Methods of treating familial adenomatous polyposis

Abstract

Familial adenomatous polyposis (FAP) patients harbor mutations in the APC gene and will develop adenoma and early colorectal cancer. Taking biopsies from non-adenomatous (NA) and adenomatous (A) colonic mucosa of FAP patients, we investigated the early events associated with FAP using the intestinal organoid model. In addition to their high proliferative capacity, NA- and A-organoids were characterized by cysts and cysts with buds, respectively, suggesting abnormal maturation. A-organoids were enriched in the stem cell marker LGR5 and dependent on EGF and TGFβ for their growth. Downstream of EGFR, AKT, β-catenin and YAP were found to be activated in A-organoids. While the p110β isoform of PI3K was predominant in A-organoids and essential for their growth, p110α was associated with the immature state of NA-organoids. Accordingly, the present invention relates to a method of treating Familial Adenomatous Polyposis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a PI3K inhibitor.

Description

[0001] METHODS OF TREATING FAMILIAL ADENOMATOUS POLYPOSIS FIELD OF THE INVENTION: The present invention is in the field of medicine, in particular gastroenterology. BACKGROUND OF THE INVENTION: Patients with familial adenomatous polyposis (FAP) harbor mutations in the Adenomatous polyposis coli (APC) gene, with an autosomal dominant inheritance. Typically, they develop adenomatous polyps in the colon during their second decade of life, requiring genetic testing around the age of 12. If the familial mutation is confirmed, a colonoscopy screening is recommended.1Indeed, FAP patients have a high risk of developing a colorectal adenocarcinoma before the age of 40. Since there is currently no preventive treatment for this cancer, they will undergo a prophylactic colectomy when the risk will be high, i.e. in the presence of high-grade dysplasia, in situ carcinoma, large and / or hundreds of polyps.1To date, no model adequately reproduces human FAP. Apc-deficient mice were developed in the 1990s, but they developed polyps in the small bowel instead of the colon, and also with microadenoma, delayed adenocarcinoma, and few metastases.2-4Thus, alternative models are needed, and colonic organoids present a promising option for studying human FAP in order to improve our understanding of the disease and to identify effective drug treatments. The colonic organoid culture is based on intestinal stem cell (ISC) properties, mainly controlled by the Wnt / APC / β- catenin pathway, and has been developed for over a decade.5-7To enhance growth efficiency and support long-term culture, several growth factors, such as Wnt3a, EGF, R-spondin, and Noggin, are added to the culture medium. ISCs are located at the bottom of the crypt. There are two kinds of ISCs, the crypt base columnar (CBC) LGR5+ (Leucine-rich repeat-containing G- protein coupled receptor 5) cells and the cells located at or near the +4 position (+4 ISC) having high phenotypic plasticity (among their markers BMI1+ member of the polycomb repressor 1, SOX9+ the transcription factor SRY-box 9, and markers of early progenitors of differentiation).8,9CBCs are highly proliferative, while +4 ISCs exhibit slow proliferation or quiescence and are more resistant to injury. These two populations of ISCs can interconvert and, following injury, +4 ISCs are able to produce CBCs. ISC proliferation and differentiation are controlled by Wnt- and EGF- induced signaling.10These signals are modulated by several factors such as Wnts and EGFR ligands, from the intestinal niche. This leads to the establishment of local gradients that result in a critical Wnt / APC / β-catenin signaling pathway for the proliferation of CBCs, while progenitors located near the +4 position are mainly influenced by EGFR signaling.11,12The transition between CBCs and progenitors of absorptive or secretory differentiated intestinal epithelial cells requires a controlled balance between Wnt- and EGF-induced signaling.10Such cross-regulation may involve the transcriptional co- activator YAP (Yes-associated protein), which plays a pivotal role in the coordination of cell adhesion and proliferation within the crypt.13Several signaling pathways, including PI3K (Phosphoinositide 3-kinase)-Akt-mTOR and Ras-Raf-MEK-ERK, can be involved downstream of EGFR and require tight control by phosphatases PTEN and DUSP6, respectively.14-16Interestingly, all of the aforementioned pathways have been implicated in epithelial regeneration following injury, involving the production of growth factors, morphogens, and their regulators (EGFR, Wnt, TGF β, R-spondin) within the crypt microenvironment.17The pathophysiology of FAP involves a supercompetitor phenotype of APC-mutant ISCs, which inhibits the growth of normal ISCs by secreting Wnt antagonists while stimulating mutant cells through Wnt and EGF signaling.18Indeed, a study has demonstrated the necessity of EGFR signaling in the development of adenomas in an ApcMinmouse model.19Studies have reported that APC inactivation and EGFR signaling promote the expression of the cyclooxygenase COX- 2, which contributes to the development of adenoma and colorectal cancer.20Chemoprevention using COX-2 inhibitors (sulindac or celecoxib) has proven efficacy in both humans and mice. However, these drugs are not recommended due to their associated side effects. Thus, new drugs for FAP chemoprevention should have a plausible mechanism of action, be well tolerated, and maintain their effectiveness.21Several drugs have been tested or are currently under investigation in the context of FAP (see https: / / clinicaltrials.gov). These treatments aim to inhibit different targets such as Wnt / APC / β-catenin (pyrvinium, azithromycin), EGFR (erlotinib), mTOR (rapamycin), or the metabolism of cancer stem cells (eflornithine, niclosamide, metformin). However, clinical trials indicate that the efficacy of these treatments may be limited to particular segments of the gut, and their potential long-term adverse effects remain unknown. Thus, studies with the organoid model holds the potential to reveal new targets for preventing the carcinogenic transformation of ISCs and to perform drug testing.22Two recent studies have analyzed gene expression and epigenetic profile of colonic organoids from several FAP patients in comparison to those from healthy patients.23,24FAP organoids were obtained from non-adenomatous tissue and these studies have unveiled significant genetic and epigenetic disparities when contrasted with organoids from healthy individuals. This underscores that even at very early stages, these changes set the stage for tumor transformation. SUMMARY OF THE INVENTION: The invention is defined by the claims. In particular, the present invention relates to a method of treating Familial Adenomatous Polyposis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a PI3K inhibitor. DETAILED DESCRIPTION OF THE INVENTION: Our objective was to evaluate the utility of human colonic organoids to study the early events that occur in the pathophysiology of FAP, with the aim of identifying potential therapeutic targets. To address this question, we designed a preclinical trial using colonoscopic biopsies obtained from both adenomatous (A) and non-adenomatous (NA) areas of FAP patients, as well as from healthy controls (HC). These biopsies were used for colonic organoid experiments and colonic crypt analyses. We characterized a new structure, a cyst with buds, representative of adenoma in vitro. Notably, EGF is of importance, while its deprivation led to the mortality of A-organoids. Moreover, we found differences downstream EGFR, i.e. involving MAPK and PI3K-Akt pathways, as well as TGFβ, which could be of therapeutic interest. Organoid culture is a valuable tool for studying FAP, and it should be useful either in the identification of potential new therapeutic drugs and / or the assessment of their efficacy. Accordingly, the present invention relates to a method of treating Familial Adenomatous Polyposis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a PI3K inhibitor. As used herein, the term “Familial Adenomatous Polyposis” or “FAP” refers to an autosomal dominant inherited cancer predisposition caused by a defect in a polyposis gene, particularly in the adenomatous polyposis coli (APC) gene. FAP is characterized with the appearance of polyps (i.e. adenoma) with low-grade dysplasia at an early stage, polyps with high-grade dysplasia appearance at a later age, which finally progresses into malignant in situ adenocarcinoma. Almost all affected individuals develop colon and / or rectal cancer if they are not identified and treated at an early stage. Symptoms of Familial Adenomatous Polyposis includes, but are not limited to, bowel polyps, large intestine polyps, small intestine polyps, colon polyps, rectum polyps, rectal bleeding, diarrhoea, constipation, abdominal pain, gas pain, bloating and / or unexplained weight loss. FAP is typically diagnosed with screening tests, such as sigmoidoscopy, colonoscopy, esophagogastroduodenoscopy, duodenoscopy but also computed tomography scans (CT-scans), magnetic resonance imaging (MRI) or genetic testing with a blood test. Treatments includes removing the polyps individually (i.e. polypectomy) in the gastrointestinal tract (e.g. esophagus, stomach, small intestine, large intestine), colectomy or proctocolectomy but polyps can continue to form in the remaining gastrointestinal tract. As used herein, the term “subject” or “patient” denotes a mammal, preferably human. Typically, a subject according to the invention refers to any subject (preferably human) afflicted with or susceptible to be afflicted with Familial Adenomatous Polyposis. In some embodiments, the subject harbors a mutation in a polyposis gene. In some embodiments, the subject harbors a mutation in the APC gene. In some embodiments, the mutation is selected in Table 1. In some embodiments, the subject has undergone or will undergo a surgery. In some embodiments, the surgery is a gastrointestinal surgery. In some embodiments, the surgery is a bowel surgery, in particular a small intestine or large intestine (i.e. colon, rectum and / or anus) surgery. In some embodiments, the surgery is a polypectomy, a colectomy or a proctocolectomy. In some embodiments, the subject is a child (e.g.2 y / o to 12 y / o), an adolescent (e.g.12 y / o to 18 y / o), an adult (e.g.18 y / o to 70 y / o) or an elderly (e.g. from 70 y / o). As used herein, the term "treatment" or "treat" refer 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. By "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. The phrase "maintenance regimen" or "maintenance period" 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 subject in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at 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., pain, disease manifestation, etc.]). More particularly, the term “treatment of Familial Adenomatous Polyposis” includes treatment to prevent polyp formation in a subject harboring a polyposis gene mutation, in particular an APC gene mutation without polyps in the gastrointestinal tract; and / or treatment to delay or eradicate the polyp formation in a subject harboring a polyposis gene mutation, in particular an APC gene mutation; and / or treatment to delay the development of polyps in the gastrointestinal tract; and / or treatment to reduce the amount of polyps in the gastrointestinal tract; and / or treatment to remove the polyps in the gastrointestinal tract; and / or treatment to delay FAP disease progression in the subject; and / or treatment to delay the need for endoscopic excision or surgical resection; and / or treatment to reduce or ameliorate one or more symptoms associated with FAP; and / or treatment to prevent or delay the formation of adenocarcinomas in a subject suffering from FAP, in particular colonic adenocarcinoma; and / or treatment to eradicate the formation of adenocarcinomas in a subject suffering from FAP, in particular colonic adenocarcinomas; and / or treatment to prevent or delay the formation of cancer in a subject suffering from FAP, in particular gastrointestinal cancer, even more particularly colorectal cancer; and / or treatment to eradicate the formation of cancer in a subject suffering from FAP, in particular gastrointestinal cancer, even more particularly colorectal cancer. As used herein, the term “PI3K” refers to phosphoinositide 3-kinases also called phophatidylinositide 3-kinases. PI3K belongs to a family of enzymes which phosphorylate the 3’hydroxyl group of the inositol ring of the phosphatidylinositol (PtdIns). The PI3K family is divided into four different classes. The classifications are based on primary structure, regulation, and in vitro lipid substrate specificity. Class IA and IB encompass: PIK3CA (p110α), PIK3CB (p110β), PIK3CG (p110-γ), PIK3CD (p110-δ), PIK3R1 (p85-α), PIK3R2 (p85-β), PIK3R3 (p55-γ), PIK3R4 (p150), PIK3R5 (p101), PIK3R6 (p87). Class II encompasses: PIK3C2A (PI3K-C2α), PIK3C2B (PI3K-C2β), PIK3C2G (PI3K-C2γ). Class III encompasses PIK3C3 (Vps34). In some embodiments, the PI3K is PIK3CA. PIK3CA is encoded by PIK3CA gene (Entrez Gene: 5290; Ensembl: ENSG00000121879). An exemplary amino acid sequence for PIKCA is represented in SEQ ID NO: 1. SEQ ID NO: 1> sp|P42336|PK3CA_HUMAN Phosphatidylinositol 4,5- bisphosphate 3-kinase catalytic subunit alpha isoform OS=Homo sapiens OX=9606 GN=PIK3CA PE=1 SV=2 MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN In some embodiments, the PI3K is PIK3CB. PIK3CB is encoded by PIK3CB gene (Entrez Gene: 5291; Ensembl: ENSG00000051382). An exemplary amino acid sequence for PIKCB is represented in SEQ ID NO: 2. SEQ ID NO: 2> sp|P42338|PK3CB_HUMAN Phosphatidylinositol 4,5- bisphosphate 3-kinase catalytic subunit beta isoform OS=Homo sapiens OX=9606 GN=PIK3CB PE=1 SV=1 MCFSFIMPPA MADILDIWAV DSQIASDGSI PVDFLLPTGI YIQLEVPREA TISYIKQMLW KQVHNYPMFN LLMDIDSYMF ACVNQTAVYE ELEDETRRLC DVRPFLPVLK LVTRSCDPGE KLDSKIGVLI GKGLHEFDSL KDPEVNEFRR KMRKFSEEKI LSLVGLSWMD WLKQTYPPEH EPSIPENLED KLYGGKLIVA VHFENCQDVF SFQVSPNMNP IKVNELAIQK RLTIHGKEDE VSPYDYVLQV SGRVEYVFGD HPLIQFQYIR NCVMNRALPH FILVECCKIK KMYEQEMIAI EAAINRNSSN LPLPLPPKKT RIISHVWENN NPFQIVLVKG NKLNTEETVK VHVRAGLFHG TELLCKTIVS SEVSGKNDHI WNEPLEFDIN ICDLPRMARL CFAVYAVLDK VKTKKSTKTI NPSKYQTIRK AGKVHYPVAW VNTMVFDFKG QLRTGDIILH SWSSFPDELE EMLNPMGTVQ TNPYTENATA LHVKFPENKK QPYYYPPFDK IIEKAAEIAS SDSANVSSRG GKKFLPVLKE ILDRDPLSQL CENEMDLIWT LRQDCREIFP QSLPKLLLSI KWNKLEDVAQ LQALLQIWPK LPPREALELL DFNYPDQYVR EYAVGCLRQM SDEELSQYLL QLVQVLKYEP FLDCALSRFL LERALGNRRI GQFLFWHLRS EVHIPAVSVQ FGVILEAYCR GSVGHMKVLS KQVEALNKLK TLNSLIKLNA VKLNRAKGKE AMHTCLKQSA YREALSDLQS PLNPCVILSE LYVEKCKYMD SKMKPLWLVY NNKVFGEDSV GVIFKNGDDL RQDMLTLQML RLMDLLWKEA GLDLRMLPYG CLATGDRSGL IEVVSTSETI ADIQLNSSNV AAAAAFNKDA LLNWLKEYNS GDDLDRAIEE FTLSCAGYCV ASYVLGIGDR HSDNIMVKKT GQLFHIDFGH ILGNFKSKFG IKRERVPFIL TYDFIHVIQQ GKTGNTEKFG RFRQCCEDAY LILRRHGNLF ITLFALMLTA GLPELTSVKD IQYLKDSLAL GKSEEEALKQ FKQKFDEALR ESWTTKVNWM AHTVRKDYRS PI3K inhibitors As used herein, the term “PI3K inhibitor” refers to a natural or synthetic compound that has a biological effect to inhibit the activity (e.g. kinase) or the expression of PI3K. More particularly, such compound is able to inhibit the kinase activity of at least one member of PI3K family, for example, at least one member of Class I PI3K. In a particular embodiment, said PI3K inhibitor may be a pan-inhibitor of Class I PI3K (known as p110) or isoform specific of Class I PI3K isoforms (among the four types of isoforms, p110α, p110β, p110γ or p110δ). In some embodiments, the PI3K inhibitor is a PIK3CA inhibitor. In some embodiments, the PI3K inhibitor is a PIK3CB inhibitor. In some embodiments, the PI3K inhibitor is a PIK3CA and / or a PIK3CB inhibitor. A PI3K inhibitor can be a molecule of any type that interferes with the signalling associated with PI3K in a cell, for example, either by decreasing transcription or translation of PI3K-encoding nucleic acid, or by inhibiting or blocking PI3K polypeptide activity, or both. Examples of PI3K inhibitors include, but are not limited to, antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, PI3K-specific aptamers, anti-PI3K antibodies, PI3K-binding fragments of anti-PI3K antibodies, PI3K-binding small molecules, PI3K-binding peptides, and other polypeptides that specifically bind PI3K (including, but not limited to, PI3K-binding fragments of one or more PI3K ligands, optionally fused to one or more additional domains), such that the interaction between the PI3K inhibitor and PI3K results in a reduction or cessation of PI3K activity or expression. In some embodiments, the PI3K inhibitor according to the invention may be a low molecular weight compound, e. g. a small organic molecule (natural or not). The term "small organic molecule" refers to a molecule (natural or not) of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macromolecules (e. g., proteins, nucleic acids, etc.). Preferred small organic molecules range in size up to about 10000 Da, more preferably up to 5000 Da, more preferably up to 2000 Da and most preferably up to about 1000 Da. In some embodiments, the PI3K inhibitor is selected from the list comprising Alpelisib (Novartis), Copanlisib (Bayer), Dactolisib (Novartis), TQ-B3525 (Chia Tau Tianqing Pharmaceutical), ART-001 (ARTham Therapeutics), Buparlisib (Novartis), Inavolisib (Hoffman-La Roche), ASN-003 (Asana BioSciences), CLL-442 (Novatis), CYH33 (Shangai Haihe Biopharma), Pictilisib (Genentech), Serabelisib (Takeda Pharmaceuticals), RP903 (Junshi Runjia), STX-478 (Scorpion Therapeutics), Taselisib (Hoffman-La Roche), BPI-21668 (Betta Pharmaceuticals), HS-10352 (Jiangsu Hansoh Pharmaceuticals), LOX-22783 (Eli Lilly), LX-086 (Shandong Luoxin Pharmaceuticals), OB-318 (Oneness Biotech), OKI-219 (OnKure), RLY-2608 (Relay Therapeutics), RLY-5836 (Relay Therapeutics), TOS-358 (Totus Medicines), YS-001 (Jiangsu Wuzhong Medicine), AFNT-212 (Affini-T Therapeutics), AL- 58922 (Advenchen Laboratories Nanjing), CT-365 (Sunshine Lake Pharma), DYR-726 (University of Arizona), FD-274 (Fudan University), GSK-2702926 (GSK), HP-567 (Hinova Pharmaceuticals), PF-06843195 (Pfizer), PQR-401 (PIQUR Therapeutics), SNV-4818 (Synnovation Therapeutics), SPR-965 (Sphaera Pharma), UCL-TRO-1938 (AstraZeneca), ZX- 3262 (Nanjing Zenshine Pharmaceuticals), SF-2558HA (SignalRx Pharmaceuticals), AZD- 8835 (AstraZeneca), CBL-1309 (Cerylid Biosciences), BAY-1082439 (Bayer), KKA-2237 (Kareus Therapeutics), TBO-309 (The George Institute for Global Health), AZD-8186 (AstraZeneca), FD-274 (Fundan University), LS-008 (Changzhou Innoshengkang Biomedical Technology), Acalisib (Gilead), BBP-472 (BridgeBio Pharma), KAR-4139 (Karus Therapeutics), GSK-418 (GSK), RP-5002 (Incozen), TQB-3525 (Chia Tai Tianquing Pharmaceutical), HZ-H (HealZen Therapeutics), Bimiralisib (Piqur Therapeutics), ETX-363 (Shanghai Haihe Biopharma), HHCYH-33 (Shanghai Haihe Biopharma), RLY-2608 (Relay Therapeutics), CGT-6297 (Cogent Biosciences), GSC-002639 (Changchun GeneScience Pharmaceutical), H1047R-specific (Relay Therapeutics), HP-567 (Hinova Pharmaceuticals), LAE-118 (Laekna Inc), Ly-4045004 (Eli Lilly), MBTC-101 (MagicBullet Therapeutics), NSC- 765844 (National Cancer Institute), OKI-TBD 1 (OnKure Therapeutics), Omipalisib (GSK), PQR-514 (Piqur Therapeutics), REC-7735 (Recursion Pharmaceuticals), WX-008 (Chia Tai Tianquing Pharmaceuticals), LCI-139 (Atrium Health), OKI-TBD 2 (OnKure Therapeutics), Petra-03 (Eli Lilly), SF-2523 (SignalRx Pharmaceuticals), AEZS-129 (Cosciens Biopharma), CGT-4824 (Cogent Biosciences), CLR-457 (Novartis), CNX-1351 (Bristol-Myers Squibb), Fimepinostat (Curis), HM-032 (Hutchison MediPharma), HM-5016699 (Hutchison MediPharma), HS-159 (Inha University), ON-146040 (Traws Pharma), PQR-530 (Piqur Therapeutics), PWT-33597 (Pathway Therapeutics), Samotolisib (Eli Lilly), SN-202 (Sichuan Sinovation Bio-technology), AZD-8835 (AstraZeneca), LY-3849524 (Eli Lilly) or P7170 (Piramal Pharma). In some embodiments, the PI3K inhibitor is a PIK3CA inhibitor selected from the list comprising Alpelisib (Novartis), Copanlisib (Bayer), ART-001 (ARTham Therapeutics), Inavolisib (Hoffmann-La Roche), CYH33 (Shanghai Haihe Biopharma), Serabelisib (Takeda Pharmaceuticals), RP903 (Junshi Runjia), STX-478 (Scorpion Therapeutics), Taselisib (Hoffman-La Roche), BPI-21668 (Betta Pharmaceuticals), HS-10352 (Jiangsu Hansoh Pharmaceutical), LX-086 (Shandong Luoxin Pharmaceutical), RLY-5836 (Relay Therapeutics), TOS-358 (Totus Medicines), (GSK-2702926A (GSK), HP-567 (Hinova Pharmaceuticals), PF-06843195 (Pfizer), ZX-3252 (Nanjing Zenshine Pharmaceuticals), CBL- 1309 (Cerylid Biosciences), GSK-615 (GSK), PX-867 (Seagen), VT-30 (Venthera), UCL- TRO-1938 (AstraZeneca), CL-27c (Kither Biotech), CNX-1351 (Avila Therapeutics) or GDC- 0326 (Genentech). In some embodiments, the PIK3CA inhibitor is Alpelisib (CAS No: 1217486-61-7). In some embodiments, the PIK3CA inhibitor is A66. In some embodiments, the PIK3CA inhibitor is (2S)-1-N-[5-(2-tert-butyl-1,3-thiazol-4-yl)-4-methyl-1,3-thiazol-2-yl]pyrrolidine-1,2- dicarboxamide. In some embodiments, the PI3K inhibitor is a PIK3CB inhibitor selected from the list comprising AZD-6482 (AstraZeneca), AZD-6484 (AstraZeneca), GSK-2636771 (GSK), TBO- 309 (The George Institute for Global Health), BBP-472 (BridgeBio Pharma) or SAR-260301 (Sanofi). In some embodiments, the PIK3CB inhibitor is AZD-6482 (CAS No: 1173900-33-8). In some embodiments, the PI3K inhibitor is an antibody having specificity for PI3K. In some embodiments, the PI3K inhibitor is an anti-PI3K antibody. As used herein, the term "antibody" is thus used to refer to any antibody-like molecule that has an antigen binding region, and this term includes antibody fragments that comprise an antigen binding domain such as Fab', Fab, F(ab')2, single domain antibodies (DABs), TandAbs dimer, Fv, scFv (single chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody (scFv-Fab fusions, bispecific or trispecific, respectively); sc- diabody; kappa(lamda) bodies (scFv-CL fusions); BiTE (Bispecific T-cell Engager, scFv-scFv tandems to attract T cells); DVD-Ig (dual variable domain antibody, bispecific format); SIP (small immunoprotein, a kind of minibody); SMIP ("small modular immunopharmaceutical" scFv-Fc dimer; DART (ds-stabilized diabody "Dual Affinity ReTargeting"); small antibody mimetics comprising one or more CDRs and the like. The techniques for preparing and using various antibody-based constructs and fragments are well known in the art (see Kabat et al., 1991, specifically incorporated herein by reference). Diabodies, in particular, are further described in EP 404, 097 and WO 93 / 11161; whereas linear antibodies are further described in Zapata et al. (1995). Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments. Papain digestion can lead to the formation of Fab fragments. Fab, Fab' and F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques or can be chemically synthesized. Techniques for producing antibody fragments are well known and described in the art. For example, each of Beckman et al., 2006; Holliger & Hudson, 2005; Le Gall et al., 2004; Reff & Heard, 2001; Reiter et al., 1996; and Young et al., 1995 further describe and enable the production of effective antibody fragments. The residues in antibody variable domains are conventionally numbered according to a system devised by Kabat et al. This system is set forth in Kabat et al., 1987, in Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA (hereafter “Kabat et al.”). This numbering system is used in the present specification. The Kabat residue designations do not always correspond directly with the linear numbering of the amino acid residues in SEQ ID sequences. The actual linear amino acid sequence may contain fewer or additional amino acids than in the strict Kabat numbering corresponding to a shortening of, or insertion into, a structural component, whether framework or complementarity determining region (CDR), of the basic variable domain structure. The correct Kabat numbering of residues may be determined for a given antibody by alignment of residues of homology in the sequence of the antibody with a “standard” Kabat numbered sequence. The CDRs of the heavy chain variable domain are located at residues 31-35B (H- - 9 - CDR1), residues 50-65 (H-CDR2) and residues 95-102 (H-CDR3) according to the Kabat numbering system. The CDRs of the light chain variable domain are located at residues 24-34 (L-CDR1), residues 50-56 (L-CDR2) and residues 89-97 (L-CDR3) according to the Kabat numbering system. (http: / / www.bioinf.org.uk / abs / #cdrdef) In some embodiments, the amino acid residues of the antibody of the invention are numbered according to the IMGT numbering system. The IMGT unique numbering has been defined to compare the variable domains whatever the antigen receptor, the chain type, or the species (Lefranc M.-P., "Unique database numbering system for immunogenetic analysis" Immunology Today, 18, 509 (1997) ; Lefranc M.-P., "The IMGT unique numbering for Immunoglobulins, T cell receptors and Ig-like domains" The Immunologist, 7, 132-136 (1999).; Lefranc, M.-P., Pommié, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin- Contet, V. and Lefranc, G., "IMGT unique numbering 15 for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains" Dev. Comp. Immunol., 27, 55- 77 (2003).). In the IMGT unique numbering, the conserved amino acids always have the same position, for instance cysteine 23, tryptophan 41, hydrophobic amino acid 89, cysteine 104, phenylalanine or tryptophan 118. The IMGT unique numbering provides a standardized delimitation of the framework regions (FR1- 20 IMGT: positions 1 to 26, FR2-IMGT: 39 to 55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to 128) and of the complementarity determining regions: CDR1-IMGT: 27 to 38, CDR2-IMGT: 56 to 65 and CDR3-IMGT: 105 to 117. If the CDR3-IMGT length is less than 13 amino acids, gaps are created from the top of the loop, in the following order 111, 112, 110, 113, 109, 114, etc. If the CDR3-IMGT length is more than 13 amino acids, additional positions are created between positions 111 and 112 at the top of the CDR3-IMGT loop in the following order 112.1,111.1, 112.2, 111.2, 112.3, 111.3, etc. (http: / / www.imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition.html). As used herein, the term “specificity” refers to the ability of an antibody to detectably bind an epitope presented on an antigen, such as PI3K, while having relatively little detectable reactivity with non-PI3K proteins or structures. Specificity can be relatively determined by binding or competitive binding assays, using, e.g., Biacore instruments, as described elsewhere herein. Specificity can be exhibited by, e.g., an about 10:1, about 20:1, about 50:1, about 100:1, 10.000:1 or greater ratio of affinity / avidity in binding to the specific antigen versus nonspecific binding to other irrelevant molecules (in this case the specific antigen is a PI3K polypeptide). The term “affinity”, as used herein, means the strength of the binding of an antibody to an epitope. The affinity of an antibody is given by the dissociation constant Kd, defined as [Ab] x [Ag] / [Ab-Ag], where [Ab-Ag] is the molar concentration of the antibody-antigen complex, [Ab] is the molar concentration of the unbound antibody and [Ag] is the molar concentration of the unbound antigen. The affinity constant Ka is defined by 1 / Kd. Preferred methods for determining the affinity of mAbs can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988), Coligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1992, 1993), and Muller, Meth. Enzymol. 92:589-601 (1983), which references are entirely incorporated herein by reference. One preferred and standard method well known in the art for determining the affinity of mAbs is the use of Biacore instruments. In natural antibodies, two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (l) and kappa (k). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct sequence domains. The light chain includes two domains, a variable domain (VL) and a constant domain (CL). The heavy chain includes four domains, a variable domain (VH) and three constant domains (CH1, CH2 and CH3, collectively referred to as CH). The variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR). The Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain. The specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant. Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from nonhypervariable or framework regions (FR) influence the overall domain structure and hence the combining site. Complementarity Determining Regions or CDRs refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, L-CDR3 and H-CDR1, H-CDR2, H-CDR3, respectively. An antigen-binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region. Framework Regions (FRs) refer to amino acid sequences interposed between CDRs. The term “Fab” denotes an antibody fragment having a molecular weight of about 50,000Da and antigen binding activity, in which about a half of the N-terminal side of H chain and the entire L chain, among fragments obtained by treating IgG with a protease, papaine, are bound together through a disulfide bond. The term “F(ab')2” refers to an antibody fragment having a molecular weight of about 100,000Da and antigen binding activity, which is slightly larger than the Fab bound via a disulfide bond of the hinge region, among fragments obtained by treating IgG with a protease, pepsin. The term “Fab'”refers to an antibody fragment having a molecular weight of about 50,000 and antigen binding activity, which is obtained by cutting a disulfide bond of the hinge region of the F(ab')2. A single chain Fv (“scFv”) polypeptide is a covalently linked VH::VL heterodimer which is usually expressed from a gene fusion including VH and VL encoding genes linked by a peptide-encoding linker. “dsFv” is a VH::VL heterodimer stabilised by a disulfide bond. Divalent and multivalent antibody fragments can form either spontaneously by association of monovalent scFvs, or can be generated by coupling monovalent scFvs by a peptide linker, such as divalent sc(Fv)2. The term "diabodies" refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Monoclonal antibodies may be generated using the method of Kohler and Milstein (Nature, 256:495, 1975). To prepare monoclonal antibodies useful in the invention, a mouse or other appropriate host animal is immunized at suitable intervals (e.g., twice-weekly, weekly, twice-monthly or monthly) with the appropriate antigenic forms (i.e. PI3K or cell that express PI3K). Following the immunization regimen, lymphocytes are isolated from the spleen, lymph node or other organ of the animal and fused with a suitable myeloma cell line using an agent such as polyethylene glycol to form a hydridoma. Following fusion, cells are placed in media permissive for growth of hybridomas but not the fusion partners using standard methods. Following culture of the hybridomas, cell supernatants are analyzed for the presence of antibodies of the desired specificity, i.e., that selectively bind the antigen. Suitable analytical techniques include ELISA, flow cytometry, immunoprecipitation, and western blotting. Other screening techniques are well-known in the field. Preferred techniques are those that confirm binding of antibodies to conformationally intact, natively folded antigen, such as non- denaturing ELISA, flow cytometry, and immunoprecipitation. Significantly, as is well-known in the art, only a small portion of an antibody molecule, the paratope, is involved in the binding of the antibody to its epitope (see, in general, Clark, W. R. (1986) The Experimental Foundations of Modern Immunology Wiley & Sons, Inc., New York; Roitt, I. (1991) Essential Immunology, 7th Ed., Blackwell Scientific Publications, Oxford). The Fc' and Fc regions, for example, are effectors of the complement cascade but are not involved in antigen binding. An antibody from which the pFc' region has been enzymatically cleaved, or which has been produced without the pFc' region, designated an F(ab')2 fragment, retains both of the antigen binding sites of an intact antibody. Similarly, an antibody from which the Fc region has been enzymatically cleaved, or which has been produced without the Fc region, designated as Fab fragment, retains one of the antigen binding sites of an intact antibody molecule. Proceeding further, Fab fragments consist of a covalently bound antibody light chain and a portion of the antibody heavy chain denoted Fd. The Fd fragments are the major determinant of antibody specificity (a single Fd fragment may be associated with up to ten different light chains without altering antibody specificity) and Fd fragments retain epitope-binding ability in isolation. In some embodiments, the antibody is a humanized antibody. As used herein, "humanized" describes antibodies wherein some, most or all of the amino acids outside the CDR regions are replaced with corresponding amino acids derived from human immunoglobulin molecules. Methods of humanization include, but are not limited to, those described in U.S. Pat. Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762 and 5,859,205, which are hereby incorporated by reference. In some embodiments, the antibody is a fully human antibody. Fully human monoclonal antibodies also can be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Pat. Nos. 5,591,669, 5,598,369, 5,545,806, 5,545,807, 6,150,584, and references cited therein, the contents of which are incorporated herein by reference. These animals have been genetically modified such that there is a functional deletion in the production of endogenous (e.g., murine) antibodies. The animals are further modified to contain all or a portion of the human germ-line immunoglobulin gene locus such that immunization of these animals will result in the production of fully human antibodies to the antigen of interest. Following immunization of these mice (e.g., XenoMouse (Abgenix), HuMAb mice (Medarex / GenPharm)), monoclonal antibodies can be prepared according to standard hybridoma technology. These monoclonal antibodies will have human immunoglobulin amino acid sequences and therefore will not provoke human anti-mouse antibody (KAMA) responses when administered to humans. In vitro methods also exist for producing human antibodies. These include phage display technology (U.S. Pat. Nos.5,565,332 and 5,573,905) and in vitro stimulation of human B cells (U.S. Pat. Nos. 5,229,275 and 5,567,610). The contents of these patents are incorporated herein by reference. The antibody of the present invention may be of any isotype. The choice of isotype typically will be guided by the desired effector functions, such as ADCC induction. Exemplary isotypes are IgGl, IgG2, IgG3, and IgG4. Either of the human light chain constant regions, kappa or lambda, may be used. If desired, the class of a human monoclonal antibody of the present invention may be switched by known methods. Typical, class switching techniques may be used to convert one IgG subclass to another, for instance from IgG1 to IgG2. Thus, the effector function of the human monoclonal antibodies of the present invention may be changed by isotype switching to, e.g., an IgGl, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody for various therapeutic uses. In some embodiments, the antibody of the present invention is a full- length antibody. In some embodiments, the full-length antibody is an IgG1 antibody. In some embodiments, the full-length antibody is an IgG4 antibody. In some embodiments, the specific IgG4 antibody is a stabilized IgG4 antibody. Examples of suitable stabilized IgG4 antibodies are antibodies wherein arginine at position 409 in a heavy chain constant region of human IgG4, which is indicated in the EU index as in Kabat et al. supra, is substituted with lysine, threonine, methionine, or leucine, preferably lysine (described in WO2006 / 033386) and / or wherein the hinge region comprises a Cys-Pro-Pro-Cys sequence. Other suitable stabilized IgG4 antibodies are disclosed in WO2008 / 145142, which is hereby incorporated by reference in its entirety. In some embodiments, the human monoclonal antibody of the present invention is an antibody of a non-IgG4 type, e.g. IgGl, IgG2 or IgG3 which has been mutated such that the ability to mediate effector functions, such as ADCC, has been reduced or even eliminated. Such mutations have e.g. been described in Dall'Acqua WF et al., J Immunol. 177(2): 1129-1138 (2006) and Hezareh M, J Virol.75(24): 12161-12168 (2001). In some embodiments, the antibody of the present invention is a single chain antibody. As used herein the term “single domain antibody” has its general meaning in the art and refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such single domain antibody are also “nanobody®”. For a general description of (single) domain antibodies, reference is also made to the prior art cited above, as well as to EP 0368684, Ward et al. (Nature 1989 Oct 12; 341 (6242): 544-6), Holt et al., Trends Biotechnol., 2003, 21(11):484-490; and WO 06 / 030220, WO 06 / 003388. The amino acid sequence and structure of a single domain antibody can be considered to be comprised of four framework regions or "FRs" which are referred to in the art and herein as "Framework region 1" or "FRl "; as "Framework region 2" or "FR2"; as "Framework region 3 " or "FR3"; and as "Framework region 4" or “FR4” respectively; which framework regions are interrupted by three complementary determining regions or "CDRs", which are referred to in the art as "Complementarity Determining Region for "CDRl”; as "Complementarity Determining Region 2" or "CDR2” and as "Complementarity Determining Region 3" or "CDR3", respectively. Accordingly, the single domain antibody can be defined as an amino acid sequence with the general structure: FRl - CDRl - FR2 - CDR2 - FR3 - CDR3 - FR4 in which FRl to FR4 refer to framework regions 1 to 4 respectively, and in which CDRl to CDR3 refer to the complementarity determining regions 1 to 3. In some embodiments, the antibody leads to the depletion of PI3K expressing cells. As used herein, the term “depletion” refers to a measurable decrease in the number of PI3K expressing cells in the patient. The reduction can be at least about 10%, e.g., at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more. In some embodiments, the term refers to a decrease in the number of PI3K cells in the patient below detectable limits. In some embodiments, the antibody suitable for depletion of PI3K cells mediates antibody-dependent cell-mediated cytotoxicity. As used herein the term “antibody-dependent cell-mediated cytotoxicity” or “ADCC” refer to a cell-mediated reaction in which non-specific cytotoxic cells (e.g., T gamma delta lymphocytes, Natural Killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and subsequently cause lysis of the target cell. While not wishing to be limited to any particular mechanism of action, these cytotoxic cells that mediate ADCC generally express Fc receptors (FcRs). In some embodiments, the PI3K inhibitor is an inhibitor of PI3K expression. An “inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene. In a preferred embodiment of the invention, said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme. For example, anti- sense oligonucleotides, including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of PI3K mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of PI3K, and thus activity, in a cell. For example, antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding PI3K 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) can also function as inhibitors of expression in the method of the present invention. PI3K gene expression can be reduced by contacting a subject 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 PI3K gene expression is specifically inhibited (i.e. RNA interference or RNAi). Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector. In its broadest sense, 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 PI3K. Typically, 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. In general, 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. One can readily employ other vectors not named but known to the art. By a "therapeutically effective amount" of the inhibitor as above described is meant a sufficient amount to provide a therapeutic effect. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Typically, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg / kg to about 20 mg / kg of body weight per day, especially from about 0.001 mg / kg to 7 mg / kg of body weight per day. Typically, the inhibitor of the present invention is combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions. "Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Typically, the pharmaceutical compositions contain vehicles, which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Sterile injectable solutions are prepared by incorporating the inhibitor at the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum- drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Any mode of administration that produces desired therapeutic effect without unacceptable adverse effects is relevant in practicing the invention. Such modes of administration may include oral, rectal, topical, transdermal, sublingual, intramuscular, parenteral, intravenous, intracavity, vaginal and adhesive matrix to be used during surgery. Certain carriers that may contain the PI3K inhibitor or the pharmaceutical composition comprising the PI3K inhibitor should be considered such as pill, patch, spray, injection or implant. In some embodiments, the PI3K inhibitor of the present invention is administered to the subject in combination with at least one other therapeutic compound. As used herein, the term “combination” is intended to refer to all forms of administration that provide a first drug together with a further (second, third…) drug. The drugs may be administered simultaneous, separate or sequential and in any order. Drugs administered in combination have biological activity in the subject to which the drugs are delivered. In some embodiments, the PI3K inhibitor is administered in combination with at least one further therapeutic agent selected from the list comprising a chemotherapeutic agent, an EGFR (Epidermal Growth Factor Receptor) inhibitor, an AKT inhibitor, a COX-2 inhibitor, a mTOR inhibitor, a YAP (Yes-Associated Protein) inhibitor, a TGF-B (Transforming Growth Factor Beta) inhibitor, a B-catenin / Wnt inhibitor, a non-steroidal anti-inflammatory drug (NSAID) and / or a FZD4 (Frizzled Class Receptor 4) inhibitor. In some embodiments, the at least one further therapeutic agent is Sirolimus, Celecoxib, Ursodiol, Eicosapentaenoic Acid, CEQ-508, TAK-733, Lorpucitinib, Exisulind, Tilmacoxib Eflornithine, Niclosamide and / or Metformin. In some embodiments, the at least one further therapeutic agent is a chemotherapeutic agent selected from the list comprising alkylating agents, anthracyclines, antimetabolites, topoisomerase inhibitors, antibiotics, mitotic inhibitors or protein kinase inhibitors. In some embodiments, the chemotherapeutic agent is selected from the group consisting in Carboplatin, Paclitaxel, Doxorubicin, Methotrexate, Pemetrexed, Cytarabine, 5-Fluorouracil, Capecitabine, Gemcitabine, 6-Mercaptopurine, Azathioprine, Fludarabine, Cladribine, Hydroxyurea, Cyclophosphamide, Ifosfamide, Chlorambucil, Melphalan, Temozolomide, Carmustine, Lomustine, Streptozocin, Busulfan, Procarbazine, Cisplatin, Oxaliplatin, Irinotecan, Topotecan, Etoposide, Vincristine, Vinblastine, Vinorelbine, Docetaxel, Eribulin, Ixabepilone, Epothilone, Bleomycin, Actinomycin D, Daunorubicin, Epirubicin, Pirarubicin, Zorubicin, Aclarubicin, Mitoxantrone, Pixantrone, Idarubicin, Mitomycin, Imatinib, Nilotinib, Gefitinib, Afatinib, Osimertinib, Cabozantinib, Pazopanib, Sunitinib, Sorafenib, Tivozanib, Axitinib, Lenvatinib, Regorafenib, Vandetanib, Alectinib, Crizotinib, Dabrafenib, Encorafenib, Vemurafenib, Trametinib, Ibrutinib, Ruxolitinib, L-Asparaginase, Bortezomib, Carfilzomib, Ixazomib or Olaparib. In some embodiments, the at least one further therapeutic agent is an EGFR (Epidermal Growth Factor Receptor) inhibitor selected from the list comprising Sunvozertinib, Befotertinib, Mococertinib, Amivantamab, Alflutinib, Lazertinib, Cetuximab, Ripretinib, Almonertinib, Dacomitinib, Erlotinib, Pyrotinib, Neratinib, Brigatinib, Olmutinib, Necitumumab, Osimertinib, Afatinib, Icotinib, Vendetinib, Lapatinib, Panitumumab, Nimotuzumab, Erlotinib, Cetuximab, Gefitinib, Nepidermin, Triptolide. In some embodiments, the at least one further therapeutic agent is an AKT inhibitor selected from the list comprising Capivasertib, Afuresertib, Dordaviprone, Honokiol, Ipatasertib, Paxalisib, SR-0379. In some embodiments, the at least one further therapeutic agent is a COX-2 inhibitor selected from the list comprising Polmacoxib, Imrecoxib, Etoricoxib, Parecoxib, Celexocib, Piroxicam, Flurbiprofen, Antipyrine, Niflumic acid. In some embodiments, the at least one further therapeutic agent is a mTOR inhibitor selected from the list comprising Sirolimus, Rapamycin, Zotarolimus, Umirolimus, Temsirolimus, Dactolisib, Gedatolisib, Paxalisib, SR-0379. In some embodiments, the at least one further therapeutic agent is a TGF-B inhibitor selected from the list comprising Sotatercept, TU-2218, KER-065, IOA-360, AB-204. In some embodiments, the at least one further therapeutic agent is a B-catenin / Wnt inhibitor selected from the list comprising pyrvinium, azithromycin, LF-3, NEXC-1004, Dalosirvat, SST-102. In some embodiments, the at least one further therapeutic agent is a non-steroidal anti- inflammatory drug (NSAID) selected from the list comprising Celecoxib, Diclofenac, Ibuprofen, Indomethacin, Meloxicam, Naproxen, Rofecoxib, Sulindac. In some embodiments, the at least one further therapeutic agent is a PAR1 and / or PAR2 agonist. Managing Familial Adenomatous Polyposis Taking biopsies from non-adenomatous (NA) and adenomatous (A) colonic mucosa of FAP patients, we investigated the early events associated with FAP using the intestinal organoid model. While the p110β isoform of PI3K was predominant in A-organoids and essential for their growth, p110α was associated with the immature state of NA-organoids. Thus, early chemoprevention proposed for FAP patients could be based on strategies enhancing the differentiation of NA ISCs by targeting p110α or metabolic pathways. In a further step, for advanced FAP cases characterized by a carpet of polyps, targeting p110β and / or TGFβ and / or FZD4 may be considered. In some embodiments, the present invention relates to a method for preventing Familial Adenomatous Polyposis in a subject harbouring a polyposis gene mutation, in particular an APC gene mutation comprising administering to the subject a therapeutically effective amount of a PIK3CA inhibitor and / or a PIK3CB inhibitor. In some embodiments, the present invention relates to a method for preventing Familial Adenomatous Polyposis in a subject harbouring a polyposis gene mutation, in particular an APC gene mutation, without polyps in the gastrointestinal tract comprising administering to the subject a therapeutically effective amount of a PIK3CA inhibitor and / or a PIK3CB inhibitor. In some embodiments, the present invention relates to a method for preventing the development of polyps in a subject suffering from Familial Adenomatous Polyposis comprising administering to the subject a therapeutically effective amount of a PIK3CA inhibitor and / or a PIK3CB inhibitor. In some embodiments, the present invention relates to a method for preventing the development of polyps with high-grade dysplasia in a subject suffering from Familial Adenomatous Polyposis, said subject having polyps with low-grade dysplasia (e.g.10, 20, 30, 40, 50, 60, 70, 80, 90, 100) in the gastrointestinal tract, comprising administering to the subject a therapeutically effective amount of a PI3KCA inhibitor and / or a PIK3CB inhibitor. In some embodiments, the present invention relates to a method for preventing the development of adenocarcinoma in a subject suffering from Familial Adenomatous Polyposis comprising administering to the subject a therapeutically effective amount of a PIK3CA inhibitor and / or a PIK3CB inhibitor. In some embodiments, the adenocarcinoma is a colonic adenocarcinoma. In some embodiments, the present invention also relates to a method of preventing colorectal cancer is a subject suffering from Familial Adenomatous Polyposis comprising administering to the subject a therapeutically effective amount of a PI3K inhibitor. In some embodiments, the PI3K inhibitor is a PIK3CA inhibitor and / or a PIK3CB inhibitor. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention. FIGURES: Figure 1. Characterization of FAP organoids. A, B-Oppositely to organoids from Healthy Controls (HC), growth of FAP organoids (Non Adenomatous NA, Adenomatous A) is independent on Wnt3a-conditioned medium or recombinant Wnt3a. A: n patients HC=6, NA / A=7 (with Wnt3a-conditioned medium), NA / A=4 (without Wnt3a-conditioned medium), organoid size mean±SEM (diameter, around 200-300 organoids per condition), Anova comparison A to HC ***p<0.001 ****p<0.0001, A to NA ##p<0.01 ####p<0.0001, NA to HC §p<0.05 §§p<0.01 §§§§p<0.0001. B: n patients HC=3, NA / A=3, % variation of organoid size from D2 mean±SEM (diameter at D2, mean±SEM: HC 144±18 µm, NA 117±16 µm, A 76±17 µm; around 10 organoids per condition), Anova comparison *p<0.05 **p<0.01 ****p<0.0001. C- Expression of the proliferation marker KI67 (immunolabeling, mRNA) is increased in FAP organoids compared to HC. n patients HC=4, NA / A=5, Anova comparison ***p<0.001. IF: Labeling of nuclei by DAPI is shown, representative of two independent experiments. D, E, F- From D2 to D9 of culture, HC organoids develop as immature forms with a thin monolayer boarding a central lumen (cysts) to mature forms as colonospheres with a larger and polarized monolayer and then as colonoids with buds of neo-crypts in formation. NA-organoids show a delayed maturation with very large cysts displaying high CD44 labeling. A-organoid culture contains unique structures as cysts with budding crypts where CD44 is enriched at bottom. E: n patients HC=3, NA / A=3, % cysts of total organoids mean±SEM, Anova comparison *p<0.05 **p<0.01. F: n patients NA / A=3, % budding structures of total organoids mean±SEM, paired (NA to A) t test comparison *p<0.05. A typical cyst with budding crypts, structure unique to A-organoid culture, is shown. G- Markers of CBC stem cells (LGR5, EPHB2) are enriched in mRNA from A-organoids compared to HC and NA-organoids. Markers of endocrine cells are decreased in mRNA from NA-organoids compared to HC. n patients HC=3-5, NA / A=5, Anova comparison *p<0.05 **p<0.01. Figure 2. EGF-dependence of FAP organoids. A- Several regulators of the EGF pathway were studied through their mRNA expression in organoids. None was increased in FAP (Non Adenomatous NA, Adenomatous A) organoids compared to HC (Healthy Controls). n patients HC=4-5, NA / A=4-5, Anova comparison *p<0.05 ***p<0.001. B- Compared to HC and NA-organoids, growth of A-organoids is greatly more dependent on the presence of EGF in the culture medium. EGF was starved from D2 of the organoid culture since it was required for organoid closure between D0-D2. n patients HC=6 NA / A=3, organoid size mean±SEM (diameter, around 100-300 organoids per condition), Anova comparison +EGF to -EGF *p<0.05 **p<0.01 ***p<0.001 ****p<0.0001. C- EGF starvation induces death in A- organoids. The number of dead organoids (example is shown with the brightfield image of black and dense structure in A culture) vs total number organoids was calculated at D7 of culture and variation of this percentage in EGF-starved conditions is shown. n patients NA / A=2, % variation mean±SEM (around 50 organoids per condition), NA to A t test comparison *p<0.05. IF: Labeling of Caspase 3 (yellow) and nuclei by DAPI at D9 of culture is shown. D- EGF- dependent ERK pathway is decreased in FAP organoids. Heatmap of protein expression in EGF signaling pathway (D7 of culture) is shown. n patients HC=3, NA / A=2, normalization of expression to HC MEK1. IF: Labeling of Pthr202 / tyr204-ERK1 / 2 (green) and nuclei by DAPI at D7 of culture is shown. E- EGF-dependent AKT pathway is increased in FAP organoids. IF: Labeling of Pser473-AKT (green) and nuclei by DAPI at D7 of culture is shown and quantified. n patients HC=2, NA / A=2, NA / A to HC Anova comparison and A-EGF to A t test comparison **p<0.01. Figure 3. Signaling partners of EGF in FAP organoids. A- R-spondin 1 (RSP) starvation from D0 of the culture has a negative impact on FAP (Non Adenomatous NA, Adenomatous A) organoid growth. n patients NA / A=5, organoid size mean±SEM (diameter, around 100-300 organoids per condition), Anova comparison A with RSP to A without RSP and NA with RSP to NA without RSP: *p<0.05 ***p<0.001 ****p<0.0001. B- Wnt secretion inhibition by IWP12 (5 µM) impairs survival of NA-organoids and growth of A-organoids. n patients NA / A=3, % variation of organoid death and size between D2 and D7 of culture compared to control (DMSO 0.02%), mean±SEM calculated through the analysis of around 10 organoids per condition, t-test comparison +IWP12 to -IWP12 *p<0.05 ****p<0.0001. C- Several regulators of the WNT pathway were studied through their mRNA expression in organoids. None was increased in FAP (NA, A) organoids compared to HC (Healthy Controls). n patients HC=4, NA / A=3-5, Anova comparison *p<0.05. D- TGFβ receptor is implicated in growth of FAP adenoma. Addition of the TGFβ receptor I inhibitor LY2157299 (LY, 0.5 µM) along the culture of FAP organoids induced a decrease of A-organoids growth. n patients NA / A=3, % variation of organoid size between D2 and D7 of culture compared to control (without treatment), mean±SEM calculated through the analysis of around 10 organoids per condition, t-test comparison +LY to -LY **p<0.01 A to NA *p<0.05. E- YAP controls growth and survival of adenoma. Addition of the YAP inhibitor Verteporfin (VP, 0.5 µM) to FAP organoids culture inhibited growth / survival of A-organoids. n patients NA / A=2 (growth) NA / A=3 (survival), % variation of organoid size / death between D2 and D7 of culture compared to control (DMSO 0.02%), mean±SEM calculated through the analysis of around 10 organoids per condition, t-test comparison +VP to -VP **p<0.01 A to NA *p<0.05 **p<0.01. F- YAP is activated (nuclear localization and Ptyr357 phosphorylation) specifically in FAP A-organoids. IF: Labeling of YAP or P-YAP (green) and nuclei by DAPI at D7 of culture is shown as well as Verteporfin (YAP inhibitor) negative impact on it. n patients NA / A=2, images representative of 5 structures per condition and zoomed to show nuclear localization of YAP. G- An activated form of β-catenin (Ser552-phosphorylated β-catenin, P-β CATENIN) is specifically found in FAP A-organoids. IF: Labeling of Pser552-β catenin (green) and nuclei by DAPI at D7 of culture is shown. Representative images from NA / A=2 patients. H- Activated forms of YAP (nuclear localization and Ptyr357 phosphorylation) and β-catenin (Pser552-β CATENIN) are dependent on EGF. IF quantification of total and phosphorylated forms of YAP and β-catenin in FAP A-organoids is shown as well as representative images of the impact of EGF starvation on that labeling. IF: Labeling of YAP / Pser552-β catenin (green) and nuclei by DAPI at D7 of culture is shown. n patients A=2, unpaired t test comparison *p<0.05 ****p<0.0001. I- EGF controls the mRNA expression of several targets implicated in proliferation (TGFβ, SOX9) as well as differentiation (KRT20) in FAP A-organoids. n patients HC=3-5, NA / A=5, Anova comparison *p<0.05. Figure 4. p110 isoforms of PI3K as pharmacological targets in FAP. A- p110 isoforms (α, β) of PI3K were studied through their mRNA expression in organoids. None showed an increase in FAP (Non Adenomatous NA, Adenomatous A) organoids compared to Healthy Controls (HC). n patients HC=5, NA / A=4-5. B- Immunolabeling of p110 isoforms in FAP organoids. Immunofluorescence (IF) quantification and representative images of labeling are presented. IF: Labeling of p110α and p110 (green) and nuclei by DAPI at D7 of culture is shown. n patients NA / A=2, Anova comparison ****p<0.0001. C- Pharmacological inhibition of p110α (A66, 0.5 µM) and p110β (AZD6482, 0.5 µM) induces maturation of NA-organoids and death of A-organoids, respectively. Growth (n patients NA / A=3, diameter size of around 20 organoids analyzed per condition) and epithelial monolayer width (n patients NA=4) quantifications are shown as well as representative images at D7 of culture (n patients NA / A=3) of actin labeling and organoid death (brightfield images). IF: Labeling of actin (magenta) and nuclei by DAPI is shown. Organoid size: Anova comparison vs Control (CTL, DMSO 0.005%) or between NA+A66 and NA+AZD *p<0.05. Epithelial monolayer width: t-test comparison *p<0.05. D- PAR1 and PAR2 agonist peptides (PAR1 a. p. and PAR2 a. p., respectively TFLLR-NH2 and SLIGRL-NH2, 100 µM) or control peptides (Ctl a. p., mixture of reversed sequences, 100 µM) were added daily from D2 to D5 of NA-organoid culture and immunofluorescence (IF) of p110 isoforms (α, β) and its quantification, as well as the measurement of the epithelial monolayer width, were performed. IF quantification and width measurement: n patients NA=3, Anova comparison ****p<0.0001. E- In A-organoid culture, PAR1 and PAR2 activation was performed as in D. Immunofluorescence (IF) of p110 isoforms (α, β), their quantification and the measurement of the number of organoids, were performed. IF quantification and organoids number measurement: respectively n patients A=2 and A=4, Anova comparison *p<0.05 **p<0.01. Figure 5. Schematic synthesis of data and hypothesis. Organoids from non- adenomatous (NA) and adenomatous (A) FAP colons have displayed different phenotypes during investigations, summarized as delayed maturation in intestinal primitive cells from NA and overactive proliferation and migration in those from A. Delayed maturation in intestinal primitive cells from NA seems to impact secretory differentiation (ATOH1 pathway) and may be linked to APC and LGR4 dysfunctions as well as to p100α (P110A) activation. In the proliferation and migration of intestinal primitive cells from A, in addition to APC dysfunction, EGFR and TGFβ (TGFb), but probably also LGR5- and WNT-dependent pathways, play a critical role by regulating p110β (P110B), β-catenin (B cat) and YAP. Notably, both NA and A areas differ in their survival pathways. APC*, mutant APC. Figure 6. Schematic synthesis of an exemplary therapeutic strategy. FAP is characterized with the appearance of polyps with low-grade dysplasia at an early stage, with polyps with high-grade dysplasia appearance at a later age, which finally progresses into in situ adenocarcinoma and metastatic cancer. The practitioner can, for example, take into consideration the number, size and ulcerated appearance of the polyps to decide whether to administer an alpha or beta isoform inhibitor. When a subject harbours an APC gene mutation, a PIK3CA inhibitor can be administered to prevent or delay polyp formation. From a predetermined reference number of polyps with low-grade dysplasia (e.g.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 polyps, preferably 10), it is preferable to prevent the formation of polyps with high-grade dysplasia by administering a PIK3CB inhibitor. Beyond said predetermined reference number of polyps, both isoforms can be administered to inhibit polyps formation and transformation to adenocarcinoma. EXAMPLE: Material and Methods Patients. Colonic biopsies were obtained at the Toulouse University Hospital, France, from patients included in the protocol NCT02874365 (Intestinal Stem Cells Characterization in Intestinal Organoid Culture From Inflammatory Bowel Disease and Intestinal Polyposis Patients (BIODIGE)). This monocentric trial was approved by the French ethic committee (South-West and Oversea IV) the 18 / MAR / 2016 and the French Drug Security Agency the 17 / MAR / 2016. Biopsies were obtained during colonoscopy; 4 biopsies from each non- adenomatous and adenomatous tissues of FAP patient or from tissue per healthy control (HC). Main characteristics of FAP and HC patients are indicated in Table 1. Organoid culture experiments. The culture protocol was adapted from the work of Jung and Sato.6,7Colonic biopsies were incubated 4x5 minutes in antibiotics and antifungals solutions, then incubated in 3x5-minutes baths of Dithiothreitol (10 mM, sterile solution in PBS-phosphate-buffered saline), at room temperature. Then, the mucosal pieces were incubated in EDTA (Ethylene Diamine Tetra-Acetic, 8 mM) for 1 hour at 4°C under gentle agitation. The supernatant was replaced by 10 mL of PBS. A strong manual agitation then isolates the crypts from the rest of the mucosa. The crypt-rich supernatant was recovered and 5% fetal calf serum (FCS) was added, centrifuged for 2 minutes at 40xg at 4°C to eliminate isolated cells and keep entire crypts. The pellet was resuspended three times in the base medium (Advanced Dulbecco’s Modified Eagle medium / F12 supplemented with Hepes 10 mM, Glutamax 2 mM and 5% SVF) for effective washing. Finally, the pellet was taken back in 5 mL in order to count the number of crypts extracted from each sample. The crypts were then resuspended in a volume of Matrigel (Matrigel hESC-qualified Matrix, BD Biosciences, previously placed at 4°C to allow its thawing and manipulated in the ice), in order to obtain a concentration of 50 crypts for 25 µL of Matrigel. 25 µL of this suspension were then deposited by well of 48-well plates, previously heated to 37°C. For immunostaining, 15-well Ibidi plates were used in which 10 µL of Matrigel containing 20 crypts were seeded. The Matrigel was polymerized during 20 minutes at 37°C, then the day (D) 0 complete medium was added (Table 2). This D0 complete medium was a mixture of DMEM / F12 (Advanced Dulbecco’s Modified Eagle medium / F12) supplemented with 10 mM Hepes, 2 mM Glutamax, 1x B-27 without vitamin A, 1x N2, 10 mM nicotinamide, 1 mM N-acetylcysteine, 10 nM PGE2, 50 ng / mL h-EGF, 100 ng / mL h-Noggin, 1 µg / mL h-R-Spondin, 10 nM gastrin, 10 µM SB202190 (p38MAPK inhibitor), 0.5 µM LY2157299 (TGF-β inhibitor). Recombinant Wnt3a was added in HC organoid culture only (Table 2) and, in some experiments, conditioned medium Wnt3a from subcutaneous connective tissue transfected with a Wnt3a expression vector (ATCC, L Wnt-3a, n°CRL-2648) was added both in FAP and HC organoid cultures. The medium was changed every 2-3 days with maintenance medium which corresponds to the D0 complete medium without N-acetylcysteine and LY2157299 (Table 2, 250 µL / well in 48-well plates, 50 µL / well in Ibidi plates). The growth and morphology of organoids were followed from D2 to D9, every 2 days under a wide- field transmission microscope (Apotome Zeiss, 10x lens). The size (largest diameter) of the organoids and the width of their epithelial monolayer were assessed with Image J. Counting of cystic / budding / dead structures was manually conducted through brightfield microscopy. Immunostaining. The organoids were fixed at the end of culture with 3.7% paraformaldehyde (PFA) for 40 minutes. Then the permeabilization of structures was performed with 0.5% Triton x100 (in HBSS) for 40 minutes followed by blocking of aspecific antigenic sites with 3% BSA (in HBSS) for 1.5 hours. Wells were washed and incubated with primary antibodies at 4°C overnight. Secondary antibodies were incubated for 1 hour at 37°C. A nuclei and actin labeling respectively by DAPI (ThermoFisher Scientific ref. D21490, 1 / 100) and phalloidin Alexa Fluor-647 (ThermoFisher Scientific ref. A22287, diluted to 1 / 500 in the DAPI solution) was performed (incubation for 20 minutes at room temperature). After extensive washing, a drop of liquid Vectashield mounting medium was deposited. The different antibodies used are summarized in Table 3. The slides were observed under a Zeiss 710 confocal microscope, 20x and 63x lenses. For each experiment, control wells were performed under the same conditions, without any antibody (autofluorescence control) and with secondary antibodies alone. Acquired images were analyzed and fluorescence quantified with the Image J software. Control images were processed identically. Proteomic screening and transcriptomic analysis. At the end of the organoid culture, medium was replaced by 250 µL Cell Recovery Solution (Corning ref. 354253) and 48-well plates were put on ice for 45 minutes. After dissolution of Matrigel, organoids from 10 wells of a same assay were collected by pipetting and mixed in 10 mL of the base medium (Advanced Dulbecco’s Modified Eagle medium / F12 supplemented with Hepes 10 mM, Glutamax 2 mM) and centrifuged for 5 minutes at 40xg at 4°C. Organoid pellet was then resuspended in 350 µL of lysis buffer RP1 (Macherey-Nagel ref.740934.50) and conserved at -80°C until protein and RNA extractions using the Macherey-Nagel kit (ref. 740933.250). Protein expression of different EGF pathway actors was quantified using the PathScan® EGFR Signaling Antibody Array Kit (Cell Signaling ref. 12622), according to the instructions provided by the supplier. The chemiluminescent reaction was measured on ChemiDocTMXRS (Bio-Rad) and presented as heatmap (GraphPad Prism). The quantity and quality of RNAs were assessed by Nanodrop (NanoPhotometer® P-330 Implen). The desired amount of RNA (between 0.5 and 5µg / qsp 14 µL water) was taken and added to 4 µL reaction buffer and 2 µL enzyme (RT Life Technology Fermentas, ref. K1642). Reverse transcription was performed using GeneAmp® PCR System 9700. Quantitative PCR was performed with Fluidigm technology at GENOTOUL facility (Toulouse, France). The primers were selected with PrimerBlast software and ordered at Eurogentec. The primers used had PCR efficiency >85% (data not shown). The minus delta Ct was calculated from housekeeping genes (mean, HPRT, GAPDH). Fold changes in the mRNA levels were calculated with comparative 2-ΔΔCtmethod using healthy tissue (HC) as control. Statistical analysis. Statistical analyses and graphs were performed with GraphPad Prism software (version 10.0, GraphPad Software, USA). The quantitative variables were compared by the one-way Anova test or t-test. The graphical representation includes the standard error to the mean. The significance threshold was p < 0.05. Results FAP organoids Since more than 10 years, the 3D organoid system was developed to reproduce mini-gut in vitro.5,7ISCs are able to form organoids when they are cultured in Matrigel with a medium containing several factors, notably Wnt3a. Using a Wnt3a-conditioned medium, we found a growth of FAP (A, NA) and HC organoids from D2 to D9 (Figure 1A). However, in FAP, the Wnt / APC / β-catenin pathway remains active because of APC mutation. Thus, at first, we studied the effect of Wnt3a starvation; as expected, we found that the growth of FAP organoids, either A or NA, was not altered, while it was blocked in HC organoids (Figure 1A). Later on, Wnt3a was not used in the culture medium of FAP organoids, while we used recombinant Wnt3a in HC ones (Figure 1B). Regardless the culture conditions, FAP organoids from A were larger than NA. However, when their proliferative capacity was assessed by Ki67 immunostaining or mRNA quantification, we found a proliferative activity very high in both NA and A compared to HC organoids (Figure 1C). As expected, the proliferative capacities are increased in colonic organoids from FAP patients compared to HC, and our data are pointing to the fact that these proliferative capacities are not sufficient to explain differences between NA and A. Different kinds of colonic organoids were reported in the literature.25As previously described, in the organoid culture from HC patients, we found cysts, colonospheres, and colonoids that are respectively characterized by a thin monolayer, a thick monolayer of epithelial cells without or with the presence of buds (Figure 1D). The maturity of these organoids progresses from cyst to colonosphere and to colonoid (Figure 1D). Indeed, the thick monolayer corresponds to colonic cells with an apical-basal orientation and the buds are equivalent to intestinal crypts in organoids. By contrast, in the culture of NA-organoids, the cystic phenotype is maintained at 40% of total organoids until D9, whereas HC- and A-cystic organoids decreased from D2 (40 and 20%, respectively) to D9 (5 and 10%, respectively) (Figures 1D and 1E). Accordingly, by immunostaining, we found a higher expression of CD44, a marker of epithelial immaturity, in NA-organoids compared to HC and A-organoids (Figure 1D). Surprisingly, in A-organoid culture, we early found a new organoid structure characterized by the presence of buds in cysts (Figure 1D). Of note, these budding cysts were not found in the organoid culture from NA area of FAP patients (Figure 1F). The total number of buds, which included colonoids and budding cysts, was higher in A- vs. NA-organoids (Figure 1F) and represents the signature of crypt fission events increasing the size of A- organoids as measured in Figures 1A and 1B. These above data suggest that in NA-organoids, the epithelial maturation may be delayed. A study of mRNA expression of different markers of ISCs (LGR5, EPHB2, BMI1, SOX9, LRIG1) did not show their increase in NA-organoids compared with HC and A- organoids (Figure 1G) as well as in crypts (data not shown). By contrast, compared to HC organoids, NA-organoids displayed lower expression of CHGA and LGR4 (Figure 1G), which have been linked to the metabolic / endocrine regulation in the crypt.26,27Also, ATOH1 was specifically decreased in NA crypts compared to HC crypts (data not shown), arguing again in favor of a specific coupling of metabolism and ISC fate in NA area of FAP.28Altogether, these data suggest that specific metabolic changes could occur early in APC-deficient ISCs as it has been shown that APC controls pyruvate metabolism in mitochondria and therefore intestinal differentiation.29As shown in Figure 1G, LGR5 and EPHB2 mRNA expression are increased in A-organoids compared to HC and NA-organoids, such as in crypts (data not shown), suggesting an enrichment of CBC ISCs. These results are in accordance with previous published data in FAP crypts.30Then, we aimed to investigate FAP ISC regulation. Given the important role of EGFR signaling in the establishment of adenomas in a ApcMinmouse model,19we have investigated the EGF pathway in our organoid model. First, mRNA expression of EGF and TIMP1, two important ISC regulators, was significantly decreased in FAP organoids compared to HC (Figure 2A). As EGF and TIMP1 mRNA were not deficient in crypts (data not shown), overall these data suggest a strong dependence of FAP ISCs and progenitors to their microenvironment. Indeed, the deprivation of EGF significantly blocked the growth of A- organoids compared to HC and NA (Figure 2B). Moreover, an important finding was that the absence of EGF increased the mortality of FAP A-organoids compared to NA-organoids (Figure 2C). These results, obtained with human organoids, confirm that besides β-catenin activity, APC-deficient ISCs and progenitors require EGFR signaling to develop adenoma. It was thus important to investigate signaling pathways downstream of EGFR in FAP organoids. A proteomic screening showed that the MEK / ERK pathway was strictly dependent on EGF in HC organoids (Figure 2D). The MEK / ERK activity declines in NA-organoids and was abolished in A-organoids, independently on the presence of EGF in the culture medium (Figure 2D). Importantly, the expression of the hepatocyte growth factor receptor (MET) capable to interfere with EGFR-signaling pathway was also absent in A-organoids (Figure 2D). These findings were confirmed by immunostaining experiments, with an activation of ERK in NA but not in A colonic organoids (Figure 2D). Further, labeling of activated AKT was found increased in A compared to NA and HC organoids, and dependent on the presence of EGF in the culture medium (Figure 2E). We then looked for a possible synergy of EGFR with signaling partners. It has been recently shown that R-spondin 1 could inhibit adenoma development in the ApcMinmouse model.31By contrast, our data show that R-spondin 1 is required in the culture medium to promote growth of FAP organoids (Figure 3A). Given that FAP organoids are APC-deficient with active β-catenin, these data could indicate that another Wnt / Frizzled signaling pathway is active in FAP. To check this hypothesis, we applied an inhibitor of Wnt secretion (IWP12, Sigma-Aldrich ref. SML0677) on FAP organoids. This treatment induced death and growth inhibition in NA- and A-organoids, respectively (Figure 3B). Interestingly, the metabolic regulator HIF2 has recently been shown to drive WNT5A expression in duodenal organoids, which promotes epithelial survival through β-catenin-independent (non-canonical) signaling.32As shown in Figure 3C, we did not observe increased WNT5A expression in FAP organoids compared to HC, as well as in crypts (data not shown). However, the Wnt receptor Frizzled 4, which can mediate canonical activity of WNT5A, was found specifically decreased in NA- organoids (Figure 3C).33Altogether these data suggest that WNT5A, known to play a critical role in the crypt regeneration, may regulate cell survival and growth in APC-deficient ISCs of NA and A areas, respectively.34In the intestinal crypt, an important signaling partner of EGF and WNT5A is TGFβ. Its role in tumorigenesis is ambiguous, acting either as tumor suppressor or pro-metastatic factor.35We did not observe a significant difference in its mRNA expression between HC and FAP organoids (Figure 3C), as well in crypts (data not shown). As shown in Figure 3D, the pharmacological inhibition of TGFβ receptor did not affect the size of NA-organoids while it significantly decreased by around 40% the size of A-organoids. These data show that growth of adenoma is dependent on both EGF and TGFβ. YAP is an important signaling target of morphogens (Wnts, TGFβ) and EGF in the intestinal crypt and its inhibition by Verteporfin (Sigma-Aldrich ref. SML0534) induced specifically in FAP A-organoids, growth inhibition and death (Figure 3E). Moreover, specifically in A-organoids, YAP was found at nuclear location and phosphorylated on the residue Tyrosine 357 (Figure 3F). This regulation of the active form of YAP was abolished by Verteporfin (Figure 3F). It has been previously shown that AKT can phosphorylate β-catenin at serine 552 to promote its nuclear localization in a context of increased ISC proliferation and adenoma formation.36Our results show a specific labeling of β-catenin Pser552 in buds of FAP A- organoids (Figure 3G). This form of phosphorylated β-catenin is not found in FAP NA- organoids (Figure 3G). Importantly, both active forms of YAP (Ptyr357-YAP) and β-catenin (Pser552-β catenin) were under the control of EGF in FAP A-organoids (Figure 3H). TGF-β receptor inhibition also blocked the phosphorylation of β-catenin at the residue Serine 552 (data not shown). Thus, these data show that the modulation of β-catenin activity in adenoma is dependent of both EGF and TGFβ. Also, external EGF was required to regulate mRNA of TGFβ, SOX9, KRT20 in FAP A-organoids (Figure 3I). Taken together, these data argue in favor of an increased β-catenin-dependent proliferation in APC-deficient ISCs that could be modulated by an EGF-dependent specific regulation of β-catenin, associated with EGF- dependent regulation of genes involved in cell proliferation and migration, which are implicated in adenoma formation. PI3K inhibitors for use in the treatment of FAP AKT is activated downstream of PI3K, and inhibitors targeting PI3K isoforms are now being considered in therapeutic protocols for several pathologies.37-39While a quantitative PCR did not show differences in the expression of p110α and p110β isoforms of PI3K between HC and FAP organoids (Figure 4A), immunolabeling revealed enrichment of p110α and p110β in NA- and A-organoids from FAP, respectively (Figure 4B). Furthermore, p110β was specifically found to be enriched in buds of A-organoids (Figure 4B). Pharmacological inhibitors of p110α (A66, Selleckchem ref. S2636) and p110β (AZD6482, Selleckchem ref. S1462) led to a reduction in the growth of A-organoids (Figure 4C). Moreover, the death of A- organoids was observed by microscopy following treatment with AZD (Figure 4C). In contrast, inhibition of p110α resulted in increased growth in NA-organoids, associated with epithelial maturation, as evidenced by an enlarged width of epithelial monolayer (Figure 4C). Of note, the expression of the regulatory subunit p85 of PI3K, associated with p110 isoforms, was not different between NA- and A-organoids, and not significantly changed upon the treatment with pharmacological inhibitors of p110 isoforms (data not shown). It has been previously shown that the p110α isoform predominates in the non-transformed immature intestinal epithelial cell line (HIEC6) and may play a role in its survival.40Here, the survival of NA-organoids following treatment with a p110α inhibitor is possibly due to compensatory mechanisms involving the p110β isoform.37Additionally, both β-catenin and PI3K (p110β) activation have been implicated in the progression of intestinal adenocarcinoma.41However, our results suggest that such a combination of β-catenin and oncogenic PI3K (mutant p110β) may be required at an earlier stage for adenoma formation to promote cell survival. It is important to note that somatic mutations of PI3K (p110β) found in diverse cancers have demonstrated that this kinase possesses the capacity to promote all oncogenic functions, including cell survival, proliferation, and migration.42Finally, considering the role of the protease-activated receptor PAR1 in impeding adenoma formation in APCMin / +mice, we investigated the impact of PAR1 and PAR2 activation using agonist peptides (TFLLR-NH2 and SLIGRL-NH2 respectively, Genscript) on p110 isoforms expression and FAP organoids behavior.43Compared to control peptides (reversed sequences, Genscript or Ezbiolab Inc., Carmel, IN, USA), we measured a specific decrease of p110α level in NA-organoids induced by both PAR1 and PAR2 agonist peptides (Figures 4D and 4E). However, only PAR1 activation proved capable of enhancing the maturation of NA- organoids (Figure 4D), whereas PAR2 activation was the most efficient to decrease the p110β level in A-organoids, associated with a decrease in the number of organoids and budding in the culture (Figures 4E and data not shown). Importantly, it is worth noting that PAR1 and PAR2 mRNA expression did not significantly differ in FAP organoids compared to HC, while a lower expression of PAR2 was measured in FAP crypts (data not shown). Once again, these results highlight the distinct phenotypes between NA and A areas and strongly suggest that pharmacological tools aimed at modulating p110 isoforms expression / activation could be of therapeutic interest in FAP. CONCLUSION Our work allows us to propose a design for the phenotypes of FAP organoids. Firstly, survival pathways differ between NA and A ISCs, with the former relying on a WNT receptor pathway, while the latter depends on the EGF receptor pathway (Figure 5). Secondly, the main defect in NA ISCs could be a deficiency in their capacities of differentiation associated with a metabolic switch, whereas A ISCs display mainly high proliferative and migratory capacities. Thus, early chemoprevention proposed for FAP patients could be based on strategies enhancing the differentiation of NA ISCs by targeting p110α or metabolic pathways. In a further step, for advanced FAP cases characterized by a carpet of polyps, targeting p110β and / or TGFβ and / or FZD4 may be considered (see as example Figure 6). TABLES Table 1 : Main characteristics of patients

[0002] Abbreviations: F, female; M, male; FAP, familial adenomatous polyposis; NA, not available Table 2: Organoid culture medium components Abbreviations: HC, healthy control. Table 3 : Primary and secondary antibodies REFERENCES: Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure. 1. Hyer, W., et al. Management of Familial Adenomatous Polyposis in Children and Adolescents: Position Paper From the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr 68, 428-441 (2019). Moser, A. R., Pitot, H. C. & Dove, W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322-324 (1990). Moser, A. R., Dove, W. F., Roth, K. A. & Gordon, J. I. The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. 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Claims

CLAIMS:

1. A method of treating Familial Adenomatous Polyposis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a PI3K inhibitor.

2. The method according to claim 1 for the preventive treatment of Familial Adenomatous Polyposis in a subject harbouring a polyposis gene mutation, in particular an APC gene mutation.

3. The method according to claim 2, wherein the subject has no polyps in his gastrointestinal tract.

4. The method according to claim 1, wherein the subject has polyps in his gastrointestinal tract.

5. The method according to any of claims 1 to 4 for preventing the development of polyps with high-grade dysplasia in the subject suffering from Familial Adenomatous Polyposis.

6. The method according to any of claims 1 to 5 for preventing the development of adenocarcinoma in the subject suffering from Familial Adenomatous Polyposis.

7. The method according to claim 6, wherein the adenocarcinoma is a colonic adenocarcinoma.

8. The method according to any of claims 1 to 7 for preventing colorectal cancer in the subject suffering from Familial Adenomatous Polyposis.

9. The method according to any of claims 1 to 3, wherein the PI3K inhibitor is a PIK3CA inhibitor.

10. The method according to any of claims 1 to 8, wherein the PI3K inhibitor is a PIK3CA inhibitor and / or a PIK3CB inhibitor.

11. The method according to any of claims 1 to 10, wherein the PI3K inhibitor is a small organic molecule.

12. The method according to any of claims 1 to 10, wherein the PI3K inhibitor is Alpelisib.

13. The method according to any of claims 1-8 to 10, wherein the PI3K inhibitor is AZD-

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