WO2010021843A1 - Use of antifolates in patients with detectable levels of tff-1 for the cancer treatment - Google Patents

Use of antifolates in patients with detectable levels of tff-1 for the cancer treatment Download PDF

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WO2010021843A1
WO2010021843A1 PCT/US2009/052823 US2009052823W WO2010021843A1 WO 2010021843 A1 WO2010021843 A1 WO 2010021843A1 US 2009052823 W US2009052823 W US 2009052823W WO 2010021843 A1 WO2010021843 A1 WO 2010021843A1
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mir
hsa
cancer
patient
method
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PCT/US2009/052823
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French (fr)
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Lawrence Mark Gelbert
Shuyu Li
Brian Paul Mullaney
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Eli Lilly And Company
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The expression levels of genes, gene transcripts, or gene products can be used as biological markers to improve treatment of cancer in a patient using antifolate drugs. The present invention relates to thyroid transcription factor 1 as a biological marker for treating cancer in a patient using an antifolate, such as pemetrexed.

Description

TIFOLATES IN PATIENTS WITH DETECTABLE LEVELS OF TFF-1 FOR THE CANCER TREATMENT

The present invention relates to methods of using particular biological markers to improve treatment of cancer using antifolate drugs. Although much progress has been made toward understanding the biological basis of cancer and in its treatment, it is still one of the leading causes of death. Variations in patient response to drugs are a significant therapeutic issue. It is widely recognized that most drugs are effective in only 40% to 60% of patients for whom they are prescribed [Hu Y, et al. (2005) Current Molecular Medicine 5: 29-38]. In the remaining patient population, the medication either does not work as intended or is not well tolerated.

Many factors play a role in the variations in patient responses to drugs including genetics, concomitant drug therapies, environment, lifestyle, health status, and disease status.

A medical need exists to identify patients that will best respond to chemotherapy regimens. Few predictive biological markers have been identified and fewer developed into diagnostic tests to definitively guide treatment decisions. Thus, there exists a need for improved therapies for the treatment of cancer, especially those involving the use of antifolate drugs. It would be great value to have methods to quickly determine if a patient will likely respond to treatment with antifolate drugs. It would also be of great value to have methods for predetermining whether a patient will respond favorably to an antifolate.

Ventana Medical Systems, Inc. supplies a mouse monoclonal antibody for thyroid transcription factor 1 (catalog number 760-2829, lot # 21028, clone 8G7G3/1). Thyroid transcription factor 1 is useful in differentiating primary adenocarcinoma of the lung from metastatic carcinomas from other organ sites, such as the ovary, breast and malignant mesothelioma, etc. It can also be used to differentiate small cell lung carcinoma from lymphoid infiltrates. Thyroid transcription factor 1 is widely used in the diagnosis of lung carcinomas. Lung cancer is the leading cause of cancer mortality. Diagnosis of non-small cell lung cancer (NSCLC), the most common type of lung cancer, generally occurs at later stage with advanced disease at which time many standard treatment chemotherapy regimens are less effective. Over the years multiple clinical trials have demonstrated the effectiveness of platinum doublet combination chemotherapy to improve patient outcome; although, five-year survival of patients with advanced lung cancer is less than 5% despite treatment [Breathnach, et al. (2001) Journal of Clinical Oncology 19: 1734-42].

The present invention relates to methods of treating cancer by determining the expression levels of genes, gene transcripts, or gene products which can be used as biological markers, comprising administering an effective amount of an antifolate.

The present invention includes a method of treating cancer in a patient, comprising administering an effective amount of an antifolate to a patient wherein the patient has a detectable level of thyroid transcription factor 1. In one embodiment of this method, the cancer is selected from the group consisting of non-small cell lung cancer, ovarian cancer, endometrial and endocervical cancer, thyroid cancer, malignant pleural mesothelioma, colon cancer and breast cancer, and the antifolate is selected from the group consisting of 5-fluorouracil, methotrexate, aminopterin, trimetrexate, pemetrexed, raltitrexed, nolatrexed, UFT, Sl and capecitabine. The method also includes an effective amount of cisplatin being administered to the patient. Furthermore, the present invention provides a method of treating cancer in a patient, comprising: a) obtaining a sample comprising cancer cells from the patient; b) determining whether thyroid transcription factor 1 is detectable in the cancer cells; and c) administering an effective amount of an antifolate drug to the patient if thyroid transcription factor 1 is detectable in the cancer cells. In one embodiment of this method, the cancer is selected from the group consisting of non-small cell lung cancer, ovarian cancer, endometrial and endocervical cancer, thyroid cancer, malignant pleural mesothelioma, colon cancer and breast cancer, and the antifolate is selected from the group consisting of 5-fluorouracil, methotrexate, aminopterin, trimetrexate, pemetrexed, raltitrexed, nolatrexed, UFT, Sl and capecitabine. The method also includes an effective amount of cisplatin being administered to the patient.

Many of the major genetic alterations that drive the development of human carcinomas involve transcription factors. Thyroid transcription factor-1 (TTF-I) is a homeodomain transcription factor specific to the thyroid and lung. TTF-I (also known as NKX2-1 or TITFl for thyroid transcription factor 1) is speculated to be an appealing candidate cell lineage-survival oncogene in lung cancer. While TTF-I is a diagnostically useful marker, it is not 100% specific for lung and thyroid neoplasms. Expression of TTF-I has also been reported in tumors other than those originating in the lung or thyroid. The present invention includes the identification of biological markers relating to TTF- 1 to aid in the prediction of patient outcome and the informed selection of currently available therapies for the use in cancer treatment. The present invention employs TTF-I as the preferred biological marker. Also, the genes known to be direct targets of TTF-I are also biological markers of success with antifolate therapy. These biological markers include folate receptor alpha, carcinoembryonic antigen-related cell adhesion molecule 6, claudin 3, homeodomain-only protein, selenium binding protein 1, mucin 1, and B surfactant.

The present invention relates to treating a cancer that is selected from the group consisting of non-small cell lung cancer, ovarian cancer, endometrial and endocervical cancer, thyroid cancer, malignant pleural mesothelioma, colon cancer and breast cancer. Most preferably, the present invention includes non-small cell lung cancer.

Antifolate drugs (or "antifolates") are the oldest of the antimetabolite class of anticancer agents and were one of the first modern anticancer drugs. The first clinically useful antifolate, described in 1947, was 2,4-diamino-pteroylglutamate (4-amino-folic acid; aminopterin; AMT) which yielded the first-ever remissions in childhood leukemia. AMT was soon superseded by its 10-methyl congener, methotrexate.

The basic pharmacology of methotrexate has led to the development of several new antifolate compounds with unique clinical properties and promising therapeutic potential. Methotrexate's actions at the cellular and biological level have served as a paradigm for the rational design of many new antifolate compounds. Thus, nearly 50 years after their first use as anticancer agents, the antifolates remain a diverse and growing class of drugs with great promise and potential for improving the ability to treat a broad range of cancers. The present invention includes antifolates that are selected from the group consisting of 5-fluorouracil, methotrexate, aminopterin, trimetrexate, pemetrexed, raltitrexed, nolatrexed, UFT, Sl and capecitabine. In the present invention, the most preferred antifolate is pemetrexed.

ALIMTA® (pemetrexed for injection) is an antifolate antineoplastic agent that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[2-(2-amino-4,7dihydro-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate and is disclosed in U.S. Patent 5,344,932. The use of pemetrexed as an agent for the treatment of malignant pleural mesothelioma and advanced non-small cell lung cancer is disclosed in U.S. Patent 5,217,974 and U.S. Patent 7,053,065. When a cancer spreads, or metastasizes, it often becomes incurable. New factors that may regulate tumor cell growth and differentiation are microRNAs (or "miRNAs"). MicroRNAs are small, single-stranded forms of RNA (-22 nucleotides in length) that are generated from endogenous hairpin-shaped transcripts encoded in the genomes of humans, animals, plants and viruses. MicroRNAs regulate protein production in a process known as base pairing - in which complementary codes found on microRNA bind to the corresponding mRNAs much like a lock and key. This process leads to inhibition of protein translation and, in some cases, to degradation of the mRNA itself.

Most microRNAs are associated with dozens of predicted protein targets, and are believed to be a major regulator of protein machinery. Furthermore, many genes may have multiple microRNA binding sites that represent targets for one or more microRNAs. It is suggested that the existence of multiple target sites is essential for proper protein regulation, indicating that microRNA regulation reflects an effective and complex expression control mechanism associated with an assortment of influences and impacts. MicroRNAs have also already been extensively implicated in several forms of cancer, neurological disorders, infectious diseases and other illnesses. Lu, et al. [(2005) Nature 435 (7043): 834-838] provided evidence that miRNA profiling has already been able to determine whether patients with chronic lymphocytic leukemia had slow growing or aggressive forms of the cancer.

MicroRNAs are differentially expressed in TTF-I positive and negative lung tumors and can be used as biological marker surrogates for TTF-I. These microRNAs include hsa-miR-375, hsa-miR-634, hcmv-miR-UL14, kshv-miR-K12-9, hsa-miR-326, hsa-miR-563, hsa-miR-181a, hsa-miR-29b, hsa-miR-191, hsa-miR-34a, hsa-miR-125a, hsa-miR-29a, hsa-miR-181b, hsa-miR-193a, hsa-miR-181a, hsa-miR-99b, hsa-let-7e, hsa- miR-193b, hsa-miR-202, hsa-miR-92b, hsa-miR-552, hsa-miR-628, hsa-miR-365, hsa- miR-181d, hsa-miR-181c, ebv-miR-BART4, hsa-miR-370, hsa-miR-326, hsa-miR-100, hsa-miR-542-5p, hsa -miR-137, hsa -miR-205, hsa -miR-149, hsa -miR-203, hsa-miR- 196b, hsa-miR-204, hsa-miR-34c, hsa-miR-378, hsa-miR-33, hsa-miR-627, hsa-miR- 520b, hsa-miR-373, hsa-miR-630, hsa-miR-492, ebv-miR-BART13, hsa-miR-422b, hcmv-miR-US4, hsa-miR-129, hsa-miR-520e, hsa-miR-769-5p, hsa-miR-557, hsa-miR- 572, hsa-miR-141, hsa-miR-629, hsa-miR-338, hcmv-miR-US25-l, hcmv-miR-US4, hsa- miR-126, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-150, hsa-miR-155, hsa-miR-18a, hsa-miR-192, hsa-miR-194, hsa-miR-199a, hsa-miR-199b, hsa-miR-19a, hsa-miR-19b, hsa-miR-203, hsa-miR-20a, hsa-miR-215, hsa-miR-218, hsa-miR-223, hsa-miR-296, hsa- miR-302c, hsa-miR-374, hsa-miR-421 , hsa-miR-483, hsa-miR-502, hsa-miR-518c, hsa- miR-518f, hsa-miR-519e, hsa-miR-520d, hsa-miR-552, hsa-miR-560, hsa-miR-571, hsa- miR-583, hsa-miR-584, hsa-miR-592, hsa-miR-601, hsa-miR-602, hsa-miR-650, hsa- miR-137, hsa-miR-504, and hsa-miR-542-5p.

MicroRNAs are differentially expressed in adenocarcinoma compared to squamous cell carcinoma of the lung. These microRNAs include hsa-miR-375, hsa-miR- 634, hcmv-miR-UL14, kshv-miR-K12-9, hsa-miR-326, hsa-miR-563, hsa-miR-181a, hsa- miR-29b, hsa-miR-191, hsa-miR-34a, hsa-miR-125a, hsa-miR-29a, hsa-miR-181b, hsa- miR-193a, hsa-miR-181a, hsa-miR-99b, hsa-let-7e, hsa-miR-193b, hsa-miR-202, hsa- miR-92b, hsa-miR-552, hsa-miR-628, hsa-miR-365, hsa-miR-181d, hsa-miR-181c, and ebv-miR-BART4.

MicroRNAs are differentially expressed in TTF-I positive lung tumors. This group of microRNAs includes hsa-miR-202, hsa-miR-370, hsa-miR-326, hsa-miR-100, hsa-miR-542-5p, hsa-miR-137, and hsa-miR-375.

MicroRNAs are differentially expressed in TTF-I negative lung tumors. These microRNAs include hsa-miR-205, hsa-miR-149, hsa-miR-203, hsa-miR- 196b, hsa-miR- 204, hsa-miR-34c, hsa-miR-378, hsa-miR-33, hsa-miR-627, hsa-miR-520b, hsa-miR-373, hsa-miR-630, hsa-miR-492, ebv-miR-BART13, hsa-miR-422b, hcmv-miR-US4, hsa- miR-129, hsa-miR-520e, hsa-miR-769-5p, hsa-miR-557, hsa-miR-572, hsa-miR-141, hsa- miR-629, and hsa-miR-338.

MicroRNAs are differentially expressed in TTF- 1 positive adenocarcinoma lung tumors. This group of microRNAs includes hcmv-miR-US25-l, hcmv-miR-US4, hsa- miR-126, hsa-miR- 142-3p, hsa-miR- 142-5p, hsa-miR-150, hsa-miR-155, hsa-miR-18a, hsa-miR-192, hsa-miR-194, hsa-miR-199a, hsa-miR-199b, hsa-miR-19a, hsa-miR-19b, hsa-miR-203, hsa-miR-20a, hsa-miR-215, hsa-miR-218, hsa-miR-223, hsa-miR-296, hsa- miR-302c, hsa-miR-338, hsa-miR-373, hsa-miR-374, hsa-miR-378, hsa-miR-421 , hsa- miR-483, hsa-miR-492, hsa-miR-502, hsa-miR-518c, hsa-miR-518f, hsa-miR-519e, hsa- miR-520b, hsa-miR-520d, hsa-miR-552, hsa-miR-560, hsa-miR-571, hsa-miR-583, hsa- miR-584, hsa-miR-592, hsa-miR-601, hsa-miR-602, hsa-miR-627, hsa-miR-650, hsa- miR-769-5p, hsa-miR-137, hsa-miR-504, and hsa-miR-542-5p. Many methods are now available to determine gene expression in a cancer cell.

Advances in molecular diagnostic methods have significantly improved and simplified the quantification of proteins and nucleic acids. Immunohistochemistry, microarrays, and polymerase chain reaction (PCR) have been used to distinguish many cancer types, identify subclasses of cancers, and to define specific phenotypes of cancers. The development of these methods for gene expression makes it possible to search systematically for biological markers of cancer classification and outcome prediction in a variety of tumor types.

In the present invention, TTF-I is preferably assayed or detected by immunohistochemistry. The expression of genes known to be direct targets of TTF-I, such as folate receptor alpha, carcinoembryonic antigen-related cell adhesion molecule 6, claudin 3, homeodomain-only protein, selenium binding protein 1, mucin 1, and B surfactant can be evaluated by immunohistochemistry, microarrays, and/or PCR. The microRNAs can be determined by microarrays and/or PCR.

The following definitions are provided to aid those of ordinary skill in the art in understanding the disclosure herein. These definitions are intended to be representative of those known in the art, and are therefore not limited to the specific elements presented, but encompass concepts and features disclosed in cited and/or contemporary publications or patents.

The term "treating" (or "treat" or "treatment") means slowing, stopping, reducing, or reversing the progression or severity of a symptom, disorder, condition, or disease. A "patient" is a mammal, preferably a human.

The term "effective amount" refers to the amount or dose of cisp latin or an antifolate or pharmaceutically acceptable salt, upon which single or multiple dose administration to a patient, provides the desired treatment. The term "detectable level" refers to the gene, gene transcript, or gene product being present at a level that is detected in a biological sample by a diagnostic method or assay, such as immunohistochemistry. The term "expression level" refers to the amount of the gene, gene transcript, or gene product, wherein the amount of the gene, gene transcript, or gene product is different than would normally be expected to be present in a biological sample compared to a standard reference control, such as a housekeeping gene. The specific expression level amount depends upon the particular gene, gene transcript, or gene product.

The term "hazard ratio" refers to the ratio between the predicted hazard for a member of one group and that for a member of the other group, holding everything else constant. The hazard ratio describes the relative risk of an endpoint at any given time.

Example 1

Phase III Study Comparing Cisplatin/Gemcitabine with Cisplatin/Pemetrexed in Chemonaive Patients with Advanced Stage Non-small Cell Lung Cancer and TTF-I

Immunohistochemistry Staining

A large randomized phase III clinical trial in first-line advanced stage NSCLC demonstrated efficacy of the combination of pemetrexed/cisplatin [Scagliotti, et al.

(2008) Journal of Clinical Oncology 28:3543-3551]. Furthermore in this trial superiority of pemetrexed/cisplatin compared to gemcitabine/cisplatin was demonstrated based on predominantly non-squamous histology (eg., median overall survival in adenocarcinoma patients of 12.6 months (95% confidence interval 10.7-13.6 months) vs. 10.9 months (95% confidence interval 10.1-11.7 months) respectively with a hazard ratio of 0.84, p=0.03). Pharmacogenomic efforts on tumor samples from this trial [Scagliotti, et al. (2008) Journal of Clinical Oncology 28:3543-3551] have been ongoing in parallel to identify biological markers that predict improved outcome for pemetrexed. The lung oncogene TTF-I is identified as a predictive biomarker of pemetrexed efficacy in NSCLC.

For a full disclosure of the Phase III Study, see Scagliotti, G. et al. [Scagliotti, G et al. (2008) Journal of Clinical Oncology 26, 21 : 1-11]

TTF-I staining was performed on 101 lung tumors collected from the Phase III Study using a mouse monoclonal antibody supplied by Ventana Medical Systems, Inc. (catalog number 760-2829, lot # 21028, clone 8G7G3/1). The antibody is supplied pre- diluted in a dispenser for use on Ventana automated staining instruments and is intended for in vitro diagnostic use. Tissue sections were freshly prepared from paraffin blocks following standard procedures and mounted on Superfrost Plus glass microscope slides. Sections were baked for 1 hour at 65°C before loading onto a Ventana BenchMark® XT. Default instrument settings were used to deparaffinize the sections and epitope unmasking utilized the "Standard" setting in combination with CCl buffer. Antibody was applied to each section for 32 minutes at 37°C. The remaining steps (washing, secondary antibody incubation, peroxidase-H2θ2-diaminobenzidine reaction and counterstaining) were all performed by the instrument using default times and temperatures. The ultraView™ Universal DAB detection kit used contains all reagents necessary for detection of the primary antibody. At the end of the automated staining run the slides were dehydrated through graded alcohols followed by three separate xylene baths. Cytoseal 60 mounting medium was used to affix a coverslip to each slide. For comparison of staining among tissues, the results were quantified by calculation of a complete H-score that considers both staining intensity and the percentage of cells stained at a specific range of intensities. A complete H-score was calculated by summing the products of the percentage cells stained at a given staining intensity (0-100) and the staining intensity (0-3). For example: a specimen with 10% of cells staining 3+ , 30% of cells staining 2+, 20% of cells staining 1+, and 40% of cells unstained would have a complete H-score of (3 X 10) + (2 X 30) + (1 X 20) = 110. Statistical analysis of the complete H-scores obtained for the normal tissue and tumor sample populations was carried out by using the two-tailed Student's T -test with unpaired data of equal variance.

Patients with TTF-I positive tumors, that is tumors in which TTF-I was detectable, had a statistically significantly improved median overall survival of approximately 20 months when treated with pemetrexed/cisplatin compared to 11 months when treated with the gemcitabine/cisplatin control arm. Specifically, an analysis of approximately 100 patient samples, using a high:low interaction model for TTF-I in pemetrexed/cisplatin arm resulted in a hazard ratio of 0.17 with a 95% confidence interval of 0.07 to 0.44, p=0.004. In comparison the high:low interaction model for TTF-I in gemcitabine/cisplatin arm resulted in a hazard ratio of 0.97 with a 95% confidence interval of 0.42 to 2.0, p=1.0. The median overall survival was similar between TTF-I negative pemetrexed/cisplatin treated patients, TTF-I negative gemcitabine/cisplatin treated patients, and TTF-I positive gemcitabine/cisplatin treated patients. Thus high tumor TTF-I was predictive of improved outcome for patients treated with pemetrexed/cisplatin but neither high nor low TTF- 1 status was associated with improved outcome with gemcitabine/cisplatin. Therefore, a patient with TTF-I positive tumors will likely respond to treatment with antifolate drugs. Thus, TTF-I and related genes, proteins and pathways are useful to predict drug response.

Claims

WE CLAIM:
1. A method of treating cancer in a patient, comprising administering an effective amount of an antifolate to a patient wherein the patient has a detectable level of thyroid transcription factor 1.
2. The method of Claim 1, wherein the cancer is selected from the group consisting of non-small cell lung cancer, ovarian cancer, endometrial and endocervical cancer, thyroid cancer, malignant pleural mesothelioma, colon cancer, and breast cancer.
3. The method of Claim 1, wherein the cancer is non-small cell lung cancer.
4. The method of any one of Claims 1 to 3, wherein the antifolate is selected from the group consisting of 5-fluorouracil, methotrexate, aminopterin, trimetrexate, pemetrexed, raltitrexed, nolatrexed, UFT, Sl and capecitabine.
5. The method of any one of Claims 1 to 3, wherein the antifolate is pemetrexed.
6. A method of treating cancer in a patient, comprising: a) obtaining a sample comprising cancer cells from the patient; b) determining whether thyroid transcription factor 1 is detectable in the cancer cells; and c) administering an effective amount of an antifolate to the patient if the patient sample has a detectable level of thyroid transcription factor 1.
7. The method of Claim 6, wherein the cancer is selected from the group consisting of non-small cell lung cancer, ovarian cancer, endometrial and endocervical cancer, thyroid cancer, malignant pleural mesothelioma, colon cancer, and breast cancer.
8. The method of Claim 6, wherein the cancer is non-small cell lung cancer.
9. The method of any one of Claims 6 to 8, wherein the antifolate is selected from the group consisting of 5-fluorouracil, methotrexate, aminopterin, trimetrexate, pemetrexed, raltitrexed, nolatrexed, UFT, S 1 and capecitabine.
10. The method of any one of Claims 6 to 8, wherein the antifolate is pemetrexed.
11. The method of any one of Claims 1 to 10, wherein an effective amount of cisplatin is also administered to the patient.
PCT/US2009/052823 2008-08-20 2009-08-05 Use of antifolates in patients with detectable levels of tff-1 for the cancer treatment WO2010021843A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015128671A1 (en) * 2014-02-27 2015-09-03 Queen Mary University Of London Biomarkers for endometriosis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030104499A1 (en) * 2001-03-12 2003-06-05 Monogen, Inc. Cell-based detection and differentiation of lung cancer
US20060079480A1 (en) * 2000-06-30 2006-04-13 Clet Niyikiza Novel antifolate combination therapies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060079480A1 (en) * 2000-06-30 2006-04-13 Clet Niyikiza Novel antifolate combination therapies
US20030104499A1 (en) * 2001-03-12 2003-06-05 Monogen, Inc. Cell-based detection and differentiation of lung cancer

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
GHOSH L ET AL: "Management of patients with metastatic cancer of unknown primary" CURRENT PROBLEMS IN SURGERY, YEAR BOOK MEDICAL PUBLISHERS, CHICAGO, IL, US, vol. 42, no. 1, 1 January 2005 (2005-01-01), pages 12-66, XP004767317 ISSN: 0011-3840 *
SCAGLIOTTI GIORGIO VITTORIO ET AL: "New data integrating multitargeted antifolates into treatment of first-line and relapsed non-small-cell lung cancer." 2008, CLINICAL LUNG CANCER 2008, VOL. 9 SUPPL 3, PAGE(S) S122 - S128 , XP002552743 ISSN: 1938-0690 abstract; table 2 page 123, left-hand column, paragraph 2 - right-hand column, paragraph 1 page 125, left-hand column, paragraph 1 page 127, right-hand column, paragraph 2-3 *
SCAGLIOTTI GIORGIO VITTORIO ET AL: "Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer." 20 July 2008 (2008-07-20), JOURNAL OF CLINICAL ONCOLOGY : OFFICIAL JOURNAL OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY 20 JUL 2008, VOL. 26, NR. 21, PAGE(S) 3543 - 3551 , XP002552741 ISSN: 1527-7755 abstract; figures 2-3 page 3543, left-hand column, paragraph 1 - right-hand column, paragraph 1 page 3549, right-hand column, paragraph 2 - page 3550, left-hand column, paragraph 2 *
TAYLOR PAUL ET AL: "Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program." JOURNAL OF THORACIC ONCOLOGY : OFFICIAL PUBLICATION OF THE INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER JUL 2008, vol. 3, no. 7, July 2008 (2008-07), pages 764-771, XP002552742 ISSN: 1556-1380 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015128671A1 (en) * 2014-02-27 2015-09-03 Queen Mary University Of London Biomarkers for endometriosis

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