WO2021001431A1 - Utilisation d'inhibiteurs sélectifs de pi3ka pour traiter une maladie métastatique chez des patients souffrant de cancer du pancréas - Google Patents

Utilisation d'inhibiteurs sélectifs de pi3ka pour traiter une maladie métastatique chez des patients souffrant de cancer du pancréas Download PDF

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WO2021001431A1
WO2021001431A1 PCT/EP2020/068536 EP2020068536W WO2021001431A1 WO 2021001431 A1 WO2021001431 A1 WO 2021001431A1 EP 2020068536 W EP2020068536 W EP 2020068536W WO 2021001431 A1 WO2021001431 A1 WO 2021001431A1
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pi3ka
cancer
cell
metastatic
pi3k
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PCT/EP2020/068536
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Julie GUILLERMET-GUIBERT
Benoît THIBAULT
Carmen Fernanda RAMOS DELGADO
Elvire PONS-TOSTIVINT
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paul Sabatier Toulouse Iii
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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
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles 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
    • A61K31/535—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
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is in the field of oncology.
  • PI3Ks are composed of 8 isoforms distributed into 3 classes.
  • Each class I PI3K dimers called RI3Ka, RI3Kb, RI3Kg and PI3K6 are composed of a catalytic subunit (pi 10a, pi 10b, pi lOy and p 11 Od) and a regulatory subunit (p85 for a, b and g, and pl01/p87 for g).
  • PI3Ka and RI3Kb are ubiquitously expressed
  • RI3Kg and RI3Kd are restricted to cardiovascular system and leukocytes in normal tissues but can be found overexpressed in solid tumours (1).
  • PI3Ks are lipid kinases which phosphorylate phosphatidyl inositol 4,5 - biphosphate (PIP2) into PIP3 that acts as a second messenger and regulates various functions in normal and tumour cells via the PI3K/Akt/mTOR pathway.
  • PIP2 phosphatidyl inositol 4,5 - biphosphate
  • the PI3K/Akt axis is frequently hyper-activated in cancers and has been tested as a clinical target in the recent years (2,3).
  • PI3K inhibitors are currently described as cytostatic agents, since PI3K activity is critically driving oncogenesis in a cell-autonomous manner.
  • tumoural PI3K activity by itself contributes to the rewiring of tumoural immune microenvironment. This demonstration could pave the road for the use of PI3K-targeted therapies in combination with immunotherapies and/or chemotherapies (3,5).
  • Pancreatic ductal adenocarcinoma is a cancer with dramatic prognostic (6) where activation of class I PI3K is high and linked with a poor prognostic (7).
  • Localised, locally advanced and metastatic PDAC is characterised by early relapse of surgery and failure of long term disease control with chemotherapies.
  • PI3K/Akt is one of the most critically affected (8).
  • the lipid kinase PI3Ka was shown by us and others to drive initiation of pancreatic cancer downstream of oncogenic Kras (9, 10). However, little is known concerning the importance of this PI3K isoform in the progression of existing tumours towards a metastatic disease.
  • cfDNA Cell free DNA
  • ctDNA tumour DNA
  • ctDNA represents a variable fraction of cfDNA (12) and can be distinguished by the presence of specific cancer-associated mutations.
  • the exact biological mechanisms underlying the release of cfDNA remain unclear: it can be due to apoptosis and necrosis of cancer cells (or healthy cells), and it can be secreted directly by tumour or micro-environment cells such as immune and inflammatory cells (13).
  • cfDNA had been studied as an exploratory biomarker of micrometastatic disease in PD AC (15), we propose that cfDNA as a sign of micro-metastatic disease could predict signal targeted efficiency towards metastatic dissemination and have chosen pancreatic ductal adenocarcinoma (PD AC) as a paradigmatic model of inflammatory micrometastatic disease to demonstrate our hypothesis.
  • PD AC pancreatic ductal adenocarcinoma
  • the present invention relates to methods for treating metastatic disease in patients suffering from pancreatic cancer.
  • Pancreatic ductal adenocarcinoma is a paradigmatic model of undetected micrometastatic disease. This clinical situation being poorly investigated, we devised a novel preclinical protocol using circulating cell-free DNA (cDNA) as a micrometastatic disease biomarker. Amongst actionable markers of disease progression, a novel PI3Ka activation signature specifically correlated with poor prognosis independently of patient tumour staging as confirmed in patient-derived early metastatic cultures. Tumour-restricted genetic or pharmacological RI3Ka inhibition reduced micro-metastatic disease by acting on both tumoural cell migratory behaviour independently of genetic alterations and on the protumoural CD206- positive stroma. RI3Ka therefore drives pro-inflammatory metastatic features that could be pharmacologically targeted to delay macro-metastatic dissemination. Thus the results herein disclosed justify that patients with high cDNA levels should be treated with PI3Ka-selective inhibitors.
  • the first object of the present invention relates to a method of treating micrometastatic disease in a patient suffering from pancreatic cancer comprising administering to the patient a therapeutically effective amount of a PI3Ka- selective inhibitor.
  • pancreatic cancer or “pancreas cancer” as used herein relates to cancer which is derived from pancreatic cells.
  • pancreatic cancer included pancreatic adenocarcinoma (e.g., pancreatic ductal adenocarcinoma) as well as other tumors of the exocrine pancreas (e.g., serous cystadenomas), acinar cell cancers, and intraductal papillary mucinous neoplasms (IPMN).
  • pancreatic adenocarcinoma e.g., pancreatic ductal adenocarcinoma
  • other tumors of the exocrine pancreas e.g., serous cystadenomas
  • acinar cell cancers e.g., serous cystadenomas
  • IPMN intraductal papillary mucinous neoplasms
  • the pancreatic cancer is KRAS mutated.
  • KRAS refers to v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog.
  • KRAS is also known in the art as NS3, KRAS1, KRAS2, RASK2, KI-RAS, C-K-RAS, K-RAS2A, K-RAS2B, K-RAS4A and K-RAS4B.
  • This gene a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution can be responsible for an activating mutation.
  • KRAS mutations are well known in the art and are frequently found in neoplasms include those at exon 1 (codons 12 and 13) and exon 2 (codon 61) (e.g., the 34A, 34C, 34T, 35 A, 35C, 35T or 38A mutations).
  • Other examples of KRAS mutations include, but are not limited to, G12C, G12D, G13D, G12R, G12S, and G12V. Somatic KRAS mutations are found at high rates in leukemias, colorectal cancer (Burmer et al. Proc. Natl. Acad. Sci.
  • KRAS mutations are well known in the art and are commercially available (e.g. In Therascreen (Qiagen) assay, Taqman® Mutation Detection Assays powered by castPCRTM technology (Life Technologies)).
  • tumor metastasis has its general leaning in the art and refers to the condition of spread of cancer from the organ or tissue of origin to additional distal sites in the patient.
  • the process of tumor metastasis is a multistage event involving local invasion and destruction of intracellular matrix, intravasation into blood vessels, lymphatics or other channels of transport, survival in the circulation, extravasation out of the vessels into secondary sites and growth in the new location(s).
  • Increased malignant cell motility has been associated with enhanced metastatic potential in animal as well as human tumors.
  • micrometastatic disease has its general meaning in the art and refers to a locally invasive cancer from the organ or tissue of origin, for example, to proximal tissues or sentinel lymph nodes. Therefore the RI3Ka- selective inhibitor is thus particularly suitable for reducing metastatic dissemination and progression.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • PI3K has its general meaning in the art and refers to a phosphoinositide 3-kinase.
  • PI3Ks belong to a large family of lipid signaling kinases that phosphorylate phosphoinositides at the D3 position of the inositol ring (Cantley, Science, 2002, 296(5573): 1655-7).
  • PI3Ks are divided into three classes (class I, II, and III) according to their structure, regulation and substrate specificity.
  • Class I PI3Ks which include RI3Ka, RI3Kb, RI3Kg, and PI3K5, are a family of dual specificity lipid and protein kinases that catalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate (PIP2) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP3).
  • PIP3 functions as a second messenger that controls a number of cellular processes, including growth, survival, adhesion and migration. All four class I PI3K isoforms exist as heterodimers composed of a catalytic subunit (pi 10) and a tightly associated regulatory subunit that controls their expression, activation, and subcellular localization.
  • RI3Ka, RI3Kb, and PI3K5 associate with a regulatory subunit known as p85 and are activated by growth factors and cytokines through a tyrosine kinase-dependent mechanism (Jimenez, et al, J Biol Chem., 2002, 277(44):41556-62) whereas RI3Kg associates with two regulatory subunits (plOl and p84) and its activation is driven by the activation of G-protein- coupled receptors (Brock, et al., J Cell Biol., 2003, 160(1): 89-99).
  • Non-limiting examples of PI3Ka- selective inhibitors are disclosed in Schmidt-Kittler et al, Oncotarget (2010) l(5):339-348; Wu et al., Med. Chem. Comm. (2012) 3 :659-662; Hayakawa et al, Bioorg. Med. Chem. (2007) 15(17): 5837-5844; and PCT Patent Application Nos. WO2013/049581 and WO2012/052745, the contents of which are herein incorporated by reference in their entireties.
  • the PI3Ka- selective inhibitor is derived from imidazopyridine or 2-aminothiazole compounds.
  • Non-limiting examples include those described in William A Denny (2013) Phosphoinositide 3-kinase a inhibitors: a patent review, Expert Opinion on Therapeutic Patents, 23:7, 789-799. Further non limiting examples include BYL719, INK-11 14, INK-1117, NVP-BYL719 (Alpelisib), SRX2523, LY294002, PIK-75, PKI-587, A66, CH5132799 and GDC-0032 (taselisib).
  • One inhibitor suitable for the present invention is the compound 5-(2,6-di-morpholin-4-yl- pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine that is described in W02007/084786, which is hereby incorporated by reference in its entirety hereto.
  • Another inhibitor suitable for the present invention is the compound (S)-Pyrrolidine-l,2-dicarboxylic acid 2-amide l-( ⁇ 4- methyl-5-[2-(2,2,2-trifluoro-l,l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl ⁇ -amide) that is described in WO 2010/029082, which is hereby incorporated by reference in its entirety hereto.
  • the PI3Ka- selective inhibitor is an inhibitor of PI3Ka expression.
  • An“inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
  • said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme.
  • anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of PI3KA mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of PI3KA, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding PI3KA can be synthesized, e.g., by conventional phosphodiester techniques.
  • Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6, 107,091; 6,046,321; and 5,981,732).
  • Small inhibitory RNAs siRNAs
  • siRNAs can also function as inhibitors of expression for use in the present invention.
  • PI3KA gene expression can be reduced by contacting a patient or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that PI3KA gene expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector.
  • a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically cells expressing PI3KA.
  • the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus.
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus
  • adenovirus adeno-associated virus
  • SV40-type viruses polyoma viruses
  • Epstein-Barr viruses Epstein-Barr viruses
  • papilloma viruses herpes virus
  • vaccinia virus
  • the endonuclease is CRISPR-cas.
  • the endonuclease is CRISPR-cas9, which is from Streptococcus pyogenes.
  • the CRISPR/Cas9 system has been described in US 8697359 B1 and US 2014/0068797.
  • the endonuclease is CRISPR-Cpfl, which is the more recently characterized CRISPR from Provotella and Francisella 1 (Cpfl) in Zetsche et al. (“Cpfl is a Single RNA- guided Endonuclease of a Class 2 CRISPR-Cas System (2015); Cell; 163, 1-13).
  • the micrometastatic disease correlated with high cfDNA levels in the patients. Therefore qualifying the cfDNA level in sample obtained from the patient is suitable for determining whether the patient is eligible to the treatment with the RBKa-selective inhibitor.
  • the method of the present invention comprises the steps of i) quantifying the cfDNA level in a sample obtained from the patient ii) comparing said level with a predetermined reference level and iii) administering to the patient the therapeutically effective amount of the a PI3Ka-selective inhibitor when the level determined at step i) is higher than the predetermined reference value.
  • the term“cell free DNA” or“cfDNA” has its general meaning in the art and refers to the DNA nucleic acid is released by the cell and present in the sample.
  • Methods for determining the total concentration of cell free nucleic acids are well known in the art. For example, the method is described in WO2012/028746. Q-PCR is thus the preferred method for determining said concentration.
  • the method comprises the step of amplifying and quantifying a nuclear target nucleic acid sequence
  • the nuclear target nucleic acid sequence is a sequence which is located in the nucleus human genome. The skilled person can thus easily select the appropriate nuclear target nucleic acid sequences.
  • Cell free nucleic acid in a patient suffering from a cancer is constituted of nucleic acids of tumor and non-tumor origin.
  • the nuclear target nucleic sequence is a mutant target nucleic acid sequence.
  • the term“mutant nucleic acid” refers to a nucleic acid bearing a point mutation of interest. It is thus important to select a mutation which has a tumor origin to quantify only the nucleic acids which derives from cancer cells.
  • the mutation is located in a the KRAS gene or TP53 gene.
  • the mutation is located in a gene selected from the group consisting of TP53 (394, 395, 451, 453, 455, 469, 517, 524, 527, 530, 586, 590, 637, 641, 724, 733, 734, 743, 744, 817, 818, 819, 820, 839, 844, 916) or PIK3CA (1530, 1624, 1633, 1634, 1636, 1656, 3140, 3140, 3140).
  • KRAS mutation may include any mutation as described above.
  • the target nucleic acid sequences have a length between 160 and 210 base pairs.
  • the target nucleic acid sequence has a length of 160; 165; 170; 175; 180; 185; 190; 195; 200; 205; or 210 base pairs.
  • sample refers to any biological sample obtained from the subject that is liable to contain cell free nucleic acids.
  • samples include but are not limited to body fluid samples, such as blood, ascite, urine, amniotic fluid, feces, saliva or cerebrospinal fluids.
  • the sample is a blood sample.
  • blood sample it is meant a volume of whole blood or fraction thereof, e.g., serum, plasma, etc. Any methods well known in the art may be used by the skilled artisan in the art for extracting the free cell nucleic acid from the prepared sample.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount of drug may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of drug to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
  • the efficient dosages and dosage regimens for drug depend on the disease or condition to be treated and may be determined by the persons skilled in the art. A physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a suitable dose of a composition of the present invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen.
  • Such an effective dose will generally depend upon the factors described above.
  • a therapeutically effective amount for therapeutic use may be measured by its ability to stabilize the progression of disease.
  • a therapeutically effective amount of a therapeutic compound may decrease tumor size, or otherwise ameliorate symptoms in a subject.
  • An exemplary, non-limiting range for a therapeutically effective amount of drug is about 0.1-100 mg/kg, such as about 0.1-50 mg/kg, for example about 0.1-20 mg/kg, such as about 0.1-10 mg/kg, for instance about 0.5, about such as 0.3, about 1, about 3 mg/kg, about 5 mg/kg or about 8 mg/kg.
  • An exemplary, non-limiting range for a therapeutically effective amount of an antibody of the present invention is 0.02-100 mg/kg, such as about 0.02-30 mg/kg, such as about 0.05-10 mg/kg or 0.1-3 mg/kg, for example about 0.5-2 mg/kg.
  • Administration may e.g. be intravenous, intramuscular, intraperitoneal, or subcutaneous, and for instance administered proximal to the site of the target. Dosage regimens in the above methods of treatment and uses are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered overtime or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • treatment according to the present invention may be provided as a daily dosage of the agent of the present invention in an amount of about 0.1-100 mg/kg, such as 0.2, 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg/kg, per day, on at least one of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively, at least one of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 after initiation of treatment, or any combination thereof, using single or divided doses every 24, 12, 8, 6, 4, or 2 hours,
  • the RI3Ka- selective inhibitor is administered to the patient in the form of a pharmaceutical composition which comprises a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, di sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, polyethylene glycol and wool fat.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • the used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • Sterile injectable forms of the compositions of this invention may be aqueous or an oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include, e.g., lactose.
  • the active ingredient is combined with emulsifying and suspending agents.
  • certain sweetening, flavoring or coloring agents may also be added.
  • the compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • the compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Patches may also be used.
  • the compositions of this invention may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • an antibody present in a pharmaceutical composition of this invention can be supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials.
  • the product is formulated for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for Injection. The pH is adjusted to 6.5.
  • An exemplary suitable dosage range for an antibody in a pharmaceutical composition of this invention may between about 1 mg/m 2 and 500 mg/m 2 .
  • schedules are exemplary and that an optimal schedule and regimen can be adapted taking into account the affinity and tolerability of the particular antibody in the pharmaceutical composition that must be determined in clinical trials.
  • a pharmaceutical composition of the invention for injection e.g., intramuscular, i.v.
  • a further object of the present invention relates to a method of determining whether a patient achieve a response with a PI3Ka-selective inhibitor that is used for the treatment of the micrometastatic disease in patient suffering from pancreatic cancer comprising determining the cfDNA level in a sample obtained from the patient during the course of the treatment wherein a decrease in said level indicates that the patient achieves a response or wherein a stable level or an increase level indicates that the patient does not achieve a response.
  • the method is thus particularly suitable for discriminating responder from non responder.
  • the term“responder” in the context of the present disclosure refers to a patient that will achieve a response, i.e. a patient where the micrometastatic disease is eradicated, reduced or improved.
  • the responders have an objective response and therefore the term does not encompass patients having a stabilized cancer such that the disease is not progressing after the therapy with the PI3Ka- selective inhibitor.
  • a non responder or refractory patient includes patients for whom the micrometastatic disease does not show reduction or improvement after the therapy with the PI3Ka- selective inhibitor.
  • the term“non-responder” also includes patients having a stabilized cancer.
  • the characterization of the patient as a responder or non-responder can be performed by reference to a standard or a training set.
  • the standard may be the profile of a patient who is known to be a responder or non-responder or alternatively may be a numerical value.
  • Such predetermined standards may be provided in any suitable form, such as a printed list or diagram, computer software program, or other media.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1 PI3Ka inhibition delays the rapid progression of PD AC in KPC mice.
  • KPC mice diagnosed with aggressive carcinoma (6 mice per group) were given daily oral doses of vehicle or BYL-719 (50 mg/kg) for 10 days.
  • BYL-719 reduces the phosphorylation of Akt and ERK in pancreatic tissues as analysed by WB in whole tissue lysates 6h after gavage.
  • B Representative images and C, quantification of Ki67 positive cells in pancreatic tumours and in metastasized liver sections.
  • D Evaluation of PI3Ka inhibition on tumour growth rate.
  • E Development of ascites in KPC mice.
  • F Percentage of micro metastases in liver, lung and spleen in KPC mice.
  • H Quantification of cfDNA in KPC mice at different stages of the disease.
  • I Quantification of cfDNA in KPC mice after PI3Ka inhibition.
  • J Quantification of the 160 - 210bp fragment in KPC mice. Mean +/- SEM (* p ⁇ 0.05, ** p ⁇ 0.005, *** pO.0001)
  • PI3Ka activation signature was designed as the intersection of genes up- and down-regulated by shRNA against PIK3CA in a human PIK3CA mutated breast cancer cell line as well as PI3ka_human_LINCS_CMAP and PBKa human mTOR CMAP LINCS gene signatures (42,43). Hierarchical clustering between patients was performed using PI3Ka activation signature. Confirmed PD AC samples from public data bases were selected for further bioinformatical analysis. In details, mRNA expression data and clinical data from confirmed PDAC patients of PAAD (TCGA) (175 patients), PACA-AU (267 patients) and GSE21501 (102 patients - cohort enriched in locally advanced PDAC) cohorts were retrieved.
  • PI3K inhibitors All PI3K inhibitors were purchased (Clinisciences) and dissolved in DMSO to obtain a final concentration of 10 mM. PI3K inhibitors we stored in 10 mM stock solution in dimethyl sulfoxide (DSMO):
  • R211, PDAC8661, DT4994, 10158, 10593, R6344, R6430, R6065, R6141 are murine pancreatic cell lines obtained from KPC mice.
  • PANC-1 ATCC CRL-1469
  • Capan-2 ATCC HTB-80
  • AsPC-1 ATCC CRL-1682
  • HL-60 ATCC CCL- 240
  • NOMO-1 CVCL 1609
  • PC3 ATCC CRL- 1435
  • MDA-MB-231 (HTB-26) and MDA-MB-468 (HTB-132) are breast cancer cell lines. All the cell lines were obtained from the American Type Culture Collection (ATCC, Manassas, VA).
  • R211, PDAC8661, DT4994, 10158, 10593, R6344, R6430, R6065, R6141, PANC-1, MDA-MB-231 and MDA-MB-468 were cultured in DMEM (Dulbecco's Modified Eagle Medium) 4.5g of glucose supplemented with 10% foetal bovine serum, 1% L-Glutamine, 1% penicillin/streptomycin and 0.01% plasmocin.
  • Capan-2, AsPC-1, HL-60, NOMO-1 and PC3 were cultured in RPMI (Roswell Park Memorial Institute) supplemented as described previously. Cells were maintained in culture at 37°C in a humidified 5% CO2 atmosphere.
  • AML Acute myeloid leukaemia
  • WT WT
  • a-selective A66, BYL719
  • b-selective TGX-221, TGX-155
  • b/d-selective TGX-115, AZD8186
  • g-selective AS252424
  • pan PI3K inhibitors LY294002, BKM120, GDC0941, PI- 103 at 0.1, 1 and 10 mM in complete medium.
  • R211 and PDAC8661 cells (lxlO 5 cells) were seeded in 24-well plates. When cells reached confluence, a scratch was realised using a pipette tip and cells were treated or not with a-selective (A66, BYL719) and pan-PI3K inhibitors (LY294002, BKM120, GDC0941) at 0.01, 0.1 or 1 pM. Cells were observed after 8h and 24h by microscopy and the scratch surface was analysed using ImageJ software. Control cells were treated with 0.01% DMSO. 5 pictures were taken by condition and each experiment was performed at least three times.
  • Cells were transfected with Lipofectamine 2000 (ThermoFisher Scientic) transfection reagent in OptiMEM medium with SMARTpool ON-TARGETplus mouse siRNA (Dharmacon) targeting: Pik3ca, Pik3cb, Pik3cg, Pik3cd according to the manufacturer’s protocols.
  • ON-TARGETplus Non-targeting control siRNAs (Dharmacon) were used as negative controls. Twenty-four hours after transfection, cells were used for migration or qPCR experiments.
  • Membranes were then saturated 45 minutes in TBS (50 mM Tris, 150 mM NaCl)/0.1% Tween 20 (TBST)/5% milk and incubated overnight at 4°C under agitation with the corresponding primary antibody (see below). Membranes were washed 3 times with TBST and incubated lh30 with the corresponding secondary antibody coupled with horseradish peroxidase (see below). Membranes were washed 3 times with TBST and immunocomplexes were visualized using ECL RevelBlot Plus (Ozyme).
  • PDAC8661 (5xl0 4 cells) were seeded in 6-well plates containing glass slides. Twenty- four hours after seeding, cells were treated with a-selective (A66, BYL719) PI3K inhibitors at 1 or 10 mM. Fifteen minutes or 8 hours after treatment, cells were washed twice with PBS then fixed 10 minutes with paraformaldehyde (PFA) 4%/PBS. Cells were washed three times with PBS during 5 minutes then permeabilised 5 minutes with Triton X-100 1 %/PBS. Cells were washed three times with PBS during 5 minutes then non-specific antibody fixation was prevented with Bovine Serum Albumin (BSA) 1 %/PBS during 30 minutes.
  • BSA Bovine Serum Albumin
  • Actin was marked with 1 :200 phalloidin Texas-red (Sigma) during 30 minutes in the dark. Cells were washed three times with PBS during 5 minutes then marked one minute with 0.1 pg/mL DAPI. Cells were washed three times with PBS during 5 minutes then mounted with Mowiol on a glass slide. Cells were observed with a Cell Observer video microscope (Zeiss) with a 63x objective and the number of podosomes was counted using Zen software (Zeiss). Around 10 pictures were taken per slide. Control cells were treated with 0.1% DMSO.
  • Cells were cultured in 100 mm petri dishes until they reach 80% confluence. They were washed twice with cold PBS, scraped in cold PBS then centrifuged 5 minutes at 300g at 4°C. Cell pellet was resuspended and homogenized in 1 mL Trizol (Invitrogen). Chloroform was added (1/5 of Trizol volume), the suspension was vortexed then incubated 3 minutes at room temperature. The suspension was centrifuged 10 minutes at 18,000g at 4°C. The aqueous phase was isolated and completed with isopropanol (equal volume). The suspension was vortexed, incubated 10 minutes at 4°C then centrifuged 10 minutes at 18,000g at 4°C.
  • RNA concentration was determined with the NanoDrop (Thermofischer).
  • RT-qPCR 1 pg of RNA was used to obtain cDNA using the RevertAid H minus reverse transcriptase, random hexamers and the corresponding mix (ThermoScientific). Primers were all designed with Primer-BLAST (NCBI). qPCRs were realized using the SsoFast EvaGreen supermix (Bio-Rad). Actin was used as a housekeeping gene.
  • LSL-Kras G12D and LSL-p53 R172H knock-in from D. Tuveson, Mouse Models of Human Cancers Consortium repository, National Cancer Institute-Frederick
  • Pdxl-Cre from D.A. Melton, Harvard University, Cambridge, MA
  • pi 10a lox/lox from B.
  • Ultrasound imaging was performed using the VisualSonics Vevo2100 High Resolution System equipped with an ultrasound transducer in the 25-55MHz range. Animal preparation and imaging procedures were performed as described in Sastra et al (54). KPC mice were monitored once per week from 12 weeks old onwards; when a tumour was detected, the ultrasounds were performed every other day. Tumour area was measured by delimiting the tumour border and then obtaining the major axis, at least 5 replicates were performed per mice per ultrasound. Tumour growth rate corresponds to the increase (%) of the tumour size after the onset of the treatment.
  • cfDNA was extracted from blood plasma using the QIAmp DNA Mini Kit (QIAGEN) according to the kit’s protocol except for eluting the cfDNA in 50pL of elution buffer. cfDNA samples were stored at -20°C until further use.
  • cfDNA thresholds were calculated by compiling all cfDNA measurements from mice with normal pancreas, high grade Panins, localised and metastatic PD AC. For the survival curve (Kaplan-Meier), mice were assigned as normal, medium or high level of cfDNA according to the average of all their cfDNA values.
  • the Fragment AnalyzerTM was used to determine the size of DNA in blood plasma.
  • the DNF-474 High Sensitivity NGS Fragment Kit was used for characterizing the cfDNA.
  • Three different profiles of cfDNA fragmentation were obtained: for normal and healthy mice, the electropherogram did not present any fragment; for mice bearing high grade Panins and localised PD AC, a 160-210bp fragment was always found; for mice with metastatic PD AC, the electropherogram presented the aforementioned 160-210bp fragment, in addition to larger fragments but at lower concentrations.
  • BYL-719 was dissolved in 0.5% methyl cellulose with 0.2% Tween-80 and administered by oral gavage at 50mg/kg daily.
  • Tissues were fixed in 10% neutral-buffered formalin (Sigma HT501128) and embedded in paraffin.
  • tissues were serially sectioned (4pm), and then stained with haematoxylin eosin (H&E). All tissues were analysed in blinded fashion. Histopathological scoring of pancreatic lesions was performed on sections 100 pm apart, 3 sections per pancreas.
  • Immunostaining was conducted using standard methods on formalin-fixed, paraffin- embedded tissues. After rehydration, slides were permeabilised for 10 min in 0.1% Triton/1% PBS; they were later subjected to heat-antigen retrieval in citrate buffer. Slides were incubated 20 min with Protein Block (Dako X0909) for preventing non-specific binding. Subsequently, sections were incubated overnight with primary antibodies (See Table below), washed, incubated 15 min with 3% H2O2 and then washed. All antibodies were revealed using the HRP- Detection Reagent Signal Stain®Boost (CST 8114) and developed through AEC (Dako K3464) incubation. Slices were counterstained with haematoxylin and mounted using Glycergel Mounting Medium (Dako C0563).
  • a MILLIPLEX® MAP (Merc Millipore # MCYTMAG70PMX32BK) assay was performed using 25 pL of non-diluted mouse blood plasma. The assay was performed according to the manufacturer’s protocol. We tested for a panel of 32 mouse chemokines and cytokines: Eotaxin, G-CSF, GM-CSF, PTNGg, IL-la, IL-Ib, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, KC, LIF, LIX, MCP-1, M-CSF, MIG, MIP-la, MIR-Ib, MIP-2, RANTES, TNFa, and VEGF. Only the statistically significant results were presented. Statistical analysis
  • a RI3Ka specific transcriptomic signature inversely correlates with patients’ prognosis and correlates with pancreatic tumour cells aggressiveness
  • mPDAC metastatic PDAC
  • PDAC localised PDAC
  • CP chronic pancreatitis
  • PI3Ka activation gene signature based on expression levels of PI3Ka-regulated curated genes.
  • RI3Ka is a key enzyme necessary for insulin signalling (16), angiogenesis (17) and PDAC initiation (9).
  • PI3K/Akt/mTOR hallmark was significantly increased in mPDAC patients (data not shown).
  • PI3Ka activation scoring allowed to cluster 8/9 mPDAC patients (data not shown).
  • High scoring of PI3Ka activation was significantly increased in patients with poorest prognosis regardless of their stage (data not shown); patient cohorts enriched in locally advanced cancers had mostly a low scoring level of PI3Ka activation (data not shown).
  • PI3Ka activation signature can discriminate, amongst patients diagnosed as localised, those with better overall survival (OS) (data not shown).
  • PI3Ka is necessary for pancreatic cancer cell migration and survival in a Kras mutated context
  • a-selective inhibitors A66 and BYL-719 presented a concentration-dependent capacity to inhibit pancreatic cancer cell F-actin positive podosomes, cell motility and directed cell migration with strong effects observed at the low concentration of 1 mM, independently from effects on cell proliferation at the same concentration. All a-selective were able to strongly inhibit numbers of viable cells and Akt phosphorylation on Ser473, main downstream target of PI3K, at high concentrations (data not shown). As expected, pan-PI3K inhibitors were more efficient for decreasing cell numbers, however, for motility, migration and levels of p-Akt, the efficiency varied depending on the inhibitors.
  • a-selective inhibitors specifically reduced the phosphorylation of a protein of a lower molecular weight, possibly corresponding to Akt2.
  • Inhibiting pi 10a expression or the expression of all class I PI3K catalytic subunits induced the same inhibition of PDAC8661 migration, confirming the specific role of PI3Ka in pancreatic tumour cell migration (data not shown).
  • pan-PI3K inhibitors In order to find a pattern that could explain differences observed with pan-PI3K inhibitors, we tested the correlation between the in vitro IC50 of PI3K inhibitors (determined on recombinant proteins) for each class I PI3K isoform, and their capacity to inhibit migration in R211, PDAC8661 and PANC-1 cells (data not shown). We showed that, at 1 mM, the ability of all PI3K inhibitors to regulate cell migration strongly depends on their capacity to target PI3Ka, but not RI3Kb (data not shown). We reported the p-value of effect vs.
  • PI3Ka regulates pancreatic adenocarcinoma cell motility and migration regardless the driving oncogenic mutation
  • pancreatic tumour cell lines (10158 and 10593) induced by oncogenic PIK3CA (gene encoding for PI3Ka catalytic domain).
  • Most pancreatic cancer bearing patients harbour a Kras oncogenic mutation. Less of 5% patients present a PIK3CA oncogenic mutation; however, this mutation mimics Kras oncogenic pathway (18).
  • PI3Ka oncogenicity is also commonly described as directly coupled only to oncogenic Kras or tyrosine kinase receptors (19).
  • PI3Ka inhibition delays the rapid progression of PD AC and prevents protumoural M2 macrophages infiltration
  • KPC mice diagnosed with an aggressive carcinoma, detected through high-resolution ultrasound (US) imaging (data not shown), were treated with the PI3Ka-selective inhibitor, BYL-719, or vehicle ( Figure 1A).
  • BYL-719 In pancreas and not in spleen or lung, BYL-719 drastically reduces pS473-Akt and pT202/Y204-Erkl/2 phosphorylation (Figure 1A). BYL-719 line of treatment significantly reduced tumour cell proliferation in both primary and metastatic sites ( Figure 1 B, CT resulting in a delay in tumour growth rate, in ascites development as a marker of peritoneal dissemination, and in the development of distant metastases in liver, lung and spleen ( Figure 1D-F). While PDAC patients with increased levels of circulating tumoural DNA (ctDNA) present a worse prognostic (15), cell free circulating DNA (cfDNA) is a recognized marker of inflammation (11).
  • ctDNA circulating tumoural DNA
  • cfDNA cell free circulating DNA
  • PI3Ka hyper-activated oncogenic PI3Ka also increased the number of infiltrating macrophages around tumours as compared to oncogenic Kras-induced tumours (data not shown).
  • BYL-719 tended to increase IL-6-positive cells in pancreatic sections (data not shown); the genetic inactivation of half the expression of PI3Ka significantly increased IL-5 levels, decreased IL-6 production and CDCL5/LIX levels in plasma (data not shown).
  • CXCL5/LIX levels was found responsible of CD206-polarization and prostate cancer progression in metastatic stage (24).
  • the in vivo inhibition of PI3Ka delays the rapid progression of aggressive cfDNA-positive PD AC by preventing the infiltration of M2 pro- tumoural macrophages in peritumoural tissue.
  • Neoptolemos JP Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH.
  • Schlieman MG Fahy BN, Ramsamooj R, Beckett L, Bold RJ. Incidence, mechanism and prognostic value of activated ART in pancreas cancer. Br J Cancer. 2003;89:2110-5.
  • Vanhaesebroeck B Ali K, Bilancio A, Geering B, Foukas LC. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem Sci. 2005;30: 194-204.

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Abstract

L'adénocarcinome canalaire pancréatique est un modèle paradigmatique de maladie micrométastasique non détectée. Cette situation clinique étant mal étudiée, selon la présente invention, nous avons conçu un nouveau protocole préclinique utilisant de l'ADN libre circulant (ADNc) en tant que biomarqueur de maladie micrométastatique. Parmi les marqueurs exploitables de la progression de la maladie, une nouvelle signature d'activation de PI3Kα corrélée spécifiquement à un pronostic médiocre indépendamment de la stadification de la tumeur du patient est confirmée dans des cultures métastatiques précoces dérivées du patient. L'inhibition génétique ou pharmacologique de PI3Kα restreinte à une tumeur réduit une maladie micrométastatique en agissant à la fois sur le comportement migratoire des cellules tumorales indépendamment des altérations génétiques et sur le stroma positif pour CD206 protumoral. Par conséquent, PI3Kα induit des caractéristiques métastatiques pro-inflammatoires qui pourraient être ciblées de façon pharmacologique afin de retarder la dissémination macrométastatique. Par conséquent, les résultats décrits dans la spécification justifient que des patients avec des taux élevés d'ADNc devraient être traités avec des inhibiteurs sélectifs de PI3Kα.
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