WO2013049859A1 - Treating pancreatic cancer and non-small cell lung cancer with atr inhibitors - Google Patents

Treating pancreatic cancer and non-small cell lung cancer with atr inhibitors Download PDF

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WO2013049859A1
WO2013049859A1 PCT/US2012/058374 US2012058374W WO2013049859A1 WO 2013049859 A1 WO2013049859 A1 WO 2013049859A1 US 2012058374 W US2012058374 W US 2012058374W WO 2013049859 A1 WO2013049859 A1 WO 2013049859A1
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patient
cells
combination
cancer
gemcitabine
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PCT/US2012/058374
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English (en)
French (fr)
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John Robert POLLARD
Philip Michael Reaper
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Vertex Pharmaceuticals Incorporated
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Priority to JP2014533486A priority Critical patent/JP6162126B2/ja
Priority to MX2019006684A priority patent/MX392542B/es
Priority to NZ623119A priority patent/NZ623119B2/en
Priority to EP12772860.8A priority patent/EP2750679B1/en
Priority to EP20180337.6A priority patent/EP3733185B1/en
Priority to CN201280057951.1A priority patent/CN103957917A/zh
Priority to BR112014007690-1A priority patent/BR112014007690B1/pt
Priority to MX2014003785A priority patent/MX373340B/es
Priority to SG11201401095YA priority patent/SG11201401095YA/en
Priority to RU2014117666A priority patent/RU2648507C2/ru
Priority to IN2501CHN2014 priority patent/IN2014CN02501A/en
Priority to AU2012315384A priority patent/AU2012315384B2/en
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to CA2850491A priority patent/CA2850491C/en
Priority to ES12772860T priority patent/ES2899880T3/es
Priority to KR1020147011670A priority patent/KR102056586B1/ko
Publication of WO2013049859A1 publication Critical patent/WO2013049859A1/en
Priority to IL231813A priority patent/IL231813B/en
Priority to ZA2014/02627A priority patent/ZA201402627B/en
Priority to AU2017206224A priority patent/AU2017206224A1/en
Priority to AU2019203240A priority patent/AU2019203240B2/en

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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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines 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
    • 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
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1092—Details
    • A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device

Definitions

  • Pancreatic cancer is the tenth most common site of new cancers and is responsible for 6% of all cancer related deaths.
  • the 5-year survival rate is less than 5%.
  • Lung cancer is the second most common form of cancer and is the leading cause of cancer-related mortality.
  • NSCLC non-small cell lung cancer
  • chemotherapy for the majority of patients therapy involves chemotherapy and / or radiation treatment. The selection of chemotherapy is highly variable based on disease stage, patient performance criteria and geographical regional preference.
  • chemotherapy is based on a doublet that includes a platinating agent such as Cisplatin or carboplatin and a second cytotoxic drug such as gemcitabine, etoposide or taxotere.
  • therapy can include treatment with agents that target specific proteins that are mutated or disregulated such as ALK and EGFR (eg crizotinib, gefitinib and erlotinib).
  • agents that target specific proteins that are mutated or disregulated such as ALK and EGFR (eg crizotinib, gefitinib and erlotinib).
  • crizotinib, gefitinib and erlotinib eg crizotinib, gefitinib and erlotinib.
  • ATR ATM and Rad3 related
  • ATM and Rad3 related kinase is a protein kinase involved in cellular responses to certain forms of DNA damage (eg double strand breaks and replication stress).
  • ATR kinase acts with ATM ("ataxia telangiectasia mutated") kinase and many other proteins to regulate a cell's response to double strand DNA breaks and replication stress, commonly referred to as the DNA Damage Response ("DDR").
  • DDR DNA Damage Response
  • the DDR stimulates DNA repair, promotes survival and stalls cell cycle progression by activating cell cycle checkpoints, which provide time for repair.
  • Healthy cells can rely on a host of different proteins for DNA repair including the DDR kinases ATR and ATM. In some cases these proteins can compensate for one another by activating functionally redundant DNA repair processes. On the contrary, many cancer cells harbour defects in some of their DNA repair processes, such as ATM signaling, and therefore display a greater reliance on their remaining intact DNA repair proteins which include ATR.
  • ATR inhibitors may be useful for cancer treatment, either used alone or in combination with DNA damaging agents, because they shut down a DNA repair mechanism that is more important for cellular survival in many cancer cells than in healthy normal cells.
  • disruption of ATR function e.g. by gene deletion
  • ATR inhibitors may be effective both as single agents and as potent sensitizers to radiotherapy or genotoxic chemotherapy.
  • hypoxic cancer cells are known to be resistant to treatment, most notably IR treatment, and are highly aggressive.
  • components of the DDR can be activated under hypoxic conditions and it has also been shown that hypoxic cells are more reliant on components of the DDR for survival.
  • This invention relates to uses of ATR inhibitors for treating pancreatic cancer and non-small cell lung cancer.
  • this invention relates to methods of treating pancreatic cancer in a patient (e.g., a human) with an ATR inhibitor in combination with gemcitabine and/or radiation therapy.
  • Applicants have demonstrated synergistic efficacy of ATR inhibitors in combination with gemcitabine and/or radiation therapy in clonogenic and viability assays on the pancreatic cancer cell lines, (e.g. PSN-1, MiaPaCa-2 and Panc-1) as well as in a primary tumor line (e.g., Panc-M).
  • Disruption of ATR activity was measured by assessing DNA damage induced phosphorylation of Chkl (Ser 345) and by assessing DNA damage foci and RAD51 foci following irradiation.
  • non-small cell lung cancer With respect to non-small cell lung cancer, his invention relates to methods of treating non-small cell lung cancer with an ATR inhibitor in combination with cisplatin or carboplatin, etoposide, and ionizing radiation.
  • Applicants have demonstrated synergy of ATR inhibitors in combination with cisplatin, etoposide, gemcitabine, oxaplatin and irinotecan in viability assays against a panel of 35 human lung cancer cell lines as well as demonstrated in vivo efficacy in a lung cancer mouse model in combination with cisplatin.
  • FIG. 1 VE-821 radiosensitises pancreatic tumour cells. A) Western blot analysis of Chkl inhibition.
  • Cells were treated with 100 nM gemcitabine for 1 h, 1 ⁇ VE-821 was added 1 h later and cells were irradiated (6 Gy) 1 h after that. Drugs were left for the duration of the experiment and cells were lysed at 2 h post- irradiation and subjected to Western blot analysis.
  • VE-821 radiosensitizes pancreatic tumour cells but not normal fibroblasts.
  • PSN-1, Panc-1, MiaPaCa-2 pancreatic cancer cell lines and MRC5 fibroblasts were treated with increasing concentrations of VE-821 for 96 h combined with or without 4 Gy radiation at 1 h after VE-821 addition.
  • Cell viability was measured after 8 days and shown as normalized to DMSO-treated cells.
  • PSN-1 cells were plated as single cells, treated with 1 ⁇ VE-821 at different time points in relation to 4 Gy irradiation and assessed for colony formation after 10 days.
  • the survival fraction at 4 Gy for each of the treatment schedules was determined by taking into account the relevant plating efficiency of unirradiated cells.
  • VE-821 radiosensitises pancreatic tumour cells under hypoxic conditions.
  • Cells were treated with increasing concentrations of gemcitabine for 24 h followed by 72 h treatment of 1 ⁇ VE-821. Colony forming ability was assessed after 10 to 21 days.
  • VE-821 perturbs the irradiation-induced cell cycle checkpoint in pancreatic cancer cells.
  • VE-821 increases 53BP1 and ⁇ 2 ⁇ foci number and reduces RAD51 foci formation.
  • PSN-1 cells were plated as single cells, treated with luM VE-821 for various time periods and assessed for colony formation after 10 days.
  • VE-821 perturbs the irradiation-induced G2/M checkpoint in pancreatic cancer cells in hypoxic conditions.
  • Fig 2X Assessment of radiosensitivity in tumour cells and normal cells.
  • PS 1 and MiaPaca cells were plated at low densities, treated with the drugs indicated and assessed for clonogenic survival.
  • MiaPaca cells were plated at low densities and drug was added at various time points in relation to the 4Gy radiation treatment: lh prior to IR, 5min after IR, 2h or 4h after IR; and removed at various time points: 5min after, lh after, or 19h after IR. Clonogenic survival was assessed after 14 days. Results are shown as the surviving fraction at 4Gy (top panel) or the percentage radiosensitisation (middle panel) compared to the DMSO-treated cells. The different treatment schedules did not cause differences in plating efficiency (bottom panel).
  • Fig 4X DNA damage foci analysis after Compound 822 treatment and irradiation.
  • MiaPaca cells were treated with 80nM Compound 822 lh prior or lh post irradiation and drug was washed away at 5min after or lh after IR. Cells were fixed after 6h (for RAD51 foci) or 24h (for gH2AX and 53BP 1 foci). The percentage of cells containing more than a certain number of foci was quantitated.
  • Fig 5X Cell cycle analysis of Compound 822-treated cells after 6Gy irradiation.
  • PSN1 cells were treated with 40nM Compound 822 lh prior to 6Gy irradiation in triplicate wells. Cells were lifted and fixed at several time points after IR, stained with propidium iodide and analysed by flow cytometry.
  • Figure 5Y Effect of VE-822 and cisplatin on tumor volume and body weight in a primary adenocarcinoma NSCLC xenograft in SCID mice.
  • Figure 6Y Effect of VE-822 administered PO q2d at 10, 30 or 60 mg/kg in combination with gemcitabine (15 mg/kg IP q3d) on the tumor volume of mice bearing PS 1 pancreatic cancer xenografts.
  • One aspect of this invention provides methods for treating pancreatic cancer in a patient by administering to the patient an ATR inhibitor in combination with another known pancreatic cancer treatment.
  • One aspect of the invention includes administering the ATR inhibitor in combination with gemcitabine.
  • the pancreatic cancer comprises one of the following cell lines: PSN-1, MiaPaCa-2 or Pane- 1.
  • the cancer comprises the primary tumor line Panc-M.
  • Another aspect of the invention provides methods for treating cancer (e.g., pancreatic or non-small cell lung) in a patient by administering to the patient an ATR inhibitor in combination with radiation therapy.
  • cancer e.g., pancreatic or non-small cell lung
  • Another aspect of the invention provides methods for treating non-small cell lung cancer in a patient by administering to the patient an ATR inhibitor in combination with cisplatin or carboplatin, etoposide, and/or ionizing radiation.
  • ATR inhibitors in combination with cisplatin, etoposide, gemcitabine, oxaliplatin and irinotecan in viability assays against a panel of 35 human lung cancer cell lines as well as demonstrated in vivo efficacy in a lung cancer mouse model in combination with cisplatin.
  • This invention also relates to the use of ATR inhibitors in combination with cisplatin or carboplatin, etoposide, and/or ionizing radiation for treating non-small cell lung cancer.
  • Another aspect provides a method of treating pancreatic cancer by administering to pancreatic cancer cells an ATR inhibitor selected from a compound in Table 1 in combination with one or more cancer therapies.
  • the ATR inhibitor is combined with chemoradiation, chemotherapy, and/or radiation therapy.
  • chemoradiation refers to a treatment regime that includes both chemotherapy (such as gemcitabine) and radiation.
  • the chemotherapy is gemcitabine.
  • Yet another aspect provides a method of increasing the sensitivity of pancreatic cancer cells to a cancer therapy selected from gemcitabine or radiation therapy by administering an ATR inhibitor selected from a compound in Table 1 in combination with the cancer therapy.
  • the cancer therapy is gemcitabine. In other embodiments, the cancer therapy is radiation therapy. In yet another embodiment the cancer therapy is chemoradiation.
  • Another aspect provides a method of inhibiting phosphorylation of Chkl (Ser 345) in a pancreatic cancer cell comprising administering an ATR inhibitor selected from a compound in Table 1 after treatment with gemcitabine (e.g., 100 nM) and/or radiation (e.g., 6 Gy) to a pancreatic cancer cell.
  • an ATR inhibitor selected from a compound in Table 1 after treatment with gemcitabine (e.g., 100 nM) and/or radiation (e.g., 6 Gy) to a pancreatic cancer cell.
  • Another aspect provides method of radiosensitizing hypoxic PSN-1, MiaPaCa-2 or PancM tumor cells by administering an ATR inhibitor selected from a compound in Table 1 to the tumor cell in combination with radiation therapy.
  • Yet another aspect provides a method of sensitizing hypoxic PSN-1, MiaPaCa-2 or PancM tumor cells by administering an ATR inhibitor selected from a compound in Table 1 to the tumor cell in combination with gemcitabine.
  • Another aspect provides a method of sensitizing PSN-1 and MiaPaCa-2 tumor cells to chemoradiation by administering an ATR inhibitor selected from a compound in Table 1 to the tumor cells in combination with chemoradiation.
  • Another aspect provides a method of disrupting damage-induced cell cycle checkpoints by administering an ATR inhibitor selected from a compound in Table 1 in combination with radiation therapy to a pancreatic cancer cell.
  • Another aspect provides a method of inhibiting repair of DNA damage by homologous recombination in a pancreatic cancer cell by administering an ATR inhibitor selected from a compound in Table 1 in combination with one or more of the following treatments: chemoradiation, chemotherapy, and radiation therapy.
  • the chemotherapy is gemcitabine.
  • Another aspect provides a method of inhibiting repair of DNA damage by homologous recombination in a pancreatic cancer cell by administering an ATR inhibitor selected from a compound in Table 1 in combination with gemcitabine and radiation therapy.
  • the pancreatic cancer cells are derived from a pancreatic cell line selected from PSN-1, MiaPaCa-2 or Panc-1.
  • the pancreatic cancer cells are in a cancer patient. In other embodiments, the cancer cells are part of a tumor.
  • Another embodiment provides methods for treating non-small cell lung cancer in a patient by administering to the patient an ATR inhibitor in combination with other known non-small cell lung cancer treatments.
  • One aspect of the invention includes administering to a patient an ATR inhibitor in combination with cisplatin or carboplatin, etoposide, and / or ionizing radiation.
  • Another aspect provides a method of treating non-small cell lung cancer by administering to a patient an ATR inhibitor selected from a compound in Table 1 in combination with one or more cancer therapies.
  • the ATR inhibitor is combined with chemoradiation, chemotherapy, and/or radiation therapy.
  • chemoradiation refers to a treatment regime that includes both chemotherapy (such as cisplatin, carboplatin, or etoposide) and radiation.
  • the chemotherapy comprises Cisplatin or carboplatin, and etoposide.
  • Yet another aspect provides a method of increasing the sensitivity of non-small cell lung cancer cells to a cancer therapy selected from cisplatin or carboplatin, etoposide, and ionizing radiation by administering to a patient an ATR inhibitor selected from a compound in Table 1 in combination with one or more cancer therapy.
  • the cancer therapy is cisplatin or carboplatin. In other embodiments, the cancer therapy is radiation therapy. In yet another embodiment the cancer therapy is etoposide.
  • the cancer therapy is a combination of cisplatin or carboplatin, etoposide, and ionizing radiation.
  • the cancer therapy is cisplatin or carboplatin and etoposide.
  • the cancer therapy is cisplatin or carboplatin and etoposide and ionizing radiation.
  • the cancer therapy is cisplatin or carboplatin and ionizing radiation.
  • Another aspect provides a method of inhibiting phosphorylation of Chkl (Ser 345) in a non-small cell lung cancer cell comprising administering to a patient an ATR inhibitor selected from a compound in Table 1.
  • the ATR inhibitor is administered in combination with gemcitabine (e.g., 100 nM), cisplatin or carboplatin, etoposide, ionizing radiation or radiation (e.g., 6 Gy) to a non-small cell lung cancer cell.
  • the non-small cell lung cancer cells are in a cancer patient.
  • the ATR inhibitor is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the ATR inhibitor is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Another aspect provides use of an ATR inhibitor selected from a compound in Table 1 in combination with gemcitabine and radiation therapy for treating pancreatic cancer.
  • Another aspect provides use of an ATR inhibitor selected from a compound in Table 1 in combination with cisplatin or carboplatin, etoposide, and ionizing radiation for treating non-small cell lung cancer.
  • the ATR inhibitor is Compound VE-821. In other embodiments, the ATR inhibitor is Compound VE-822. Manufacture of Medicaments
  • Another aspect provides use of an ATR inhibitor selected from a compound in Table 1 in combination with gemcitabine and radiation therapy for the manufacture of a medicament for treating pancreatic cancer.
  • Another aspect provides use of an ATR inhibitor selected from a compound in Table 1 in combination with cisplatin or carboplatin, etoposide, and ionizing radiation for the manufacture of a medicament for treating non-small cell lung cancer.
  • the ATR inhibitor is Compound VE-821. In other embodiments, the ATR inhibitor is Compound VE-822.
  • MiaPaCa-2, PSN-1, Panel and MRC5 cells (5 x 104) were plated in 96-well plates and after 4 h treated with increasing concentrations of VE-821 at 1 h before irradiation with a single dose of 6 Gy. Medium was replaced 96 h post-irradiation at which point viability was measured using the using the Alamar Blue assay (Resazurin substrate, SIGMA). Cells were allowed to proliferate and cell viability was again analyzed at day 8 for the different treatment conditions. Cell viability and surviving fraction were normalized to the untreated (control) group.
  • VE-821 (1 ⁇ ) was added 1 h prior to irradiation (6 Gy) and was washed away 72 h after irradiation.
  • cells were initially exposed to increasing concentrations of gemcitabine (5, 10 and 20 nM) for 24 h before addition of the VE-821 (1 ⁇ ) for another 72 h.
  • the effect of triple combination of irradiation with VE-821 and gemcitabine was examined as well.
  • Cells were incubated for 10-21 days until colonies were stained with 0.5% crystal violet and counted in a CellCount automated colony counter (Oxford Optronix). Clonogenic survival was calculated and data were fitted in the GraphPad Prism 4.0 (GraphPad Software, CA).
  • MiaPaCa-2 and PSN-1 cells were exposed to gemcitabine and/or 1 ⁇ VE- 821 drug 1 h prior to irradiation with a single dose of 6 Gy.
  • Cells were lysed in RIPA buffer 2 h post- irradiation and subjected to SDS-PAGE electrophoresis and immunoblotting.
  • Chemoluminescence (SuperSignal, Millipore) and film exposure was used to detect antibody binding. Exposed film was digitized and figures were assembled using Microsoft PowerPoint.
  • All cell lines were seeded in 30 ⁇ of tissue culture medium containing 10% FBS into 384-well opaque-bottom assay plates. The seeding density was based on the logarithmic growth rate of each cell line. After 24 hours, compound stock solutions were added to each well to afford a matrix consisting of 5 concentrations for VE-822 and 6 concentrations for chemotoxics. Each well contains either, agent alone or a combination of both agents. The final concentration range for VE-822 was 25 nM- 2 ⁇ .
  • the concentration ranges for the chemotoxics were as follows: Etoposide, 10 nM-10 ⁇ ; Gemcitabine, 0.16 nM-160 nM; Cisplatin, 20 nM-20 ⁇ ; Oxaliplatin, 40 nM-40 ⁇ ; Irinotecan (SN-38), 0.12 nM-120 nM. The cells were then incubated for 96 hours at 37°C in an atmosphere of 5% CO 2 and 95% humidity.
  • All cell lines were seeded in 30 ⁇ of tissue culture medium containing 10% FBS into 384-well opaque-bottom plates. The seeding density was based on the logarithmic growth rate of each cell line. After 24 hours, compound stock solutions were added to each well to afford a matrix consisting of 9 concentrations for VE-822 and 7 concentrations for Gemcitabine and Cisplatin. Each well contains either, agent alone or a combination of both agents. The final concentration ranges were as follows: VE-822, 0.3 nM-2 ⁇ ; Gemcitabine, 0.3 nM-0.22 ⁇ ; Cisplatin, 30 nM-20 ⁇ . The cells were then incubated for 96 hours at 37°C in an atmosphere of 5% CO 2 and 95% humidity.
  • This assay measures the number of viable cells in a culture based on the quantitation of ATP, which is present in metabolically active cells.
  • CellTiter-Glo Reagent Promega, Madison, WI, USA was prepared according to the manufacturer's instructions and added 96 hours after compound addition (25 ⁇ /well) to measure cell viability. Luminescence signal was measured with the PHERAStarFS (BMG Labtech, Cary, NC, USA) automated plate reader. All cell lines were screened in duplicate.
  • Raw luminescence CellTiter-Glo (CTG) values were normalized to the mean CTG value for the negative control DMSO-treated samples on each assay plate.
  • IC5 0 values for chemotoxic alone were calculated using DMSO-normalized cell survival values for the samples treated with chemotoxic compound alone.
  • VE-822 -treated chemotoxic IC5 0 values were calculated using VE-822 -normalized cell survival values for all samples treated with the chemotoxic at a given concentration of VE-822.
  • a 3x or greater reduction in IC5 0 was used to identify strongly synergistic effects between VE-822 and chemotoxics.
  • Tumor tissue was excised from a patient with a poorly differentiated adenocarcinoma. This tumor tissue was implanted subcutaneously in the flank of a SCID mouse and passaged twice before compound testing. For compound testing passage-two tumor tissue was implanted subcutaneously in the flank of SCID mice and tumors grown to a volume of about 200mm 3 .
  • Cisplatin was dosed alone at either 1 or 3 mg/kg ip, once per week (ip, q7d, on day 2 of each week) for two weeks.
  • VE-822 was dosed as a solution alone at 60 mg/kg po on 4 consecutive days per weekly cycle (qd4, dosed on days 1, 2, 3 and 4 each week).
  • Two combination groups received cisplatin at 1 or 3 mg/kg plus VE-822 at 60 mg/kg po on the same schedule as the single agent group.
  • a control group received vehicle alone (10% Vitamin E TPGS in water, po qd4). All drug treatment was stopped on Day 28. Vehicle, cisplatin (1 mg/kg) and VE-822 (60 mg/kg) groups were sacrificed and the remainder monitored for a further 40 days to assess tumor re-growth.
  • PSN1 cells (1 x 10 6 cells per mouse) were implanted as a mixture in Matrigel ( ⁇ per mouse) into the flank of female nude MF1 mice and grown to a volume of about 200mm 3 prior to compound administration.
  • _Gemcitabine was dosed alone at 15 mg/kg ip, once every three days (ip, q3d) in 0.5% methylcellulose in water for a maximum of 10 cycles.
  • VE-822 was dosed, as a suspension in 0.5%
  • methylcellulose in water alone at either 10, 30 or 60 mg/kg po every other day for 28 days (po q2d).
  • Three combination groups received gemcitabine at 15 mg/kg plus VE- 822 either at 10, 30 or at 60 mg/kg po on the same schedule as the single agent groups.
  • a control group received vehicle alone (0.5% methylcellulose ip q3d). All drug treatment was stopped on Day 30. Vehicle and VE-822 groups were sacrificed on day 13 due to excessive tumor volumes.
  • Compound VE-821 inhibits phosphorylation of Chkl (Ser 345) after treatment with gemcitabine (100 nM), radiation (6 Gy) or both (see Fig. 1A).
  • Compound VE-821 radiosensitises pancreatic tumour cells but not normal cells. When cells were irradiated in the presence of Compound VE-821, a decrease in surviving fraction was observed and this radios ens itising effect increased as the drug incubation time after irradiation was extended (see figure 1C).
  • Compound VE-821 radiosensitises tumour PSN-1, MiaPaCa-2 and PancM cells under hypoxic conditions (see figure 2A-B). Compound VE-821 also sensitises normoxic and hypoxic cancer cells to gemcitabine (see figure 3B-C). Compound VE- 821 potentiates the effect of chemoradiation in both PSN-1 and MiaPaCa-2 cancer cells (see figure 3D). Compound VE-821 disrupts damage-induced cell cycle checkpoints (see supplementary figure 2). Compound VE-821 inhibits repair of DNA damage by homologous recombination (see figures 5A, 5B, and 5C).
  • Results for Compounds 821 and 822 are shown in Figures IX to 8X and 1Y to 6Y.
  • VE-821 and VE-822 sensitize cancer cells to radiation therapy (see Figures 1X-5X ).
  • VE-822 enhances the antitumor effects of cancer therapies in xenograft models
  • VE-822 enhances the antitumor effects of ionizing radiation in a MiaPaCa pancreatic cancer xenograft model (see Figure 6X) and in a PSN-1 pancreatic cancer xenograft model (see Figures 7X and 8X).
  • VE-822 enhances the antitumor effects of cisplatin in a primary
  • Black filled circles are vehicle treatment; Red filled diamonds are Cisplatin treatment (lmg kg q7d); Blue filled diamonds are Cisplatin treatment (3mg/kg q7d); Green filled squares are VE- 822 treatment (60mg/kg qd4); Green empty triangles are Cisplatin (lmg/kg) and VE- 822 (60mg/kg qd4); Blue empty triangles are Cisplatin (3mg/kg) and VE-822 (60mg/kg qd4) (see Figure 5Y).
  • VE-822 also enhances the antitumor effects of gemcitamine in a PSN1 pancreatic cancer xenograft model.
  • Red filled circles are VE-822 treatment; Black filled squares are vehicle treatment; Green filled circles are gemcitabine treatment; Blue filled circles are gemcitabine and VE-822 (lOmg/kg) treatment; Red filled circles are gemcitabine and VE-822 (30mg/kg) treatment; Pink filled circles are gemcitabine and VE-822 (60mg/kg) treatment;
  • VE-822 synergizes with chemotoxics across a panel of lung cancer cell lines
  • the heat map represents the maximum shift in IC5 0 of each chemotoxic achieved when combined with VE-822 for 96 hours. Colors represent an IC5 0 shift range from -10 (antagonism, blue) to 10 (synergy, red) (see Figure 1Y). VE-822 exhibits greater than 3 -fold synergy with cisplatin, etoposide, gemcitabine, oxaplatin and irinotecan in lung cancer cell lines (see Figure 2Y).
  • VE-822 Synergizes with Cisplatin and Gemcitabine in pancreatic cancer cell lines.
  • the heat map represents the maximum shift in IC5 0 of each chemotoxic achieved when combined with VE-822 for 96 hours. Colors represent an IC5 0 shift range from -10 (antagonism, blue) to 10 (synergy, red) (see Figure 3Y).

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