WO2016193955A1 - Combinaisons d'inhibiteurs de kinase pour le traitement du cancer colorectal - Google Patents

Combinaisons d'inhibiteurs de kinase pour le traitement du cancer colorectal Download PDF

Info

Publication number
WO2016193955A1
WO2016193955A1 PCT/IB2016/053297 IB2016053297W WO2016193955A1 WO 2016193955 A1 WO2016193955 A1 WO 2016193955A1 IB 2016053297 W IB2016053297 W IB 2016053297W WO 2016193955 A1 WO2016193955 A1 WO 2016193955A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
pharmaceutical combination
use according
small molecule
egfr
Prior art date
Application number
PCT/IB2016/053297
Other languages
English (en)
Inventor
Giorgio Stassi
Matilde Todaro
Ruggero De Maria Marchiano
Original Assignee
Giorgio Stassi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Giorgio Stassi filed Critical Giorgio Stassi
Publication of WO2016193955A1 publication Critical patent/WO2016193955A1/fr

Links

Classifications

    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes

Definitions

  • the present invention relates to a combination [composition] of three different inhibitors for use in the curative and/or preventive treatment of colorectal cancer, and to methods for the curative and/or preventive treatment of a subject affected by colorectal cancer or at risk of said cancer, comprising the administration of a therapeutically effective amount of said composition to said subject.
  • Colorectal cancer is one of the cancers most frequently diagnosed worldwide, and one of the most lethal ones. It is caused by a multistage process linked to accumulation of genetic and epigenetic aberrations.
  • CSC cancer stem cells
  • CSCs cancer stem cells
  • CSCs are accountable for post-treatment tumor recurrence, as they are particularly resistant to traditional antitumor drugs. Therefore, it is strongly necessary to single out new curative approaches allowing to effectively intervene on CSCs by increasing, on the one hand, the effectiveness of current treatments and by reducing, on the other hand, the possibility of local recurrences and of metastases.
  • K. Connolly and colleagues report a case of treatment combined with pathwayB-Raf and EGFR inhibitors of a colorectal carcinoma with B-Raf V600E mutation.
  • the above-mentioned Patent Application relates to the EGFR inhibitors Cetuximab and Panitumumab, having as side effects cutaneous reactions of various intensity that were found also in patients for which associations of said drugs with B-Raf inhibitors were carried out.
  • CSCs cancer stem cells
  • the Authors of the present invention have identified a pharmaceutical combination comprising active principles x + y + z wherein x is a B-Raf inhibitor or a MEK inhibitor;
  • y is a HER-2 and/or an EGFR inhibitor
  • z is a PI3K inhibitor or an AKT inhibitor
  • colorectal cancer stem cells for use in the depletion of colorectal cancer stem cells in the curative or preventive treatment of colorectal cancer.
  • the Authors of the present invention have demonstrated that also in case a B-RAF or K-RAS mutation is present, while differentiated (non-stem) cells are sensitive to treatments with HER-2 or EGFR inhibitors and with B-Raf or MEK inhibitors, cancer stem cells are resistant to this treatment.
  • the Authors of the present invention have surprisingly found that, irrespectively of the presence of PI3K mutations, the addition of an inhibitor of this kinase (PI3K) or of the kinase immediately downstream (AKT) is capable of significantly reducing CSCs survival. Therefore, objects of the present invention are a pharmaceutical combination comprising active principles x + y + z wherein
  • x is a B-Raf inhibitor or a MEK inhibitor
  • y is a HER-2 and/or a EGFR inhibitor and
  • z is a PI3K inhibitor or an AKT inhibitor
  • colorectal cancer stem cells for use in the depletion of colorectal cancer stem cells in the curative or preventive treatment of colorectal cancer, by simultaneous, separate or sequential administration; said combination for use in the treatment of colorectal cancer, including the depletion of cancer stem cells (CSCs) of said tumor, and methods for the treatment of a subject affected by colorectal cancer, or at risk of recurrence or metastasis of said tumor, comprising the administration of a therapeutically effective amount of said composition to said subject.
  • CSCs cancer stem cells
  • Figure 1 panel A shows how the combined treatment with Vemurafenib (B- Raf inhibitor) and EGFR (Cetuximab) or Her2 (Trastuzumab) inhibitors is unable to reduce cell viability of all cells treated, irrespectively of the presence or absence of B-Raf mutation, whereas panel B shows how the cells surviving the double treatment are those cells with stem cell characteristics, as having a high CD44V6 expression and strong beta catenin activity.
  • Figure 2 shows how the combined treatment, using the B-Raf inhibitor (Vemurafenib, Vem in figure), in combination with the HER- 2 inhibitor (Trastuzumab, Trast in figure) or the EGFR inhibitor (Cetuximab, Ctx in figure) and the PI3K inhibitor (BKM120) or the AKT inhibitor (Perifosine, Perif in figure) succeeds to reduce the viability of cancer stem cells coming from 5 different patients affected by colon carcinoma.
  • the B-Raf inhibitor Vemurafenib, Vem in figure
  • HER- 2 inhibitor Trastuzumab, Trast in figure
  • EGFR inhibitor Cetuximab, Ctx in figure
  • BKM120 the PI3K inhibitor
  • Perifosine, Perif in figure succeeds to reduce the viability of cancer stem cells coming from 5 different patients affected by colon carcinoma.
  • the in vitro treatment was carried out by plating 250 cells per well and adding on day 0 the BRAF inhibitor (10 ⁇ Vemurafenib, Vem in figure), the inhibitors of EGFR (2C ⁇ g/ml Cetuximab, Ctx in figure) or Her2 (2C ⁇ g/ml Trastuzumab, Trast in figure) and the PI3K inhibitor (1 ⁇ BKM120) or the AKT inhibitor (10 ⁇ Perifosine). After the first administration, all inhibitors were added every two days.
  • Figure 3 highlights the reduced growth of tumors in vivo following combined treatment with B-Raf inhibitor (Vemurafenib), in combination with HER-2 inhibitor (trastuzumab) or EGFR (Cetuximab) and PI3K inhibitor (BKM120) or AKT inhibitor (Perifosine, Perif in figure).
  • B-Raf inhibitor Vemurafenib
  • HER-2 inhibitor tacuzumab
  • EGFR Cetuximab
  • BKM120 PI3K inhibitor
  • AKT inhibitor Perifosine, Perif in figure.
  • Cancer stem cells of two patients (2 and 3) affected by colon carcinoma were inoculated in the underskin of immunocompromised mice (Charles River). The mice were monitored for about 4 weeks, until appearance of a palpable tumor (day 0), date on which the treatment described below was initiated: PBS as Trastuzumab and Cetuximab control
  • Vemurafenib was utilized at 20mg/Kg/day with oral administration, in two administrations per day, for four weeks.
  • Trastuzumab was utilized at 5mg/Kg with intraperitoneal administration once a week, for four weeks.
  • Cetuximab was utilized at 40mg/Kg with intraperitoneal administration, twice a week for four weeks.
  • BKM120 was utilized at 20mg/Kg with oral administration, once a day, for four weeks.
  • Perifosine was utilized at 25mg/Kg/ with oral administration, once a day for four weeks.
  • x is a B-Raf inhibitor or a MEK inhibitor
  • y is an HER-2 and/or an EGFR inhibitor, and
  • z is a PI3K inhibitor or an AKT inhibitor.
  • the present invention provides a pharmaceutical combination comprising the active principles x + y + z wherein
  • x is a B-Raf inhibitor or a MEK inhibitor
  • y is a HER-2 and/or an EGFR inhibitor, and
  • z is a PI3K inhibitor or an AKT inhibitor
  • colorectal cancer stem cells for use in the depletion of colorectal cancer stem cells in the curative or preventive treatment of colorectal cancer.
  • the pharmaceutical composition of the invention is a pharmaceutical combination comprising, as sole active principles, the active principles x + y+ z wherein
  • x is a B-Raf inhibitor or a MEK inhibitor
  • y is an HER-2 and/or an EGFR inhibitor, and; z is a PI3K inhibitor or an AKT inhibitor
  • colorectal cancer stem cells for use in the depletion of colorectal cancer stem cells in the curative or preventive treatment of colorectal cancer.
  • the present invention also relates to a pharmaceutical combination comprised of the active principles x + y+ z wherein
  • x is a B-Raf inhibitor or a MEK inhibitor
  • y is a HER-2 and/or an EGFR inhibitor and
  • z is a PI3K inhibitor or an AKT inhibitor
  • colorectal cancer stem cells for use in the depletion of colorectal cancer stem cells in the curative or preventive treatment of colorectal cancer.
  • the treatment with the combination of the invention in fact, besides being a treatment that can be carried out against an already existing colorectal cancer, can also be carried out as a preventive treatment in patients having a dissemination of cancer stem cells, even a non-visible one, e.g. after having undergone surgery for colorectal cancer removal.
  • B-Raf inhibitor can refer to a single inhibitor for each category or to a set of inhibitors for each category, therefore the above-mentioned terms can be replaced, in the present invention, by the terms “one or more B-Raf inhibitors”; “one or more HER-2 and/or EGFR inhibitors”; “one or more PI3K inhibitors” and “one or more AKT inhibitors”.
  • inhibitor/inhibitors moreover has the meaning commonly accepted in biology, therefore indicating an agent or a group of agents capable of inhibiting, and therefore of preventing, the function of the target molecule.
  • HER-2 has the meaning commonly known in the literature, and therefore corresponds to receptor 2 for human epidermal growth factor, encoded by gene ErbB2.
  • HER-2 is a protein having membrane receptor tyrosine kinase-type function, positioned externally to the cell (external face), involved in signal transduction pathways leading to cell growth and differentiation.
  • inhibitor when referred, e.g., to a membrane receptor, has a very clear meaning for a person skilled in the art and indicates an agent able to inhibit, i.e. to prevent, the function of the receptor.
  • HER-2 being a membrane receptor
  • a HER-2 inhibitor or inhibitors are to be understood as an agent or a group of agents able to inhibit the function of said receptor.
  • HER-2 inhibitors are known in the state of the art with no need of any inventive activity by a person skilled in the art in the identification of such agents.
  • HER-2 inhibitor it is meant an inhibitor able to specifically inhibit said receptor and optionally also the EGFR receptor as defined below.
  • EGFR also known as HER-1 too is a protein having membrane receptor function (in particular, it is the epidermal growth factor receptor). Therefore, in the case of EFGR as well, EGFR being a membrane receptor, an EGFR inhibitor or inhibitors are to be understood as an agent or a group of agents able to inhibit the function of said receptor.
  • HER-2 inhibitors EGFR inhibitors or inhibitors of both, therefore also HER-2 and EGFR inhibitors, inhibitors inhibiting also EGFR (HER-1) are included in the invention.
  • the present invention relates in particular to a therapeutic combination wherein said HER-2 and/or EGFR inhibitor is anyone HER-2 inhibitor or anyone EGFR inhibitor or anyone HER-2 and EGFR inhibitor useful for curative purposes known to a person skilled in the art.
  • inhibitors specific for each of these receptors or for both of these receptors are known (by "specific” it is meant inhibiting only HER-2 or only EGFR or only HER-2 and EGFR).
  • Such an inhibitor for the purposes of the present invention, may be, e.g., a monoclonal antibody or a small molecule, as long as said inhibitor be specific for HER-2 as mentioned above, or for EGFR or for both.
  • the term "specific" when referred to an inhibitor is synonymous, in the entire description, with a selectivity of the inhibitor for the molecule of interest and with a non-interaction thereof with other molecules, meant as ability to inhibit the function of a molecule and not of other ones.
  • an inhibitor specific for HER-2 is an inhibitor inhibiting only HER-2 function
  • an inhibitor specific for EGFR is an inhibitor inhibiting only EGFR function
  • a HER-2 and EGFR inhibitor is an inhibitor inhibiting only HER-2 and EGFR functions.
  • HER-2 inhibitors useful in the combination of the present invention can be selected in the group comprising the monoclonal antibody trastuzumab (trade name Herceptin), Trastuzumab emtansin (trastuzumab antibody conjugated to the mertansin molecule (trade name Kadcila), the monoclonal antibody pertuzumab, Lapatinibe, the small molecule CP-724714 (2-Methoxy-N-[(E)-3-[4-[3-methyl-4-(6- methylpyridin-3-yl) oxyaniline]quinazolin-6-yl]prop-2-enyl]acetamide), which is a potent HER-2 inhibitor.
  • trastuzumab trade name Herceptin
  • Trastuzumab emtansin tacuzumab antibody conjugated to the mertansin molecule
  • Kadcila the monoclonal antibody pertuzumab
  • Lapatinibe
  • said inhibitor is the monoclonal antibody trastuzumab or conjugates thereof.
  • EGFR inhibitors useful in the combination of the present invention can be selected in the group comprising: Cetuximab, Futuximab, Imgatuzumab, Matuzumab, Necitumumab, Nimotuzumab, Panitumumab, Zalutumumab.
  • the EGFR inhibitor is selected from Cetuximab and panitumumab.
  • HER-2 and EGFR inhibitors useful in the combination of the present invention can be selected in the group comprising
  • the HER-2 inhibitor is selected from Pertuzumab and Trastuzumab.
  • B-Raf inhibitor anyone agent known in the literature specifically inhibiting the pathway triggered by B-Raf protein, which is an intracellular protein encoded, in humans, by the BRAF gene.
  • B-Raf inhibitors against active and inactive conformations of the kinase domain of the protein have been developed and are known in the literature.
  • Known B-Raf inhibitors classically belong to the category of small molecules, as B-Raf is a protein found inside the cell.
  • the B-Raf inhibitor is selected from Vemurafenib, dabrafenib and LGX818.
  • the Ras-Raf-MEK-ERk pathway is a set of proteins allowing signal transmission from surface receptors to the nucleus. In many tumors, a defect in the MAP/ERK pathway leads to uncontrolled cell growth. When a mitogenic stimulus activates EGFR through a series of phosphorylations, Ras activation is had, which in turn stimulates RAF protein kinase activity. RAF kinase activates downstream MEK (both MEK1 and MEK2, which in turn activates MAPK which regulates the activities of many transcriptional factors.
  • the known MEK inhibitors (acting on MEK, MEK1 , MEK2, MEK5) useful in the combination of the present invention can be selected in the group comprising: Selumetinib (AZD6244), PD0325901 , Trametinib (GSK1120212), U0126-EtOH, PD184352, PD98059, BIX02189, Pimasertib (AS-703026), BIX02188, TAK-733, AZD8330, Binimetinib, SL-327, Refametinib (BAY86-9766), PD318088.
  • the EGFR inhibitor is selected from: Selumetinib (AZD6244), PD0325901 , Trametinib (GSK1 120212), Binimetinib, Refametinib (BAY86-9766).
  • PI3K it is meant a family of enzymes also referred to as phosphoinositide 3- kinase or phosphatidylinositol-3-kinase or PI 3-kinase, which are enzymes involved in cell mechanisms such as cell growth, proliferation, differentiation, motility and intracellular survival, and are also involved in cancer development.
  • PI3K inhibitors are known to the technician in the field, e.g., Patent Application WO2010/029082 describes numerous PI3K inhibitors (derivatives of 2-carboxamide cycloamino urea of formula (I) of the cited Patent Application) and anyhow in the literature numerous other commercially available small molecules are known, such as, according to a non-limiting example of the present invention, the small molecule BEZ235 (NVP-BEZ235, Dactolisib) (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)- 2,3-Dihydroimidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile), the small molecule Pictilisib (GDC-0941)2-(1 H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)- 4-morpholinylthieno[3,2-d
  • said inhibitor is BKM120, BYL719, I P1145, PX866, GDC-0941 , BEZ235, ZSTK474, GS-9973 and GS-1 10.
  • the AKT or PI3K-AKT pathway is a signal transduction pathway promoting cell survival and growth following extracellular stimuli.
  • AKT is a serin/treonin kinase, that is recruited on the membrane following activation of a surface receptor and consequently PI3K phosphorylation, which, via PIP3 activates AKT. Its activation triggers responses leading to cell survival, growth, proliferation, cell migration and angiogenesis increase.
  • the term "AKT inhibitor” indicates a pharmacological agent able to inhibit AKT kinase activity.
  • the AKT inhibitor is selected from the group comprising: ARQ 092.MK-2206, Perifosine (KRX-0401), GSK690693, GSK2141795, Ipatasertib (GDC-0068), AZD5363, PF-04691502, AT7867.
  • the AKT inhibitor is selected from ARQ 092, MK-2206, Perifosine.
  • each of the three inhibitors can be, e.g., administered according to the administration methods commonly used for each inhibitor.
  • the doctor in charge could modulate each time, depending on the patient's age, gender, weight and state of health, the dosage of inhibitors x y and z in the combination of the invention.
  • pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms that are suitable to be placed into contact with the tissues of a subject, e.g. a mammal or in particular a human being, without causing toxicity, or excessive allergic responses, or without causing complications not commensurated to a reasonable benefit-risk ratio.
  • kit preparation refers to a kit of parts, in the sense that the combination partners, (the above-defined inhibitors, or pharmaceutical compositions comprising them as sole active principles) can be dosed independently or can be used as fixed combinations with distinct amounts for each partner, simultaneously or at different time instants.
  • the components of the kit of parts may be, e.g., administered concomitantly or in set chronological orders, i.e. at different time instants and with time intervals equal or different for each component of the kit of parts.
  • a first inhibitor could be administered at time to with a periodicity x
  • the second one could be administered at time t1 with a periodicity y
  • the third one could be optionally administered at time t2 with a periodicity z
  • to, t1 and t2 can be the same or different
  • x, y and z can be the same or different.
  • each of the inhibitors according to the invention could be administered in a formulation and according to an administration pathway independent and optionally different from the other ones, therefore an inhibitor could e.g. be administered orally, whereas another one could, e.g., be administered injectably, etc.
  • coadministration or combined administration comprises the administration of the selected therapeutic treatments to an individual patient, and encompasses treatment regimens in which the agents are not necessarily administered along the same administration pathway and/or at the same time instant.
  • treat comprises a therapy that alleviates, reduces or mitigates at least one symptom in a subject, or that causes a slowing down or a partial or complete regression of the progression of the disease treated.
  • the treatment can result in the decrease of one of the various symptoms of the disease or in the complete eradication thereof.
  • the term “treat” also indicates stop, delay the development of a disease, or reduce the risk of the disease developing or getting worse.
  • Protected from a disease means instead prevent, delay or treat the development or the continuation or the worsening of a disease in a subject.
  • joint therapeutically active or the term “joint therapeutic effect” means that the therapeutic agents can be administered separately (in a staggered and possibly sequence-specific manner) in selected time intervals, to the subject to be treated, and that they exhibit an interaction having a cooperative effect, such as, e.g., a synergistic effect, as described herein.
  • pharmaceutically effective amount or “therapeutically effective amount” referred to a combination of agents is an amount sufficient to provide a clinically observable improvement of at least one of the symptoms of the disease with respect to the baseline.
  • subject or “patient” includes animals that can be affected by colorectal cancer, such as, e.g., mammals, in particular domestic or farmed mammals, rodents, and human beings. According to a preferred embodiment, the subject is a human being affected by said tumor or at risk of said tumor.
  • inhibitor and the term “specific” are as defined above.
  • cancer stem cells means “kill” or “prevent proliferation” and therefore substantially reducing and preferably eliminating the population of cancer stem cells.
  • the pharmaceutical combination as described herein is suitable for use in the curative and/or preventive treatment of colon cancer (where the preventive treatment can be carried out in subjects at risk of recurrence or of metastasis).
  • object of the present invention is also a kit of parts for a simultaneous, separate or sequential administration comprising one or more aliquots of a pharmaceutically acceptable formulation comprising the active principles x + y + z, wherein
  • x is a B-Raf inhibitor or a MEK inhibitor
  • y is a HER-2 and/or an EGFR inhibitor, and
  • z is a PI3K inhibitor or an AKT inhibitor
  • colorectal cancer stem cells for use in the depletion of colorectal cancer stem cells in the curative and/or preventive treatment of colorectal cancer.
  • the invention also relates to a therapeutic treatment wherein a pharmaceutical combination as described above or a kit of parts as described above are administered according to any one of the modes as described herein, to a subject in need of a curative or preventive treatment against colorectal cancer.
  • each inhibitor can be administered by administration pathways commonly used therefor according to a dosage that will be evaluated by the physician on the basis of age, gender and state of health of the patient to be treated.
  • the dosage used for each inhibitor could be similar to or lower than the minimum dosage commonly used for said inhibitor when administered in an independent manner and not in a combined one as in the present description.
  • the present invention therefore relates to
  • a pharmaceutical combination comprising the active principles x + y + z wherein
  • x is a B-Raf inhibitor or a MEK inhibitor
  • y is a HER-2 and/or an EGFR inhibitor and
  • z is a PI3K inhibitor or an AKT inhibitor
  • colorectal cancer stem cells for use in the depletion of colorectal cancer stem cells in the curative or preventive treatment of colorectal cancer.
  • HER-2 and/or EGFR inhibitor is a monoclonal antibody or a small molecule.
  • said HER-2 and/or EGFR inhibitor is selected from the group comprising the monoclonal antibody Trastuzumab, Trastuzumab emtansine, the monoclonal antibody Pertuzumab, the monoclonal antibody Erutmaxomab, Lapatinib, the small molecule CP-724714, Cetuximab, Futuximab, Imgatuzumab, Matuzumab, Necitumumab, Nimotuzumab, Panitumumab, Zalutumumab.
  • B- Raf inhibitor is selected from Vemurafenib (PLX4032, RG7204), PLX-4720, Dabrafenib (GSK2118436), GDC-0879, RAF265 (CHIR-265), AZ 628, NVP- BHG712, SB590885, ZM 336372, GW5074, TAK-632, CEP-32496, Encorafenib (LGX818).
  • MEK inhibitor is selected in the group comprising: Selumetinib, PD0325901 , Trametinib, U0126-EtOH, PD184352, PD98059, BIX02189, Pimasertib, BIX02188, TAK-733, AZD8330, Binimetinib, SL-327, Refametinib, PD318088.
  • MEK inhibitor is selected from Selumetinib, PD0325901 , Trametinib, Binimetinib, Refametinib.
  • PI3K inhibitor is selected from BEZ235 (NVP-BEZ235, Dactolisib), Pictilisib (GDC- 0941), LY294002, CAL-101 (Idelalisib, GS-1 101), BKM120 (NVP-BKM120, Buparlisib), PI-103, NU7441 (KU-57788), TGX-221 , IC-87114, XL147, ZSTK474, BIL719, AS-605240, PIK-75, 3-Methyladenine (3-MA), A66, SAR245409 (XL765), PIK-93, GSK2126458 (GSK458), PIK-90, PF-04691502, AZD6482, Apitolisib (GDC- 0980, RG7422), GSK1059615, Duvelisib (IPI-145, INK1 197), PF-05212384 (PK
  • AKT inhibitor is selected in the group comprising: ARQ 092, MK- 2206, Perifosine (KRX-0401), GSK690693, GSK2141795, Ipatasertib (GDC-0068), AZD5363, PF-04691502, AT7867.
  • kits of parts for a simultaneous, separate or sequential administration comprising one or more aliquots of a pharmaceutically acceptable formulation of a B-Raf inhibitor or of a MEK inhibitor; one or more aliquots of a pharmaceutically acceptable formulation of a HER-2 inhibitor or an EGFR inhibitor or an inhibitor of both; and one or more aliquots of a pharmaceutically acceptable formulation of a PI3K inhibitor or of an AKT inhibitor.
  • the pharmaceutical combination for use according to anyone of points 1 to
  • BRAF-V600E mutated colon CSTs were plated in "stem cell medium” alone or in the presence of 30uM Vemurafenib added every 48 hours and/or Trastuzumab 1 ug/ml and/or 5ug/ml Cetuximab added every 24 hours, for 120 hours. Viability of population survived to the abovementioned treatment was analyzed by using Cell Titer Glo luminescent cell viability assay kit (Promega) following the instructions of use.
  • Colon CSTs (3x10 5 ) were inoculated in the underskin of immunocompromised mice (Charles River). Mice were monitored for about 4 weeks until appearance of a palpable tumor, on which date the treatment described herebelow was initiated: PBS as Trastuzumab and Cetuximab control
  • Vemurafenib 20mg/Kg/day, with oral administration, in two administrations per day, for three/four weeks.
  • trastuzumab 5mg/Kg, with intraperitoneal administration once a week, for three/four weeks.
  • Cetuximab 40mg/Kg, with intraperitoneal administration twice a week, for three/four weeks.
  • BKM120 20mg/Kg/day, with oral administration, once a day, for three/four weeks.
  • Colon CSTs were transduced with lentiviral -TOP-D-GFP- vectors (Addgene, 35491), were the gene D-GFP was cloned downstream of a responsive LEF-1 / TCF promoter.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une combinaison de trois inhibiteurs différents à utiliser dans le traitement curatif et/ou préventif du cancer colorectal ; l'invention concerne également des méthodes de traitement curatif et/ou préventif d'un sujet atteint d'un cancer colorectal ou à risque de développer un tel cancer, lesdites méthodes consistant à administrer audit sujet une quantité thérapeutiquement efficace de ladite composition.
PCT/IB2016/053297 2015-06-04 2016-06-06 Combinaisons d'inhibiteurs de kinase pour le traitement du cancer colorectal WO2016193955A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102015000020429 2015-06-04
ITUB20151191 2015-06-04

Publications (1)

Publication Number Publication Date
WO2016193955A1 true WO2016193955A1 (fr) 2016-12-08

Family

ID=54288886

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/053297 WO2016193955A1 (fr) 2015-06-04 2016-06-06 Combinaisons d'inhibiteurs de kinase pour le traitement du cancer colorectal

Country Status (1)

Country Link
WO (1) WO2016193955A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111918656A (zh) * 2018-03-29 2020-11-10 柏林化学股份有限公司 用于联合治疗的抗癌药物组合物
CN112675176A (zh) * 2020-12-23 2021-04-20 南京景瑞康分子医药科技有限公司 Itm-1a8在制备预防和/或治疗肿瘤药物中的应用
EP3677284A4 (fr) * 2017-08-30 2021-05-19 Chongqing Upgra Biological Sci.&Tech., Ltd. Médicament intermédiaire ayant une activité anticancéreuse synergique et un médicament anticancéreux synergique couplé au polyéthylène glycol, leur procédé de préparation et leur utilisation
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
WO2022233782A1 (fr) * 2021-05-03 2022-11-10 Lead Discovery Center Gmbh Composition comprenant un inhibiteur de la transcription mitochondriale

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014025688A1 (fr) * 2012-08-07 2014-02-13 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de b-raf, un inhibiteur d'egfr et facultativement un inhibiteur de pi3k alpha

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014025688A1 (fr) * 2012-08-07 2014-02-13 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de b-raf, un inhibiteur d'egfr et facultativement un inhibiteur de pi3k alpha

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Vemurafenib B-raf Kinase Inhibitor Oncolytic", DRUGS OF THE FUTURE, PROUS SCIENCE, ES, vol. 36, no. 3, 1 January 2011 (2011-01-01), pages 191 - 199, XP007922458, ISSN: 0377-8282, DOI: 10.1358/DOF.2011.36.3.1590788 *
AZAB F ET AL: "BUPARLISIB Phosphatidylinositol 3-Kinase Alpha Inhibitor Oncolytic", DRUGS OF THE FUTURE, vol. 38, no. 2, February 2013 (2013-02-01), pages 73 - 79, XP002753238, DOI: 10.1358/DOF.2013.38.2.1924783 *
CIOMBOR K K ET AL: "Recent therapeutic advances in the treatment of colorectal cancer", ANNUAL REVIEW OF MEDICINE 20150114 ANNUAL REVIEWS INC. USA, vol. 66, 14 January 2015 (2015-01-14), pages 83 - 95, XP002753233, ISSN: 0066-4219 *
D BOSE ET AL: "Chemoresistant colorectal cancer cells and cancer stem cells mediate growth and survival of bystander cells", BRITISH JOURNAL OF CANCER, vol. 105, no. 11, 1 November 2011 (2011-11-01), pages 1759 - 1767, XP055192975, ISSN: 0007-0920, DOI: 10.1038/bjc.2011.449 *
E JIFU ET AL: "Combine MEK inhibition with PI3K/mTOR inhibition exert inhibitory tumor growth effect on KRAS and PIK3CA mutation CRC xenografts due to reduced expression of VEGF and matrix metallopeptidase-9.", TUMOUR BIOLOGY : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR ONCODEVELOPMENTAL BIOLOGY AND MEDICINE FEB 2015, vol. 36, no. 2, February 2015 (2015-02-01), pages 1091 - 1097, XP002753235, ISSN: 1423-0380 *
FANG DOUGLAS D ET AL: "Antitumor Efficacy of the Dual PI3K/mTOR Inhibitor PF-04691502 in a Human Xenograft Tumor Model Derived from Colorectal Cancer Stem Cells Harboring a PIK3CA Mutation", PLOS ONE, vol. 8, no. 6, June 2013 (2013-06-01), XP002753236, DOI: 10.1371/JOURNAL.PONE.0067258 *
G. MIGLIARDI ET AL: "Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas", CLINICAL CANCER RESEARCH, vol. 18, no. 9, 1 May 2012 (2012-05-01), US, pages 2515 - 2525, XP055222515, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-11-2683 *
J. G. GREGER ET AL: "Combinations of BRAF, MEK, and PI3K/mTOR Inhibitors Overcome Acquired Resistance to the BRAF Inhibitor GSK2118436 Dabrafenib, Mediated by NRAS or MEK Mutations", MOLECULAR CANCER THERAPEUTICS, vol. 11, no. 4, 1 April 2012 (2012-04-01), pages 909 - 920, XP055057160, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-11-0989 *
SORBERA L A ET AL: "Trastuzumab: Antineoplastic MAb", DRUGS OF THE FUTURE, vol. 23, no. 10, October 1998 (1998-10-01), pages 1078 - 1082, XP002753237, ISSN: 0377-8282 *
TROIANI T ET AL: "Maintenance treatment with cetuximab and BAY86-9766 increases antitumor efficacy of irinotecan plus cetuximab in human colorectal cancer xenograft models", CLINICAL CANCER RESEARCH 20150915 AMERICAN ASSOCIATION FOR CANCER RESEARCH INC. USA, vol. 21, no. 18, 27 May 2015 (2015-05-27), pages 4153 - 4164, XP002753234, ISSN: 1078-0432 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
EP3677284A4 (fr) * 2017-08-30 2021-05-19 Chongqing Upgra Biological Sci.&Tech., Ltd. Médicament intermédiaire ayant une activité anticancéreuse synergique et un médicament anticancéreux synergique couplé au polyéthylène glycol, leur procédé de préparation et leur utilisation
US11484600B2 (en) 2017-08-30 2022-11-01 Chongqing Upgra Biotechnology Co., Ltd. Intermediate drug with synergistic anticancer activity and polyethylene glycol-coupled synergistic anticancer drug, and preparation method therefor and use thereof
CN111918656A (zh) * 2018-03-29 2020-11-10 柏林化学股份有限公司 用于联合治疗的抗癌药物组合物
CN111918656B (zh) * 2018-03-29 2023-08-08 柏林化学股份有限公司 用于联合治疗的抗癌药物组合物
TWI816768B (zh) * 2018-03-29 2023-10-01 德商柏林化學股份公司 用於組合療法之抗癌症醫藥組成物
CN112675176A (zh) * 2020-12-23 2021-04-20 南京景瑞康分子医药科技有限公司 Itm-1a8在制备预防和/或治疗肿瘤药物中的应用
CN112675176B (zh) * 2020-12-23 2022-04-22 南京景瑞康分子医药科技有限公司 Itm-1a8在制备预防和/或治疗肿瘤药物中的应用
WO2022233782A1 (fr) * 2021-05-03 2022-11-10 Lead Discovery Center Gmbh Composition comprenant un inhibiteur de la transcription mitochondriale

Similar Documents

Publication Publication Date Title
AU2019204938B2 (en) Mdm2 inhibitors and combinations thereof
EP1339458B1 (fr) Combinaison comprenant un agent diminuant l'activite du facteur de croissance endotelial vasculaire et un agent diminuant l'activite du facteur de croissance de l'epiderme
KR102456088B1 (ko) 폐의 비소세포 암종 및 난소암을 치료하기 위한 디안하이드로갈락티톨 및 이의 유사체 또는 유도체
JP6532878B2 (ja) 組合せ医薬
JP6280546B2 (ja) ジアンヒドロガラクチトール、ジアセチルジアンヒドロガラクチトール、ジブロモズルシトール、又はこれらの類似体若しくは誘導体を用いた、遺伝子多型又はａｈｉ１の調節不全若しくは変異を有する患者におけるチロシンキナーゼインヒビター抵抗性悪性腫瘍を処置するための方法
RU2496500C2 (ru) Применение производных пиримидина для лечения egfr-зависимых заболеваний или заболеваний с приобретенной резистентностью к агентам, направленным против членов семейства egfr
US20220184090A1 (en) Combination products with tyrosine kinase inhibitors and their use
WO2016193955A1 (fr) Combinaisons d'inhibiteurs de kinase pour le traitement du cancer colorectal
JP2019511526A (ja) がんの処置のための、Ｎｏｔｃｈ阻害剤およびＣＤＫ４／６阻害剤の併用療法
MXPA06008157A (es) Tratamiento de gliomas malignos con inhibidores de factor de crecimiento transformante-beta.
US20160129003A1 (en) Pharmaceutical Combinations
JP6768682B2 (ja) メラノーマの処置に使用するためのアピリモド
CN101222850A (zh) 治疗对药物有抗性的癌症的方法
JP2016529285A (ja) 細胞増殖性疾患を治療するためのａｌｋ阻害剤とｃｄｋ阻害剤との組合せ
Chen et al. Novel PI3K/Akt/mTOR pathway inhibitors plus radiotherapy: strategy for non-small cell lung cancer with mutant RAS gene
KR20170081261A (ko) 방사선과 함께 폐의 비-소세포 암종 및 다형성 교아종을 치료하기 위한 디안하이드로갈락티톨
WO2014177915A1 (fr) Multi-thérapie anti-cancéreuse utilisant des dérivés de imidazo[4,5-c]quinoline
JP2010534219A (ja) Ｅｇｆｒ依存性疾患またはｅｇｆｒファミリーメンバーを標的とする薬剤に対して耐性を獲得した疾患の処置のための、イミダゾキノリンの使用
WO2018092064A1 (fr) Combinaisons d'inhibiteurs de mdm2 et d'inhibiteurs de bcl-xl
RU2443418C2 (ru) КОМБИНАЦИЯ ПИРИМИДИЛАМИНОБЕНЗАМИДА И ИНГИБИТОРА КИНАЗ mTOR
RU2774612C2 (ru) Терапевтические комбинации, содержащие ингибитор raf и ингибитор erk
JP2024523861A (ja) がんを処置するための併用療法におけるｅｇｆｒ阻害剤およびｐｅｒｋ活性化剤、ならびにこれらの使用
CN117479943A (zh) 组合疗法中的egfr抑制剂和perk活化剂及其用于治疗癌症的用途
NZ786604A (en) Combination therapy with notch and cdk4/6 inhibitors for the treatment of
EA040191B1 (ru) Комбинированная терапия

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16739553

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16739553

Country of ref document: EP

Kind code of ref document: A1