FR3033499A1 - COMPOSITION FOR THE TREATMENT OF PANCREATIC NEUROENDOCRINE TUMORS - Google Patents

Abstract

The present invention relates to a composition comprising streptozotocin and at least one inhibitor of the PI3K / AKT / mTOR pathway, and their pharmaceutically acceptable salts. The present invention also relates to the use of this composition for the prevention or treatment of endocrine or neuroendocrine tumors, especially pancreatic endocrine tumors (TNEPs).

Description

The present invention relates to a composition for the treatment of neuroendocrine tumors, in particular pancreatic neuroendocrine tumors, and more particularly to a combination of at least two active principles for the treatment of these tumors. Pancreatic neuroendocrine tumors (PNEs) (or endocrine tumors of the pancreas or pancreatic islet tumors) are rare and heterogeneous tumors in their anatomopathological and clinical presentation. This makes diagnosis, prognosis and treatment relatively complicated. In addition, it has been shown that these tumors, whose proliferation is weak and whose response to apoptosis is deregulated, are chemoresistant. Therapeutic options are therefore limited and the first results of targeted therapy treatments show encouraging but partial responses. Conventional chemotherapy molecules (taxol, cisplatin) are generally ineffective for this pathology. This innate resistance is probably due to their low rate of proliferation and the increased expression of certain factors that can confer resistance to chemotherapy. Current cytotoxic treatments lead to stabilization but few tumor fonts. In addition, the sometimes slow evolution of the disease (relative survival rate of 40% at 10 years) implies a long-term therapeutic management with successive treatments with high toxicity and the appearance of acquired resistance. Streptozotocin is particularly known in the treatment of TNEPs, however it has been shown the appearance of resistance to this molecule. The PI3K / AKT / mTOR pathway is an intracellular signaling pathway regulating cell growth, cell proliferation, cell survival and angiogenesis. This signaling pathway is widely studied in the context of oncogenesis since most of the proteins constituting it are encoded by tumor suppressor genes or proto-oncogenes whose mutation can promote the development of a tumor process. This signaling pathway is in particular described by Dreyer et al (Cancero dig., 2009, vol.1, No. 3, 187-190). Among the proteins involved in the PI3K / AKT / mTOR pathway are the three PI3K, AKT and mTOR proteins. PI3K is a kinase-active heterodimer composed of two proteins (a p85 regulatory subunit and a p110 catalytic subunit). AKT is a protein kinase. mTOR (mammalian Target Of Rapamycin), also known as FRAP, RAF1 or RAPT1 is a 289-kDa serine / threonine kinase of the family of PIKKs (phosphoinositide 3-kinase-like kinases). mTOR associates with several other proteins to form two distinct complexes called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTOR is a central regulator of cell growth and proliferation. More specifically, mTOR regulates cell proliferation, cell growth, cell mobility, cell survival, protein synthesis and transcription. mTOR is activated by the PI3K / Akt axis and in turn phosphorese the effectors downstream of the PI3K / Akt signaling pathway. The mTOR signaling pathway is described in particular in Zoncu et al (Nature Rev Mol Cell Biol, 2011, 12, 21-35). The use of inhibitor of the mTOR signaling pathway for the treatment of TNEPs has been described. However, the results obtained show that the tumor melting remains limited (objective response less than 10%) and also show the appearance of resistance.

There is therefore an interest in developing new therapeutic axes for the treatment of TNEPs making it possible to overcome resistance acquired. An object of the present invention is therefore to provide new therapeutic axes for the treatment of neuroendocrine tumors, in particular TNEPs making it possible to overcome acquired resistances. Another object of the present invention is also to provide new therapeutic axes for improving the treatment of chimeroresistant tumors.

Yet another object of the present invention is to provide new therapeutic axes for obtaining better results in terms of apoptosis and tumor melting (reduction of the tumor surface). Other objectives will appear on reading the description of the invention which follows.

The subject of the present invention is therefore a composition comprising streptozotocin or a derivative thereof and at least one inhibitor of the PI3K / AKT / mTOR pathway, and their pharmaceutically acceptable salts, forms or derivatives. Preferably, the present invention relates to a composition comprising streptozotocin and at least one inhibitor of the PI3K / AKT / mTOR pathway, and their pharmaceutically acceptable salts.

The subject of the present invention is preferably a composition comprising streptozotocin and at least one inhibitor of the PI3K / AKT / mTOR pathway. Streptozotocin (STZ) is the compound 2-deoxy-2- ({[methyl (nitrosoamino) carbonyl} amino) -6-D-glucopyranose (CAS No. 18883-66-4). Synthesis are described in particular in U53027300 and FR2034735. This compound is especially marketed under the name Zanosare by the company Keocyt Among the derivatives of streptozotocin, there may be mentioned the compound of formula OH described in FR2092093 incorporated herein by reference. In the context of the present invention, the term inhibitor of the PI3K / AKT / mTOR pathway means any compounds capable of blocking this signaling pathway.The PI3K / AKT / mTOR signaling pathway is known. those skilled in the art and in particular described by Dreyer et al (Cancero dig., 2009, vol.1, No. 3, 187-190). More particularly, in the context of the present invention, the term "inhibitor of the PI3K / AKT / mTOR pathway all compounds capable of inhibiting one of the mTORC1 and / or mTORC complexes 2 and / or one of the PI3K and / or Akt enzymes intervening upstream of the mTOR pathway. Without wishing to be bound by any theory, the aforementioned inhibitors inhibit the action of the subject proteins. Preferably, in the context of the present invention, the inhibitors of the PI3K / AKT / mTOR pathway are chosen from: mTORC1 inhibitors; MTORC2 inhibitors; P13K inhibitors; Akt inhibitors; or PI3K inhibitors, mTORC1 and mTORC2, 30334994 alone or in admixture. Particularly preferably, inhibitors of the PI3K / AKT / mTOR pathway are selected from: PI3K inhibitors, mTORC1 and mTORC2; or - mTORC1 inhibitors, alone or in admixture. Such inhibitors are described in particular in documents WO2006 / 065601, WO2007 / 090913, WO2008 / 0318947, WO2008 / 144463, WO2009 / 071888, WO2009 / 032651, WO2009 / 032652, WO2009 / 032653, US5310903, WO95 / 16691, WO2008 / 070041, WO2006122806, incorporated herein by reference, alone or in admixture. Preferably, inhibitors of the PI3K / AKT / mTOR pathway are selected from BEZ235, BKM120, Everolimus (or RAD), MK-2206 dichlorate, Pictilisib, LY294002, CAL-101, PI-3065, HS-173, PI- 103, NU7441, TGX-221, I0-87114, Wortmannin, XL147, ZSTK474, BYL719, AS-605240, PIK-75, 3-methyladenine, A66, 5AR245409, PIK-93, GSK2126458, PIK-90, PF-04691502, AZD6482, Apitolisib, GSK1059615, Duvelisib, Gedatolisib, TG100-115, AS-252424, BGT226, CUDC-907, PIK-294, AS-604850, G5K2636771, BAY80-6946, YM201636, CH5132799, CAY10505, PIK-293, PKI For example: strand 2, WYE-125132, BET226, Palomid 529, PP121, PP242 WYE-687, CH5132799, WAY-600, Chrysophanic, ETP-46464, GDC-0349, GDC-0941, GDC-0068 XL388, Perifosine, G5K690693, lpatasertib , AZD5363, AT13148, PF-04691502, AT7867, Triciribine, 001128930, A-674563, P HT427, Miltefosine, Honokiol, 1I010, alone or in admixture. Preferably, the inhibitors of the PI3K / AKT / mTOR pathway are chosen in particular from the compounds defined in the documents WO2008 / 070041, US5310903, WO95 / 16691, WO2006122806 and BKM120, incorporated herein by reference, alone as a mixture. Preferably, inhibitors of the PI3K / AKT / mTOR pathway are selected from BEZ235, BKM120, Everolimus (or RAD), MK-2206 dichlorate, preferably BEZ235 or RAD, alone or in admixture.

BEZ235 is the compound of formula H2N N compound of formula BKM120 is the compound of formula Everolimus (or RAD) is MK-2206 dichlorate is the compound of formula The pharmaceutically acceptable salts may especially be addition salts with bases, they are for example pharmaceutically acceptable salts such as sodium salts, potassium salts, calcium salts, which are obtained using corresponding alkali metal and alkaline earth metal hydroxides as bases. As another type of addition salts with pharmaceutically acceptable bases, mention may be made of the salts with amines and in particular glucamine, N-methylglucamine, N, N-dimethylglucamine, ethanolamine, morpholine and N-methylmorpholine. or lysine. The salts can also be obtained with inorganic or organic acids and preferably pharmaceutically acceptable acids such as hydrochloric, phosphoric, fumaric, citric, oxalic, sulfuric, ascorbic, tartaric, maleic, mandelic, methanesulphonic, lactobionic, gluconic acids. glucaric, succinic, sulfonic or hydroxypropane sulfonate.

By pharmaceutically acceptable forms or derivatives are meant forms modified or derived from the above compounds allowing them to be assimilated by the organism. Preferably, in the compositions of the present invention, the weight ratio of streptozotocin to the inhibitor of the PI3K / AKT / mTOR pathway is from 100 to 500, preferably from 100 to 300. The present invention is preferably pharmaceutical compositions and may further comprise at least one pharmaceutically acceptable excipient. Said pharmaceutically acceptable excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art. The pharmaceutical compositions according to the invention may be presented in forms intended for parenteral, intravenous, oral, rectal, permucosal or percutaneous administration. They will therefore be presented as solutes or injectable suspensions or multi-dose vials, in the form of naked or coated tablets, dragees, capsules, capsules, pills, cachets, powders, suppositories or capsules. rectal, solutions or suspensions, for percutaneous use in a polar solvent, for permselective use. Suitable excipients for such administrations include cellulose derivatives or microcrystalline cellulose, alkaline earth carbonates, magnesium phosphate, starches, modified starches, lactose for solid forms.

For rectal use, cocoa butter or polyethylene glycol stearates are the preferred excipients. For parenteral use, water, aqueous solutes, physiological saline, isotonic solutes are the most conveniently used vehicles.

The present invention also relates to a kit comprising, on the one hand, streptozotocin, one of its derivatives or a pharmaceutically acceptable salt thereof and, on the other hand, at least one inhibitor of the PI3K / AKT / mTOR pathway or a salt thereof pharmaceutically acceptable forms or derivatives as defined above. Preferably, the kit comprises on the one hand streptozotocin and on the other hand at least one inhibitor of the PI3K / AKT / mTOR pathway. In this kit, streptozotocin and inhibitors of the PI3K / AKT / mTOR pathway can be packaged in separate preparations each with a pharmaceutically acceptable excipient, optionally capable of being mixed especially extemporaneously.

The invention also relates to the use of a composition or kit according to the invention for the preparation of a medicament. The invention also relates to the composition or kit according to the invention for its use as a medicament.

The invention also relates to the use of a composition or kit according to the invention for the prevention or treatment of neuroendocrocrine tumors (also called endocrine tumors), in particular pancreatic neuroendocrine tumors (TNEPs). ).

The invention also relates to the compositions or kit of the invention for use in the prevention or treatment of neuroendocrine tumors (also known as endocrine tumors), particularly pancreatic neuroendocrine tumors (TNEPs).

Surprisingly and advantageously, the inventors have shown that the combination of STZ and at least one inhibitor of the PI3K / AKT / mTOR pathway according to the invention has a synergistic activity on the treatment of neuronal tumors. endocrine diseases, including NETs. Surprisingly, the inventors have shown a synergistic action of the combination of these compounds on apoptosis and tumor melting (or reduction of the tumor surface).

The present invention relates in particular to the compositions, especially pharmaceutical compositions, or the kit of the invention for their use for the prevention or treatment of neuroendocrine tumors, in particular neuroendocrine tumors of the pancreas.

The present invention particularly relates to a method of preventing or treating neuroendocrine tumors, especially pancreatic neuroendocrine tumors, comprising administering an effective amount of a composition or kit according to the invention to a patient. who needs it.

The present invention relates in particular to the compositions or kit of the invention for the preparation of medicaments for the treatment of neuroendocrine tumors, especially neuroendocrine tumors of the pancreas. The present invention finally relates to a composition according to the invention or kit comprising STZ and at least one inhibitor of the PI3K / AKT / mTOR pathway as defined above, or a pharmaceutically acceptable salt, form or derivative thereof, for simultaneous, separate or sequential administration to a patient in need. For simultaneous administration, STZ and PI3K / AKT / mTOR inhibitor can be admixed in the same preparation containing them with a pharmaceutically acceptable vehicle or excipient. They can also be packaged in separate preparations each with a pharmaceutically acceptable excipient or vehicle, able to be mixed especially extemporaneously. In the case of separate or sequential administration, each of the active ingredients is packaged in a clean preparation containing a pharmaceutically acceptable vehicle or excipient.

The dosage may vary within important limits depending on the therapeutic indication, and the route of administration, as well as the age and weight of the subject. The identification of the patient who needs the above treatment is defined by those skilled in the art. By patient is meant a human being or an animal. A physician or veterinarian can identify, through clinical tests, physical examination, biological tests or diagnoses, and family and / or medical history, subjects who require such treatment. By sufficient amount is meant a quantity of composition according to the invention or the combination of STZ and at least one inhibitor of the PI3K / AKT / mTOR pathway of kit 35 according to the present invention effective to prevent or treat conditions. pathological, especially for the prevention or treatment of endocrine or neuroendocrine tumors, especially pancreatic neuroendocrine tumors. The sufficient amount can be determined by those skilled in the art, by means of conventional technique and by observation of the results obtained in similar circumstances. In order to determine the amount sufficient, various factors must be taken into account by those skilled in the art, including, but not limited to: the subject, its size, age, general state of health, the disease involved and its degree of severity ; the subject's response, the type of compound, the mode of administration, the bioavailability of the administered composition, the dosage, the concomitant use of other concomitant medications, etc. Preferably, in the composition or kit of the invention, the streptozotocin / PI3K / AKT / mTOR inhibitor ratio is such that streptozotocin is administered in an amount of 500 mg / day to 1500 mg / day, preferably from 750 mg / day to 1000 mg / day and the inhibitor of the PI3K / AKT / mTOR pathway is administered from 1 mg / day to 15 mg / day, preferably from 2.5 mg / day to 10 mg / day preferably 5 mg every other day at 10 mg / day.

The present invention will now be detailed by way of non-limiting examples. Figure 1 shows the STZ + inhibitory effects of the PI3K / AKT / mTOR pathway on mTOR pathway activation and apoptosis (cleavage of caspase-3).

Figures 2 to 4 show the intrahepatic tumor area after treatment with Streptozotocin, PI3K / AKT / mTOR inhibitors (Everolimus, BEZ-235, BKM-120) or Streptozotocin / PI3K / AKT inhibitor combination. / mTOR (ND = Not determined).

Additivity test: The MIN6 cells are seeded in 384-well plates at a density of 5000 cells per well in medium 251..11 (DMEM (Dulbecco's Modified Eagle Medium), 5mM glucose, 15% FCS (Fetal Calf Serum). 1% Penicillin / Streptomycin (100 IU / ml penicillin and 100 μg / ml streptomycin), 0.1% [3-mercaptoethanol) in an incubator at 37 ° C under 5% CO 2. 72 hours later, the medium is changed to medium containing or not containing streptozotocin or not to an inhibitor of the PI3K / AKT / mTOR pathway (everolimus, BKM-120, MK-2206, BEZ-235, Table 1), the The cells are incubated in the medium described above with or without streptozotocin additive and / or inhibitor of the PI3K / AKT / mTOR pathway. 24h after incubation in this medium, the plates are equilibrated for 30 minutes at room temperature. 25111 cell reagent glo reagent (Promega) is added according to the manufacturer's instructions. After 2 minutes stirring, the plates are allowed to incubate for 10 minutes at room temperature and the luminometry is read on a luminometer (Luminoskan Ascent 2.5, Thermo Scientific) for 1 second. A cell-free well is treated similarly, the result obtained for this negative control is deducted from the results obtained for the samples. The 5 test results are shown in Tables 2 to 5 below. The delta Bliss corresponds to the difference between the theoretical value obtained by the calculation A + B-AxB where A is the response for streptozotocin alone, B is the response for the inhibitor alone, and the value obtained. Bliss sum is then calculated by adding, for each streptozotocin / inhibitor pair, all the delta Bliss obtained. If Bliss sum is less than 0 the response is considered antagonistic, if Bliss sum is 0 the response is considered additive and if Bliss sum is greater than 0 the response is considered synergistic (Borisy et al. , Proc Natl Acad Sci U SA., 2003; 100 (13): 7977-82 Concentration Concentration Concentration Concentration Concentration 1 2 3 4 5 Streptozotocin 0.5mM 1mM 2mM 4mM 8mM Everolimus 0.05pM 0.1pM 0.5pM 1 pM 5pM BKM-120 0.01 μM 0.1 μM 1 μM 10 μM 100 μM MK-2206 0.05 μM 0.5 μM 5 μM 25 μM 50 μM BEZ-235 0.005 μM 0.001 μM 0.05 μM 0.1 μM 0.5 μM Table 1: Concentrations used for the additivity tests Delta Bliss (0/0) STZ (concentration in mM) Bliss sum 0 0.5 1 2 4 8 78 Everolimus 0 0 0 0 0 0 0 (concentration in μM) 0.05 0 5 5 9 4 1 0.1 0 4 2 4 2 1 0.5 0 7 5 7 1 1 1 0 4 -1 4 2 1 5 0 8 1 -1 0 0 Table 2 20 3033499 11 Delta Bliss (0/0) STZ (concentration in mM) Bliss sum 0 0.5 1 2 4 8 38 MK-2206 0 0 0 0 0 0 0 (concentration in μM) 0.05 0 1 4 12 5 3 0.5 0 -1 3 8 5 2 5 0 0 0 6 -5 0 25 0 0 0 0 -1 -1 50 0 0 0 0 -1 -1 Table 3 Delta Bliss (0/0) STZ (concentration) in mM) Bliss sum 0 0.5 1 2 4 8 188 BKM-120 0 0 0 0 0 0 0 (concentration in μM) 0.01 0 9 13 13 13 18 0.1 0 4 6 11 10 15 1 0 7 16 16 12 16 10 0 2 7 5 -3 7 100 0 5 6 -3 -7 -10 Table 4 Delta Bliss (0/0) STZ (concentration in mM) Bliss sum 0 0.5 1 2 4 8 96 BKM- 120 0 0 0 0 0 0 0 (concentration in μM) 0.005 0 3 8 16 13 27 0.001 0 2 2 12 8 21 0.05 0 18 4 24 9 28 0.1 0 14 -24 -7 -20 -9 0 TABLE 5 The results of the tests therefore show a synergism of the STZ association and inhibitor of the PI3K / AKT / mTOR pathway.

Evaluation of Activation of the mTOR Pathway and of Caspase-3 in Western Blot: The INS-13 Cells are Seeded in 6-well Plates at a Specific Gravity of 800,000 Cells per Well in 2m1 Medium (RPMI (Roswell) Park Memorial Institute Medium) 5mM glucose, 10% FCS, 1% Hepes, 1% sodium Pyruvate, 1% Penicillin / Streptomycin Streptomycin (100 IU / ml penicillin and 100 μg / ml streptomycin), 0.1% [ 3-mercaptoethanol) in an incubator at 37 ° C under 5% of 002. 72h later the medium is changed for medium containing or not containing streptozotocin or not with an inhibitors of the PI3K / AKT / mTOR pathway (see table 3 for the concentrations used), the cells are incubated under the above conditions in the presence of the treatments for 4 to 6 hours. Concentration Streptozotocin 2mM Everolimus 0.011.1M BKM-120 11..IM MK-2206 11..1M BEZ-235 0.11.1M Table 6: Concentrations used for activation of the PI3K / AKT / mTOR and caspase-3 pathway The cells are then harvested and the proteins extracted with the RIPA lysis buffer (Santa Cruz Technology): after 30 minutes of lysis with stirring, the solutions are centrifuged for 15 minutes at 13000 rpm at 4 ° C. The supernatant containing the proteins is recovered. 204 of proteins in XT Sample Buffer 4X (BioRad) are denatured at 95 ° C for 5 minutes and then plated on a Criterion XT Bis-Tris Gel acrylamide gel, 12%, (BioRad). The proteins migrate in MOPS buffer (BioRad) at 80Volts for 30 minutes then at 160Volts for 1h30. They are then transferred to a PVDF (polyvinylidene difluoride) membrane (Immobilon, Millipore) in Tris-Glycine Methanol transfer buffer (20mM Tris-base, 150mM Glycine, 20% methanol) at 100Volts for 1h. The membranes are then blocked (TBS (tris-buffered saline) -Tween0.01% -5% milk) and then incubated with the primary antibody recognizing the protein of interest overnight at 4 ° C. (see Table 7 antibodies used ). After several washings in TBS-Tween 0.01%, the membrane is incubated for 1 hour in the presence of a secondary antibody directed against the primary antibody. After several washes in 0.01% TBS-Tween, the antibody-antigen complexes are luminescent with the Luminata Crescendo 3033499 13 reagent (Millipore) on autoradiographic films. Tubulin is used as a protein load control. Protein of interest Antibody used AKT concentration (Phospho-Thr308) 13038 Cell signaling 1/1000 in TBS -Tween technology 0.01% - 5% Milk AKT (Phospho-Ser473) 9271 Cell signaling 1/1000 in TBS -Tween technology 0 , 01% - 5% BSA p70S6K (Phospho-Thr389) 9234 Cell signaling 1/1000 in TBS -Tween (normally protein technology 0.01% - 5% mTOR-activated BSA) 4E-BP1 (Phospho-T45) 2334-1 Epitomics 1/1000 in TBS -Tween (normally 0.01% protein - 5% mTOR activated BSA) Cleaved Caspase-3 (Asp175) 9664 Cell signaling 1/1000 in TBS -Tween technology 0.01% - 5% Tubulin Milk Sigma 1/1000 in TBS -Tween 0.01% - 5% Milk Table 7: Antibodies used for the Western blot analysis The results are shown in FIG. 1. These results show, according to the inhibitors, a PI3K inhibition. , mTOR and / or AKT. As for the BKM-120, it entails a total inhibition of the PI3K / AKT / mTOR pathway. Concerning the activation of apoptosis by cleavage of caspase-3, the results show an increase in cleavage of caspase-3 and thus of apoptosis compared to the results obtained for STZ alone. Evaluation of In Vivo Combinations INS-1 insulinoma cell xenograft mice aged 5 weeks are anesthetized with isoflurane. A mini left laparotomy is performed to remove the spleen from the abdominal cavity. The cell suspension (2.5 million insulinoma cells in 501.11 PBS phosphate-buffered saline (sterile) is injected into the spleen, and the abdominal wall and skin are sewn in two planes using resorbable surgical wire. They are weighed twice a week and start at 7 days after transplant and last for 3 to 5 weeks (as shown in Table 8).

The solution of STZ is prepared extemporaneously in a citrate solution prepared extemporaneously (stability approximately 20 minutes). PI3K / AKT / mTOR inhibitor solutions (MK-2206 and BKM-120) are prepared in DMSO and then diluted extemporaneously to the correct concentration in NaCl or water, respectively. BEZ-235 is diluted in 5% methylcellulose extemporaneously. Combination tested Treatment with STZ Treatment with P inhibitor I3K / AKT / mTOR STZ + Everolimus IP injection 5days / 7: 10mg / kg IP injection 5days / 7: 1.5mg / kg STZ + BEZ-235 IP injection 5days / 7: 10mg / kg Gavage 5days / 7: 45mg / kg STZ + BKM-120 IP injection 5days / 7: 10mg / kg Gavage 5days / 7: 60mg / kg IP = intraperitoneal Table 8: Treatment protocol for the xenograft model. The mice are treated with one or the other compound, or both in combination. The control mice are injected with NaCl and gavaged with NaCl or methylcellulose. The drinking water is supplemented with 10% sucrose. Each test is performed on 10 animals. After 3 to 5 weeks of treatment, the mice are killed, the liver, spleen and pancreas are removed and fixed in buffered formalin. After at least 24 hours, the organs are included in paraffin, cut and labeled in immunohistochemistry. A lining of the livers for chromogranin A makes it possible to identify the tumor cells. The tumor surface is analyzed in morphometry with the HISTOLAB software (Alphelys) and the data analyzed using the GraphPad Prism software (GraphPad Version 5.03). The results are shown in Figures 2 to 4 (* p <0.05, p <0.01) CTL represents the group of control mice not injected with STZ and / or PI3K pathway inhibitor. These results show that for the STZ + Everolimus and STZ + BEZ-235 combinations, the intrahepatic tumor area decreases significantly compared to untreated control mice, which is not the case in a STZ alone, Everolimus alone or BEZ-235 alone For the STZ + BKM-120 combination, the results show that the tumor area decreases sharply.

Claims (11)

A composition comprising streptozotocin or a derivative thereof and at least one inhibitor of the PI3K / AKT / mTOR pathway, and pharmaceutically acceptable salts, forms or derivatives thereof. 2. The composition according to claim 1, in which the inhibitor of the PI3K / AKT / mTOR pathway is chosen from compounds capable of inhibiting one of the mTORC1 and / or mTORC2 complexes and / or one of the PI3K enzymes. and / or Akt. 10 3. The composition according to claim 1, wherein the inhibitor of the PI3K / AKT / mTOR pathway is selected from: mTORC1 inhibitors; mTORC2 inhibitors; PI3K inhibitors; inhibitors of Akt; or PI3K inhibitors, mTORC1 and mTORC2. 4. A composition according to any one of claims 1 to 3, wherein the inhibitor of the PI3K / AKT / mTOR pathway is selected from BEZ235, BKM120, Everolimus (or RAD), MK-2206 dichlorate, Pictilisib, LY294002. , CAL-101, PI-3065, HS-173, PI-103, NU7441, TGX-221, IC-87114, Wortmannin, XL147, ZSTK474, BYL719, AS-605240, PIK-75, 3-methyladenine, A66, SAR245409 , PIK-93, GSK2126458, PIK-90, PF-04691502, AZD6482, Apitolisib, GSK1059615, Duvelisib, Gedatolisib, TG100-115, AS-252424, BGT226, CUDC-907, PIK-294, AS-604850, GSK2636771, BAY80-6946, YM201636, CH5132799, CAY10505, PIK-293, PKI-402, TG100713, VS-5584, CZC24832, Quercetin, Rapamycin, AZD8055, Temsirolimus, KU0063794, Zotarolimus, Torkinib, Tacrolimus, Ridaforolimus, INK 128, IPI-145 , SAR245409, Torin1, USI-027, WIE-354, AZD2014, Torin 2, VVYE-125132, BET226, Palomid 529, PP121, PP242 VVYE-687, CH5132799, WAY-600, Chrysophanic, ETP-46464, GDC-0349 , GDC0941, GDC-0068 XL388, Perifosine, GSK690693, Ipatasertib, AZ05363, ATI 314 8, PF04691502, AT7867, Triciribine, CCT128930, A-674563, PHT-427, "Miltefosin, Honokiol, TIC10, alone or in admixture. 35 5. A composition according to any one of claims 1 to 3, wherein the inhibitor of the PI3K / AKT / mTOR pathway is selected from BEZ235, BKM120, Everolimus (or RAD), MK-2206 dichlorate, preferably BEZ235 or RAD, alone or in mixture. 3033499 16 6. A composition according to any one of claims 1 to 5, wherein the weight ratio of streptozotocin to the inhibitor of the PI3K / AKT / mTOR pathway is between 100 and 500, preferably between 100 and 300. 7. Composition according to any one of claims 1 to 6, further colertrenant at least one pharmaceutically acceptable excipient. 8. A kit comprising streptozotocin or a derivative thereof and at least one inhibitor of the PI3K / AKT / mTOR pathway, and their pharmaceutically acceptable salts, forms or derivatives as defined in claims 1 to 5. 9. A composition or kit according to any one of claims 1 to 8 for its use as a medicament. 15 10. A composition or kit according to claim 9 for its use for the prevention or treatment of neuroendocrine tumors. 11. A composition or kit according to claim 10 for use in the prevention or treatment of pancreatic neuroendocrine tumors.