WO2017175111A1 - Fusion strn-alk en tant que cible thérapeutique dans le cancer colorectal - Google Patents

Fusion strn-alk en tant que cible thérapeutique dans le cancer colorectal Download PDF

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Publication number
WO2017175111A1
WO2017175111A1 PCT/IB2017/051890 IB2017051890W WO2017175111A1 WO 2017175111 A1 WO2017175111 A1 WO 2017175111A1 IB 2017051890 W IB2017051890 W IB 2017051890W WO 2017175111 A1 WO2017175111 A1 WO 2017175111A1
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alk
strn
patient
inhibitor
colorectal cancer
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PCT/IB2017/051890
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English (en)
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Eric SLOSBERG
Barinder KANG
August SALVADO
Steven STEIN
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57419—Specifically defined cancers of colon
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/91045—Acyltransferases (2.3)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present disclosure relates to an ALK inhibitor for use in treating a mammalian cancer, particularly colorectal cancer in human; use of an ALK inhibitor for the preparation of a medicament for the treatment of colorectal cancer; methods of selectively treating a patient having colorectal cancer with an ALK inhibitor or a drug other than ALK inhibitor; a method of or a kit for use in predicting the likelihood that a patient having a colorectal cancer will respond to treatment with an ALK inhibitor; a kit for use in treating a patient having colorectal cancer and other closely related methods and kits.
  • CRC Colorectal cancer
  • mCRC metastatic CRC
  • mCRC metastatic CRC
  • mAbs epidermal growth factor receptor
  • VEGF vascular endothelial growth factor
  • KRAS mutation analysis is an accepted molecular approach in colorectal cancer.
  • NSCLC non-small cell lung cancer
  • a novel STRN-ALK gene fusion was surprisingly identified as a targetable genomic alteration by comprehensive genomic profiling in a patient with advanced metastatic colorectal cancer, who failed standard therapy.
  • the patient was subsequently treated with ALK targeted tyrosine kinase inhibitor ceritinib achieving a dramatic clinical response.
  • Present disclosure provides an evidence that patients with colorectal cancer characterized by the presence a STRN-ALK gene fusion or a STRN-ALK fusion polypeptide benefit from the treatment with an ALK inhibitor.
  • STRN-ALK fusion can drive the proliferation of colorectal cancer and that the cancer can respond to an ALK inhibitor can be applied, among others, when characterizing a sample of a colorectal cancer, or for providing means to detect said alteration in the colorectal cancer, such as for example a method for detecting the STRN-ALK gene fusion or a STRN-ALK fusion polypeptide in a biological sample or a kit comprising a probe that is capable of detecting the STRN-ALK gene fusion or the STRN-ALK fusion polypeptide.
  • the present disclosure relates to an ALK inhibitor for use in treating colorectal cancer characterized by the presence a STRN-ALK gene fusion or a STRN- ALK fusion polypeptide.
  • the disclosure provides the use of an ALK inhibitor for the preparation of a medicament for the treatment of colorectal cancer, wherein the colorectal cancer is characterized by the presence of a STRN-ALK gene fusion or a STRN-ALK fusion polypeptide.
  • the present disclosure relates to a method of selectively treating a patient having colorectal cancer with an ALK inhibitor, wherein the method comprises the steps of:
  • the present disclosure relates to a method of selectively treating a patient having colorectal cancer, comprising either:
  • the present disclosure relates to a method of selectively treating a patient having colorectal cancer with an ALK inhibitor, comprising:
  • the present disclosure relates to a method of selectively treating a patient having colorectal cancer, comprising:
  • the present disclosure relates to a method of predicting the likelihood that a patient having a colorectal cancer will respond to treatment with an ALK inhibitor, comprising assaying a biological sample obtained from the patient for the presence or absence of a STRN-ALK gene fusion or a STRN-ALK fusion polypeptide, wherein:
  • the present disclosure relates to a kit for use in predicting the likelihood that a patient having colorectal cancer will respond to the treatment with an ALK inhibitor comprising:
  • kits for use in treating a patient having colorectal cancer comprising:
  • FIG. 1 Histologic Analysis of the Tumor. Gross image of a 15.1 cm cecal tumor (panel A). A Representative histologic section of the tumor shows moderately differentiated adenocancer containing glands exhibiting prominent infoldings, pseudopapillary structures, and a prominent mucinous component (Panel B, hematoxylin and eosin).
  • FIG. 2 Molecular Analysis of the Tumor.
  • Screenshot of Integrative Genomics Viewer demonstrating uniquely mapped paired-end reads in the intronic regions of STRN (Intron 3) and ALK (Intron 19) on chromosome 2 (Panel C).
  • Exons 1-3 of STRN containing the caveolin-binding domain (CB) and coiled-coil domain (CC) are shown in blue.
  • Exons 20-29 of ALK containing the tyrosine kinase domain (TK) are shown in orange.
  • fusion partners are located on the short arm of chromosome 2 (2p22.2 and 2p23, separated by ⁇ 7.69 Mb), indicating that the fusion is a result of intrachromosomal paracentric rearrangement.
  • the coiled-coil STRN domain may act as a dimerization motif that could constitutively activate ALK tyrosine kinase (Panel D).
  • FIG. 3 Immunohistochemical Analysis of the Tumor. Immunohistochemistry with the D5F3 anti-ALK antibody showing strong diffuse intracytoplasmic immunoreactivity confirming ALK overexpression as a result of STRN-ALK fusion. The loss of ALK extracellular and intramembrane domains detected by sequencing is associated with intracellular localization of the fusion protein (Panel E). Dual-color break-apart fluorescence in situ hybridization (FISH) analysis of the tumor cells performed with a 5' ALK probe (green) and 3' ALK probe (red) (panel F). Single isolated red probe signals (arrow) indicate the ALK chromosomal rearrangement. An unsplit red and green probe signals indicate the non-rearranged wild type ALK locus (arrowhead).
  • FISH Dual-color break-apart fluorescence in situ hybridization
  • FIG. 4 Umbilical Skin Metastasis and Imaging Studies before and after Ceritinib Treatment.
  • a pretreatment photograph shows the tumor metastasis involving periumbilical skin (Panel A). Skin metastasis significantly decreased within 7 weeks of treatment with ceritinib (Panel B). After an additional 2 weeks of treatment there is marked decrease in periumbilical thickening (Panel C) At 6 months follow-up the mass protruding through the skin resolved, leaving a scar (Panel D).
  • Pretreatment CT scan shows large pelvic tumor mass (Panel E). Six months after ceritinib therapy a CT scan demonstrates resolution of all contrast-enhancing tumor (panel F).
  • FIG. 5 Schematic representation of the STRN-ALK fusion of the N-terminal portion of STRN and C-terminal portion of ALK.
  • the disclosure can be used for predicting the likelihood that a patient having a colorectal cancer will respond to treatment with an ALK inhibitor based on the presence or absence of STRN-ALK gene fusion, and thus specifically select patients having colorectal cancer who will benefit from treatment with an ALK inhibitor.
  • the present disclosure relates to an ALK inhibitor for use in treating colorectal cancer characterized by the presence a STRN-ALK gene fusion or a STRN- ALK fusion polypeptide.
  • An ALK inhibitor can also be used in treating colorectal cancer characterized by the presence a STRN-ALK gene fusion or a STRN-ALK fusion polypeptide that has progressed or is intolerant to chemotherapy.
  • the ALK inhibitor can be used in treating colorectal cancer characterized by the presence a STRN-ALK gene fusion or a STRN-ALK fusion polypeptide that has progressed or is intolerant to epidermal growth factor receptor (EGFR) inhibitor.
  • EGFR epidermal growth factor receptor
  • ALK refers to anaplastic lymphoma kinase, also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246).
  • CD246 cluster of differentiation 246
  • the Entrez Gene ID is 238.
  • STRN refers to striatin (calmodulin binding protein).
  • the Entrez Gene ID is 6801.
  • STRN encodes a calcium-dependent calmodulin-binding protein.
  • STRN-ALK gene fusion refers to abnormal DNA rearrangement where the STRN gene is fused to the ALK gene. This abnormal gene fusion leads to the production of a fusion protein (STRN-ALK), referred herein as "STRN-ALK fusion polypeptide".
  • STRN-ALK fusion protein
  • both fusion partners are located on the short arm of chromosome 2 (2p22.2 and 2p23, separated by ⁇ 7.69 Mb)
  • the fusion is a result of intrachromosomal paracentric rearrangement.
  • an STRN-ALK gene fusion may involve the intrachromosomal translocation of exons 1-3 of STRN to exons 20-29 of ALK (Fig. 2, panel D).
  • the predicted fusion protein resulting from this gene fusion does not have a calmodulin-binding domain and the WD-repeats, but retains the N-terminal caveolin-binding and the coiled-coil binding domains of STRN, fused to the intracellular juxtamembrane region of ALK, containing the kinase domain (Fig. 2, panel D and Fig. 5).
  • the STRN-ALK fusion protein comprises amino acids residues 1 - 137 of STRN portion and 1059 - 1620 of ALK portion (Fig. 2, panel D and Fig. 5).
  • the fusion between the fusion partners is between amino acid 137 of STRN and amino acid 1059 of ALK.
  • an ALK inhibitor can be a compound that inhibits ALK with the IC50 of less than 100 ⁇ , preferably less than 10 ⁇ , more preferably less than ⁇ , measured by a Caliper mobility shift assay.
  • the Caliper mobility shift technology is based on the separation of particles of different charges and sizes in an electrical field, similar to capillary electrophoresis.
  • the Caliper kinase assays utilize fluorescently labeled peptides as kinase substrates.
  • the phosphorylation of the peptide in the course of the reaction introduces additional negative charges via the phosphate and hence permits its separation from the phosphorylated peptide.
  • Both, the separation and the detection of the labeled peptides take place in the microfluidic system of the Caliper Lab Chip.
  • the LabChips have 12 "sippers" enabling the parallel analysis of 12 samples at the same time. The fact that both, unphosphorylated peptide (substrate) and phosphorylated peptide (product) are measured and that the separation makes the readout relatively insensitive to interference by fluorescent compounds results in the excellent data quality of this assay.
  • General assay procedure can be performed at 30°C for 60 min in a total volume of 9 ⁇ ⁇ including 0.050 ⁇ ⁇ of compound dilution or pure DMSO, respectively.
  • the reaction can be terminated by the addition of 16 of stop solution (100 mM Hepes, 5 % (v/v) DMSO, 0.1 % (v/v) Coating reagent, 10 mM EDTA, 0.015 % (v/v) Brij 35).
  • stop solution 100 mM Hepes, 5 % (v/v) DMSO, 0.1 % (v/v) Coating reagent, 10 mM EDTA, 0.015 % (v/v) Brij 35.
  • the plates are transferred into the Caliper LabChip 3000 workstation for analysis.
  • the effect of a compound on the enzymatic activity is obtained from the linear progress curves in the absence and presence of the compound and routinely determined from one reading (end point measurement).
  • the ALK inhibitor can be for example a compound selected from the group consisting of
  • salts refers to salts that retain the biological effectiveness and properties of the compound when used according to this disclosure and, which typically are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate, trifluoroacetate salt or the like.
  • the present disclosure relates to the ALK inhibitor 5- chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.
  • the compound 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine, also known under name ceritinib, is a compound of formula I, and is described in Example 7 (Compound 66) of
  • colonal cancer refers to cancer in the colon or rectum, also known as colon cancer, rectal cancer or bowel cancer.
  • the present disclosure relates to metastatic colorectal cancer.
  • treatment comprises a treatment relieving, reducing or alleviating at least one symptom in a subject, increasing progression-free survival, overall survival, extending duration of response or delaying progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • the term “treatment” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease in a patient, e.g., a mammal, particularly the patient is a human.
  • treatment as used herein comprises an inhibition of the growth of a tumor incorporating a direct inhibition of a primary tumor growth and / or the systemic inhibition of metastatic cancer cells.
  • An ALK inhibitor can be used in treating colorectal cancer characterized by the presence a STRN-ALK gene fusion or a STRN-ALK fusion polypeptide, wherein the presence of the STRN-ALK gene fusion or the STRN-ALK fusion polypeptide has been detected in a biological sample from the cancer obtained from a patient having said cancer.
  • biological sample refers to a biological specimen taken by sampling so as to be representative of any other specimen taken from the source of the specimen.
  • a biological sample is cells or tissue from the cancer obtained from a patient having said cancer.
  • a “subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, simians, humans, farm animals, sport animals, and pets.
  • a patient population can be stratified according to the presence of the STRN-ALK gene fusion or the STRN-ALK fusion polypeptide.
  • a patient having colorectal cancer can be first selected for the treatment with an ALK inhibitor on the basis of the patient having STRN-ALK gene fusion or the STRN-ALK fusion polypeptide; and thereafter, a therapeutically effective amount of an ALK inhibitor is administered to the patient.
  • Patient can be selected based on the presence of the fusion.
  • the patient can be administered an ALK inhibitor.
  • a patient can be administered a therapeutically effective dose of the ALK inhibitor once it has been determined that the fusion is present in the cancer.
  • the patient can be administered some other drug which may be better suited to treat the special cancer subtype.
  • the presence of the STRN-ALK gene fusion or the STRN-ALK fusion polypeptide can also be used as an indicator of an increased likelihood that the patient will respond to treatment with an ALK inhibitor. Therefore, the result of detection step can tell a physician or an informed person whether a patient is likely going to respond to the treatment with an ALK inhibitor.
  • the presence of the STRN-ALK gene fusion or the STRN-ALK fusion polypeptide can be indicative of an increased likelihood that the patient will respond to treatment with an ALK inhibitor; and the absence of the STRN- ALK gene fusion or the STRN-ALK fusion polypeptide can be indicative of a decreased likelihood that the patient will respond to treatment with an ALK inhibitor.
  • selecting and “selected” in reference to a patient is used to mean that a particular patient is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criteria.
  • selectively treating refers to providing treatment to a patient having a particular disease, where that patient is specifically chosen from a larger group of patients on the basis of the particular patient having a predetermined criteria.
  • selectively administering refers to administering a drug to a patient that is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criteria.
  • selectively treating and selectively administering it is meant that a patient is delivered a personalized therapy based on the patient's particular biology, rather than being delivered a standard treatment regimen based solely on the patient having a particular disease.
  • Selecting in reference to a method of treatment as used herein, does not refer to fortuitous treatment of a patient that has the biomarker, but rather refers to the deliberate choice to administer treatment to a patient based on the patient having the biomarker.
  • selective treatment differs from standard treatment, which delivers a particular drug to all patients, regardless of their biomarker.
  • a therapeutically effective amount of a compound of the present disclosure refers to an amount of the compound of the present disclosure that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount of an ALK inhibitor in vivo may range depending on the route of administration, between about 0.05 to about 50 mg per kg body weight per day, preferably about 0.1-25 mg/kg/day, more preferably from about 0.5-10 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to a preferable dosage range of about 35-700 mg per day.
  • Daily dose of ceritinib can be for example 750 mg.
  • the recommended dose and schedule for crizotinib is 250 mg orally, twice daily, with or without food.
  • Alectinib can be for example used by administering 300 mg twice daily.
  • the patient having colorectal cancer can be selected for the treatment with an ALK inhibitor based on assaying a biological sample obtained from the patient for STR -ALK gene fusion or the STRN-ALK fusion polypeptide.
  • An ALK inhibitor can be then used in treating a patient having colorectal cancer characterized in that:
  • a therapeutically effective amount of an ALK inhibitor is selectively administered to the patient on the basis of the biological sample from the patient having STRN-ALK gene fusion or the STRN-ALK fusion polypeptide.
  • the term "assaying" is used to refer to the act of identifying, screening, probing or determining, which act may be performed by any conventional means. For example, a sample may be assayed for the presence of a particular marker by using an ELISA assay, a Northern blot, imaging, etc. to detect whether that marker is present in the sample.
  • testing and determining contemplate a transformation of matter, e.g., a transformation of a biological sample, e.g., a blood sample or other tissue sample, from one state to another by means of subjecting that sample to physical testing. Further, as used herein, the terms “assaying” and “determining” are used to mean testing and/or measuring.
  • the phrase “assaying a biological sample from the patient for" and the like is used to mean that a sample may be tested (either directly or indirectly) for either the presence or absence of a given factor or for the level of a particular factor. It will be understood that, in a situation where the presence of a substance denotes one probability and the absence of a substance denotes a different probability, then either the presence or the absence of such substance may be used to guide a therapeutic decision.
  • the assaying or detection for STRN-ALK gene fusion or the STRN-ALK fusion polypeptide can comprise a technique selected from the group consisting of Next Generation Sequencing (NGS), Northern blot analysis, polymerase chain reaction (PCR), reverse transcription-polymerase chain reaction (RT-PCR), TaqMan-based assays, direct sequencing, dynamic allele-specific hybridization, high-density oligonucleotide SNP arrays, restriction fragment length polymorphism (RFLP) assays, primer extension assays, oligonucleotide ligase assays, Southern Blot, immunoassays, immunohistochemistry, ELISA, fluorescence in situ hybridization analysis (FISH), kinase activity assays, flow cytometry, Western blot, HPLC, and mass spectrometry.
  • NGS Next Generation Sequencing
  • PCR polymerase chain reaction
  • RT-PCR reverse transcription-polymerase chain reaction
  • the step of assaying or detection for STRN-ALK gene fusion comprises PCR, RT-PCR or fluorescence in situ hybridization analysis (FISH).
  • the step of assaying or detection for the STRN-ALK fusion polypeptide comprises immunohistochemistry. Techniques are generally known to a person skilled in biochemistry, microbiology and diagnostic tests. In addition, the techniques can be applied according to explanation and instruction found in further references such as for example WO2008/127248, WO2012162373 or references cited therein.
  • An ALK inhibitor can be administered for at least 6 months.
  • a therapeutically effective amount of the ALK inhibitor is administered for at least 6 months.
  • the ALK inhibitor leads to a progression free survival of at least 6 months.
  • the ALK inhibitor can be administered as a first line or as a second line treatment.
  • the ALK inhibitor is administered after a patient has been given a standard of care, but has relapsed or has become intolerant to the standard of care, or the cancer has become resistant to the first line medicaments.
  • targeted therapy may provide clinical benefit over the standard of care and thus it can be valuable to administer the ALK inhibitor as a first line treatment. Therefore, the present disclosure also relates to the administration of the ALK inhibitor as a first line treatment.
  • An ALK inhibitor can also be used for the preparation of a medicament for the treatment of colorectal cancer, wherein the colorectal cancer is characterized by the presence of a STRN-ALK gene fusion or a STRN-ALK fusion polypeptide.
  • predicting indicates that the methods described herein provide information to enable a health care provider to determine the likelihood that an individual having the disorder will respond to or will respond more favorably to treatment. It does not refer to the ability to predict response with 100% accuracy. Instead, the skilled artisan will understand that it refers to an increased probability.
  • “likelihood” and “likely” is a measurement of how probable an event is to occur. It may be used interchangeably with “probability”. Likelihood refers to a probability that is more than speculation, but less than certainty. Thus, an event is likely if a reasonable person using common sense, training or experience concludes that, given the circumstances, an event is probable. In some embodiments, once likelihood has been ascertained, the patient may be treated (or treatment continued, or treatment proceed with a dosage increase) with the test compound. In one embodiment, the "likelihood” and “likely” denote a chance in percent of how probable an event is to occur.
  • the phrase "increased likelihood" refers to an increase in the probability that an event will occur.
  • some methods herein allow prediction of whether a patient will display an increased likelihood of responding to treatment with the test molecule or an increased likelihood of responding better to treatment with the test molecule.
  • the increased likelihood means that there is more than 50% chance, more than 60 % chance, more than 70 % or more than 80 % chance that an event will occur.
  • a decreased likelihood means, that the chance is lower than 50%, lower than 60 %, lower than 70 % or lover than 80 %, respectively, that an event will occur.
  • the diagnosis or the determination of whether a patient with a colorectal cancer can be done by using a kit for use in predicting the likelihood that a patient having colorectal cancer will respond to the treatment with an ALK inhibitor comprising:
  • the probe is an oligonucleotide that specifically hybridizes to a region of a nucleic acid coding for the STRN-ALK gene fusion, or an oligonucleotide that specifically hybridizes to a region of a nucleic acid coding for an equivalent genetic marker of the STR -ALK gene fusion, or the probe is an antibody that binds to the STRN-ALK fusion polypeptide. Further details on how to prepare for example an antibody that binds to a specific region of a polypeptide can be found in literature such as in WO2008/127248, WO2012162373 or references cited therein.
  • the probe can be an oligonucleotide that specifically hybridizes to a region of a nucleic acid coding for the STRN-ALK gene fusion, or an oligonucleotide that specifically hybridizes to a region of a nucleic acid coding for an equivalent genetic marker of the STRN-ALK gene fusion, or the probe is an antibody that binds to the STRN-ALK fusion polypeptide.
  • a novel STRN-ALK gene fusion was identified as a targetable genomic alteration by comprehensive genomic profiling utilizing the FoundationOne (Foundation Medicine, Cambridge, MA) test platform in a patient with advanced metastatic colorectal cancer who failed standard therapy.
  • the patient was treated with ALK targeted tyrosine kinase inhibitor ceritinib achieving a dramatic clinical response. This case provides evidence that patients with colorectal cancer driven by ALK tyrosine kinase may benefit from specific targeted monotherapy.
  • the patient is an 87-year old woman without significant past medical history who presented three years ago with fatigue, hemoglobin of 8.6 gm/dL and iron deficiency.
  • Colonoscopy revealed a cecal mass and the patient underwent a right hemicolectomy.
  • Pathologic examination of the specimen revealed a 5.1 cm tumor that penetrated to the visceral peritoneal surface and involved 7 of 28 lymph nodes (Fig. 1, panel A).
  • the tumor exhibited features of a moderately differentiated adenocarcinoma with glands showing infolding, cribriforming, pseudopapillary structures and a prominent mucinous component (Fig. 1, panel B).
  • Analysis of mismatch repair proteins by immunohistochemistry revealed loss of expression of MLH1 and PMS2 with retained expression of MSH2 and MSH6.
  • Staging chest computed tomography (CT) revealed small bilateral pulmonary nodules suspicious for metastatic disease.
  • Clinical NGS-based comprehensive genomic profiling was performed using DNA extracted from formalin-fixed paraffin-embedded sections cut at 10 ⁇ thickness in a CLIA-certified laboratory (Foundation Medicine, Cambridge, MA).
  • the sample forwarded for DNA extraction contained a minimum of 20% DNA derived from tumor cells.
  • DNA sequencing was performed for the entire coding region of 315 cancer-related genes plus introns from 28 genes frequently rearranged in cancer on an indexed, adaptor- ligated, hybridization-captured library and fully sequenced using 49 bp reads (Illumina HiSeq 2500, Hayward, CA) to a median exon coverage of 555X for this specific case.
  • the bait set used in sequencing included key genes involved in colorectal carcinogenesis, such as KRAS, BRAF, PIK3CA, PTEN, CTNNB 1, APC, and MMR MLH1, PMS2, MSH2 and MSH6. Sequence reads were mapped to the reference human genome (hgl9) and analyzed for genomic alterations including base substitutions, small insertions and deletions (indels), copy number alterations (amplifications and homozygous deletions), and select gene fusions/rearrangements as previously described (Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013;31 : 1023-1031.).
  • Fluorescence in situ hybridization was performed on 4- ⁇ paraffin sections using the Vysis LSI ALK Dual Color Break Apart rearrangement probe (Abbott Molecular, Abbott Park, IL).
  • genomic profiling of the tumor sample identified 14 genomic alterations: a STR -ALK fusion (Fig. 2, panel C) and mutations in KRAS R164Q, STK11, TP53, AEID1A, BCOR, CDH2, MLL2, MLL3, PAX5, and RAD50 genes. Although no BRAF mutations were identified, genomic alterations were not detected in genes encoding the mismatch repair proteins MLH1, PMS2, MLH2, and MLH6, consistent with a sporadic microsatellite instable (MSI) CRC.
  • the KRAS R164Q mutation identified in this case is outside of the "hotspot" codons and is phenotypically equivalent to wild type KRAS.
  • a STRN-ALK fusion involved the intrachromosomal translocation of exons 1-3 of STRN to exons 20-29 of ALK (Fig. 2, panel D). Both fusion partners are located on the short arm of chromosome 2 (2p22.2 and 2p23, separated by ⁇ 7.69 Mb), indicating that the fusion is a result of intrachromosomal paracentric rearrangement.
  • the predicted fusion protein does not have a calmodulin-binding domain and the WD-repeats, but retains the N-terminal caveolin-binding and the coiled-coil binding domains of STRN, fused to the intracellular juxtamembrane region of ALK, containing the kinase domain (Fig. 2, panel D).
  • the coiled-coil STRN domain may act as a dimerization motif that could constitutively activate ALK tyrosine kinase.
  • a patient was reported with progressive metastatic colon cancer with a novel STRN-ALK gene fusion identified by comprehensive genomic profiling.
  • the patient had a dramatic response to the tyrosine kinase ALK inhibitor ceritinib and remains on treatment after 6 months of therapy.
  • This is the first case report of a transforming ALK fusion as a therapeutic target in colorectal cancer and illustrates the potential for personalized molecular based therapy for the treatment of advanced malignancies.

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Abstract

La présente invention concerne un inhibiteur de l'ALK destiné à être utilisé dans le traitement du cancer colorectal, caractérisé par la présence d'une fusion génique STRN-ALK ou d'un polypeptide de fusion STRN-ALK ; un inhibiteur d'ALK destiné à être utilisé dans un procédé de traitement sélectif d'un patient présentant un cancer colorectal ; un kit destiné à être utilisé dans la prédiction de la probabilité qu'un patient présentant un cancer colorectal réponde à un traitement avec un inhibiteur de l'ALK ; et un kit destiné à être utilisé dans le traitement d'un patient présentant un cancer colorectal.
PCT/IB2017/051890 2016-04-04 2017-04-03 Fusion strn-alk en tant que cible thérapeutique dans le cancer colorectal WO2017175111A1 (fr)

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WO2012162373A1 (fr) 2011-05-23 2012-11-29 Cell Signaling Technology, Inc. Kinase ros dans le cancer du poumon
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WO2008127248A1 (fr) 2007-04-13 2008-10-23 Cell Signaling Technology, Inc. Défauts de gène et alk kinase mutante dans des tumeurs solides humaines
WO2012162373A1 (fr) 2011-05-23 2012-11-29 Cell Signaling Technology, Inc. Kinase ros dans le cancer du poumon
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