor of TGF [beta] signaling is an antisense oligonucleotide specific to TGF [beta] 2. In one embodiment, the antisense oligonucleotide specific for TGF [beta] 2 is trabeverser or variant, derivative or analog thereof.

In some embodiments, a method for treating, inhibiting, reducing the severity of, or preventing the metastasis of cancer in a subject in need of treatment comprises first administering the tumor using a TGFß signaling inhibitor as described herein Sensitizing, and subsequently administering an exogenous therapeutic agent, including a chemotherapeutic agent, radiation therapy, or a combination thereof.

In some embodiments, the inhibitors of TGFβ signaling is not required but it is sensitized to tumor therapy in the sub sequence, or reducing the IC ₅₀ of the chemotherapeutic agent or reducing.

In various embodiments, the trabeverser or variant, derivative or analog thereof is administered prior to the administration of cancer therapy, e.g., chemotherapy or radiation therapy, or a combination thereof. Administration of trabedenline or a variant, derivative or analog thereof in a sufficient number of cycles as described herein prior to the administration of cancer therapy sensitizes the tumor to cancer therapy.

Brief Description of Drawings
Figure 1 depicts a dose-dependent increase in overall survival (OS) ratio in pancreatic cancer patients when trabadercene is used as an adjunct therapy, according to various embodiments of the present invention. The OS and PFS of patients treated with Trabadersen were compared with the reported central OS and PFS. PFS was not significantly different, but the OS was higher than that reported in the existing literature.
FIG. 2 depicts, according to various embodiments of the present invention, an increase in response to chemotherapy following trabechecenotherapy as indicated by an increase in overall survival. This suggests that trabodensee sensitizes tumors to chemotherapy.
3 shows that, according to various embodiments of the present invention, when trabadercan alone does not have a significant effect on tumors as indicated by low overall survival, but when trabadercan therapy is followed by chemotherapy, And there is a significant increase in survival rate. This suggests that trabodensee sensitizes tumors to chemotherapy.
FIG. 4 depicts, in accordance with various embodiments of the present invention, there is an increase in response to chemotherapy following Travadersen's therapy, as indicated by an increase in overall survival. This suggests that trabodensee sensitizes tumors to chemotherapy.
Figure 5 depicts the synergistic effect of Travadersen and Dakar Vazine, according to various embodiments of the present invention. Travadersen and Dakarbazin are administered sequentially, wherein trabadercan is administered prior to the administration of Dakarbazine, as described herein. This combination therapy resulted in synergistic inhibition of tumor growth.
Figure 6 depicts the synergistic effect of trabadercan and saccharose according to various embodiments of the present invention. Travadersen and Dakarbazin are administered sequentially, wherein trabadercan is administered prior to the administration of Dakarbazine, as described herein. These combined therapies resulted in a synergistic improvement in the survival of animals inoculated with melanoma tumor xenografts.

DESCRIPTION OF THE INVENTION

All references cited herein are incorporated by reference in their entirety as if fully set forth. Unless otherwise specified, the technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. .. Allen et al, Remington: The Science and Practice of Pharmacy 22 nd ed, Pharmaceutical Press (September 15, 2012); Hornyak et al., Introduction to Nanoscience and Nanotechnology, CRC Press (2008); Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology 3 ^rd ed., Revised ed., J. Wiley & Sons (New York, NY 2006); . Smith, March's Advanced Organic Chemistry Reactions, Mechanisms and Structure 7 th ed, J. Wiley & Sons (New York, NY 2013); Singleton, Dictionary of DNA and Genome Technology 3 ^rd ed., Wiley-Blackwell (November 28, 2012); And Green and Sambrook, Molecular Cloning: A Laboratory Manual 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 2012 provide the general practitioner with a general report of many of the terms used in the present application. In the case of references to methods of making antibodies, see Greenfield, Antibodies A Laboratory Manual 2 ^nd ed., Cold Spring Harbor Press (Cold Spring Harbor NY, 2013); K

hler and Milstein, Derivation of specific antibody-producing tissue culture and tumor lines by cell fusion, Eur. J. Immunol. 1976 Jul, 6 (7): 511-9; Queen and Selick, Humanized immunoglobulins, US Patent No. 5,585,089 (1996 Dec); And Riechmann et al., Reshaping human antibodies for therapy, Nature 1988 Mar 24, 332 (6162): 323-7.

Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which may be utilized in the practice of the invention. Other features and advantages of the present invention will become apparent from the following detailed description when taken in conjunction with the accompanying drawings, which illustrate, by way of illustration, various features of embodiments of the present invention. Indeed, the invention is in no way limited to the methods and materials described. For convenience, certain terms used in the specification, examples, and appended claims are collected herein.

Unless otherwise specified or implied from the context, the following terms and phrases include the meanings provided below. Unless expressly stated otherwise, or apparent from the context, the following terms and phrases do not exclude the meaning obtained in the art to which such term or phrase is associated. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It is to be understood that the invention is not to be limited to the particular methodology, protocols, and reagents described herein, but may be varied as such. The definitions and terminology used herein are provided to aid in describing the specific embodiments and are not intended to limit the claimed invention, as the scope of the invention is limited only by the claims.

Justice

In the event of any discrepancy in terms set forth herein and in the patents, published applications and non-patent documents incorporated herein by reference, the definitions herein shall have priority.

Unless otherwise specified, the terms "a "," an ", "the ", and similar indicia used in the context of describing the specific embodiments of the present application (especially in the context of the claims) Can be interpreted as doing. The enumeration of ranges of values herein is only intended to serve as a shorthand method of referring to each distinct value falling within the range individually. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples provided herein for specific embodiments or examples language (e.g., "for example") is intended solely to more effectively illuminate the present application and, No limitation is imposed on the scope of the application. The abbreviation, "for example, " is derived from the Latin word for example, gratia, and is used herein to indicate an unlimited example. Thus, the abbreviation "is" is synonymous with the term "as an example. &Quot; No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present application.

As used herein, the terms "comprises" or "comprising" are intended to encompass the compositions, methods, and individual components thereof, still useful in embodiments, (S). In general, terms used herein will be understood by those skilled in the art as generally intended to be "open" (e.g., the term "comprising" should be interpreted as "including but not limited to" "Having" should be interpreted as having at least, and the term " including "should be interpreted as" including but not limited to, " Although the use of the open terminology " comprising ", for example, as a synonym for "comprising," " including, "or" having, " Embodiments thereof may alternatively be described using alternative terms, for example, "consisting" or "consisting essentially of. &Quot;

As used herein, the terms " treat, "" treat, "" treat," " treat, " or "improve," when used in reference to a disease, disorder or disease, Wherein the purpose is to prevent, reverse, alleviate, ameliorate, inhibit, reduce, slow down, or stop the progression or severity of a symptom or disorder. The term "treating" includes reducing or alleviating at least one negative effect or symptom of the disease. Treatment is generally "effective" when one or more symptoms or clinical markers are reduced. Alternatively, the treatment is "effective" when the progression of the disease, disorder or disease is reduced or discontinued. In other words, "treatment" includes not only the improvement of symptoms or markers, but also the pause or at least delay of progression or deterioration of symptoms expected in the absence of treatment. Also, "treatment" may mean seeking or obtaining beneficial results, or even lessening the chance that the onset of the disease in the subject, even if the treatment ultimately fails. The individual in need of treatment includes not only those individuals already suffering from the disease, but also those individuals susceptible to the disease or those in which the disease should be prevented.

By "beneficial result" or "desired result" is meant reducing or alleviating the severity of the disease state, preventing the disease state from worsening, treating the disease state, preventing the disease state from developing, But are not limited to, lowering the chances of development, reducing morbidity and mortality, and prolonging the patient's lifespan or life expectancy. As an unlimited example, a "beneficial outcome" or "desired outcome" refers to a reduction in the severity of one or more symptoms (s), a decrease in the degree of deficiency, a stable (ie, Delay or slowing of cancer (e. G., Melanoma), and amelioration or palliation of symptoms associated with cancer (e. G., Melanoma).

As used herein, "disease", "disease" and "disease state" may include, but are not limited to, any form of malignant neoplasia cell proliferative disorder or disease. Examples of such disorders include, but are not limited to, cancers and tumors.

As used herein, "cancer" or "tumor" refers to all neoplastic cell growth and proliferation, whether uncontrolled growth of cells that interfere with the normal function of the body organs and / or malignant or benign, And all pre-cancerous and cancerous cells and tissues. An individual suffering from cancer or a tumor is an individual having an objectively measurable cancer cell present in the body of the individual. Disease tumors or micro metastasis as well as benign and malignant tumors are included within this definition. Cancer that migrates from its original location and sheds on important organs can ultimately cause death of an individual through functional deterioration of the affected organ. As used herein, the term "invasive" refers to the ability to infiltrate and destroy surrounding tissue. Melanoma is an invasive form of skin tumor. As used herein, the term "carcinoma" refers to a cancer arising from epithelial cells. Examples of cancer include neurogenic tumors, brain tumors, neuroleptic tumors, breast cancer, colon cancer, colon cancer, rectal cancer, bowel cancer, carcinoma, lung cancer, hepatocellular carcinoma, stomach cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, But are not limited to, prostate cancer, including, but not limited to, renal cancer, renal cell carcinoma, carcinoma, melanoma, head and neck cancer, brain cancer, androgen-dependent prostate cancer and androgen-independent prostate cancer. Examples of brain tumors include benign brain tumors, malignant brain tumors, primary brain tumors, secondary brain tumors, metastatic brain tumors, glioma, glioblastoma, glioblastoma multiforme (GBM), hematoblastoma, ependymoma, astrocytoma, Glioma, ganglioglioma, optic nerve glioma, mixed glioma, e. G., Glioma glioma, low grade glioma, high grade glioma, subepithelial glioma, subepithelial glioma, Glioma, meningioma, pituitary adenoma, and neuroleptic tumors. Neurogenic tumors or nervous system neoplasms refer to any tumors that affect the nervous system. Neural tumors can be tumors in the central nervous system (CNS), the peripheral nervous system (PNS), or both in the CNS and PNS. Examples of neoplastic tumors include, but are not limited to, brain tumors, neuroleptic tumors, and optic neuritis.

As used herein, the term "administering " refers to the placement of an agent or composition as disclosed herein into a subject by a route or route that results in at least partial localization of the agonist or composition at the desired site. "Route of administration" means any route of administration known to the art, including, but not limited to, oral, topical, aerosol, nasal, inhalation, anal, anal, perianal, transmucosal, transdermal, parenteral, &Lt; RTI ID = 0.0 > and / or < / RTI > The term "parenteral" refers to the administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, solvate, Refers to the route of administration generally associated with injection, including intraperitoneal, intrathecal, intrathecal, intrauterine, intravenous, intravenous, intraarterial, subarachnoid, subcapsular, subcutaneous, Through the parenteral route, the agent or composition may be in the form of a solution or suspension for injection or injection, or a lyophilized powder. Through the root route, the agonist or composition can be in the form of a capsule, a gel capsule, a tablet, a sugar-coated tablet, a syrup, a suspension, a solution, a powder, a granule, an emulsion, a microsphere or a nano- It can be in the form of a parcel. Through the topical route, the agent or composition can be in the form of an aerosol, lotion, cream, gel, ointment, suspension, solution or emulsion. In one embodiment, the agent or composition is provided in powder form and may be mixed with a liquid, e.g., water, to form a beverage. According to the present invention, "administering" may be self-administration. For example, it is considered "administering " that an individual consume a composition as disclosed herein.

As used herein, "individual" means human or animal. Typically, the animal is a vertebrate animal, such as a primate, rodent, livestock, or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, for example, rhesus monkeys. Rodents include mice, mice, wood chucks, ferrets, rabbits and hamsters. Livestock and game animals include cattle, horses, pigs, deer, bison, buffalo, cat species, eg cattle, and dogs, eg, dogs, foxes and wolves. The terms "patient," "subject," and "subject" are used interchangeably herein. In one embodiment, the subject is a mammal. Mammals may be humans, non-human primates, mice, mice, dogs, cats, horses, or bees, but are not limited to these examples. In addition, the methods described herein can be used to treat livestock and / or pets.

As used herein, "mammal" includes, without limitation, human and non-human primates, such as chimpanzees and other apes and monkey species; Cervical animals such as cows, sheep, pigs, goats and horses; Livestock mammals, such as dogs and cats; Refers to any member of the mammal (Mammalia), including rodents, including, for example, mice, rats and laboratory animals including guinea pigs, and the like. The term does not denote a particular age or sex. Thus, regardless of whether male or female, adult and newborn as well as fetus is intended to be included within the scope of such term.

Means an individual who has suffered from, or has previously been, diagnosed or identified with a disorder in need of treatment (e.g., cancer, e.g., a melanoma) or one or more complications associated with the disorder, and optionally, And may have already undergone treatment for the disease or one or more complications associated with the disease. Alternatively, the subject may also be an individual that has not previously been diagnosed as having a disease or one or more complications related to the disease. For example, an individual may be an individual exhibiting one or more risk factors for a disease or one or more complications related to the disease, or an entity that does not exhibit a risk factor. For example, an individual may be an individual that does not exhibit one or more symptoms of the disease or exhibit one or more complications related to the disease or exhibit symptoms. A "subject in need of diagnosis or treatment" for a particular disease is one which is suspected of suffering from the disease, diagnosed as suffering from the disease, has been already treated or is being treated for the disease, , Or an individual at risk of developing the disease.

The term "functional" when used in conjunction with an "equivalent", "analog", "derivative" or "variant" or "fragment" means that the entity or molecule of such equivalent, analog, derivative, Or possess biological activity substantially similar to the biological activity of the molecule.

As used herein, the term "small molecule" is intended to encompass a peptide, a peptide mimetic, an amino acid, an amino acid analog, a polynucleotide, a polynucleotide analog, an aptamer, a nucleotide, a nucleotide analog, An organic or inorganic compound having a molecular weight less than about 5,000 grams per mole, an organic or inorganic compound having a molecular weight less than about 1,000 grams per mole, a molecular weight less than about 500 grams per mole, Including, but not limited to, organic or inorganic compounds having at least two, and salts, esters, and other pharmaceutically acceptable forms of such compounds.

As described herein, "nucleic acid" can be RNA or DNA, and can be single or double stranded, and can be selected from the group comprising, for example, a nucleic acid encoding a protein of interest, Oligonucleotides, nucleic acid analogs such as peptide-nucleic acid (PNA), caustic-complementary PNA (pc-PNA), locked nucleic acid (LNA), and the like. Such nucleic acid sequences include, for example, but are not limited to, RNAi, shRNAi, siRNA, microRNAi (mRNAi), nucleic acid sequences that encode proteins that act as transcriptional repressors, antisense molecules, ribozymes, small inhibitory nucleic acid sequences, , Antisense oligonucleotides, and the like, including but not limited to.

As used herein, an "inhibitor" of TGF [beta] can function in a competitive or noncompetitive manner and, in one embodiment, can function by interfering with the expression of TGF [beta] protein. In one embodiment, the TGFβ protein is TGFβ2 having the sequence as set forth in SEQ ID NO: 2 (NM_003238.3). One of a number of different approaches can be taken to inhibit TGF [beta] (e.g., TGF [beta] 2) expression or activity. TGFβ (eg, TGFβ2) inhibitors include any chemical or biological entity that, upon treatment of a cell, causes inhibition of biological activity caused by activation of TGFβ (eg, TGFβ2) in response to a cell signal. TGFβ (eg, TGFβ2) inhibitors include, but are not limited to, small molecules, antibodies or antigen-binding antibody fragments, intrabodies, aptamers, antisense constructs, RNA interference agents, and ribozymes. In one exemplary embodiment, the small molecule inhibitor of TGF beta is a small molecule inhibitor of TGF beta receptor type I kinase (ALK5; the inhibitor is an ALK5 inhibitor). In another exemplary embodiment, the antibody inhibitor of TGF [beta] is selected from the group consisting of a neutralizing anti-TGF-beta-1, -2, -3 antibody or a TGF-beta binding fragment thereof or a neutralizing anti-TGF-beta receptor type I, III antibody or a TGF-beta receptor binding fragment thereof or a TGF beta trap. In another exemplary embodiment, the inhibitor of TGF beta is selected from the group consisting of TGF-beta 1, -2, and -3 isotypes or modified nucleosides such as locked nucleic acid LNAs (e.g., oxy-LNA, amino- TiO 2, also known as -LNA) ^{"-0, 4"} -C- methylene linked cyclic double ribonucleotides, phosphorothioate dia mi date morpholino oligomer (PMO), phosphorothioate (PS), 2 ^"-0 -methyl- (2 ^"-Ome), 2 ^'- fluoro ^(2' - fluoro ^(2" -F), or 2 ^'- methoxyethyl ^(2' -MOE) TGF- beta signaling, including the derivatives optionally in any In another illustrative embodiment, the inhibitor of TGF [beta] is selected from the group consisting of Bellagene Pumatu-L and / or TGF-beta l-mRNA or TGF-beta 3-mRNA, or an antisense oligonucleotide encoding mRNA- Beta 2-mRNA-specific antisense, such as other components of mRNA encoding the TGF-beta signaling assembly In another exemplary embodiment, the inhibitor of TGF [beta] is selected from the group consisting of mRNA-specific silencing RNAs encoding TGF-beta1, -2, and / or -3 isotype or other components of a TGF- In another illustrative embodiment, an inhibitor of TGF [beta] is conjugated to an mRNA encoding another component of a TGF-beta1, -2, and / or -3 isotype or a TGF-beta signaling assembly In a further embodiment, an inhibitor of TGF [beta] is administered to an mRNA encoding a TGF-beta1, -2, and / or -3 isotype or other component of a TGF-beta signaling assembly In other exemplary embodiments, the inhibitor of TGF [beta] comprises an aptamer specific to TGF-beta1, -2, and / or -3 isotype or other components of a TGF-beta signaling assembly, and / Other examples include < RTI ID = 0.0 > In a poetic embodiment, an inhibitor of TGF [beta] comprises a ribozyme molecule specific for an mRNA encoding a TGF-beta1, -2, and / or -3 isotype or other component of a TGF-beta signaling assembly. Antisense oligonucleotides (ASOs) include 13-25 nucleotides that hybridize to complementary RNA, inhibit mRNA function and prevent protein synthesis through, for example, accelerated mRNA degradation by RNAse H or steric hindrance, Is a single-stranded polynucleotide molecule comprising 15-20 nucleotides, more preferably 15, 16, 17, 18, 19, 20, 21, 22 or 23 nucleotides. In some embodiments, the TGFβ2 inhibitor is an antisense oligonucleotide ASPH_0047 (from Isarna Therapeutics, as described in WO2014 / 154835), which is an optional LNA-modified ASO gapmer targeting TGF-β2. In one embodiment, ASPH_0047 (ISTH0047) has the sequence 5'-CAAAGTATTTGGTCTCC-3 'as set forth in SEQ ID NO: 3.

(ASPH47; SEQ ID NO: 3), ACCTCCTTGGCGTAGTA (ASPH01; SEQ ID NO: 4), ACCTCCTTGGCGTAGTA (ASPH02; SEQ ID NO: 5), and the like. CTCCTTGGCGTAGTA (ASPH03; SEQ ID NO: 6), CCTCCTTGGCGTAGTA (ASPH04; SEQ ID NO: 7), CTCCTTGGCGTAGTA (ASPH05; SEQ ID NO: 8), CTCCTTGGCGTAGTA TCCTTGGCGTAGTA (ASPH08; SEQ ID NO: 11), CAGAAGTTGGCAT (ASPH09; SEQ ID NO: 12), CAGAAGTTGGCAT (ASPH10; SEQ ID NO: 13), CTGCCCGCGGAT (ASPH15; SEQ ID NO: 14), TCTGCCCGCGGAT GGATCTGCCGGCGGA (ASPH26; SEQ ID NO: 17), GGATCTGCCCGCGGA (ASPH27; SEQ ID NO: 18), CGATCCTCTTGCGCAT (ASPH30; SEQ ID NO: 19), GGCGGGATGGCAT (ASPH35; SEQ ID NO: 20), TCGCGCTCGCAGGC (ASPH22; GACCAGATGCAGGA (ASPH36; SEQ ID NO: 21), CTTGCTCAGGATCTGCC (ASPH37; SEQ ID NO: 22), TCTGTAGGAGGGC (ASPH45; SEQ ID NO: 23), CCTTAAGCCATCCATGA (ASPH48; SEQ ID NO: 24), TCTGAACTAGTACCGCC (ASPH65; SEQ ID NO: 25), TACTATTATGGCATCCC (ASPH69; SEQ ID NO: 26), AGCGTAATTGGTCATCA 27), GCGACCGTGACCAGAT (ASPH80; SEQ ID NO: 28), AACTAGTACCGCCTTT (ASPH82; SEQ ID NO: 29), GCGCGACCGTGACC (ASPH98; SEQ ID NO: 30), ACCACTAGAGCACC (ASPH105; SEQ ID NO: 31), AGCGCGACCGTGA (ASPH111; SEQ ID NO: 32), GGATCGCCTCGAT (ASPH112; SEQ ID NO: 33), CTAGTACCGCCTT (ASPH115; (SEQ ID NO: 34), CCGCGGATCGCC (ASPH119; SEQ ID NO: 35), GACCGTGACCAGAT (ASPH121; SEQ ID NO: 36), and / or GACCGTGACCAGAT (ASPH153; SEQ ID NO: 37) &Lt; / RTI > oligonucleotides (from Isarna Therapeutics). In various embodiments, one or more of the nucleotide (s) of the oligonucleotide described herein (e.g., in SEQ ID NOS: 1-37) is LNA modified, wherein the modified nucleotide is an LNA, and / or ENA, Oxide-, 2'-fluoro-, 2'-O-methoxy-, and / or 2'0-methyl-modified nucleotides.

As used herein, the term "cycle" refers to the number of days when an inhibitor of TGFβ is administered and the number of days when no inhibitor of TGFβ is administered. In one embodiment, one cycle is defined as administering the inhibitor at a specific dose per day for 7 days, and thereafter, not administering the inhibitor for 7 days. This is referred to as the "7 day on and 7 day off" period. In another embodiment, one cycle is defined as administering an inhibitor at a specific dose per day for 4 days, and thereafter, not administering an inhibitor for 10 days. This is referred to as the "4 days on and 10 days off" periods.

As used herein, the term "PFS" refers to progression-free survival and is a measure of the activity of a therapeutic agent for a disease. As used herein, the term "OS" refers to overall survival and is a measure of the effectiveness of treatment for disease and subsequent treatment. As described herein, in some embodiments, the PFS does not improve upon administration of trabadercene or variants, derivatives, or analogs thereof, but the OS is administered at the administration of trabadercene or a variant, derivative or analog thereof If this is improved, this indicates the sensitization of the tumor by trabeverser or its variants, derivatives or analogues for further treatment.

As used herein, the term "sensitization" refers to making a tumor susceptible to treatment. In one embodiment, trabeverser or a variant, derivative or analog thereof sensitizes the tumor to a therapy that is subsequently administered exogenously, such as chemotherapy, radiation therapy, hormone therapy, or a combination thereof. In another embodiment, trabeverser or a variant, derivative or analog thereof sensitizes the tumor to the patient ' s own endogenous immune system. In an exemplary embodiment, when the tumor is sensitized with trabexercene or a variant, derivative or analogue thereof prior to chemotherapy, one or more chemotherapeutic agents may be added after treatment with trabadercene or variants, derivatives or analogs thereof , 20%, 30%, 40%, 50%, 60%, 50%, 50%, 50%, 50%, 50%, 50% 70%, 80%, 90% or 100%.

As used herein, "trabadercene" or "trabadercene" is a transforming growth factor (TGF) -beta2 having the sequence 5'-CGGCATGTCTATTTTGTA-3 ' (TGF [beta] 2) specific phosphorothioate antisense oligodeoxynucleotides. In an exemplary embodiment, an inhibitor of TGF [beta], including an inhibitor of TGF [beta] 2 (e.g., trabedenin), is disclosed in WO94 / 25588, WO95 / 17507, WO95 / 02051, WO98 / 33904, WO99 / 63975, WO01 / 68146, WO01 / WO2003 / 064457, WO2005 / 016412, WO2005 / 014812, WO2004 / 093945, WO2005 / 084712, WO2006 / 11740, WO2008 / 077956A2, WO2010 / 055148, WO2011 / 012713A1, WO2011 / 154542, EP Application Nos. 20100191103, WO2014154835 A2, WO2015 / 140150A1, the contents of each of which are incorporated herein by reference. In one embodiment, the trabadercene is LNA modified. LNA is a modified RNA nucleotide, in which the ribose moiety is transformed into an additional bridging linking the 2 'oxygen and the 4' carbon (2'-4 'ribonucleoside). Such bridges are often found in A-shaped double helixes, which "lock" the ribose in the 3'-endo-2D form. LNA nucleosides and nucleotides each comprise a form of thio-LNA, oxy-LNA, or amino-LNA in, for example, alpha-D- or beta-L-form, and each contain DNA or RNA residues in the oligonucleotide &Lt; / RTI >

The inventor finds that administration of trabedenline to an individual suffering from melanoma causes an increase in the overall survival rate of the individual prior to administration of the chemotherapeutic agent. Without being bound by a single theory, the inventors have found that administration of trabadercene or variants, derivatives or analogs thereof, prior to administration of a chemotherapeutic agent, can be used to treat a tumor (such as a melanoma or pancreatic tumor) with a chemotherapeutic agent, Hypersensitivity to therapy and / or the individual's own endogenous immune system of the individual. As shown herein, sensitizing tumors prior to administration of therapeutic agents results in therapeutic benefits in multiple cancers including pancreatic and melanoma. Accordingly, compositions and methods for treating cancer in a subject in need of treatment are provided herein using trabeverser, or a variant, derivative or analog thereof first, followed by other agents that treat cancer.

Composition

A composition comprising a TGFß signaling inhibitor and a pharmaceutically acceptable carrier is provided herein. In various embodiments, "TGFβ signaling inhibitor", "TGFβ signaling antagonist", "TGFβ signal transduction inhibitor", or "TGFβ signal transduction inhibitor" refers to any of the TGFβ signaling receptors It is any reagent that inhibits / blocks / reduces TGFß signaling, including inhibition / blocking / reduction of molecular signal transduction steps. As used herein, TGFβ includes, but is not limited to, TGFβ1, TGFβ2, or TGFβ3, or combinations thereof. In one embodiment, the TGFβ signaling inhibitor inhibits TGFβ1, TGFβ2 or TGFβ3. In another embodiment, the TGFβ signaling inhibitor inhibits TGFβ1 and TGFβ2 or TGFβ1 and TGFβ3 or TGFβ2 and TGFβ3. In a further embodiment, the TGFβ signaling inhibitor inhibits TGFβ1, TGFβ2 and TGFβ3.

In some embodiments, the TGFβ signaling inhibitor is a direct inhibitor of TGFβ or an indirect inhibitor of TGFβ. Indirect inhibitors of TGF [beta] may be inhibitors of the TGF [beta] receptor. In various embodiments, the TGF [beta] signaling inhibitor includes, but is not limited to, small molecules, antibodies or antigen-binding antibody fragments, intrabodies, aptamers, antisense oligonucleotides, RNA interference agents, and ribozymes.

Antibodies that specifically bind to TGF beta (e.g., TGF beta 2) may be used for inhibition of TGF beta (e.g., TGF beta 2) in vivo. Alternatively, protein ligands for the construction of TGF [beta] traps are also covered by the compositions and methods described herein. Antibodies to TGF [beta] (e.g., TGF [beta] 2) are commercially available and can be prepared by those skilled in the art using well known methods. The TGFβ (eg, TGFβ2) inhibitory activity of any given TGFβ (eg, TGFβ2) inhibitor may be assessed using methods known in the art or described herein. Antibody inhibitors of TGFβ (eg, TGFβ2) may include multiple clones and monoclonal antibodies and antigen-binding derivatives or fragments thereof. Well-known antigen binding fragments include, for example, Fv fragments, Fab fragments, and F (ab ') fragments, including single domain antibodies (dAbs, which are essentially composed of a single VL or VH antibody domain), single chain Fv fragments (scFv) ) &Lt; / RTI > Methods for the construction of such antibody molecules are well known in the art.

In one embodiment, the TGFβ signaling inhibitor is an antisense molecule that specifically targets TGFβ. In some embodiments, the antisense molecule is an antisense nucleic acid, an antisense polynucleotide, an antisense polydeoxynucleotide, an antisense oligonucleotide, or an antisense oligodeoxynucleotide. 20%, 30%, 40%, 50% or more of the activity or level of TGFβ encoded by the TGFβ gene not targeted by the expression of the TGFβ gene or by the TGFβ gene not targeted by the antisense oligonucleotide, , 60%, 70%, 80%, 90%, 95% or 99% or more. In certain embodiments, the TGFβ signaling inhibitor is a phosphorothioate antisense oligodeoxynucleotide that is specific for human TGFβ2 mRNA. In one embodiment, the TGF [beta] signaling inhibitor is Travadersen (AP12009) or a variant, derivative or analog thereof. In one embodiment, the TGFβ signaling inhibitor comprises, consists of, or consists essentially of the sequence 5'-CGGCATGTCTATTTTGTA-3 'as set forth in SEQ ID NO: 1. In some embodiments, the trabadercene or variant, derivative or analogue thereof does not need to reduce the IC ₅₀ of the chemotherapeutic agent and / or the trabadercene or variant, derivative or analog thereof has an IC ₅₀ of the chemotherapeutic agent . For example, as described in Examples 1 and 2 herein, trabadercene is co-administered with temozolomide in glioma cells, or trabadercen is co-conjugated with 5-fluorouracil in pancreatic or colon cancer cells There was no advantage.

Antisense oligodeoxynucleotide molecules need not be confined to molecules that contain only RNA, but rather include, for example, chemically modified nucleotides and non-nucleotides, and also that the ribose sugar molecules carry other sugar molecules or similar functions Lt; RTI ID = 0.0 > molecules. &Lt; / RTI > In addition, non-naturally occurring chains such as phosphorothioate (sulfur group), methylphosphonate chain (methyl group) or phosphoramidate (amine group) chain can be used between nucleotide residues. The antisense oligonucleotide strand may be derivatized to a reactive functional group of the reporter group, e.g., a fluorophore. Particularly useful derivatives are modified at the ends or ends of the antisense oligonucleotide strand, typically at the 3 'end of the sense strand. For example, 2 ' -hydroxyl at the 3 ' end can be easily and selectively derivatized with various groups. Other useful antisense oligonucleotide derivatives include modified carbohydrate moieties such as 2'-O-alkylated residues or 2'-O-methyl ribosyl derivatives or 2'-O-fluorocarboxyl derivatives or 2'-O -Methylethylribosyl < / RTI > derivative is incorporated. RNA bases can also be modified. Any modified base useful for inhibiting or interfering with the expression of the target sequence may be used. For example, halogenated bases such as 5-bromouracil and 5-iodouracil may be incorporated. The base can also be alkylated, for example, 7-methylguanosine can be incorporated in place of the guanosine residue. Non-natural bases that produce successful inhibition of TGF [beta] may also be incorporated. In some embodiments, the antisense oligonucleotide variants are modified to include 2'-deoxy-2'-fluorouridine or a locked nucleic acid (LNA) nucleotide, a peptide nucleic acid (PNA) nucleotide, a morpholinophosphoramidate (MF) , Or a phosphodiester or an RNA duplex containing a variable number of phosphorothioate chains. Such modifications are known to those skilled in the art and are described, for example, in Braasch et al., Biochemistry, 42: 7967-7975, 2003 or Mansoor and Melendez, Gene Regulation and Systems Biology, 2: 275-295 2008.

In some embodiments, as described herein, a TGFβ signaling inhibitor (eg, trabedener or a variant, derivative, or analog thereof) inhibits TGFβ2 and treats an individual suffering from a disease state that overexpresses TGFβ2 . &Lt; / RTI > In one embodiment, the disease state is cancer. In one embodiment, the cancer is a melanoma.

In a further embodiment, a TGFβ2-specific antisense oligonucleotide (eg, trabedener or variant, derivative or analog thereof) is administered sequentially with a chemotherapeutic agent. In one embodiment, the TGFβ2-specific antisense oligonucleotide is administered prior to the administration of the chemotherapeutic agent. In one embodiment, trabasederen or a variant, derivative or analog thereof is administered prior to and / or after administration of one or more chemotherapeutic agents to sensitize the tumor to a chemotherapeutic agent and / or radiation therapy Lt; / RTI > In some embodiments, a TGFβ2-specific antisense oligonucleotide (eg, trabedener or a variant, derivative or analog thereof) sensitizes the tumor to a chemotherapeutic agent. In one embodiment, the TGFβ signaling inhibitor comprises, consists of, or consists essentially of the sequence 5'-CGGCATGTCTATTTTGTA-3 'as set forth in SEQ ID NO: 1. In some embodiments, the trabadercene or variant, derivative or analogue thereof does not need to reduce the IC ₅₀ of the chemotherapeutic agent and / or the trabadercene or variant, derivative or analog thereof has an IC ₅₀ of the chemotherapeutic agent . For example, as described in Examples 1 and 2 herein, trabadercene is co-administered with temozolomide in glioma cells, or trabadercen is co-conjugated with 5-fluorouracil in pancreatic or colon cancer cells There was no advantage.

A typical dose of an effective amount of a TGFβ signaling inhibitor (eg, a TGFβ2 inhibitor) is recommended by the manufacturer when known molecules or compounds are used, and also by an in vitro response in a cell or an in vivo response in an animal model And may be within the ranges as indicated to those skilled in the art. This capacity can typically be reduced to about one order of magnitude in concentration or amount without losing the relevant biological activity. Actual dose may depend on the judgment of the physician, the condition of the patient, and the availability of treatment methods based on, for example, the in vitro response of the relevant cultured cell or tissue cultured tissue sample, or the response observed in the appropriate animal model have.

In various embodiments, a TGFβ signaling inhibitor (eg, trabedener or a variant, derivative or analog thereof) is administered at a dose of about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, Kg, < / RTI >< RTI ID = 0.0 > kg, Or a combination thereof. In various embodiments, a TGFβ signaling inhibitor (eg, trabedener or a variant, derivative or analog thereof) is administered at a dose of about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg inhibitor / m ² body Surface area, or a combination thereof. Here, "mg inhibitor / kg body weight " refers to the mg inhibitor per kg of body weight of the individual, and" mg inhibitor / m ² body surface area "refers to the mg inhibitor per m ² body surface area of the individual.

In various embodiments, the effective amount of a TGFβ signaling inhibitor (eg, trabedener or a variant, derivative or analog thereof) is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10 -20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 μg / kg / Day, or any combination thereof. In various embodiments, the effective amount of a TGFβ signaling inhibitor (eg, trabedener or a variant, derivative or analog thereof) is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10 -20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 μg / m ² / day, or any combination thereof. In various embodiments, the effective amount of a TGFβ signaling inhibitor (eg, trabedener or a variant, derivative or analog thereof) is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10 -20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg / kg / Day, or any combination thereof. In various embodiments, the effective amount of a TGFβ signaling inhibitor (eg, trabedener or a variant, derivative or analog thereof) is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10 -20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg / m ² / day, or any combination thereof. Here, "μg / kg / day" or "mg / kg / day" refers to μg or mg inhibitor per kg body weight of individual per day and, and "μg / m ² / day" or "mg / m ² / Day "refers to μg or mg inhibitor per m ² body surface area of an individual per day.

In various embodiments, the TGFβ signaling inhibitor is trabadercene (AP12009) or a variant, derivative or analogue thereof, and is about 50-100, 100-150, 150-200, 200-250, 250-300, 300- 350, 350-400, 400-450, or 450-500 mg / m ² / day. In some embodiments, the trabevereren or a variant, derivative or analog thereof is administered at about 140, 150, 160, 170, or 180 mg / m ² / day. In some embodiments, trabasederen or a variant, derivative or analog thereof is administered at about 310, 320, 330, 340, 350 mg / m ² / day or a combination thereof.

In various embodiments, the TGFβ signaling inhibitor (eg, trabedener or a variant, derivative or analog thereof) may be administered once, twice, three times, or more. In various embodiments, the TGFβ signaling inhibitor (eg, trabedener or a variant, derivative or analog thereof) is administered one to three times a day, one to seven times per week, one to nine times per month, or one to two times per year &Lt; / RTI > In various embodiments, the TGFβ signaling inhibitor (eg, trabadercene or variant, derivative, or analog thereof) is administered at about 1-10 days, 10-20 days, 20-30 days, 30-40 days, , 50-60 days, 60-70 days, 70-80 days, 80-90 days, 90-100 days, 1-6 months, 6-12 months, or 1-5 years. In various embodiments, a TGFβ signaling inhibitor (eg, trabasederen or a variant, derivative or analogue thereof) is administered once daily (SID / QD), twice daily (2 days) to deliver an effective amount of a TGFβ signaling inhibitor (BID), three times a day (TID), four times a day (QID), or more, wherein the effective amount is any one or more of the amounts set forth herein.

In some embodiments, the trabasederen or a variant, derivative or analog thereof is administered once, twice, three times, four times a day, seven days on and seven days off prior to the administration of the chemotherapeutic agent, radiation therapy, 5, or more cycles. In some embodiments, the trabadercene or variant, derivative or analogue thereof is administered at a dose of 1, 2, 3, 4, 5, 10, or 10 days of onset of 4 days and 10 days prior to administration of the chemotherapeutic agent, 5, or more cycles. In one embodiment, Travaderscene or a variant, derivative or analog thereof is administered intravenously via continuous infusion for one cycle of 4 days on and 10 days off, prior to administration of the chemotherapeutic agent or radiotherapy. In one embodiment, the trabadercene or variant, derivative or analog thereof is administered intravenously via continuous infusion for two cycles of 4 days on and 10 days off, prior to administration of the chemotherapeutic agent, . In one embodiment, trabasederen or a variant, derivative or analog thereof is administered intravenously via continuous infusion for three cycles of 4 days on and 10 days off, prior to administration of a chemotherapeutic agent, radiation therapy, . In one embodiment, trabasederen or a variant, derivative or analog thereof is administered intravenously via continuous infusion for four cycles of 4 days on and 10 days off, prior to administration of a chemotherapeutic agent, radiation therapy, .

According to the present invention, examples of chemotherapeutic agents are selected from the group consisting of temozolomide, actinomycin, alitretinoin, alltransretinoic acid, azacytidine, azathioprine, bevacizumab, bexatotene, bleomycin, bortezomib, But are not limited to, liposome-coated doxorubicin, such as carboplatin, caffectavin, cetuximab, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, (Pegylated form), Mioket (non-pegylated form), and Cericos, epirubicin, epothilone, erlotinib, etoposide, fluorouracil, polinic acid, zetitib, gemcitabine, (Nal-IRI), mechlorethamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, ocrelliumum, oocyte, mycotoxin, PATUMUMAP, oxaliplatin, Paclitaxel, pemetrexed, rituximab, tafluposide, teniposide, thioguanine, topotecan, tretinoin, valvicin, paclitaxel, paclitaxel, , 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), cladribine (5-fluorouracil), vinblastine, vincristine, vindesine, vinorelbine, , Clofarabine, fluoxidyne, fludarabine, pentostatin, mitomycin, xavapilone, estramustine, prednisone, methylprednisolone, dexamethasone, or combinations thereof.

In some embodiments, the chemotherapeutic agent is selected from the group consisting of Dakar Vazine, 5-fluorouracil, polynic acid, oxaliplatin, paclitaxel, mitomycin, capecitabine, gemcitabine, fluorouracil, eloxatin, oxaliplatin, Nip, oxaliplatin, 5-Fu, erlotinib, or a combination thereof.

In some embodiments, the chemotherapeutic agent is selected from the group consisting of radiation therapy 20 Gy, carboplatin, paclitaxel, vindesine, eicilimumab, stereotactic radiation therapy, Mek 162, carboplatin and paclitaxel, , Radiotherapy 36gy, or any combination thereof.

In various embodiments, the chemotherapeutic agent is a platinum-based anti-neoplastic agent. Examples of platinum-based anti-neoplastic agents include but are not limited to oxaliplatin, cisplatin, lipoflatin (liposome of cisplatin), carboplatin, satraprapatin, picoplatin, nedaplatin and triplatin, Analogs, derivatives, variants or salts thereof.

In various embodiments, the chemotherapeutic agent is taxane. Illustrative examples of taxanes include, but are not limited to, paclitaxel, docetaxel, and cabazitaxel, and functional equivalents, analogs, derivatives, variants or salts or preparations thereof, such as, for example, ablactic acid, taxol, and genexol.

In various embodiments, the chemotherapeutic agent is anthracycline. Examples of anthracyclines include but is not limited to doxorubicin, daunorubicin, epirubicin, darubicin, pyrabicin, aclarubicin, valivin, and mitoxantrone, and functional equivalents, analogs, derivatives, But are not limited to these.

A typical dose of an effective amount of a chemotherapeutic agent is one that is recommended by the manufacturer when known molecules or compounds are used and may also be a range as directed to those skilled in the art by in vitro response in a cell or in vivo response in an animal model Can be in. This capacity can typically be reduced to about one order of magnitude in concentration or amount without losing the relevant biological activity. Actual dose may depend on the judgment of the physician, the condition of the patient, and the availability of treatment methods based on, for example, the in vitro response of the relevant cultured cell or tissue cultured tissue sample, or the response observed in the appropriate animal model have.

In various embodiments, the chemotherapeutic agent is administered at a dose of about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg agonist / kg body weight, or a combination thereof. In various embodiments, the chemotherapeutic agent is administered at a dose of about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg agonist / m ² body surface area, or a combination thereof. Here, "mg agonist / kg body weight " refers to mg agonist per kg body weight of an individual, and" mg agonist / m ² body surface area "refers to mg agonist per m ² body surface area of an individual.

In various embodiments, the effective amount of the chemotherapeutic agent is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200 300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 μg / kg / day, or any combination thereof . In various embodiments, the effective amount of the chemotherapeutic agent is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200 300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 μg / m ² / day, or any combination thereof to be. In various embodiments, the effective amount of the chemotherapeutic agent is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200 -300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg / kg / day, or any combination thereof . In various embodiments, the effective amount of the chemotherapeutic agent is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200 -300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg / m ² / day, or any one or more among these combinations to be. Here, "μg / kg / day," or "mg / kg / day" refers to μg or mg agent per kg body weight of the individual per day, and "μg / m ² / day," or "mg / m ² / Day "refers to the μg or mg agonist per m ² body surface area of an individual per day.

In various embodiments, the chemotherapeutic agent may be administered once, twice, three times, or more. In various embodiments, the chemotherapeutic agent may be administered 1-3 times per day, 1-7 times per week, 1-9 times per month, or 1-12 times per year. In various embodiments, the chemotherapeutic agonist is administered at a dose of about 1-10 days, 10-20 days, 20-30 days, 30-40 days, 40-50 days, 50-60 days, 60-70 days, 70-80 days, 80-90 days, 90-100 days, 1-6 months, 6-12 months, or 1-5 years. In various embodiments, the chemotherapeutic agent is administered once daily (SID / QD), twice daily (BID), three times daily (TID), four times daily (QID ), Or more, wherein the effective amount is any one or more of the amounts set forth herein.

In accordance with the present invention, TGF [beta] signaling inhibitors and / or chemotherapeutic agents can be administered using suitable modes of administration, for example, administration modes as recommended by the manufacturer, if known molecules or compounds are used. As described herein, a TGFβ signaling inhibitor (eg, trabedener or a variant, derivative or analog thereof) and a chemotherapeutic agent are administered sequentially, wherein a TGFβ signaling inhibitor (eg, Derivatives, or analogs) are administered prior to administration of chemotherapy or radiation therapy. In accordance with the present invention there is also provided a method for the treatment or prophylaxis of a disease or condition selected from the group consisting of intratumoral, intravascular, intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, aerosol, nasal, inhalation, oral, transmucosal, transdermal, Various routes may be utilized to administer TGFβ signaling inhibitors and chemotherapeutic agents of the compositions and methods of the various routes including, but not limited to, infusion, topical application, topical application, topical application, capsules and / or injection. In various embodiments, the TGF [beta] signaling inhibitor is administered to a mammal in need of treatment, such as intracranial, intracapsular, intrathecal, epidural, intrathecally, topically, intratumorally, intravenously, intravenously, intramuscularly, subcutaneously, Orally. In various embodiments, the chemotherapeutic agonist may be administered to a mammal, such as intracranially, intracisternally, intrathecally, intrathecally, intrathecally, topically, intratumorally, intravascularly, intravenously, intramuscularly, subcutaneously, intraperitoneally, intranasally, &Lt; / RTI > In some embodiments, a TGFβ signaling inhibitor (eg, trabedener or a variant, derivative or analogue thereof) and a chemotherapeutic agent are administered using the same route. In some embodiments, the TGFβ signaling inhibitor and the chemotherapeutic agent are administered using a different route.

In various embodiments, the composition according to the present invention may contain any pharmaceutically acceptable excipient. As used herein, "excipient" is a natural or synthetic material prepared with the active ingredient of the composition or formula, included for bulking up the composition or formula. Thus, "excipients" are often referred to as "extenders "," fillers ", or "diluents. For an unlimited example, one or more excipients may be added to the compositions described herein, and the volume or size of the composition may be increased such that one serving of the composition is compatible with one capsule or tablet. In addition, "excipients" may confer enhancement of the active ingredient in the final formulation, e. G., Promote absorption or solubility of the active ingredient. "Pharmaceutically acceptable excipient" means an excipient which is generally safe, non-toxic, useful for preparing the desired pharmaceutical composition, and includes excipients which are acceptable for veterinary use as well as human pharmaceutical use. Such excipients may be a solid, liquid, semi-solid or, in the case of an aerosol composition, a gas. Examples of excipients include starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, wetting agents, emulsifiers, colorants, release agents, coatings, sweeteners, flavors, fragrances, preservatives, antioxidants, , Gelling agents, thickeners, hardeners, adhesives, suspending agents, surfactants, humectants, carriers, stabilizers, and combinations thereof.

In various embodiments, the composition according to the present invention may contain any pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to encompass pharmaceuticals which are involved in carrying or transporting a compound of interest to one or more tissues, organs, or parts of the body, Quot; refers to an acceptable material, composition, or carrier. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be "pharmaceutically acceptable" in the sense that it must be compatible with the other ingredients of the formulation. Each component must also be suitable for use in contact with any tissue or organ that it may come into contact with, which means that the component is excessively toxic, irritating, allergic, immunogenic, or therapeutic benefit Should not lead to any other complications.

The compositions according to the invention may also be in liposomes, or be encapsulated, tableted, or prepared in emulsions or syrups for oral administration. In some embodiments, liposomes comprising trabevereren or variants, derivatives or analogs thereof are coated with a tissue specific antibody. In certain embodiments, a composition comprising trabasederen or a variant, derivative or analog thereof is prepared for administration by injection (e. G., Intravenous, subcutaneous, intramuscular, etc.). In certain such embodiments, the pharmaceutical composition comprises a carrier and is formulated in an aqueous solution, for example, water or a physiologically compatible buffer, for example, a Hank solution, a Ringer's solution, or a physiological saline buffer. In certain embodiments, other ingredients (e.g., ingredients that aid in solubility or assist as a preservative) are included. In certain embodiments, the injectable suspension is prepared using suitable liquid carriers, suspending agents, and the like. Certain pharmaceutical compositions for injection are provided in unit dosage form, for example, in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain adjuvants, such as suspending, stabilizing and / or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils such as homomachae, synthetic fatty acid esters such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, for example, sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of pharmaceutical agents to allow for the production of highly concentrated solutions.

A pharmaceutically acceptable solid or liquid carrier may be added to enhance or stabilize the composition or to facilitate the manufacture of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohol and water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, clay, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also contain a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax.

The compositions may be dry-milled, mixed and blended in the case of powder form; Crushing, mixing, granulating in the case of tablets, and compression when necessary; Or in the case of hard gelatin capsules, in accordance with conventional techniques of pharmacy involving milling, mixing and filling. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, tackifier, or aqueous or nonaqueous suspension. Such liquid preparations can be prepared directly from p.o. Or may be filled into a soft gelatin capsule.

The compositions according to the present invention may be delivered in a therapeutically effective amount. The precise therapeutic effect amount is the amount of the composition that will yield the most effective outcome in terms of efficacy of treatment in a given subject. Such an amount will vary with the nature of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological status of the individual (including age, sex, disease type and timing, overall physical condition, ), The nature of the pharmaceutically acceptable carrier or carrier (s) in the formulation, and the route of administration. In the clinical and pharmacological arts, the skilled artisan will be able to determine the therapeutic effect amount through routine experimentation, for example, by monitoring the response of an individual to the administration of the compound and thus adjusting the dose. For further reporting, see Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

Prior to administration to a patient, a formulant may be added to the composition. Liquid formulations may be preferred. For example, they may include oils, polymers, vitamins, carbohydrates, amino acids, salts, buffers, albumin, surfactants, extenders or combinations thereof.

Carbohydrate fractions include sugars or sugar alcohols, such as monosaccharides, disaccharides, or polysaccharides, or water-soluble glucans. Saccharide or glucan may be selected from the group consisting of fructose, dextrose, lactose, glucose, mannose, sorbose, xylose, maltose, sucrose, dextran, pullulan, dextrin, alpha and beta cyclodextrins, soluble starch, hydroxyethyl starch And carboxymethylcellulose, or mixtures thereof. "Sugar alcohols" are defined as C4 to C8 hydrocarbons having -OH groups and include galactitol, inositol, mannitol, xylitol, sorbitol, glycerol and arabitol. These sugars or sugar alcohols described above can be used individually or jointly. There is no fixed limit in the amount used, as long as the sugar or sugar alcohol is soluble in the aqueous preparation. In one embodiment, the sugar or sugar alcohol concentration is 1.0 w / v% to 7.0 w / v%, more preferably 2.0 to 6.0 w / v%.

Amino acid fractions include the left-handed (L) form of carnitine, arginine, and betaine; However, other amino acids may be added.

Polymeric phalanxes include polyvinylpyrrolidone (PVP) having an average molecular weight between 2,000 and 3,000, or polyethylene glycol (PEG) having an average molecular weight between 3,000 and 5,000.

It is also preferred to use a buffer in the composition to minimize pH changes in the solution before or after lyophilization. Most physiological buffers can be used including, but not limited to, citrates, phosphates, succinates, and glutamate buffers, or mixtures thereof. In some embodiments, the concentration is from 0.01 to 0.3 moles. Surfactants that may be added to the formulation are shown in EP Nos. 270,799 and 268,110.

Another drug delivery system for increasing circulating half-life is liposomes. Methods for preparing liposome delivery systems are described in Gabizon et al., Cancer Research (1982) 42: 4734; Cafiso, Biochem Biophys Acta (1981) 649: 129; And Szoka, Ann Rev Biophys Eng (1980) 9: 467. Other drug delivery systems are known in the art and include, for example, Poznansky et al., DRUG DELIVERY SYSTEMS (R. L. Juliano, ed., Oxford, N. Y. 1980), pp. 253-315; M. L. Poznansky, Pharm Revs (1984) 36: 277.

After the liquid composition is prepared, it can be lyophilized to prevent degradation and preserve sterility. Methods for lyophilizing liquid compositions are known to those skilled in the art. Immediately prior to use, the composition may be reconstituted with a sterile diluent (such as Ringer's solution, distilled water, or sterile saline) that may contain additional ingredients. Upon reconstitution, the composition is administered to a subject using methods known to those skilled in the art.

The compositions of the present invention may be sterilized by conventional, well-known sterilization techniques. The resulting solution may be packaged for use or filtered under aseptic conditions and lyophilized, and the lyophilized product is co-mingled with the sterile solution prior to administration. The composition may contain pharmaceutically acceptable auxiliary substances such as pH adjusting agents and buffers and tonicity adjusting agents as necessary, for example sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sodium chloride, And stabilizers (e.g., 1-20% maltose, etc.).

Many variations and alternative elements have been disclosed in embodiments of the present invention. More variations and alternative elements will be apparent to those skilled in the art. These variations include, without limitation, selection of a variety of diseases, disorders and disorders that can be diagnosed, predicted or treated with the inventive methods, compositions, kits, and component modules for the system. Various embodiments of the invention may specifically include or exclude one of these variations or elements.

In some embodiments, numerals representing quantities of ingredients, properties, such as concentrations, reaction conditions, and the like, used to describe and claim certain embodiments of the invention, are in some cases modified by the term "about " I understand. Thus, in some embodiments, the numerical parameters set forth in the written specification and the appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the particular embodiment. In some embodiments, numerical parameters should be construed in light of the number of significant digits reported and by applying routine rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values stated in the specific examples are reported as precisely as possible. The numerical values provided in some embodiments of the present invention may include certain errors that inevitably arise from the standard deviation found in their individual test measurements.

The grouping of alternative elements or embodiments of the invention disclosed herein is not to be construed as limiting. Each group member may be referred to and claimed individually or in combination with other members of the group or with other elements found herein. One or more members of the group may be included or excluded from the group for reasons of convenience and / or patentability. When any such inclusion or exclusion arises, the specification is considered to encompass a modified group herein and thus to realize a written description of all the groups of macros used in the appended claims.

In various embodiments, the subject is a human. In various embodiments, the subject is a mammalian subject, including, but not limited to, a human, a monkey, an ape, a dog, a cat, a cow, a horse, a goat, a pig, a rabbit, a mouse and a mouse. In some embodiments, the subject is an animal model of cancer.

Way

Methods are provided herein for sensitizing tumors to antitumor therapy in individuals in need of treatment. These methods comprise, comprise, consist essentially of, or consist of administering to a subject an effective amount of the composition to provide a composition comprising an inhibitor of TGF [beta] signaling and to sensitize the tumor. In one embodiment, the tumor is a melanoma. In another embodiment, the inhibitor of TGF [beta] signaling is an antisense oligonucleotide specific to TGF [beta] 2. In one embodiment, the antisense oligonucleotide specific for TGF [beta] 2 is trabeverser or variant, derivative or analog thereof.

Methods for treating cancer in a subject in need thereof are also provided herein. These methods comprise, comprise, consist essentially of, or consist of administering to a subject an effective amount of the composition to treat a cancer in a subject, and a composition comprising an inhibitor of TGF [beta] signaling. In one embodiment, the cancer is a melanoma. In another embodiment, the inhibitor of TGF [beta] signaling is an antisense oligonucleotide specific to TGF [beta] 2. In one embodiment, the antisense oligonucleotide specific for TGF [beta] 2 is trabeverser or variant, derivative or analog thereof. These methods further include administering an exogenous therapy, including chemotherapy, radiation therapy, hormone therapy, or a combination thereof. In some embodiments, trabasederen or a variant, derivative or analog thereof is administered prior to administration of a chemotherapeutic agent, radiation therapy, or combination thereof, as described herein.

Methods for inhibiting cancer in an individual in need thereof are also provided herein. These methods comprise, comprise, consist essentially of, or consist of administering to a subject an effective amount of the composition to provide a composition comprising an inhibitor of TGF [beta] signaling and to inhibit cancer in the subject. In one embodiment, the cancer is a melanoma. In another embodiment, the inhibitor of TGF [beta] signaling is an antisense oligonucleotide specific to TGF [beta] 2. In one embodiment, the antisense oligonucleotide specific for TGF [beta] 2 is trabeverser or variant, derivative or analog thereof. These methods further include administering an exogenous therapy, including chemotherapy, radiation therapy, hormone therapy, or a combination thereof. In some embodiments, trabasederen or a variant, derivative or analog thereof is administered prior to administration of a chemotherapeutic agent, radiation therapy, or combination thereof, as described herein.

Methods for reducing the severity of cancer in an individual in need of treatment are also provided herein. These methods include providing a composition comprising an inhibitor of TGF [beta] signaling, and comprising, consisting, consisting essentially of, or consisting essentially of, administering to the subject an effective amount of the composition to reduce the severity of the cancer in the subject do. In one embodiment, the cancer is a melanoma. In another embodiment, the inhibitor of TGF [beta] signaling is an antisense oligonucleotide specific to TGF [beta] 2. In one embodiment, the antisense oligonucleotide specific for TGF [beta] 2 is trabeverser or variant, derivative or analog thereof. These methods further include administering an exogenous therapy, including chemotherapy, radiation therapy, hormone therapy, or a combination thereof. In some embodiments, trabasederen or a variant, derivative or analog thereof is administered prior to administration of a chemotherapeutic agent, radiation therapy, or combination thereof, as described herein.

Methods for preventing cancer metastasis in an individual in need of treatment are further provided herein. These methods include providing a composition comprising an inhibitor of TGF [beta] signaling, and comprising, consisting or consisting essentially of, or consisting essentially of, an effective amount of the composition to prevent metastasis of the cancer in the subject do. In one embodiment, the cancer is a melanoma. In another embodiment, the inhibitor of TGF [beta] signaling is an antisense oligonucleotide specific to TGF [beta] 2. In one embodiment, the antisense oligonucleotide specific for TGF [beta] 2 is trabeverser or variant, derivative or analog thereof. These methods further include administering an exogenous therapy, including chemotherapy, radiation therapy, hormone therapy, or a combination thereof. In some embodiments, trabasederen or a variant, derivative or analog thereof is administered prior to administration of a chemotherapeutic agent, radiation therapy, or combination thereof, as described herein.

Methods for reducing tumor burden (e.g., of a melanoma) in a subject in need of treatment are further provided herein. These methods comprise, comprise, consist essentially of, or consist of administering to a subject an effective amount of the composition to provide a composition comprising an inhibitor of TGF [beta] signaling and to reduce tumor burden in the subject . In one embodiment, the inhibitor of TGF [beta] signaling is an antisense oligonucleotide specific to TGF [beta] 2. In one embodiment, the antisense oligonucleotide specific for TGF [beta] 2 is trabeverser or variant, derivative or analog thereof. These methods further include administering an exogenous therapy, including chemotherapy, radiation therapy, hormone therapy, or a combination thereof. In some embodiments, trabasederen or a variant, derivative or analog thereof is administered prior to administration of a chemotherapeutic agent, radiation therapy, or combination thereof, as described herein.

In some embodiments of the methods described herein, the TGFβ signaling inhibitor is an antisense molecule that specifically targets TGFβ. In some embodiments, the antisense molecule is an antisense nucleic acid, an antisense polynucleotide, an antisense polydeoxynucleotide, an antisense oligonucleotide, or an antisense oligodeoxynucleotide. 20%, 30%, 40%, 50% or more of the activity or level of TGFβ encoded by the TGFβ gene not targeted by the expression of the TGFβ gene or by the TGFβ gene not targeted by the antisense oligonucleotide, , 60%, 70%, 80%, 90%, 95% or 99% or more. In certain embodiments, the TGFβ signaling inhibitor is a phosphorothioate antisense oligodeoxynucleotide that is specific for human TGFβ2 mRNA. In one embodiment, the TGF [beta] signaling inhibitor is Travadersen (AP12009) or a variant, derivative or analog thereof. In one embodiment, the TGFβ signaling inhibitor comprises, consists of, or consists essentially of the sequence 5'-CGGCATGTCTATTTTGTA-3 'as set forth in SEQ ID NO: 1. In some embodiments, the trabadercene or variant, derivative or analogue thereof does not need to reduce the IC ₅₀ of the chemotherapeutic agent and / or the trabadercene or variant, derivative or analog thereof has an IC ₅₀ of the chemotherapeutic agent . For example, as described in Examples 1 and 2 herein, trabadercene is co-administered with temozolomide in glioma cells, or trabadercen is co-conjugated with 5-fluorouracil in pancreatic or colon cancer cells There was no advantage.

In some embodiments of the methods described herein, trabasederen or a variant, derivative or analog thereof is administered once, twice, or three times a day, 7 days on and 7 days off, prior to administration of the chemotherapeutic agent or radiotherapy , 4 times, 5 times, or more. In some embodiments, trabasederen or a variant, derivative or analog thereof is administered at a dose of one, two, three, four, five, or more times of 4 days on and 10 days off prior to the administration of the chemotherapeutic agent or radiotherapy RTI ID = 0.0 > and / or < / RTI > In one embodiment, Travaderscene or a variant, derivative or analog thereof is administered intravenously via continuous infusion for one cycle of 4 days on and 10 days off, prior to administration of the chemotherapeutic agent or radiotherapy. In one embodiment, the trabadercene or variant, derivative or analog thereof is administered intravenously via continuous infusion for two cycles of 4 days on and 10 days off, prior to administration of the chemotherapeutic agent or radiation therapy. In one embodiment, the trabadercene or variant, derivative or analog thereof is administered intravenously via continuous infusion for three cycles of 4 days on and 10 days off, prior to administration of the chemotherapeutic agent or radiation therapy. In one embodiment, the trabadercene or variant, derivative or analog thereof is administered intravenously via continuous infusion for four cycles of 4 days on and 10 days off, prior to administration of the chemotherapeutic agent or radiation therapy.

In various embodiments of the methods described herein, the chemotherapeutic agent for use in the methods described herein is selected from the group consisting of temozolomide, actinomycin, alitretinoin, all-trans retinoic acid, azacytidine, azathioprine, Cortex, ciclopramide, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxiflubin, docetaxel, doxorubicin, But are not limited to, lipid, lipid, lipid, lipid, lipid, lipid, lipid, lipid, lipid, (Nal-IRI), mechlorethamine, melphalan, mercuric acid, erythromycin, irinotecan, irinotecan, irinotecan, Lt; / RTI > Paclitaxel, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituxim, rituxim, rituxim, rituxim, rituxim, rituxim, rituxim, rituxim, rituxim, rituxim, rituximab, 5-fluorouracil, 5-fluorouracil, 5-fluorouracil, 5-fluorouracil, 5-fluorouracil, thiophene, thioguanine, topotecan, tretinoin, valvicin, bemurafenib, vinblastine, vincristine, vindesin, vinorelbine, -FU), 6-mercaptopurine (6-MP), cladribine, clofarabine, fluoxidyne, fludarabine, pentostatin, mitomycin, ixabepilone, estramustine, prednisone, methylprednisolone, &Lt; / RTI > dexamethasone, or combinations thereof.

In various embodiments of the methods described herein, the exogenous therapy for use in the methods described herein comprises radiation therapy. The radiation used in the radiation therapy may be ionizing radiation. Radiotherapy may also be gamma rays, X-rays, or proton beams. Examples of radiotherapy include external beam radiation therapy, ischemic implantation of radioactive isotopes (I-125, palladium, iridium), radioactive isotopes such as strontium-89, chest radiotherapy, intraperitoneal P-32 radiation therapy , And / or total abdominal and pelvic radiation therapy. See Hellman, Chapter 16: Principles of Cancer Management: Radiation Therapy, 6th edition, 2001, DeVita et al., Eds., J. B. Lippencott Company, Philadelphia, for a general overview of radiotherapy. Radiation therapy may be administered as external beam radiation or telemetry, wherein the radiation is directed from a remote source. Radiotherapy may also be administered as an internal therapy or as a proximal therapy, wherein the radiation source is placed within the body close to a cancer cell or tumor mass. Also included are photosensitizers such as hematoporphyrin and derivatives thereof, veraportin (BPD-MA), phthalocyanine, photosensitizer Pc4, demethoxy-hypocreelin A; And the use of photodynamic therapy, including the administration of 2BA-2-DMHA.

In various embodiments of the methods described herein, the extrinsic therapy for use in the methods described herein comprises hormone therapy. Hormone therapy may include, for example, hormone agonists, hormone antagonists (e.g., flutamide, bicalutamide, tamoxifen, raloxifene, leuprolide acetate (LUPRON), LH-RH antagonist), inhibitors of hormone biosynthesis and treatment, It is also possible to use steroids such as dexamethasone, retinoid, deltoid, betamethasone, cortisol, cortisone, prednisone, dehydrouro testosterone, glucocorticoid, mineralocorticoid, estrogen, testosterone, progestin, vitamin A derivatives )); Vitamin D3 analogs; Anti-progesterone (e. G., Mifepristone, onapristone), or antiandrogens (e. G., Ciproterone acetate salt).

As described herein, a typical dose of an effective amount of a TGFβ inhibitor (eg, a TGFβ2 inhibitor) is recommended by the manufacturer when known therapeutic compounds are employed, and also by in vitro reactions or by reaction in animal models And may be within the ranges as indicated to those skilled in the art. This capacity can typically be reduced to about one order of magnitude in concentration or amount without losing the relevant biological activity. Actual dose may be based on physician judgment, patient condition and, for example, in vitro reactivity of relevant cultured cells or tissue cultured tissue specimens, such as biopsied malignancy, Depending on the usefulness of the treatment method. In various embodiments, a composition of the invention comprising a TGFβ inhibitor (eg, a TGFβ2 inhibitor) is administered once daily (SID / QD), twice daily (2 days) to administer an effective amount of a TGFβ inhibitor (eg, a TGFβ2 inhibitor) (BID), three times a day (TID), four times a day (QID), or more, wherein the effective amount is any one or more of the amounts set forth herein.

In various embodiments, the subject is selected from the group consisting of a human, a non-human primate, a monkey, an ape, a dog, a cat, a cow, a horse, a rabbit, a mouse and a rat.

A typical dose of an effective amount of a TGF [beta] signaling inhibitor (e.g., a composition comprising a TGF [beta] 2 inhibitor or a TGF [beta] 2 inhibitor) for use in the methods of the invention is described herein. These doses may be in the range recommended by the manufacturer if known molecules or compounds are used, and also as directed to those skilled in the art by an in vitro response in a cell or an in vivo response in an animal model. This capacity can typically be reduced to about one order of magnitude in concentration or amount without losing the relevant biological activity. Actual dose may depend on the judgment of the physician, the condition of the patient, and the availability of treatment methods based on, for example, the in vitro response of the relevant cultured cell or tissue cultured tissue sample, or the response observed in the appropriate animal model have.

In various embodiments, the TGFβ signaling inhibitor is administered at a dose of about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200-300 , 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg inhibitor / kg body weight, or a combination thereof. In various embodiments, the TGFβ signaling inhibitor is administered at a dose of about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200-300 , 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg inhibitor / m ² body surface area, or a combination thereof. Here, "mg inhibitor / kg body weight " refers to the mg inhibitor per kg of body weight of the individual, and" mg inhibitor / m ² body surface area "refers to the mg inhibitor per m ² body surface area of the individual.

In various embodiments, the effective amount of a TGFβ signaling inhibitor is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 μg / kg / day, or any combination thereof to be. In various embodiments, the effective amount of a TGFβ signaling inhibitor is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 μg / m ² / day, or any combination thereof. Or more. In various embodiments, the effective amount of a TGFβ signaling inhibitor is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg / kg / day, or any combination thereof to be. In various embodiments, the effective amount of a TGFβ signaling inhibitor is about 0.001-0.01, 0.01-0.1, 0.1-0.5, 0.5-5, 5-10, 10-20, 20-50, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, or 900-1000 mg / m ² / day, or any combination thereof. Or more. Here, "μg / kg / day" or "mg / kg / day" refers to μg or mg inhibitor per kg body weight of individual per day and, and "μg / m ² / day" or "mg / m ² / Day "refers to μg or mg inhibitor per m ² body surface area of an individual per day.

In various embodiments, the TGFβ signaling inhibitor is trabadercene (AP12009) or a variant, derivative or analogue thereof, and is about 50-100, 100-150, 150-200, 200-250, 250-300, 300- 350, 350-400, 400-450, or 450-500 mg / m ² / day. In some embodiments, the trabevereren or a variant, derivative or analog thereof is administered at about 140, 150, 160, 170, or 180 mg / m ² / day. In some embodiments, the trabevereren or a variant, derivative or analog thereof is administered at about 310, 320, 330, 340 or 350 mg / m ² / day.

In various embodiments, the TGFβ signaling inhibitor may be administered once, twice, three times or more. In various embodiments, the TGFβ signaling inhibitor may be administered 1-3 times per day, 1-7 times per week, 1-9 times per month, or 1-12 times per year. In various embodiments, the TGFβ signaling inhibitor is administered at about 1-10 days, 10-20 days, 20-30 days, 30-40 days, 40-50 days, 50-60 days, 60-70 days, 70-80 days , 80-90 days, 90-100 days, 1-6 months, 6-12 months, or 1-5 years. In various embodiments, a TGF [beta] signaling inhibitor is administered once a day (SID / QD), twice a day (BID), three times a day (TID), four times a day to deliver an effective amount of a TGF [ (QID), or more, wherein the effective amount is any one or more of the amounts set forth herein.

Advantages of the invention

TGFβ2 is overexpressed in many advanced tumors, where it produces a microenvironment that conceals tumors in the patient and promotes immune avoidance. This makes it difficult for therapeutic agents, such as chemotherapeutic agents, to reach the tumor cells. Herein we show for the first time that inhibition of TGFβ2 with trabadercene excites the tumor and thus sensitizes it to subsequent chemotherapy and demonstrates the importance of the sequence in which the therapeutic agent is administered. US Patent No. 8,476,246 shows that when the cell line is co-treated with trabadercene and a chemotherapeutic agent (such as gemcitabine or temozolomide), the IC ₅₀ of the chemotherapeutic agent is reduced; However, the efficacy of co-administration of trabodercen and a chemotherapeutic agent on tumor burden or overall survival is unclear. In contrast, the inventors show that there is a significant increase in the overall survival rate of a patient when the patient is sequentially administered traverserine and chemotherapeutic agent and traverserine is administered prior to the chemotherapeutic agent. In addition, the inventors also show that the overall patient survival rate is significantly reduced if chemotherapy precedes treatment with trabadercene or treatment with trabeverserine is not followed by chemotherapy. Thus, the present invention provides an unexpected advantage, i. E., That the treatment of a cancer (e. G., Melanoma) patient (for an effective number of cycles as described herein) with trabasederen prior to treatment with a chemotherapeutic agent, In patients with acute coronary syndromes.

Example

The present invention will be further illustrated by the following examples, which are intended to be purely exemplary of the invention and are not to be considered as limiting the invention in any way. The following examples are provided to more effectively illustrate the claimed invention and are not to be construed as limiting the scope of the invention. To the extent that a particular substance is mentioned, this is for illustrative purposes only and is not intended to limit the invention. Those skilled in the art will be able to develop equivalent means or reactants without undue experimentation and without departing from the scope of the invention.

Example 1

The aim of this study was to determine the effect of AP12009 (trabadercan) treatment in combination with 5-fluorouracil (5-FU) on TGFβ2 secretion and cell proliferation of HUP-T3 pancreatic cancer cells and WiDr colon cancer cells in vitro I was doing.

In HUP-T3 pancreatic cancer cells, 5-FU (treated for 5 h on day 1) at a concentration of> 10 μM reduced the measured cell proliferation dose-dependently after 7 days. TGF? 2 is ca. Was inhibited only at concentrations higher than 75 μM 5-FU. As a monotherapy, 10 μM AP12009 reduced cell proliferation (53% proliferation of untreated control) and TGFβ2 expression (42% of untreated control) in HUP-T3 cells. Addition of 10 μM AP12009 to 5-FU did not cause any additional inhibition of proliferation compared to 5-FU alone. The addition of 5-FU to 10 [mu] M AP12009 caused additional or even antagonistic effects with respect to inhibition of TGF [beta] 2 expression.

In WiDr colorectal cancer cells, 5-FU (treated for only 5 hours on day 1) was ca. At a concentration higher than 38 μM, cell proliferation was reduced in a concentration dependent manner. TGF? 2 is ca. Was inhibited only at concentrations higher than 75 μM 5-FU. 10 μM of AP12009 slightly reduced cell proliferation (76% of untreated control) and had a more pronounced effect on TGFβ2 expression (54% of untreated control). The combination of 10 μM AP12009 and 5-FU resulted in an additive effect on cell proliferation and TGFβ2 expression.

In summary, no beneficial results were observed with the combination of AP12009 and 5-FU in HUP-T3 and WiDr cells.

Example 2

A-172 glioma cells were treated with a combination of TMZ (temozolomide) and different concentrations of AP12009 (Trabadercene) 0-10 μM for 7 days (treatment schedule 2 ^* 2/1 ^* 3 d).

Pre-treatment of A-172 glioma cells with AP12009 (1 ^* 2/1 ^* 3d) did not show any benefit, prior to the co-treatment with AP12009 and TMZ (2 ^* 2/1 ^* 3d). A single treatment (day 0) with TMZ for one day combined with 7 days AP12009 treatment (2 ^* 1/1 ^* 2/1 ^* 3d) did not show any benefit or disadvantage. High TMZ concentrations (64/160/400 μM) reduced dose-dependent migration of A-172 cells as monotherapy. AP12009 (10 μM) as monotherapy did not affect migration compared to untreated controls. Collectively, AP12009 did not affect the effect of TMZ on migration.

TMZ reduced proliferation and TGF-2 in a dose-dependent manner in parallel. AP12009 strongly reduced TGFβ2 and slightly decreased cell proliferation. Concomitantly, an additive effect on the inhibition of TGF [beta] 2 secretion was observed, whereas no reproducible beneficial effect on cell proliferation could be detected. The lactate dehydrogenase (LDH) release assay for quantitation of cytotoxicity did not show reproducible results. In summary, there is no obvious beneficial effect in associating AP12009 with TMZ in A-172 cells.

Example 3

Half-stage test of treatment with trabadercen

Overexpression of transforming growth factor-beta2 (TGF-beta2) is associated with poor prognosis and plays a key role in the malignant progression of various tumors by inducing proliferation, metastasis, angiogenesis and immunosuppression. P-001 TREVADERSEN TEST - In patients with advanced tumors known to overproduce TGFβ2, I.V. The safety and tolerability of the administered AP 12009 (Trabadercene) was assessed with Trevaderscene to determine whether the treatment augments the tumor to subsequent chemotherapy.

In this study, the main objective was to assess the efficacy of intravenous (iv) intravenous (IV) infusion over a period of 7 days (ie 7 days on / 7 days off) or biweekly 4 days (4 days on / 10 days off) (MTD) and dose-limiting toxicity (DLT) of the two cycles. The secondary objective included the assessment of the antitumor activity of Travadersen administered intravenously for 7 days (ie, 7 days on / 7 days off) or biweekly 4 days (4 days on / 10 days off) Respectively.

Openness - Label I / II Step Capacity Increase Study

The step-wise expansion plan of this study consists of two consecutive i.v. (7 days-7 days-7 days-off) every other week for 4 days (4- day-on / 10-day-off) every other week. The purpose of this study was to determine the MTD of two cycles of trabadercans administered as injections (so-called 'core study period').

Generally, it was planned to register a cohort of at least three evaluable patients for each treatment group. For each cohort, safety data obtained until the end of the core study period (DLT-time for assessment, period 1 and period 2) was assessed in the interim analysis and assessed by the Data Safety Monitoring Board (DSMB). When these results indicated that the treated patient tolerated this regimen, the next cohort of 3 evaluable patients was given the next higher dose. When two of these three patients experienced DLT, the number of evaluable patients for the subsequent treatment group was increased to six to further assess toxicity. Patients who dropped out of the study due to DLT-induced side effects (AEs) by the treatment clinician were used to determine the MTD and assess the safety of the study drug without being replaced. If the patient was withdrawn for other reasons, they were replaced until the treatment group was complete.

The MTD was determined according to the following procedure: If two of the three patients in the cohort experienced DLT, three additional patients were enrolled in the same treatment group. At least one of these additional three patients also met the toxicity criteria for DLT, the MTD for the two cycles was determined; If not, the increase in capacity continued at the time of agreement with the DSMB. The MTD for the two cycles was then defined as the dose in which two of three patients in the same treatment group or two of the six patients experienced DLT. This procedure was followed until the MTD was reached.

After the dose increase is completed, an additional larger cohort of patients is enrolled and dosed at a dose of 140 mg / m ² / day using a 4-day-on / 10-day-off schedule at the time of approval by DSMB It was cured. These cohorts include at least 12 patients with a histologically or cytologically confirmed diagnosis of pancreatic cancer III or IV corresponding to the AJCC 1997 IVa and IVb groups, respectively, and at least 12 patients with III or IV melanoma Respectively.

The end point of the study was defined as the point at which one of the following criteria was met for all patients in the last cohort: (1) at 12 months after the last patient's registration was reached, or (2) OS) was reached for the last cohort (ie, more than half of the patients died during the follow-up).

Despite the anticipated low toxicity profiles for the lower dose groups based on preclinical toxicology results, no accelerated escalation was performed and three evaluable patients were included from the beginning for each dose group. Accelerated staging was not done because these patients typically exhibited a complex range of disease-related symptoms that might overlap with the potential toxicity of Trabaderasen; As a result, the three evaluable patients provided more information allowing for a better assessment of drug-related toxicity. In general, patients were enrolled in deduction order, but ideally at least one patient per disease population was ideally included in each treatment group, especially in the higher dose groups in which the first toxicity was observed.

Research patient

A total of 62 patients were enrolled in the study; 38 patients with pancreatic cancer, 19 patients with melanoma, and 5 patients with colorectal cancer. All patients were treated with Travadersen except 1 patient with pancreatic cancer, so the Safety Population / All-Item Assay Set (FAS) included 61 patients. Seven patients with pancreatic cancer, one patient with melanoma, and three patients with colorectal cancer were excluded during the core study; As a result, 50 patients completed the core study (30 with pancreatic cancer, 18 with melanoma, and 2 with colorectal cancer).

After the core study period, 25 patients with pancreatic cancer, 16 patients with melanoma, and 1 patient with colon admitted to treatment during an extended study period, during which time most of these patients were prematurely stopped Respectively. Three patients with pancreatic cancer and one patient with melanoma completed the entire extended study period. Interestingly, the investigator was asked to discontinue the patient's treatment after the fourth treatment cycle, if signs of progressive disease were observed at this point.

Of the 61 registered patients, 52 patients (30 with pancreatic cancer, 18 with melanoma and 4 with colorectal cancer) were presented to the DSMB for DLT assessment during the core study period (cycle 1 and cycle 2) , Because they have fulfilled the individual criteria as specified in the protocol. The mean age was 60.3 years (± 9.6 years). All patients were white. Seventeen patients (45.9%) with pancreatic cancer, eight patients with melanoma (42.1%), and five patients with colorectal cancer (100%) were males. At baseline, mean body weight was lower in pancreatic cancer patients (65.4 kg) than in melanoma (78.3 kg) or colorectal cancer patients (78.6 kg).

Inclusion criteria

The inclusion criteria for this study were: (1) the patient provided written consent prior to any research-related procedures; (2) the patient was at least 18 years old and younger than 75 years; (3) The patient was male or non-pregnant, non-lactating. (4) Patients with pancreatic cancer were diagnosed histologically or cytologically with pancreatic cancer, stage III or IV (corresponding to AJCC 2002, AJCC 1997 IVA or IVB); (5) Patients with melanoma were diagnosed histologically or cytologically with melanoma, stage III or IV (AJCC 2002); (6) Patients with colorectal cancer were diagnosed histologically or cytologically (excluding the last cohort) of colorectal cancer, stage III or IV (AJCC 2002); (7) the patient did not adhere to an established form of therapy or was no longer compliant; (8) the patient had at least one measurable lesion; (9) the patient had a Karnofsky performance status of at least 80%; (10) the patient recovered from acute toxicity induced by any prior therapy; And (11) the patient exhibited appropriate organ function when assessed by the following laboratory values: (a) twice the serum creatinine and urea (ULN); (b) alanine amino transferase (ALT) and aspartate amino transferase (AST) <3 ULN (in the case of liver metastasis: <5x ULN); Alkaline phosphatase (AP) <3 ULN; And bilirubin <2.5 mg / dL; (c) Prothrombin time (PT) <1.5 International Normalization Ratio (INR) and partial thromboplastin time (PTT) <1.5 times ULN; (d) hemoglobin> 9 g / dL; (e) platelets > 100 x 109 / L; (f) WBC count> 3.0 x 109 / L; And (g) absolute neutrophil count (ANC)> 1.5 x 109 / L.

Exclusion criteria

The exclusion criteria for this study were: (1) the patient could not comply with protocol regulations; (2) the patient was a pregnant or lactating woman; (3) Patients were given antitumor radiotherapy within 12 weeks, tumor surgery within 4 weeks, or any other therapy with antitumor effect established within 2 weeks prior to study entry; (4) the patient was or was likely to be taking other prohibited concomitant medications; Administration of corticosteroids was strictly avoided during the course of the study; (5) The patient participated in another clinical trial with a trial drug within 30 days prior to study entry; (6) The patient had a history of brain metastasis. When a brain metastasis was suspected, a computed tomography (CT) scan of the skull was performed. This was not mandatory in asymptomatic patients; (7) Patients exhibited clinically significant cardiovascular abnormalities, such as refractory hypertension, congestive heart failure, unstable angina, or poorly controlled arrhythmia, or myocardial infarction within 6 months prior to treatment; (8) Patients were at risk of gastrointestinal ulcer formation due to high stomach or duodenal ulcers or high consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) within 6 months prior to study entry; (9) The patient had active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV); (10) The patient had clinically significant acute viral, bacterial, or fungal infections; (11) The patient had an acute medical problem that could be considered an unacceptable risk, or any illness that might have been contraindicated to initiate the study treatment; (12) Patients had a history of allergies to the reagents used in this study; (13) Patients were known for drug abuse or extensive use of alcohol; (14) Patients showed significant psychiatric disability / legal incompetence or limited legal capacity; (15) Patients had a history of long QT syndrome or mean heart rate - corrected QT interval (QTc) time ≥480 msec. The mean QTc time was calculated from three separate ECGs performed prior to the beginning of the infusion: 2 ECGs at the screening / baseline (with a minimum interval of 1 hour in the middle) and 1 ECG.

The clinical onset dose for the 7-day-on and 7-day-off schedule was based on the observed lowest adverse event level (LOAEL), which is the most relevant species and lacks serious toxicity in the monomorphic monkey. This LOAEL of 4 mg / kg body weight (bw) / day is equivalent to approximately 1.3 mg / kg bw / day or 48 mg / m ² / day on an adult body surface basis. These numbers were rounded down and safe starting doses were prescribed at 40 mg / m ² / day, equivalent to approximately 1 mg / kg bw / day in humans. An alternative approach would be based on the lowest lethal dose (LLD) of 300 mg / kg bw (determined in mice at 1000 mg / kg) obtained in an acute single dose toxicity study in mice, where 1 out of 10 mice He died (LLD10). According to standard methods, 10% (30 mg / kg) of this dose at the body surface area basis will then be defined as a clinical onset dose inducing 90 mg / m ² / day. At the end, the lower of these two alternatives was selected as the starting capacity.

For the determination of the starting dose for the 4-day-on and 10-day-off schedule, the cumulative dose (instead of daily dose) of the study drug was considered every treatment cycle. The proposed 4-day-on and 10-day-off constant daily doses (140 mg / m ² / day or 560 mg / m ² / cycle or approximately 3.5 mg / Was still slightly below the daily dose of 7-day-off constant MTD (approximately 4 mg / kg / day). In addition, doses were administered for only 4 days instead of 7 days. For this reason, a starting dose of 140 mg / m ² / day for the 4-day-on, 10-day-off schedule was assessed to be safe by the DSMB as well as the clinical trial coordinator. Based on observed side effects for various doses of 7-day-on and 7-day-off schedules, the capacity for up to 330 mg / m ² / day for 4-day-on and 10-day- .

Despite the non-lipophilic nature of Travadersen, adjustment of body surface area has been performed to accommodate routine and participatory research centers in oncology.

Safety evaluation

The safety population consisted of 61 patients representing at least one patient who had at least one trial of trabodercen injection. According to the protocol, MTD was determined according to the following procedure: If two out of three patients in one cohort experienced dose-limiting toxicity, three additional patients were enrolled in the same treatment group. If at least one additional patient out of these secondary cohorts meets the toxicity criteria, the MTD for the two cycles was determined (if not, the staged dilation continued). The MTD for the two cycles was then defined as the dose in which two of three patients in the same treatment group or two of the six patients experienced DLT. Consistently, if three patients in the first cohort showed DLT, the second cohort was excluded. A second cohort could also be excluded if two patients in the first cohort experienced DLT clearly indicating the acquisition of MTD. The described procedure was pursued until the MTD was reached.

The number of patients per cohort of 7-day-on and 7-day-off and 4-day-on and 10-day-off dose increments varied between 3 and 6 patients. The last cohort treated with 140 mg / m ² / day in 4-day-on and 10-day-off schedules included 28 patients (14 with pancreatic cancer and melanoma, respectively). The median number of cycles per cohort varied between 1.5 and 5.0. During the core study, the central Troadensee dose per day reflected the individual dose cohort, with the highest daily central dose being observed for the 7-day-on and 7-day-off scheduled cohort 4 (167.9 mg / m ² / day).

The MTD for the 7 day on and 7 day off regimen (N = 11) was 160 mg / m ² / d while the MTD was 330 mg / m ² / d for the 4 day on and off- d < / RTI >

DLT was declared for a total of 4 patients, two patients with pancreatic carcinoma, and two patients with colorectal cancer. Three of these patients received DLT (two cases of grade 3 thrombocytopenia, one case of grade 3 hemispheric rash) while receiving 240 mg / m ² / day on 7-day-on and 7-day- , The next lower dosing regimen of 160 mg / m ² / day was identified as the MTD for the 7-day-on and 7-day-off schedule.

The fourth patient experienced a dose-limiting grade 3 upper gastrointestinal bleeding after injection at 140 mg / m ² / day in the 4-day-on and 10-day-off schedules. No other DLT was observed in the 4-day-on and 10-day-off schedules, and for this reason no MTD for the schedule was established (highest dose tested 330 mg / m ² / day).

During the study, 14 patients (23.0%) experienced a total of 23 treatment-related adverse events (TEAEs) that resulted in discontinuation: nine patients (24.3%) with pancreatic cancer, three patients with melanoma (15.8 %), And two patients with colorectal cancer (40.0%). The frequency of patients experiencing TEAE resulting in discontinuation of therapy was significantly lower than that of patients treated with 4-day-on and 10-day-off schedules (7 patients [15.9% Were significantly higher in patients who were treated on a regular basis (7 patients [41.2%]). And, as shown in Table 1, the severity of side effects (SAEs) was even higher for the 7-day-on, 7-day off schedule than the 4-day-on, 10-day off schedule.

Serious side effects (SAE) reported by schedule and classified by frequency and classified by frequency. Number of patients with SAE / number of SAE (%) Preferred term 7-day-on, 7-day off schedule / (N = 17) 4-day-on, 10-day off schedule / (N = 44) Total / (N = 61) Any SAE 12 (70.6) / 28 18 (40.9) / 28 30 (49.2) / 56 Cholangitis 1 (5.9) / 1 3 (6.8) / 3 4 (6.6) / 4 revenge 3 (17.6) / 3 0 3 (4.9) / 3 Catheter-Related Infections 2 (11.8) / 2 1 (2.3) / 1 3 (4.9) / 3 GI bleeding 2 (11.8) / 3 1 (2.3) / 2 3 (4.9) / 3 Pneumonia 3 (17.6) / 3 0 3 (4.9) / 3 Cancer pain 0 2 (4.5) / 2 2 (3.3) / 2 Cholestasis 1 (5.9) / 1 1 (2.3) / 1 2 (3.3) / 2 Upper GI bleeding 1 (5.9) / 1 1 (2.3) / 1 2 (3.3) / 2 N = total number of patients; No. = Number; SAE = Serious side effects.

Effectiveness evaluation

In the screening test, up to 10 "measurable lesions" (ie, lesions that could be accurately measured at least one dimension with a maximum diameter of 2 cm) representing all relevant organs were identified as "target lesions" for tumor response assessment , And measured and documented. All other lesions were defined and recorded as "non-target lesions". The tumor response was determined by the local investigator every 8 weeks after the start of the first Trabaderchen cycle during the follow-up visit, regardless of whether the patient was continuing to treat or discontinued treatment. Tumor assessments were based on response criteria (RECIST 1.0) in solid tumors. The categories of overall tumor response are: (1) Complete response (CR): loss of all target and non-target lesions and normalization of tumor marker levels; (2) partial response (PR): at least a 30% reduction in the sum of the longest diameter (LD) of the target lesion (baseline sum LD) and / or the survival and / or the normal limit of one or more non-target lesions Maintenance of tumor marker levels in excess; (3) Stable disease (SD): a decrease of less than 30% or an increase of less than 20% in total LD target lesions (as the lowest total LD since treatment initiation) and / or one or more non-target lesions Maintenance of tumor marker levels beyond survival and / or normal limits; (4) Progressive disease (PD): at least a 20% increase in total LD target lesion (as the lowest total LD since treatment has begun) and / or a clear progression of existing non-target lesions and / Emergence of new lesions; And (5) not known.

Survival without progress

Progressive survival (PFS) was defined as the time from day 1 until tumor progression or any cause to death. The date of the progression was either the date of the image showing progress or the date of termination of treatment, whichever was first, if any, in the case of tumor progression (citing clinical progress when assessed by an investigator).

Overall survival

Overall survival (OS) was defined as the time from day 1 to the time of death from any cause. All patients were followed for survival every 8 weeks during follow-up. Survival status was recorded as documentation during the final visit (29 days) and 8-weekly post-treatment follow-up, and was collected continuously after the study was completed until the database was locked or the patient was not tracked.

Pancreatic cancer

On the 4th day on and 10th off-regimen, there were 16 patients with secondary and 11 patients with three or more patients. The PFS / OS (alive / overall survival without progression) of Bilinear patients (months) were as follows: each, 140mg / m ² / day, 167mg / m ² / day and average increase in capacity of 196mg / m ² / day 1.87 / 5.60 (N = 6), 1.87 / 9.93 (N = 11) and 2.72 / 11.80 (N = 5). The OS of 9.93 and 11.80 is higher than the highest value reported in the 65 studies reported in the existing literature (range = 2.50-9.20 / median = 5.50) for the period 1997-2015. Corresponding PFS values were consistent with those reported in the literature (range = 0.00-7.65 / center = 2.43). As a result, the OS-PFS for Trabaderchen was far superior to that reported in previous literature. This proves that trabodensee makes the tumor more sensitive to future therapies. Traverseren itself did not give any impact to the tumor (Figure 1).

In the follow-up study, the chemotherapy was 2.80 mos (N = 9) OS compared to 9.93 mos (N = 11), p = 0.046, and log rank statistics. This was ineffective compared to the case of first treatment with TRAVEDERSEN in the second line and subsequent treatment with subsequent therapy. (FIG. 2). This shows once more that the tumor is sensitive to future treatment. OS of this 4/10 cohort treated with subsequent chemotherapy was 14.7 versus 2.93 mos in the absence of subsequent chemotherapy, p = 0.0023, and log rank statistics (Figure 3). This shows once more that the tumor is sensitive to chemotherapy. The chemotherapy used for these patients is shown in Table 2 below.

patient # regimen patient # regimen patient # regimen 1019 5-fluorouracil 1023 Eloxatin 1035 Polinic acid 1019 Polinic acid 1024 5-fluorouracil 1035 Paclitaxel 1019 Oxaliplatin 1024 Polinic acid 1035 Paclitaxel 1019 Paclitaxel 1024 Oxaliplatin 1035 Paclitaxel 1019 Mitomycin 1029 Caffeicitabine 1035 Gemcitabine 1019 Caffeicitabine 1029 Erlotinib 1040 Gemcitabine 1022 Gemcitabine 1029 Radiation therapy 1047 Gemcitabine 1023 Paclitaxel 1035 Oxaliplatin 1047 Erlotinib 1023 Fluorouracil 1035 5-Fu

Melanoma

Skin cancer is the most common form of cancer diagnosed in the United States. Despite constituting only 5% of skin cancer, malignant melanoma is the leading cause of skin cancer-related deaths annually. Metastatic tumors as well as supporting cells that surround them secrete extracellular matrix proteins, which appear to promote their escape and survival in remote areas. Many of these overexpressed proteins in more aggressive tumors are activated by the same cellular signaling pathway, including those that are regulated by TGFβ. TGF beta is often elevated in cancer cells (including melanoma cells). In this I / II step test of advanced metastatic melanoma, we examined the de-occlusion of melanoma tumors by anti-TGF beta 2 antisense oligonucleotides to allow deep sustained overall survival (OS).

The primary objective was to determine the maximum tolerance of the two cycles of Travadersen administered intravenously (iv) for 7 days (7 days on / 7 days off) every other week or 4 days (4 days on / 10 days off) Dose (MTD) and dose-limiting toxicity (DLT). The secondary objective is to assess the effects of i.v. on a weekly interval or four days biweekly, when assessed by survival. And the potential antitumor activity of the administered trabeverserine. These patients received a histologically or cytologically confirmed diagnosis of melanoma, stage III or IV (AJCC 2002). These patients had at least one measurable lesion that did not conform to or no longer conform to established forms of therapy, had at least 80% Carnovsky performance status, and had acute toxicity .

A total of 19 patients were treated with trabadercen. The majority of patients were triple therapy. All patients were white. Eight patients (42.1%) with melanoma were male. The mean weight at baseline was 78.3 kg. The median OS was 11.4 mos at all doses of 19 patients. Survival without median progression (PFS) was 1.77 mos in 15 patients. A subgroup analysis of the same cohort with and without subsequent chemotherapy showed that treatment with Travadersen, followed by subsequent chemotherapy at 13.70 mos (N), compared with 5.5 mos (N = 7) = 9) (p = 0.0004, log rank statistics) (Figure 4). The OS of 13.70 mos is higher than the highest OS (range = 3.50-13.00 mos / central OS = 7.20 mos) reported in the 33 trials reported in the existing literature for 1999-2015. This is true despite the fact that they are OS data for the therapies.

The chemotherapy used for these patients is shown in Table 3 below.

Subsequent chemotherapy among melanoma patients treated with trabadercan. patient # regimen patient # regimen 1025 Radiotherapy 20 Gy 1055 Emilimumum 1025 Carboplatin 1056 Carboplatin and paclitaxel 1025 Paclitaxel 1056 Bemura Fenip 1027 Vinday Shin 1056 Emilimumum 1046 Carboplatin and paclitaxel 1057 B-Raf Inhibitor Gsk 1050 Paclitaxel 1061 Radiation therapy 36gy 1050 Emilimumum 1061 Carboplatin and paclitaxel 1053 Stereotactic radiotherapy 1061 Bemura Fenip 1054 Mek 162

Example 4

Tracheodensen (OT-101) against melanoma xenograft model, followed by synergy between chemotherapy

Sixty female athymic nude mice were inoculated intradermally with C8161 human melanoma cells and randomized into 6 groups of 10 mice. The three groups received monotherapy with OT-101 (trabadercan) (16 mg / kg) (group 2) or Dakarbazine (DTIC; 1 or 10 mg / kg; groups 3 and 4). The two groups received combination therapy (groups 5 and 6) with OT-101 / DTIC at 16/1 mg / kg or 16/10 mg / kg. Carriers (0.9% saline, Groups 1, 3, and 4) and OT-101 were administered 3 times / week by subcutaneous injection. Carriers (0.9% saline, Groups 1 and 2) and DTIC (1 or 10 mg / kg) were administered intraperitoneally 4 times / week. All OT-101 / Trabadercene treatments started on day 0 of the study, and all DTIC treatments started on day 14. Mice were monitored for negative effects, body weight, and tumor size three times a week. Tumors, lungs, liver and kidneys were excised and quantified from all mice at termination.

C8161 Melanoma tumor. Tumor growth was inhibited by 2%, -2%, 78%, 27%, and 92%, respectively, in groups 2, 3, 4, 5 and 6 at day 42 compared to control group 1. A comparison of all six groups using the Kruskalwalis test showed a significant difference in tumor volume growth (p <0.0001). ANOVA statistics of repeated measures were performed in comparison with control group 1 and p-values for groups 2, 3, 4, 5 and 6 were non-significant (ns), ns, <0.0001, ns, and <0.0001 to be. DTIC inhibition of tumor growth was enhanced by 29% and 14%, respectively, when OT-101 was combined with low dose DTIC (group 5 vs. group 3) or high dose DTIC (group 6 vs. group 4). The combination and group 6 antitumor activities were much better than the high dose DTIC group 4 (p = 0.038) (Figure 5).

Conjugating OT-101 with DTIC induced a synergistic effect on tumor inhibition in the C8161 melanoma model. The linear regression model was created with two independent variables (OT-101 and DTIC) and one interaction variable. The equation was created: Y = 1302.23 -30.39 (OT-101) -1018.56 (DTIC) -1197.59 (OT-101) ^* (DTIC). The coefficients of the interaction variables have the same sign as the two independent variable coefficients, indicating a synergistic interaction effect (p <0.001).

Kaplan Meier Survival Curve. Tumor-bearing mice were sacrificed when the tumor size exceeded the ethical limit of 2,000 mm ³ . For this reason, survival analysis has been performed because it accurately reflects the non-gauss nature of the tumor data. Survival reflected tumor growth, and there was a significant difference between these groups (p <0.0001). The median survival of groups 1, 2, 3, 4, 5, and 6 was 48, 47, 47, 60, 53, and 81 days, respectively. Survival was significantly higher in group 6 compared with corresponding high dose DTIC, group 4 (p = 0.0035, log rank statistic); Also, the corresponding low-dose DTIC was superior to group 3 in comparison to group 3 (p = 0.0132, log rank statistics). This confirmed the synergistic effect of OT-101 and DTIC. Please refer to FIG.

Trevadersen treatment was characterized by an excellent OS that was not supported by PFS. This effect was mainly observed when chemotherapy was used as a trine after treatment with trabadercan; The OS benefits were not the opposite - the chemotherapy first used, and thereafter, in the case of Travadersen. These data support the enhancement of subsequent chemotherapy after treatment with trabadercan.

The various methods and techniques described above provide a number of ways to implement the present application. It is, of course, understood that not necessarily all of the objects or advantages described may be achieved in accordance with any particular embodiment described herein. Thus, by way of example, a person of ordinary skill in the art will readily appreciate that while these methods are not necessarily achieving other objects or advantages as taught or suggested herein, one way or another that achieves or optimizes a group of benefits, as taught herein &Lt; / RTI > Various alternatives are mentioned herein. Some preferred embodiments specifically include one, another, or several features, while other embodiments specifically exclude one, another, or several features, while another embodiment includes one, another, or several features , &Lt; / RTI > or by the inclusion of various beneficial properties.

In addition, those skilled in the art will recognize the applicability of various features from different embodiments. Similarly, other known equivalents to each of these elements, features, or steps, as well as the various elements, features, and steps discussed above, may be utilized in various combinations by those skilled in the art to perform the methods in accordance with the principles described herein have. Between various elements, qualities, and steps, some will be specifically included in various embodiments, and others will be specifically excluded.

Although the present application is disclosed in the context of certain embodiments and examples, it will be appreciated that embodiments of the present application extend beyond the specifically disclosed embodiments to other alternative embodiments and / or uses and modifications and equivalents thereof, Lt; / RTI >

Preferred embodiments of the present application, including the best mode known to the inventors for carrying out the present application, are described herein. Variations in these preferred embodiments will be apparent to those skilled in the art upon reading the foregoing description. Those skilled in the art will appreciate that such variations are available where appropriate and that the present application may be practiced otherwise than as specifically described herein. Accordingly, many embodiments of the present application include all variations and equivalents of the subject matter recited in the claims set forth herein, if allowed by law. In addition, any combination of the above-recited elements in all possible variations is covered by the present application unless otherwise indicated herein or otherwise clearly contradicted by context.

All patents, patent applications, patent application publications, and other materials referenced herein, such as papers, books, specifications, publications, documents, and the like, may include any filing history associated therewith, Inconsistencies, or conflicts, or any of these, which may have a limiting effect on the broadest scope of claims currently or subsequently related to this document. By way of example, if there is any discrepancy or conflict between the description, definition and / or use of terms associated with any incorporated data and the description, definition and / or use of terms associated with this document, , Definition and / or use will prevail.

It is understood that the embodiments of the application disclosed herein are illustrative of the principles of the embodiments of the application. Other variations that may be utilized may be within the scope of the present application. Thus, by way of illustration, and not limitation, alternative forms of embodiments of the present application may be utilized in accordance with the teachings herein. Accordingly, the embodiments of the present application are not limited to the embodiments exactly as shown and described.

Various embodiments of the present invention are described above in the detailed description. Although these descriptions are directly representative of the embodiments, those skilled in the art will appreciate that variations and / or variations on the specific embodiments shown and described herein are contemplated. Any such modifications or variations that fall within the scope of this description are also intended to be embraced therein. Unless specifically stated otherwise, the words and phrases in this specification and in the claims are intended by the inventors to provide ordinary and familiar meanings to those skilled in the art.

The foregoing description of the various embodiments of the invention, which are known to the applicant at the time of filing the application, is provided and is intended for purposes of illustration and description. This description is not intended to be exhaustive or is not intended to limit the invention to the precise form disclosed, and many modifications and variations are possible in light of the above teachings. The described embodiments are intended to aid in explaining the principles of the invention and its practical application and to enable those skilled in the art to utilize the invention in various ways to adapt it to various embodiments and the particular applications contemplated. For this reason, the present invention is not intended to be limited to the particular embodiments disclosed for carrying out the invention.

Although specific embodiments of the present invention have been shown and described, changes and modifications can be made without departing from the invention and its broader aspects, on the basis of the teachings herein, and for this reason, It will be apparent to those skilled in the art that variations are encompassed within the true spirit and scope of the present invention.

SEQUENCE LISTING <110> AUTOTELIC LLC TRIEU, Vuong <120> COMPOSITIONS AND METHODS FOR TREATING CANCER <130> 074271-000016WO00 <160> 37 <170> PatentIn version 3.5 <210> 1 <211> 18 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta2 antisense 자이클립 <400> 1 cggcatgtct attttgta 18 <210> 2 <211> 5882 <212> DNA <213> Homo sapiens <220> &Lt; 223 > Homo sapiens transforming growth factor beta 2 (TGFB2), transcript variant 2 <400> 2 gtgatgttat ctgctggcag cagaaggttc gctccgagcg gagctccaga agctcctgac 60 aagagaaaga cagattgaga tagagataga aagagaaaga gagaaagaga cagcagagcg 120 agagcgcaag tgaaagaggc aggggagggg gatggagaat attagcctga cggtctaggg 180 agtcatccag gaacaaactg aggggctgcc cggctgcaga caggaggaga cagagaggat 240 ctattttagg gtggcaagtg cctacctacc ctaagcgagc aattccacgt tggggagaag 300 ccagcagagg ttgggaaagg gtgggagtcc aagggagccc ctgcgcaacc ccctcaggaa 360 taaaactccc cagccagggt gtcgcaaggg ctgccgttgt gatccgcagg gggtgaacgc 420 aaccgcgacg gctgatcgtc tgtggctggg ttggcgtttg gagcaagaga aggaggagca 480 ggagaaggag ggagctggag gctggaagcg tttgcaagcg gcggcggcag caacgtggag 540 taaccaagcg ggtcagcgcg cgcccgccag ggtgtaggcc acggagcgca gctcccagag 600 caggatccgc gccgcctcag cagcctctgc ggcccctgcg gcacccgacc gagtaccgag 660 cgccctgcga agcgcaccct cctccccgcg gtgcgctggg ctcgccccca gcgcgcgcac 720 acgcacacac acacacacac acacacacgc acgcacacac gtgtgcgctt ctctgctccg 780 gagctgctgc tgctcctgct ctcagcgccg cagtggaagg caggaccgaa ccgctccttc 840 tttaaatata taaatttcag cccaggtcag cctcggcggc ccccctcacc gcgctcccgg 900 cgcccctccc gtcagttcgc cagctgccag ccccgggacc ttttcatctc ttcccttttg 960 gccggaggag ccgagttcag atccgccact ccgcacccga gactgacaca ctgaactcca 1020 cttcctcctc ttaaatttat ttctacttaa tagccactcg tctctttttt tccccatctc 1080 attgctccaa gaattttttt cttcttactc gccaaagtca gggttccctc tgcccgtccc 1140 gtattaatat ttccactttt ggaactactg gccttttctt tttaaaggaa ttcaagcagg 1200 atacgttttt ctgttgggca ttgactagat tgtttgcaaa agtttcgcat caaaaacaac 1260 aacaacaaaa aaccaaacaa ctctccttga tctatacttt gagaattgtt gatttctttt 1320 ttttattctg acttttaaaa acaacttttt tttccacttt tttaaaaaat gcactactgt 1380 gtgctgagcg cttttctgat cctgcatctg gtcacggtcg cgctcagcct gtctacctgc 1440 agcacactcg atatggacca gttcatgcgc aagaggatcg aggcgatccg cgggcagatc 1500 ctgagcaagc tgaagctcac cagtccccca gaagactatc ctgagcccga ggaagtcccc 1560 ccggaggtga tttccatcta caacagcacc agggacttgc tccaggagaa ggcgagccgg 1620 agggcggccg cctgcgagcg cgagaggagc gacgaagagt actacgccaa ggaggtttac 1680 aaaatagaca tgccgccctt cttcccctcc gaaaatgcca tcccgcccac tttctacaga 1740 ccctacttca gaattgttcg atttgacgtc tcagcaatgg agaagaatgc ttccaatttg 1800 gtgaaagcag agttcagagt ctttcgtttg cagaacccaa aagccagagt gcctgaacaa 1860 cggattgagc tatatcagat tctcaagtcc aaagatttaa catctccaac ccagcgctac 1920 atcgacagca aagttgtgaa aacaagagca gaaggcgaat ggctctcctt cgatgtaact 1980 gatgctgttc atgaatggct tcaccataaa gacaggaacc tgggatttaa aataagctta 2040 cactgtccct gctgcacttt tgtaccatct aataattaca tcatcccaaa taaaagtgaa 2100 gaactagaag caagatttgc aggtattgat ggcacctcca catataccag tggtgatcag 2160 aaaactataa agtccactag gaaaaaaaac agtgggaaga ccccacatct cctgctaatg 2220 ttattgccct cctacagact tgagtcacaa cagaccaacc ggcggaagaa gcgtgctttg 2280 gatgcggcct attgctttag aaatgtgcag gataattgct gcctacgtcc actttacatt 2340 gatttcaaga gggatctagg gtggaaatgg atacacgaac ccaaagggta caatgccaac 2400 ttctgtgctg gagcatgccc gtatttatgg agttcagaca ctcagcacag cagggtcctg 2460 agcttatata ataccataaa tccagaagca tctgcttctc cttgctgcgt gtcccaagat 2520 ttagaacctc taaccattct ctactacatt ggcaaaacac ccaagattga acagctttct 2580 aatatgattg taaagtcttg caaatgcagc taaaattctt ggaaaagtgg caagaccaaa 2640 atgacaatga tgatgataat gatgatgacg acgacaacga tgatgcttgt aacaagaaaa 2700 cataagagag ccttggttca tcagtgttaa aaaatttttg aaaaggcggt actagttcag 2760 acactttgga agtttgtgtt ctgtttgtta aaactggcat ctgacacaaa aaaagttgaa 2820 ggccttattc tacatttcac ctactttgta agtgagagag acaagaagca aatttttttt 2880 aaagaaaaaa ataaacactg gaagaattta ttagtgttaa ttatgtgaac aacgacaaca 2940 acaacaacaa caacaaacag gaaaatccca ttaagtggag ttgctgtacg taccgttcct 3000 atcccgcgcc tcacttgatt tttctgtatt gctatgcaat aggcaccctt cccattctta 3060 ctcttagagt taacagtgag ttatttattg tgtgttacta tataatgaac gtttcattgc 3120 ccttggaaaa taaaacaggt gtataaagtg gagaccaaat actttgccag aaactcatgg 3180 atggcttaag gaacttgaac tcaaacgagc cagaaaaaaa gaggtcatat taatgggatg 3240 aaaacccaag tgagttatta tatgaccgag aaagtctgca ttaagataaa gaccctgaaa 3300 acacatgtta tgtatcagct gcctaaggaa gcttcttgta aggtccaaaa actaaaaaga 3360 ctgttaataa aagaaacttt cagtcagaat aagtctgtaa gttttttttt ttctttttaa 3420 ttgtaaatgg ttctttgtca gtttagtaaa ccagtgaaat gttgaaatgt tttgacatgt 3480 actggtcaaa cttcagacct taaaatattg ctgtatagct atgctatagg ttttttcctt 3540 tgttttggta tatgtaacca tacctatatt attaaaatag atggatatag aagccagcat 3600 aattgaaaac acatctgcag atctcttttg caaactatta aatcaaaaca ttaactactt 3660 tatgtgtaat gtgtaaattt ttaccatatt ttttatattc tgtaataatg tcaactatga 3720 tttagattga cttaaatttg ggctcttttt aatgatcact cacaaatgta tgtttctttt 3780 agctggccag tacttttgag taaagcccct atagtttgac ttgcactaca aatgcatttt 3840 ttttttaata acatttgccc tacttgtgct ttgtgtttct ttcattatta tgacataagc 3900 tacctgggtc cacttgtctt ttcttttttt tgtttcacag aaaagatggg ttcgagttca 3960 gtggtcttca tcttccaagc atcattacta accaagtcag acgttaacaa atttttatgt 4020 taggaaaagg aggaatgtta tagatacata gaaaattgaa gtaaaatgtt ttcattttag 4080 caaggattta gggttctaac taaaactcag aatctttatt gagttaagaa aagtttctct 4140 accttggttt aatcaatatt tttgtaaaat cctattgtta ttacaaagag gacacttcat 4200 aggaaacatc tttttcttta gtcaggtttt taatattcag ggggaaattg aaagatatat 4260 attttagtcg atttttcaaa aggggaaaaa agtccaggtc agcataagtc attttgtgta 4320 tttcactgaa gttataaggt ttttataaat gttctttgaa ggggaaaagg cacaagccaa 4380 tttttcctat gatcaaaaaa ttctttcttt cctctgagtg agagttatct atatctgagg 4440 ctaaagttta ccttgcttta ataaataatt tgccacatca ttgcagaaga ggtatcctca 4500 tgctggggtt aatagaatat gtcagtttat cacttgtcgc ttatttagct ttaaaataaa 4560 aattaatagg caaagcaatg gaatatttgc agtttcacct aaagagcagc ataaggaggc 4620 gggaatccaa agtgaagttg tttgatatgg tctacttctt ttttggaatt tcctgaccat 4680 taattaaaga attggatttg caagtttgaa aactggaaaa gcaagagatg ggatgccata 4740 atagtaaaca gcccttgtgt tggatgtaac ccaatcccag atttgagtgt gtgttgatta 4800 tttttttgtc ttccactttt ctattatgtg taaatcactt ttatttctgc agacattttc 4860 ctctcagata ggatgacatt ttgttttgta ttattttgtc tttcctcatg aatgcactga 4920 taatatttta aatgctctat tttaagatct cttgaatctg tttttttttt ttttaatttg 4980 ggggttctgt aaggtcttta tttcccataa gtaaatattg ccatgggagg ggggtggagg 5040 tggcaaggaa ggggtgaagt gctagtatgc aagtgggcag caattatttt tgtgttaatc 5100 agcagtacaa tttgatcgtt ggcatggtta aaaaatggaa tataagatta gctgttttgt 5160 attttgatga ccaattacgc tgtattttaa cacgatgtat gtctgttttt gtggtgctct 5220 agtggtaaat aaattatttc gatgatatgt ggatgtcttt ttcctatcag taccatcatc 5280 gagtctagaa aacacctgtg atgcaataag actatctcaa gctggaaaag tcataccacc 5340 tttccgattg ccctctgtgc tttctccctt aaggacagtc acttcagaag tcatgcttta 5400 aagcacaaga gtcaggccat atccatcaag gatagaagaa atccctgtgc cgtcttttta 5460 ttcccttatt tattgctatt tggtaattgt ttgagattta gtttccatcc agcttgactg 5520 ccgaccagaa aaaatgcaga gagatgtttg caccatgctt tggctttctg gttctatgtt 5580 ctgccaacgc cagggccaaa agaactggtc tagacagtat cccctgtagc cccataactt 5640 ggatagttgc tgagccagcc agatataaca agagccacgt gctttctggg gttggttgtt 5700 tgggatcagc tacttgcctg tcagtttcac tggtaccact gcaccacaaa caaaaaaacc 5760 caccctattt cctccaattt ttttggctgc tacctacaag accagactcc tcaaacgagt 5820 tgccaatctc ttaataaata ggattaataa aaaaagtaat tgtgactcaa aaaaaaaaaa 5880 aa 5882 <210> 3 <211> 17 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 3 caaagtattt ggtctcc 17 <210> 4 <211> 17 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 4 acctccttgg cgtagta 17 <210> 5 <211> 17 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 5 acctccttgg cgtagta 17 <210> 6 <211> 16 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 6 cctccttggc gtagta 16 <210> 7 <211> 16 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 7 cctccttggc gtagta 16 <210> 8 <211> 15 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 8 ctccttggcg tagta 15 <210> 9 <211> 15 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 9 ctccttggcg tagta 15 <210> 10 <211> 15 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 10 ctccttggcg tagta 15 <210> 11 <211> 14 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 11 tccttggcgt agta 14 <210> 12 <211> 13 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 12 cagaagttgg cat 13 <210> 13 <211> 13 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 13 cagaagttgg cat 13 <210> 14 <211> 12 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 14 ctgcccgcgg at 12 <210> 15 <211> 13 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 15 tctgcccgcg gat 13 <210> 16 <211> 14 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 16 tcgcgctcgc aggc 14 <210> 17 <211> 15 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 17 ggatctgccc gcgga 15 <210> 18 <211> 15 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 18 ggatctgccc gcgga 15 <210> 19 <211> 16 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 19 cgatcctctt gcgcat 16 <210> 20 <211> 13 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 20 ggcgggatgg cat 13 <210> 21 <211> 14 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 21 gaccagatgc agga 14 <210> 22 <211> 17 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 22 cttgctcagg atctgcc 17 <210> 23 <211> 13 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 23 tctgtaggag ggc 13 <210> 24 <211> 17 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 24 ccttaagcca tccatga 17 <210> 25 <211> 17 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 25 tctgaactag taccgcc 17 <210> 26 <211> 17 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 26 tactattatg gcatccc 17 <210> 27 <211> 17 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 27 agcgtaattg gtcatca 17 <210> 28 <211> 16 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 28 gcgaccgtga ccagat 16 <210> 29 <211> 16 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 29 aactagtacc gccttt 16 <210> 30 <211> 14 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 30 gcgcgaccgt gacc 14 <210> 31 <211> 14 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 31 accactagag cacc 14 <210> 32 <211> 13 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 32 agcgcgaccg tga 13 <210> 33 <211> 13 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 33 ggatcgcctc gat 13 <210> 34 <211> 13 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 34 ctagtaccgc ctt 13 <210> 35 <211> 12 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 35 ccgcggatcg cc 12 <210> 36 <211> 14 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 36 gaccgtgacc agat 14 <210> 37 <211> 14 <212> DNA <213> Artificial Sequence <220> Synthetically constructed human TGF-beta antisense 자이클립 <400> 37 gaccgtgacc agat 14

Claims

A method for sensitizing a tumor to an anti-tumor therapy in a subject in need of treatment, comprising:
i) providing a TGFβ2 signaling inhibitor; And
ii) administering an effective amount of the inhibitor to sensitize the tumor to the anti-tumor therapy.

A method for treating cancer, inhibiting cancer or preventing cancer metastasis in a subject in need of treatment, comprising:
i) sensitizing the tumor in the subject by the method of claim 1; And
ii) administering an effective amount of a therapeutic agent to treat cancer, to inhibit cancer, or to prevent cancer metastasis in an individual;

CLAIMS What is claimed is: 1. A method for reducing tumor burden in a subject in need of treatment comprising:
i) sensitizing the tumor in the subject by the method of claim 1; And
ii) administering an effective amount of a therapeutic agent to reduce tumor burden in an individual.

The method according to claim 1, wherein the tumor is melanoma or pancreatic cancer.

5. The method of claim 4, wherein the TGFβ2 signaling inhibitor is any one or more of a small molecule, a peptide, a protein, an aptamer, an antibody or fragment thereof, or a nucleic acid molecule.

6. The method of claim 5, wherein the nucleic acid molecule is an antisense oligonucleotide.

The method of claim 6, wherein the TGFβ2-specific antisense oligonucleotide is a first generation antisense oligonucleotide comprising a sulfur group (phosphorothioate), a methyl group (methylphosphonate) or an amine (phosphoramidate) How to.

The method of claim 6, wherein the TGF beta 2 -specific antisense oligonucleotide is a second generation antisense oligonucleotide comprising 2'-O-methyl (2'-OME) or 2'-O-methylethyl (2'-MOE) Lt; / RTI >

7. The method of claim 6, wherein the TGF beta 2 -specific antisense oligonucleotide is a third generation antisense oligonucleotide comprising a locked nucleic acid (LNA), a peptide nucleic acid (PNA), or a morpholino phosphoramidate (MF) .

7. The method of claim 6, wherein the TGFβ2-specific antisense oligonucleotide comprises the sequence 5'-CGGCATGTCTATTTTGTA-3 'as set forth in SEQ ID NO: 1.

11. The method of claim 10, wherein the TGFβ2-specific antisense oligonucleotide is administered sequentially with a therapeutic agent, wherein the therapeutic agent is any one or more of a chemotherapeutic agent, radiation therapy, or a combination thereof .

12. The method of claim 11, wherein the TGFβ2-specific antisense oligonucleotide is administered prior to administration of a chemotherapeutic agent, radiation therapy, or a combination thereof.

The method according to claim 12, wherein the chemotherapeutic agent is selected from the group consisting of Dakar Vazine, 5-fluorouracil, polynic acid, oxaliplatin, paclitaxel, mitomycin, capecitabine, gemcitabine, fluorouracil, eloxatin, oxaliplatin, Nip, oxaliplatin, 5-Fu, erlotinib, or a combination thereof.

The method of claim 12, wherein the chemotherapeutic agent is selected from the group consisting of radiotherapy 20 Gy, carboplatin, paclitaxel, vindesine, eicilimumab, stereotactic radiotherapy, Mek 162, carboplatin and paclitaxel, , Radiation therapy 36gy, or a combination thereof.

The method according to claim 1, an effective amount of the inhibitor is 50-100mg / m ² / day, 100-150mg / m ² / day, 150-200mg / m ² / day 200-250mg / m ² / day, 250-300mg / m ² / day, 300-350mg / m ² / day, 350-400mg / m ² / day, 400-450mg / m ² / day, 450-500mg / m ² / day, or any one or the combination thereof from the Or more.

The method according to claim 1, wherein the effective amount of the inhibitor is administered intravenously.

The method of claim 1, wherein the inhibitor is administered at a 4 day ON and 10 day off cycle.

18. The method of claim 17, wherein the TGFβ2-specific antisense oligonucleotide is administered for one, two, three, four or five cycles prior to administration of a chemotherapeutic agent, radiation therapy, or a combination thereof. .

The method of claim 1, wherein the subject is a human.