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Title:  Method for treating diseases associated with abnormal kinase activity
United States Patent: 
6,998,391
Issued: 
February 14, 2006
Inventors: 
Lyons; John (Moraga, CA); Rubinfeld; Joseph (Danville, CA)
Assignee:
 SuperGen.Inc. (Dublin, CA)
Appl. No.: 
206854
Filed:  July 26, 2002


 

Covidien Pharmaceuticals Outsourcing


Abstract

Methods are provided for treating diseases associated with abnormal activity of kinases. The method comprises: administering a DNA methylation inhibitor to the patient in therapeutically effective amount; and administering a kinase inhibitor to the patient in therapeutically effective amount, such that the in vivo activity of the kinase is reduced relative to that prior to the treatment. The method can be used to treat cancer associated with abnormal activity of kinases such as phosphatidylinositol 3′-kinase (PI3K), protein kinases including serine/threonine kinases such as Raf kinases, protein kinase kinases such as MEK, and tyrosine kinases such as those in the epidermal growth factor receptor family (EGFR), platelet-derived growth factor receptor family (PDGFR), vascular endothelial growth factor receptor (VEGFR) family, nerve growth factor receptor family (NGFR), fibroblast growth factor receptor family (FGFR) insulin receptor family, ephrin receptor family, Met family, Ror family, c-kit family, Src family, Fes family, JAK family, Fak family, Btk family, Syk/ZAP-70 family, and Ab1 family.

Description of the Invention

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to methods, compositions, and kits for treating diseases associated with abnormal protein kinase activity, and more particularly for treating cancer associated with abnormal protein tyrosine kinase activity, such as chronic myelogenous leukemia.

2. Description of Related Art

Chronic Myelogenous Leukemia (CML) is a myeloproliferative disorder of a pluripotent hematopoietic stem cell with a particular cytogenetic abnormality, the Philadelphia chromosome. Faderl et al (1999) Ann. Intern. Med. 131: 207-219. In childhood, it accounts for only 2 to 5% of all malignant disorders and presents as either of two distinct clinical entities, adult-type CML and juvenile CML. Adult-type CML of childhood is indistinguishable from that seen in older patients. However, juvenile CML is restricted to children and is Philadelphia chromosome negative. Grier and Civin (1998) in (Nathan and Oski, eds) Hematology of Infancy and Childhood, volume 2, 5th ed, W. B. Saunders Company, 34:1286-1459.

CML is a progressive, uniformly fatal disease in untreated patients. It is characterized by three distinct phases: a chronic phase lasting three to five years; an acute or accelerated phase lasting three to six months; and a brief blastic crisis phase. The progression of the disease to blast crisis results in rapid death due to infections, bleeding and leukemic organ infiltration.

Philadelphia chromosome, the characteristic cytogenetic abnormality of CML, results from a reciprocal chromosomal translocation, t(9;22)(q34;q11), in a hematopoietic stem cell. This translocation produces a fusion gene, termed Bcr-Abl, created by the juxtaposition of the abelson murine leukemia (Abl) protooncogene on chromosome 9 with a portion of the breakpoint cluster region (Bcr) gene on chromosome 22. The Bcr-Abl fusion protein's leukomogenic potential is derived from its constitutively activated tyrosine kinase activity, which causes a perturbation of stem cell function through unclear mechanisms. This activity results in interference with basic cellular processes, such as control of proliferation, adherence, and physiological death. More advanced stages of CML are also characterized by aberrant methylation of multiple genes, including the p15/Ink-4b cell-cycle regulator gene. Cortes et al (1997) Baillieres Clin Haematol 10(2):277-90. Aberrations in DNA methylation, whether general or site specific, are common in cancer and have important roles in tumor initiation, progression and resistance. Lubbert et al (2001) Br J Haematol 114(2):349-357.

Until recently, standard therapy for chronic phase CML consisted of conventional chemotherapy, interferon-alpha (with or without Ara-C), donor lymphocyte infusions and allergenic bone marrow transplantation, each offering different risk-benefit trade-offs.

Overall, available data suggests the view that allergenic bone marrow transplantation offers to eligible patients (children and young adults with an human leukocyte antigen-matched sibling donor) their best prospect for cure. However, bone marrow transplantation has certain limitations i.e., the availability of a suitable donor (10-40%), the risk of graft-vs.-host disease (8-60%) and a high rate of transplant-related mortality (20-40%).

Long-term follow-up of patients treated in large-scale randomized trials utilizing one or two of the above therapeutic modalities has shown a significant correlation between cytogenetic responses and prolonged survival. Silver et al (1999) Blood 94:1517-1536.

Imatinib mesylate is one of the recent therapeutic breakthroughs in the treatment of CML. Imatinib mesylate is a small molecule inhibitor of tyrosine kinase activity that results in a high response rate in CML. In the pivotal Phase II studies, nearly all patients (88%) with chronic phase CML achieved a complete hematologic response, and nearly half (49%) had a major cytogenetic response. Imatinib mesylate produced remissions in 63% of accelerated phase CML patients and 26% of blast phase patients. A complete cytogenetic response was seen in 30% of chronic phase CML, 14% of accelerated phase CML, and 5% of blast phase CML patients and was maintained for four weeks in 16%, 4%, and 1%, respectively. Novartis, Gleevec package insert T-2001-14 90012401.

Imatinib mesylate was approved by the FDA in May 2001 for the treatment of CML in all phases (after failure of interferon in the chronic phase). However, in blast phase CML, the responses to imatinib mesylate are usually of very short duration, and most patients manifest resistant/refractory disease within six months of therapy. Druker et al (2001) N. Engl. J. Med. 344: 1038-1042. Resistance to imatinib mesylate was associated with reactivation of Bcr-Abl and could be conferred by a single point substitution of threonine for isoleucine in the tyrosine kinase. Gorre et al (2001) Science 293: 2163. Consequently, there exists a need for compositions and methods for treating CML patients who are resistant to imatinib mesylate.

SUMMARY OF THE INVENTION

The present invention provides compositions, kits and methods for treat a host, preferably human, having or predisposed to a disease associated with abnormal activity of protein kinase. In general, a DNA methylation inhibitor is administered to the host in combination with a protein kinase inhibitor such that the onset or progression of the disease is retarded. The DNA methylation inhibitor may exert its therapeutic effect(s) via reestablishment of transcriptional activity of disease-suppressing genes which may further inhibit the activity of the protein kinase. By using such a combination therapy, the activity of not only the protein kinase itself but also other proteins which participate in the upstream or downstream signal transduction of the protein kinase may be efficiently and synergistically inhibited by controlling expression of genes encoding these proteins through DNA hypomethylation, thus leading to more efficacious treatment of the disease.

In one aspect of the present invention, a method is provided for treating a patient with a protein tyrosine kinase inhibitor imatinib mesylate in combination with a DNA methylation inhibitor. The method is preferably directed to a patient that has a degree of resistance to imatinib mesylate, the resistance being mitigated by the administration of the DNA methylation inhibitor. In particular, the method is directed to treating a disease state associated with activity of protein tyrosine kinase such as oncoprotein Bcr-Abl involved in chronic myelogenous leukemia (CML), platelet-derived growth factor (PDGF) receptor involved in prostate cancer and glioblastoma, and c-Kit involved in gastrointestinal stromal tumor (GIST) and small cell lung cancer (SCLC), as well as other types of cancer, where the combination treatment using imatinib mesylate and a DNA methylation inhibitor is synergistic.

In one embodiment, the method comprises: administering to the patient imatinib mesylate and a DNA methylation inhibitor.

In another embodiment, the method comprises: administering to the patient having chronic myelogenous leukemia imatinib mesylate and a DNA methylation inhibitor.

In another embodiment, a method is provided for treating a patient having chronic myelogenous leukemia comprising: administering to a patient having chronic myelogenous leukemia and a degree of resistance to imatinib mesylate, a therapeutically effective amount of a DNA methylation inhibitor which mitigates the imatinib mesylate resistance.

In one variation, the patient has already manifested resistance to imatinib mesylate within 6 months of the treatment with imatinib mesylate as defined by no improvement in the prognosis or worsening of the prognosis.

In another aspect of the invention, a method is provided for treating a CML patient who is intolerant of imatinib mesylate treatment. The method comprises: administering to a patient having chronic myelogenous leukemia and manifesting intolerance to imatinib mesylate, a therapeutically effective amount of a DNA methylation inhibitor which mitigates the imatinib mesylate intolerance or the CML phenotype.

In one variation, the patient has already manifested intolerance to imatinib mesylate within 6 months of the treatment with imatinib mesylate as defined by manifesting a symptom selected from the group consisting of hepatoxicity, fluid retention syndrome, neutropenia, hemorrhage, dyspepsia, dyspnea, diarrhea, muscle cramps, skin rash, fatigue, headache, nausea, vomiting, and thrombocytopenia.

In yet another aspect of the invention, a method is provided for treating a patient having chronic myelogenous leukemia and resistant to imatinib mesylate treatment. The method comprises: administering to the patient imatinib mesylate and a DNA methylation inhibitor such that the patient's resistance to imatinib mesylate in the absence of the DNA methylation inhibitor is reduced.

In another embodiment, a method is provided for treating a patient having chronic myelogenous leukemia, comprising: administering to a patient in blast phase of chronic myelogenous leukemia a therapeutically effective amount of a DNA methylation inhibitor.

According to any of the above methods for treating chronic myelogenous leukemia, the patient's chronic myelogenous leukemia is optionally staged prior to administration. Staging the patient having chronic myelogenous leukemia optionally includes determining the number of blasts, promyelocytes, basophil, and platelets per liter of peripheral blood or bone marrow. Optionally, staging the patient having chronic myelogenous leukemia may include counting of the concentration of BCR/Abl positive cells in bone marrow and/or peripheral blood.

Also according to any of the above methods for treating chronic myelogenous leukemia, the DNA methylation inhibitor is optionally administered to the patient in the blast, chronic or accelerated phase of chronic myelogenous leukemia. In one variation, the method is performed when the patient in blast phase of chronic myelogenous leukemia has more than 30% blasts in peripheral blood or bone marrow.

Also according to any of the above methods for treating chronic myelogenous leukemia, the DNA methylation inhibitor may be administered by a variety of routes, including but not limited to orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, or intrathecally.

According to any of the above methods, it is noted that administering imatinib mesylate and the DNA methylation inhibitor to the patient may comprise administering imatinib mesylate to the patient for a period of time prior to the administration of the DNA methylation inhibitor, administering the DNA methylation inhibitor to the patient for a period of time prior to the administration of imatinib mesylate, or initiating administration of the DNA methylation inhibitor and imatinib mesylate to the patient at the same time. It is noted that the method may also comprise administering imatinib mesylate and the DNA methylation inhibitor to the patient at the same time for at least a portion of the time that the drugs are administered.

According to any of the above methods, in one variation, imatinib mesylate is administered to the patient at a dose of 100-800 mg/day, optionally at a dose of 200-400 mg/day, and optionally at a dose of 500-800 mg/day. Such administrations may optionally last for a period of at least 2, 4, 6, 8, 10 or more days.

Also according to any of the above methods, in one variation, the DNA methylation inhibitor is administered to the patient via an intravenous infusion per day at a dose ranging from 1 to 100 mg/m2, optionally at a dose ranging from 2 to 50 mg/m2, and optionally at a dose ranging from 5 to 20 mg/m2.

Also according to any of the above methods, in one variation, the DNA methylation inhibitor is administered to the patient subcutaneously at a dose ranging from 0.01 to 1 mg/Kg, optionally at a dose ranging from 0.1 to 0.5 mg/Kg at least once a week for at least 4 weeks, optionally at a dose ranging from 0.1 to 0.3 mg/Kg twice a week for at least 4 weeks, and optionally at a dose of 0.2 mg/Kg twice a week for 6 weeks, drug-free for two weeks, and then at a dose of 0.2 mg/Kg twice a week until the clinical endpoint(s) is achieved.

Also according to any of the above methods, the DNA methylation inhibitor may optionally be a cytidine analog such as cytosine arabinoside. In one variation, the cytidine analog is decitabine.

In one particular variation, the DNA methylation inhibitor is decitabine and is administered intravenously or subcutaneously. In a further particular variation, decitabine is administered to the patient via an intravenous infusion per day at a dose ranging from 1 to 100 mg/m2, optionally ranging from 2 to 50 mg/m2 and optionally ranging from 5 to 20 mg/m2.

In one example, decitabine is administered to the patient via an intravenous infusion per day for at least 3 days per treatment cycle at a dose ranging from 1 to 100 mg/m2. In a further example, decitabine is administered to the patient via an intravenous infusion at a dose ranging from 5 to 20 mg/m2 for 1 hour per day for 5 consecutive days for 2 weeks per treatment cycle.

Compositions are also provided. In one embodiment, a composition is provided that comprises a DNA methylation inhibitor and imatinib mesylate. The DNA methylation inhibitor may optionally be a cytidine analog such as cytosine arabinoside. In one variation, the cytidine analog is decitabine. In another variation, the composition is formulated for intravenous, inhalation, oral, or subcutaneous administration.

In yet another aspect of the invention, a method is provided for treating a disease associated with abnormal activity of a kinase in vivo. The method comprises: administering a DNA methylation inhibitor to a patient having a disease associated with abnormal activity of a kinase in vivo; and administering a kinase inhibitor to the patient. The DNA methylation inhibitor and the kinase inhibitor are administered in therapeutically effective amounts, preferably in therapeutically effective and synergistic amounts.

The kinase may be an enzyme that can catalyze phosphorylation of a molecule such as a protein or a nucleic acid. Preferably, the kinase may be a protein kinase such as a tyro sine kinase, a serine/threonine kinase and a protein kinase kinase.

The disease associated with abnormal kinase activity may be any pathological condition that is directly or indirectly caused by elevated levels or enhanced enzymatic activity of kinase as compared with those indexes under a normal physiological condition. Examples of the pathological condition include but are not limited to inflammation, benign tumors, malignant tumors, leukemia, asthma, allergy-associated chronic rhinitis, autoimmune diseases and mastolocytosis. Particularly, the pathological condition is cancer.

The DNA methylation inhibitor may be a cytidine analog such as cytosine arabinoside and decitabine. Particularly, the DNA methylation inhibitor is decitabine.

The DNA methylation inhibitor may be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, subcutaneously, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, or intrathecally.

In a preferred embodiment, the DNA methylation inhibitor is decitabine and is administered intravenously, intramuscularly, subcutaneously, orally, or via inhalation.

The kinase inhibitor may be in a form of chemical compound, protein, peptide, enzyme, antibody, antisense fragment, antisense fragment linked to enzyme, or antisense fragment linked to peptide.

The kinase inhibitor may be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, or intrathecally.

The kinase inhibitor may inhibit the enzymatic activity or gene expression activity of a kinase. Gene expression activity of a kinase includes, but is not limited to, transcriptional activity such as binding of transcription factor(s) to the promoter region of the kinase gene and transcribing mRNA, translational activity such as production of the kinase, and post-translational activity such as proteolytic processing of the precursor of the kinase, and differential expression of endogenenous inhibitors of the kinase.

In one variation, the kinase is a serine/threonine kinase such as a Raf kinase; and the kinase inhibitor is BAY 43-9006.

In another variation, the kinase is a protein kinase kinase such as an Raf-mitogen-activated protein kinase kinase (MEK) and protein kinase B (Akt) kinase.

In yet another variation, the kinase is an extracellular signal-regulated kinase (ERK). Examples of the inhibitor of ERK include but are not limited to PD98059, PD184352, and U0126.

In yet another variation, the kinase is a phosphatidylinositol 3′-kinase (PI3K). Examples of the inhibitor of PI3K include but are not limited to LY294002.

In a particular variation, the kinase is a tyrosine kinase. The tyrosine kinase may be a receptor tyrosine kinase and non-receptor tyrosine kinase.

Examples of the receptor tyrosine kinase include, but are not limited to, epidermal growth factor receptor family (EGFR), platelet-derived growth factor receptor (PDGFR) family, vascular endothelial growth factor receptor (VEGFR) family, nerve growth factor receptor (NGFR) family, fibroblast growth factor receptor family (FGFR) insulin receptor family, ephrin receptor family, Met family, and Ror family.

Examples of the epidermal growth factor receptor family include, but are not limited to, HER1, HER2/neu, HER3, and HER4.

Examples of the inhibitors of epidermal growth factor receptor family include, but are not limited to, HERCEPTIN®, ZD1839 (IRESSA®), PD168393, CI1033, IMC-C225, EKB-569, and inhibitors binding covalently to Cys residues of the receptor tyrosine kinase.

Examples of diseases associated with abnormal activity of the epidermal growth factor receptor family, include, but are not limited to, epithelial tumor, carcinoma, carcinoma of upper aerodigestive tract, lung cancer, and non-small cell lung cancer.

Examples of the vascular endothelial growth factor receptor family include, but are not limited to, VEGFR1, VEGFR2, and VEGFR3.

An example of the inhibitor of the vascular endothelial growth factor receptor family includes, but is not limited to, SU6668.

Examples of the disease associated with abnormal activity of the vascular endothelial growth factor receptor family include, but are not limited to, solid and metastasis-prone tumors.

Examples of the nerve growth factor receptor family include, but are not limited to, trk, trkB and trkC.

Examples of the inhibitors of the nerve growth factor receptor family include, but are not limited to, CEP-701, CEP-751, and indocarbazole compound.

Examples of the diseases associated with abnormal activity of the nerve growth factor receptor family include, but are not limited to, prostate, colon, papillary and thyroid cancers, neuromas and osteoblastomas.

Examples of the Met family include, but are not limited to, Met, TPR-Met, Ron, c-Sea, and v-Sea.

Examples of disease associated with activity of the receptor tyrosine kinase from Met family include, but are not limited to, invasively in-growing tumor, carcinoma, papillary carcinoma of thyroid gland, colon, carcinoma, renal carcinoma, pancreatic carcinoma, ovarian carcinoma, head and neck squamous carcinoma.

Examples of the non-receptor tyrosine kinase include, but are not limited to, c-kit family, Src family, Fes family, JAK family, Fak family, Btk family, Syk/ZAP-70 family, and Abl family.

Examples of the non-receptor tyrosine kinases from the Src family include, but are not limited to, Src, c-Src, v-Src, Yes, c-Yes, v-Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, c-Fgr, v-Fgr, p561ck, Tk1, Csk, and Ctk.

Examples of the inhibitors of the non-receptor tyrosine kinase from the Src family include, but are not limited to, SU101 and CGP 57418B.

Examples of the diseases associated with activity of the non-receptor tyrosine kinase from the Src family include, but are not limited to, breast cancer, carcinoma, myeloma, leukemia, and neuroblastoma.

Examples of the non-receptor tyrosine kinases from the Fes family include, but are not limited to, c-fes/fps, v-fps/fes, p94-c-fes-related protein, and Fer.

Examples of the diseases associated with activity of the non-receptor tyrosine kinase from the Fes family include, but are not limited to, tumor of mesenchymal origin and tumor of hematopoietic origin.

Examples of the non-receptor tyrosine kinases from the JAK family include, but are not limited to, Jak1, Jak2, Tyk2, and Jak3.

Examples of the inhibitors of the non-receptor tyrosine kinase from the JAK family include, but are not limited to, tyrphostin, member of CIS/SOCS/Jab family, synthetic component AG490, dimethoxyquinazoline compound, 4-(phenyl)-amino-6,7-dimethoxyquinazoline, 4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline, 4-(3′-bromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline, and 4-(3′,5′-dibromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline.

Examples of the diseases associated with activity of the non-receptor tyrosine kinase from JAK family include, but are not limited to, tumor of mesenchymal origin and tumor of hematopoietic origin.

Examples of the non-receptor tyrosine kinases from the Fak family include, but are not limited to, Fak and CAKβ/Pyk2/RAFTK.

Examples of the inhibitors of the non-receptor tyrosine kinases from the Fak family include, but are not limited to, a dominant negative mutant S1034-FRNK; a metabolite FTY720 from Isaria sinclarii, and FAK antisense oligonucleotide ISIS 15421.

Examples of the diseases associated with abnormal activity of the non-receptor tyrosine kinases from Fak family include, but are not limited to, human carcinoma, metastasis-prone tumor, and tumor of hematopoietic origin.

Examples of the non-receptor tyrosine kinase from the Btk family include, but are not limited to, Btk/Atk, Itk/Emt/Tsk, Bmx/Etk, and Itk, Tec, Bmx, and Rlk.

Examples of the inhibitors of the non-receptor tyrosine kinases from Btk family include, but are not limited to, alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide.

Examples of the diseases associated with abnormal activity of the non-receptor tyrosine kinase from the Btk family include, but are not limited to, B-lineage leukemia and lymphoma.

Examples of the non-receptor tyrosine kinases from the Syk/ZAP-70 family include, but are not limited to, Syk and ZAP-70.

Examples of the inhibitors of the non-receptor tyrosine kinases from the Syk/ZAP-70 family include, but are not limited to, piceatannol, 3,4-dimethyl-10-(3-aminopropyl)-9-acridone oxalate, acridone-related compound, Lys-Leu-Ile-Leu-Phe-Leu-Leu-Leu [SEQ ID NO: 1] peptide, and peptide containing Lys-Leu-Ile-Leu-Phe-Leu-Leu-Leu motif.

Examples of the diseases associated with abnormal activity of the non-receptor tyrosine kinases from the Syk/ZAP-70 family include, but are not limited to, benign breast cancer, breast cancer, and tumor of mesenchymal origin.
 

Claim 1 of 20 Claims

1. A method for treating a patient having a disease selected from the group consisting of inflammation, benign tumors, malignant tumors, leukemia, asthma, allergy-associated chronic rhinitis, autoimmune diseases and mastolocytosis, comprising:

administering decitabine to the patient in therapeutically effective amount; and

administering a tyrosine kinase inhibitor to the patient in therapeutically effective amount, such that the in viva activity of the tyrosine kinase is reduced relative to that prior to the treatment, wherein said tyrosine kinase is an epidermal growth factor receptor.

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