Combination therapy using psma-targeted radiopharmaceuticals and an inhibitor of pi3k, akt, and / or mtor

Abstract

The disclosure relates to kits of parts and compositions comprising a PSMA-targeted radiopharmaceutical, e.g., PSMA I&T, and an inhibitor of PI3K, AKT, and / or mTOR, e.g., bimiralisib, for the treatment of a cancer, preferably a prostate cancer.

Description

[0001] COMBINATION THERAPY USING PSMA-TARGETED RADIOPHARMACEUTICALS AND AN INHIBITOR OF PI3K, AKT, AND / OR MTOR

[0002] FIELD OF THE INVENTION

[0003] The invention relates to combinations comprising PSMA I&T and an inhibitor of PI3K, AKT, and / or mTOR for the treatment of a disease, preferably a cancer, more preferably a prostate cancer.

[0004] RELATED ART

[0005] Prostate cancer (PCa) is the second most prevalent cancer in men worldwide and the sixth leading cause of death in men. Ilic, D. et al., Cochrane Database of Systematic Reviews, 2013, Issue 1. Art. No.: CD004720.

[0006] Prostate-specific membrane antigen (PSMA) is a well-established target for nuclear imaging and therapy of PCa. Chatalic et al., Theranostics, 2016, 6(6), 849-861. Compared to healthy human prostate tissue, in almost all PCa tumors, the expression of PSMA is 10-80 fold higher. Baur et al., Pharmaceuticals, 2014, 7, 517-529. PSMA is a peptidase that catalyzes the hydrolysis of N-acetyl-L-aspartyl-L-glutamate (NAAG) into the corresponding N-acetyl-L-aspartate (NAA) and L-glutamate. Id. Based on the chemical structure of NAAG, several glutamate-urea-glutamate-based peptides bearing a 2-[3-(l,3-dicarboxypropyl)- ureido]pentanedioic acid (DUPA) moiety have been developed. Id. Molecules bearing a DUPA fragment showed high affinity and specific binding to PSMA, as demonstrated in binding studies using PSMA-expressing LNCaP cell lines. Id.

[0007] DUPA-bearing fragments can be further conjugated to a dodecane tetraacetic acid (DOTA) fragment capable of chelating a radionuclide. Such DUPA-DOTA containing molecules include PSMA-11, PSMA-617, and PSMA-I&T. Chatalic 2016. Radiolabeled small-molecule PSMA inhibitors comprising DUPA and DOTA fragments are known candidates for PCa theranostics because they rapidly and efficiently localize in tumor lesions. Id.

[0008] Despite the use of PSMA-targeted, radiolabeled molecules, morbidity and mortality remain unmet challenges for prostate cancer patients. Thus there is a need for effective treatments of prostate cancer. SUMMARY OF THE INVENTION

[0009] As set forth in the Detailed Description below, the inventive kits of parts, compositions and combinations are effective for the treatment of cancers such as prostate cancer.

[0010] Without wishing to be bound by theory, treatment of cancer cells (e.g., prostate cancer cells) with an inhibitor of PI3K, AKT, and / or mTOR can metabolically exhaust the cancer cells. The addition of the PSMA I&T, preferably a PSMA I&T chelated to a radionuclide such as161Tb or177Lu, can further damage the DNA of the cancer cells, causing additional cell death. Thus, in preferred embodiments, the inventive combinations can act synergistically to treat cancers such as prostate cancer.

[0011] In one aspect, the present disclosure provides a kit of parts comprising:

[0012] (i) a PSMA-targeted radiopharmaceutical; and

[0013] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0014] In one aspect, the present invention provides a kit of parts comprising:

[0015] (i) Compound A:

[0016] Compound A; and

[0017] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0018] In one aspect, the present disclosure provides a composition comprising:

[0019] (i) a PSMA-targeted radiopharmaceutical; and

[0020] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0021] In one aspect, the present invention provides a composition comprising:

[0022] (i) Compound A:

[0023]

[0024] Compound A; and

[0025] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0026] In one aspect, the present invention comprises a combination comprising: (i) a composition comprising a PSMA-targeted radiopharmaceutical; and

[0027] (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR.

[0028] In one aspect, the present invention comprises a combination for use in a method of treating a cancer in a subject, said combination comprising:

[0029] (i) a composition comprising a PSMA-targeted radiopharmaceutical; and (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR.

[0030] In one aspect, the present invention provides a combination comprising:

[0031] (i) a composition comprising Compound A: Compound A; and

[0032] (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR.

[0033] In one aspect, the present invention comprises a combination for use in a method of treating a cancer in a subject, said combination comprising:

[0034] (i) a PSMA-targeted radiopharmaceutical; and

[0035] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0036] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, said combination comprising:

[0037] (i) Compound A:

[0038] Compound A; and

[0039] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0040] In one aspect, the present invention provides a method of treating a cancer in a subject in need thereof, the method comprising: administering to said subject a therapeutically effective amount of (i) a PSMA-targeted radiopharmaceutical; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0041] In one aspect, the present disclosure provides an inhibitor of PI3K, AKT, and / or mTOR for use in a method of treating a cancer; wherein said inhibitor of PI3K, AKT, and / or mTOR is administered in combination with a PSMA-targeted radiopharmaceutical.

[0042] In one aspect, the present disclosure provides a PSMA-targeted radiopharmaceutical for use in a method of treating a cancer; wherein said PSMA-targeted radiopharmaceutical is administered in combination with an inhibitor of PI3K, AKT, and / or mTOR.

[0043] In one aspect, the present invention provides the use of a combination in the manufacture of a medicament for treating a cancer, preferably a prostate cancer, wherein said combination comprises: (i) a PSMA-targeted radiopharmaceutical; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0044] In some embodiments, said PSMA-targeted radiopharmaceutical comprises a DUPA targeting group.

[0045] In some embodiments, said PSMA-targeted radiopharmaceutical is selected from Compound A, PSMA-617, and PSMA-11.

[0046] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is a dual PI3K / mT0R inhibitor.

[0047] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is selected from the group consisting of Compound 1 * and Compound 2.

[0048] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is a compound of Formula (I): wherein:

[0049] X1, X2and X3are, independently of each other, N or CH; with the proviso that at least two of X1, X2and X3are N;

[0050] Y is N or CH;

[0051] W is H or F; with the proviso that when W is F, then X1, X2and X3are N;

[0052] R1and R2are independently of each other

[0053] (i) a morpholinyl of formul wherein the arrow denotes the bond in formula (I); and wherein R3and R4are independently of each other H, Ci-Ctialkyl optionally substituted with one or two OH, Ci-

[0054] C2fluoroalkyl, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4 form together a bivalent residue -R5R6- selected from Ci-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II); or

[0055] (ii) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R7; wherein R7is independently at each occurrence Ci-Csalkyl optionally substituted with one or two OH, Ci-C2fluoroalkyl, Ci-C2alkoxyCi- Csalkyl, G-G>cycloalkyl; or two R7substituents form together a bivalent residue -R8R9- selected from C-Galkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CH2CH2- O-; with the proviso that at least one of R1and R2is a morpholinyl of formula II; and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts thereof.

[0056] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib, or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to a radionuclide.

[0058] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to

[0059] 161Tb.

[0060] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to161Tb; and wherein said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

[0061] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to177LU.

[0062] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to

[0063] 177LU; and wherein said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

[0064] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to161Tb or177LU.

[0065] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to161Tb or177LU; and wherein said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

[0066] In one aspect, the present disclosure provides a kit of parts or a composition as described herein, for use in therapy.

[0067] In one aspect, the present disclosure provides a kit of parts, a composition, or a combination as described herein, for use in the treatment of a cancer. In one aspect, the disclosure provides a method of treatment of cancer in a subject in need thereof.

[0068] In some embodiments, said cancer is prostate cancer.

[0069] In some embodiments, said cancer is prostate cancer, wherein said PSMA-targeted radiopharmaceutical is Compound A, wherein said Compound A is chelated to161Tb; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0070] In some embodiments, said cancer is prostate cancer, wherein said PSMA-targeted radiopharmaceutical is Compound A, wherein said Compound A is chelated to177Lu; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0071] In some embodiments, said cancer is prostate cancer, wherein said PSMA-targeted radiopharmaceutical is Compound A, wherein said Compound A is chelated to161Tb or177Lu; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0072] In some embodiments, said cancer is castration-resistant prostate cancer, wherein said PSMA-targeted radiopharmaceutical is Compound A, wherein Compound A is chelated to161Tb; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0073] In some embodiments, said cancer is castration-resistant prostate cancer, wherein said PSMA-targeted radiopharmaceutical is Compound A, wherein Compound A is chelated to177LU; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0074] In some embodiments, said cancer is castration-resistant prostate cancer, wherein said PSMA-targeted radiopharmaceutical is Compound A, wherein Compound A is chelated to161Tb or177LU; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0075] In some embodiments, said (i) PSMA-targeted radiopharmaceutical is Compound A, wherein said Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR (preferably bimiralisib) are administered sequentially.

[0076] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, preferably a prostate cancer, wherein said combination comprises:

[0077] (i) Compound A:

[0078] Compound A; and

[0079] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0080] BRIEF DESCRIPTION OF THE FIGURES

[0081] FIG 1 is a plot showing percent survival of 22Rvl cells treated with different concentrations of Compound 1* and Compound 2 for 7 days relative to untreated cells. IC50 values were determined by non-linear regression analysis. Graphs represent the mean of three replicates ± SEM. “PQR309” refers to Compound 1* as disclosed herein.

[0082] FIG 2A is a plot showing percent survival of 22Rvl cells treated with different concentrations of Compound 1* and Compound 2 in combination with different doses of177LU-PSMA-617 (0, 0.5,1, 2.5, 5, 10, or 20 MBq) for 7 days relative to cells treated with respective dose of177Lu-PSMA-617 only (i.e., not treated with Compound 1* or Compound 2).

[0083] FIG 2B is a synergy analysis of 22Rvl cells treated with different concentrations of Compound 1* in combination with different doses of177Lu-PSMA-617, as described in Example 1. “PQR309” refers to Compound 1* as disclosed herein.

[0084] FIG 2C is a synergy analysis of 22Rvl cells treated with different concentrations of Compound 2 in combination with different doses of177Lu-PSMA-617, as described Example 1.

[0085] FIG 3 A is a plot of body weight in g of female nude mice at start of treatment period (Study day -1) in the indicated treatment groups as described in Example 2. n=8 per group. “PQR309” refers to Compound 1* as disclosed herein.

[0086] FIG 3B is a plot of tumor volume in mm3at start of treatment period (Study day -1) in the indicated treatment groups as described in Example 2. n=8 per group. “PQR309” refers to Compound 1* as disclosed herein.

[0087] FIG 4A is a plot of tumor volume (mm3) over time in mice treated with vehicle; Compound 1*;161Tb-PSMA-I&T (21.8 MBq); or both Compound 1* and161Tb-PSMA-I&T (21.8 MBq). Treatment as indicated started at study day 0. Mice received a single injection of161Tb-PSMA-I&T and / or Compound 1* daily until reaching the endpoint (tumor volume 1500 mm3). Data presented as mean - / +SEM. n=8 per group. “PQR309” refers to Compound 1 * as disclosed herein.

[0088] FIG 4B is a plot of tumor volume (mm3) over time in mice treated with vehicle; Compound 1*;161Tb-PSMA-I&T (43.7 MBq); or both Compound 1* and161Tb-PSMA-I&T (43.7 MBq). Treatment as indicated started at study day 0. Mice received a single injection of161Tb-PSMA-I&T and / or Compound 1* daily until reaching the endpoint (tumor volume 1500 mm3). Data presented as mean - / +SEM. n=8 per group. “PQR309” refers to Compound 1 * as disclosed herein.

[0089] FIG 4C is a plot of tumor volume (mm3) over time in mice treated with vehicle; Compound 1*;177Lu-PSMA-617 (30 MBq); or both Compound 1* and177Lu-PSMA-617 (30 MBq). Treatment as indicated started at study day 0. Mice received a single injection of177Lu- PSMA-617 and / or Compound 1* daily until reaching the endpoint (tumor volume 1500 mm3). Data presented as mean - / +SEM. n=8 per group. “PQR309” refers to Compound 1* as disclosed herein.

[0090] FIG 4D is a plot of tumor volume (mm3) over time in mice treated with vehicle; Compound 1*;177Lu-PSMA-617 (60 MBq); or both Compound 1* and177Lu-PSMA-617 (60 MBq). Treatment as indicated started at study day 0. Mice received a single injection of177Lu- PSMA-617 and / or Compound 1* daily until reaching the endpoint (tumor volume 1500 mm3). Data presented as mean - / +SEM. n=8 per group. “PQR309” refers to Compound 1* as disclosed herein.

[0091] FIG 5 is a series of plots of tumor volume (mm3) over time in mice treated with vehicle; Compound 1*;161Tb-PSMA-I&T (21.8 MBq);161Tb-PSMA-I&T (43.7 MBq);177Lu-PSMA- 617 (30 MBq);177Lu-PSMA-617 (60 MBq); or both Compound 1* and161Tb-PSMA-I&T (21.8 MBq) or161Tb-PSMA-I&T (43.7 MBq) or177Lu-PSMA-617 (30 MBq) or177Lu-PSMA- 617 (60 MBq). Treatment as indicated started at study day 0. Mice received a single injection of161Tb-PSMA-I&T (21.8 MBq) or161Tb-PSMA-I&T (43.7 MBq) or177Lu-PSMA-617 (30 MBq) or177Lu-PSMA-617 (60 MBq) and / or Compound 1* daily until reaching the endpoint (tumor volume 1500 mm3). Data presented as individual tumor volumes. n=8 per group. “PQR309” refers to Compound 1* as disclosed herein.

[0092] FIG 6 is a plot of days until endpoint (i.e., number of study days from treatment start until tumors reaching >1500 mm3) from all treatment groups as described in Example 2.

[0093] DETAILED DESCRIPTION OF THE INVENTION

[0094] Definitions

[0095] Each “alkyl” moiety either alone or as part of a larger group such as alkoxy is a straight or branched chain and is preferably Ci-C3alkyl, more preferably Ci-C2alkyl. Examples include in particular methyl, ethyl, / 7-propyl and prop-2-yl ( / .s -propy l ). Examples of an alkoxy include in particular methoxy, ethoxy, w-propoxy and / .so-propoxy. As described herein, alkoxy may include further substituents such as halogen atoms leading to haloalkoxy moieties.

[0096] The term “alkoxyalkyl” refers to an R-O-R’ moiety in which the R and R’ groups are alkyl groups as defined herein. Examples include methoxymethyl, methoxyethyl, ethoxyethyl and methoxypropyl.

[0097] Each alkylene moiety is a straight or branched chain and is, particularly for example, - CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-, preferably -CH2-, -CH2-CH2- or -CH(CH3)-.

[0098] Each haloalkyl moiety either alone or as part of a larger group such as haloalkoxy is an alkyl group substituted by one or more of the same or different halogen atoms. Haloalkyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents. Examples include in particular fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2,2,2-trifluoro-ethyl.

[0099] Each haloalkenyl moiety either alone or as part of a larger group such as haloalkenyloxy is an alkenyl group substituted by one or more of the same or different halogen atoms. Examples include 2-difluoro-vinyl and l,2-dichloro-2-fluoro-vinyl. Haloalkenyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.

[0100] Each cycloalkyl moiety can be in mono- or bi-cyclic form, typically and preferably in mono-cyclic form, and preferably contains 3 to 6 carbon atoms. Preferred examples of monocyclic cycloalkyl groups include in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0101] The term "heterocyclic ring" refers to a saturated or partially unsaturated carbocyclic ring containing one to three heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Preferred examples include in particular tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, dioxanyl, morpholinyl, oxazolidinyl and isooxazolidinyl.

[0102] Where a group is said to be optionally substituted, preferably there are optionally 1-3 substituents, more preferably optionally 1-2 substituents.

[0103] Certain compounds of formula (I) may contain one or two or more centers of chirality and such compounds may be provided as pure enantiomers or pure diastereoisomers as well as mixtures thereof in any ratio. The compounds of the invention also include all tautomeric forms of the compounds of formula (I).

[0104] As used herein, the terms “overexpression” or “overexpressed” refer to the abnormal or artificial expression of a gene or protein in increased quantity, e.g., as compared to wildtype cells. In some embodiments, the expression of the overexpressed gene or protein can be, e.g., 10% higher than the expression of the same gene or protein in a corresponding wild-type cell, as measured by standard techniques used in the art for quantification of gene expression. In some embodiments, the expression of the overexpressed gene or protein can be, e.g., 50% higher, 100% higher, ten times higher, 100 times higher, or 1,000 times higher or more than the expression of the same gene in a corresponding wild-type cell.

[0105] As used herein, the term “PSMA” is understood to mean prostate specific membrane antigen. In preferred embodiments, PSMA is a type II membrane protein and is expressed in all forms of prostate tissue, including carcinoma. PSMA is described by Chang, Rev. Urol., 2004 6(Suppl. 10): S13-S18.

[0106] As used herein, the term “measurable quantities”, typically and preferably when used in the context of one or both of the inhibitor of PI3K, AKT and / or mTOR and the PSMA- targeted radiopharmaceutical, is understood to mean that such compound(s) can be measured in a given sample (e.g., a blood or serum sample obtained from the subject) using techniques known to one of skill in the art. For example, a “measurable quantity” of, e.g., an inhibitor of PI3K, AKT and / or mTOR in a blood sample obtained from a subject is a quantity that is above the lower limit of quantitation (LLOQ) for a given analytical technique used to measure said inhibitor, and thus able to be quantified using that technique. Suitable analytical techniques are known to one of skill in the art and include but are not limited to, e.g., ELISA, HPLC-MS, and the like.

[0107] As used herein, the term “simultaneous” is understood to mean “at the same time as”, and the two terms are used interchangeably herein. Accordingly, in preferred embodiments, when an inhibitor of PI3K, AKT and / or mTOR is administered “simultaneously” with a PSMA-targeted radiopharmaceutical, it is understood that the inhibitor of PI3K, AKT and / or mTOR is administered at the same time as the a PSMA-targeted radiopharmaceutical. For example, if the inhibitor of PI3K, AKT and / or mTOR is administered over a period of hours or minutes (e.g., from about 1 to about 90 minutes, e.g., by intravenous administration), said PSMA-targeted radiopharmaceutical can be administered during the time period in which the inhibitor of PI3K, AKT and / or mTOR is administered. Likewise, the inhibitor of PI3K, AKT and / or mTOR can be administered during the time period in which the PSMA-targeted radiopharmaceutical is administered.

[0108] As used herein, the term “[has] previously been treated” is understood to a refer to situations in which a subject, preferably a subject who is to be treated with one of an inhibitor of PI3K, AKT and / or mTOR or a PSMA-targeted radiopharmaceutical, has earlier been treated with one of an inhibitor of PI3K, AKT and / or mTOR or a PSMA-targeted radiopharmaceutical. In preferred embodiments, said subject who is to be treated with one of (i) an inhibitor of PI3K, AKT and / or mTOR or (ii) a PSMA-targeted radiopharmaceutical has earlier been treated with the other of (i) an inhibitor of PI3K, AKT and / or mTOR or (ii) a PSMA-targeted radiopharmaceutical.

[0109] Although the term “[has] previously been treated” encompasses embodiments in which a subject was previously treated with either of a (i) an inhibitor of PI3K, AKT and / or mTOR or (ii) a PSMA-targeted radiopharmaceutical at any point in the future, in preferred embodiments, said “previous treatment” with either of the (i) inhibitor of PI3K, AKT and / or mTOR or (ii) PSMA-targeted radiopharmaceutical is administered during the course of a combination therapy as described herein. Preferably, when the two active ingredients (i.e., the (i) inhibitor of PI3K, AKT and / or mTOR and the (ii) PSMA-targeted radiopharmaceutical) are administered sequentially, the active ingredients are administered within such a time period that the two active ingredients can exert an additive, preferably synergistic effect within the body of a subject. Preferably, when a subject has “previously been treated” with one of the active ingredients described herein, said active ingredient is still present in measurable quantities in the blood of the subject (as determined by one of skill in the art) when the second of the active ingredients is administered to said subject.

[0110] In some preferred embodiments, said inhibitor of PI3K, AKT and / or mTOR is administered to a subject prior to administration of said PSMA-targeted radiopharmaceutical, wherein measurable quantities of said inhibitor of PI3K, AKT and / or mTOR are still present in the blood of said subject upon administration of said PSMA-targeted radiopharmaceutical.

[0111] In some preferred embodiments, said PSMA-targeted radiopharmaceutical is administered to a subject prior to administration of said inhibitor of PI3K, AKT and / or mTOR, wherein measurable quantities of said PSMA-targeted radiopharmaceutical are still present in the blood of said subject upon administration of said inhibitor of PI3K, AKT and / or mTOR.

[0112] Thus, in some embodiments, said “previous treatment” with either of (i) the inhibitor of PI3K, AKT and / or mTOR or (ii) the PSMA-targeted radiopharmaceutical has occurred within one month of the treatment with the other of the inhibitor of PI3K, AKT and / or mTOR or the PSMA-targeted radiopharmaceutical. In preferred embodiments, said “previous treatment” with either of (i) the inhibitor of PI3K, AKT and / or mTOR or (ii) the PSMA- targeted radiopharmaceutical has occurred within two weeks; preferably within seven days; more preferably within one day of the treatment with the other of the inhibitor of PI3K, AKT and / or mTOR or the PSMA-targeted radiopharmaceutical. In some embodiments, said “previous treatment” with either of (i) the inhibitor of PI3K, AKT and / or mTOR or (ii) the PSMA-targeted radiopharmaceutical has occurred within 12 hours; e.g., within six hours; e.g., within three hours of the treatment with the other of the inhibitor of PI3K, AKT and / or mTOR or the PSMA-targeted radiopharmaceutical.

[0113] As used herein, the term “in combination with”, preferably when used in the context of administering an inhibitor of PI3K, AKT and / or mTOR and a PSMA-targeted radiopharmaceutical to a subject, is understood to encompass both simultaneous administration (as defined herein) and to situations wherein said subject has previously been treated with (as defined herein) either said inhibitor of PI3K, AKT and / or mTOR or a PSMA- targeted radiopharmaceutical prior to treatment with the other of said inhibitor of PI3K, AKT and / or mTOR and a PSMA-targeted radiopharmaceutical. Accordingly, as used herein, the term “in combination with” is understood to encompass any embodiment in which: (i) a subject is administered a PSMA-targeted radiopharmaceutical, wherein the subject has previously been treated with an inhibitor of PI3K, AKT, and / or mTOR; (ii) a subject is administered an inhibitor of PI3K, AKT, and / or mTOR, wherein the subject has previously been treated with a PSMA-targeted radiopharmaceutical; or (iii) a subject is administered an inhibitor of PI3K, AKT, and / or mTOR at the same time as said subject is administered a PSMA-targeted radiopharmaceutical.

[0114] In some preferred embodiments, the term “in combination with” refers to situations in which: (i) a subject is administered a PSMA-targeted radiopharmaceutical, wherein the subject has previously been treated with an inhibitor of PI3K, AKT, and / or mTOR; (ii) a subject is administered an inhibitor of PI3K, AKT, and / or mTOR, wherein the subject has previously been treated with a PSMA-targeted radiopharmaceutical; or (iii) a subject is administered an inhibitor of PI3K, AKT, and / or mTOR at the same time as said subject is administered a PSMA-targeted radiopharmaceutical.

[0115] In some preferred embodiments, the term “in combination with” refers to situations in which: a subject is administered a PSMA-targeted radiopharmaceutical, wherein the subject has previously been treated with an inhibitor of PI3K, AKT, and / or mTOR.

[0116] In some preferred embodiments, the term “in combination with” refers to situations in which: a subject is administered an inhibitor of PI3K, AKT, and / or mTOR, wherein the subject has previously been treated with a PSMA-targeted radiopharmaceutical.

[0117] In some preferred embodiments, the term “in combination with” refers to situations in which: a subject is administered an inhibitor of PI3K, AKT, and / or mTOR at the same time as said subject is administered a PSMA-targeted radiopharmaceutical.

[0118] Thus, a therapeutically effective amount of each of the active ingredients (i. e. , the (i) inhibitor of PI3K, AKT and / or mTOR and the (ii) PSMA-targeted radiopharmaceutical) as described herein may be administered simultaneously or sequentially and in any order, and the active ingredients may be administered separately or as a fixed combination. For example, the method of treatment of diseases (e.g., prostate cancer) according to the invention may comprise (i) administration of the first active ingredient in free or pharmaceutically acceptable salt form and (ii) administration of the second active ingredient in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the amounts described herein. The individual active ingredients of the inventive combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.

[0119] The present invention also provides combinations for use in the treatment of a cancer, wherein said combination comprises: (i) a PSMA-targeted radiopharmaceutical; and (ii) an inhibitor of PI3K, AKT, and / or mTOR. The term “combination for use” is understood to encompass both simultaneous administration (as defined herein) and to situations wherein said subject has previously been treated with (as defined herein) either said inhibitor of PI3K, AKT and / or mTOR or a PSMA-targeted radiopharmaceutical prior to treatment with the other of said inhibitor of PI3K, AKT and / or mTOR and a PSMA-targeted radiopharmaceutical. Accordingly, a “combination for use” is understood to encompass any embodiment in which:

[0120] (i) a subject is administered a PSMA-targeted radiopharmaceutical, wherein the subject has previously been treated with an inhibitor of PI3K, AKT, and / or mTOR; (ii) a subject is administered an inhibitor of PI3K, AKT, and / or mTOR, wherein the subject has previously been treated with a PSMA-targeted radiopharmaceutical; or (iii) a subject is administered an inhibitor of PI3K, AKT, and / or mTOR at the same time as said subject is administered a P S M A-targeted radiopharmaceutical .

[0121] Accordingly, in some embodiments, the present disclosure provides a combination for use in a method of treating a cancer in a subject, said combination comprising:

[0122] (i) a composition comprising a PSMA-targeted radiopharmaceutical; and

[0123] (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR; wherein (i) said subject is administered a PSMA-targeted radiopharmaceutical, wherein the subject has previously been treated with an inhibitor of PI3K, AKT, and / or mTOR;

[0124] (ii) said subject is administered an inhibitor of PI3K, AKT, and / or mTOR, wherein the subject has previously been treated with a PSMA-targeted radiopharmaceutical; or (iii) said subject is administered an inhibitor of PI3K, AKT, and / or mTOR at the same time as said subject is administered a PSMA-targeted radiopharmaceutical.

[0125] In some embodiments, the present disclosure provides a combination for use in a method of treating a cancer in a subject, said combination comprising:

[0126] (i) a composition comprising a PSMA-targeted radiopharmaceutical; and

[0127] (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR; wherein (i) said subject is administered a PSMA-targeted radiopharmaceutical, wherein the subject has previously been treated with an inhibitor of PI3K, AKT, and / or mTOR.

[0128] In some embodiments, the present disclosure provides a combination for use in a method of treating a cancer in a subject, said combination comprising:

[0129] (i) a composition comprising a PSMA-targeted radiopharmaceutical; and

[0130] (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR; wherein (ii) said subject is administered an inhibitor of PI3K, AKT, and / or mTOR, wherein the subject has previously been treated with a PSMA-targeted radiopharmaceutical. In some embodiments, the present disclosure provides a combination for use in a method of treating a cancer in a subject, said combination comprising:

[0131] (i) a composition comprising a PSMA-targeted radiopharmaceutical; and

[0132] (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR; wherein (iii) said subject is administered an inhibitor of PI3K, AKT, and / or mTOR at the same time as said subject is administered a PSMA-targeted radiopharmaceutical.

[0133] Said inhibitor of PI3K, AKT, and / or mTOR and said PSMA-targeted radiopharmaceutical can be packaged, produced and / or stored separately. In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR and said PSMA-targeted radiopharmaceutical can be produced by different, e.g. independent vendors.

[0134] Without wishing to be bound by theory, in preferred embodiments said inhibitor of PI3K, AKT, and / or mTOR is stable (e.g., shelf-stable) and can be stored for an indefinite period (e.g., a year or more), e.g., in a clinical (e.g., hospital) setting. In contrast, said PSMA- targeted radiopharmaceutical can comprise a radionuclide with a half-life that is insufficient to allow long-term storage, and thus cannot be stored indefinitely (e.g., cannot be stored for more than a week; cannot be stored for more than a day) without losing efficacy. Accordingly, in some embodiments, an inhibitor of PI3K, AKT, and / or mTOR is stored in a clinical setting (e.g., at a hospital), and a PSMA-targeted radiopharmaceutical is delivered to and / or freshly prepared at said clinical setting (e.g., hospital) shortly before administration of said PSMA- targeted radiopharmaceutical to said subject. Such embodiments are encompassed within “combinations for use” and methods of treatment wherein an inhibitor of PI3K, AKT, and / or mTOR is administered “in combination with” a PSMA-targeted radiopharmaceutical as those terms are used herein, including in situations in which said inhibitor of PI3K, AKT, and / or mTOR and said PSMA-targeted radiopharmaceutical are packaged, produced and / or stored separately.

[0135] As a non-limiting example, a combination for use in a method of treating a cancer in a subject, e.g., a prostate cancer can comprise situations in which a clinician has in her possession one or more (therapeutically effective) doses of said inhibitor of PI3K, AKT, and / or mTOR, and wherein said clinician further requests (e.g., from an outside vendor), one or more (therapeutically effective) doses of said PSMA-targeted radiopharmaceutical. In some embodiments said PSMA-targeted radiopharmaceutical can be delivered to said clinician shortly before (e.g., within 6 hours) of administration of said PSMA-targeted radiopharmaceutical to said subject. The phrase “therapeutically effective amount” means an amount of one or more compounds of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may be reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug combinations described herein may prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0136] The terms “treatment” / “treating” as used herein include: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereol); and / or (3) relieving the condition (i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment. In one embodiment, the terms “treatment’ ’ / “treating” as used herein, refer to a therapeutic treatment. In another embodiment, the terms “treatment’ ’ / “treating” as used herein, refer to a prophylactic treatment.

[0137] The term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. The term "mammal", as used herein, preferably refers to humans.

[0138] The terms "individual," "subject" or "patient" are used herein interchangeably. In a preferred embodiment, the subject is a human.

[0139] As used herein, the term "systemic administration" refers to administration of a compound according to the invention, e.g., the inhibitor of PI3K, AKT, and / or mTOR and / or the PSMA-targeted radiopharmaceutical, such that the compound becomes widely distributed in the body in significant amounts and has a biological effect, e.g. its desired effect, in the blood and / or reaches its desired site of action via the vascular system. Typical systemic routes of administration include administration by (1) introducing the compound directly into the vascular system or (2) oral, pulmonary, or intramuscular administration wherein the compound is adsorbed, enters the vascular system, and is carried to one or more desired site(s) of action via the blood.

[0140] The terms "oral", "orally", and "oral administration", as used herein, refer to orally ingesting a compound of the present invention.

[0141] The term “parenteral” as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques.

[0142] PSMA-Targeted Radiopharmaceuticals

[0143] As used herein, the term “PSMA-targeted radiopharmaceutical” is understood as a radiopharmaceutical that is targeted in vivo or in vitro to PSMA. A “radiopharmaceutical” is understood as a pharmaceutical drug containing a radioactive isotope (also known as a radionuclide as defined herein). In preferred embodiments, the PSMA-targeted radiopharmaceutical comprises a chelating group to chelate the radionuclide. In some embodiments, the chelating group comprises a DOTA chelator or a DOTA residue. In preferred embodiments, the PSMA-targeted radiopharmaceutical comprises a PSMA-targeting fragment. In some embodiments, said targeting fragment is a dipeptide urea based PSMA- targeting fragment, preferably DUPA.

[0144] In preferred embodiments, the PSMA-targeted radiopharmaceuticals of the present disclosure are administered to a subject internally, e.g., via intravenous (IV) administration. In some embodiments, the PSMA-targeted radiopharmaceutical is administered systemically. Accordingly, in preferred embodiments, radiation from a PSMA-targeted radiopharmaceutical as described herein is not administered externally, e.g., as a beam of energy (e.g., X-rays, proton radiation, gamma knife radiation and the like) to the subject.

[0145] As used herein, a “DUPA” is understood to mean a glutamate-urea moiety of formula 1 , preferably of formula 1 * : and enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof; wherein R is preferably substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and any combination thereof; more preferably R is Ci-6-alkyl, preferably C2-C4-alkyl, substituted one or more times, preferably one time with OH, SH, NH2, or COOH, wherein one of said NH2, OH or SH or COOH group serve as the point of covalent attachment to the PSMA- targeted radiopharmaceutical. In preferred embodiments, R is -C4alkylene-NH-, wherein said -NH- forms an amide bond with the remainder of the PSMA-targeted radiopharmaceutical.

[0146] A “DOTA” chelator, also known as “tetraxetan”, as used herein is understood as a complexing agent with the formula (CH2CH2NCH2CO2H)4, or a residue thereof. In some preferred embodiments, the DOTA chelator, or residue thereof, has the structure below, wherein said DOTA chelator is connected to the remainder of the PSMA-targeted radiopharmaceutical at the position Xi or X2:

[0147] In some embodiments, the DOTA chelator is connected to the remainder of the PSMA- targeted radiopharmaceutical at position X2, and Xi is -OH. In such embodiments, the DOTA chelator is referred to as a “DOTAGA” chelator.

[0148] In some embodiments, the DOTA chelator is connected to the remainder of the PSMA- targeted radiopharmaceutical at position Xi, e.g., by an amide linkage wherein Xi is -NHR-, wherein “R” is the remainder of the PSMA-targeted radiopharmaceutical. In preferred embodiments, X2 is a Ci-Ce alkyl or -H, preferably X2 is -H.

[0149] In preferred embodiments, the PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA-I&T (i.e., “Compound A”), PSMA-617, PSMA-11, PSMA-62, PSMA-R2, PSMA-ALB-56, EB-PSMA-617, CTT1403, PSMA-617, HTK01169, LI, L14, and SibuDAB. In preferred embodiments, the PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA-I&T (i.e., “Compound A”), PSMA-617, and PSMA-11.

[0150] In preferred embodiments, the PSMA-targeted radiopharmaceutical is PSMA-I&T (i.e., “Compound A”). In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-617. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-11. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-62. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-R2. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-ALB-56. In some embodiments, the PSMA-targeted radiopharmaceutical is EB-PSMA-617. In some embodiments, the PSMA- targeted radiopharmaceutical is CTT1403. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-617. In some embodiments, the PSMA-targeted radiopharmaceutical is HTK01169. In some embodiments, the PSMA-targeted radiopharmaceutical is LI. In some embodiments, the PSMA-targeted radiopharmaceutical is LI 4. In some embodiments, the PSMA-targeted radiopharmaceutical is SibuDAB.

[0151] The structures for PSMA-I&T (i.e., Compound A), PSMA-617, and PSMA-11 are described below and by Chatalic et al., Theranostics, (2016), 6(6): 849-861.

[0152] Compound A (PSMA-I&T)

[0153] As used herein, “Compound A” has the structure below:

[0154] Compound A can also be referred to herein as “PSMA I&T”, and has the CAS number 2192281-54-0.

[0155] When Compound A is chelated to a radionuclide such as161Tb, said chelate is referred to as, e g., “161Tb-PSMA I&T” PSMA-11

[0156] As used herein, “PSMA-11” has the structure below:

[0157] When PSMA-11 is chelated to a radionuclide such as161Tb, said chelate is referred to as, e.g., “161Tb-PSMA-l l”. PSMA-11 has the CAS number 1366302-52-4.

[0158] PSMA-617

[0159] As used herein, “PSMA-617” has the structure below:

[0160]

[0161] When PSMA-617 is chelated to a radionuclide such as161Tb, said chelate is referred to as, e.g., “161Tb-PSMA-617”. PSMA-617 has the CAS number 1702967-37-0.

[0162] PSMA-62 As used herein, “PSMA-62” has the structure below:

[0163] The structure of PSMA-62 is also described by Schmidt, A. (2017). Structural modifications of PSMA ligands to optimize their pharmacokinetics. [Doctoral Dissertation, Technischen Universitat Munchen], https: / / d-nb.info / 1170872573 / 34. PSMA-R2

[0164] As used herein, “PSMA-R2” has the structure below:

[0165]

[0166] The structure of PSMA-R2 is also described in WO 2021 / 001360.

[0167] In some embodiments, the PSMA-targeted radiopharmaceutical comprises an albumin- binding fragment. In preferred embodiments, the PSMA-targeted radiopharmaceutical comprising an albumin-binding fragment is selected from the group consisting of PSMA- ALB-56, EB-PSMA-617, CTT1403, PSMA-617, HTK01169, LI, L14, and SibuDAB. The structures of PSMA-ALB-56, EB-PSMA-617, CTT1403, PSMA-617, HTK01169, LI, and L14, are described by Boinapally, S. et al., Molecules, 2023, 28, 6158; see also Choy et al, Theranoslics. 2017, 7(7): 1928-1939. The structure of SibuDAB is described by Tschan et al., Journal of Nuclear Medicine July 2023, jnumed.123.265524; DOI: https: / / doi.org / 10.2967 / jnumed.123.265524.

[0168] In preferred embodiments, the PSMA-targeted radiopharmaceutical is selected from the group consisting of Compound A, PSMA-617, and PSMA-11.

[0169] Radionuclides

[0170] As used herein, a “radionuclide” is understood as a nuclide that has excess nuclear energy, making it unstable. The excess energy can be (i) emitted from the nucleus as gamma radiation; (ii) transferred to one of its electrons to release it as a conversion electron; or (iii) used to create and emit a new particle (e.g., an alpha particle or a beta particle) from the nucleus.

[0171] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to a radionuclide. In some embodiments, said radionuclide is selected from:nC,13N,15O,18F,43Sc,44Sc,47Sc,61Cu,64Cu,67Cu,68Cu,68Ga,89Sr,89Zr,90Y, "mTc,1231,125I,1311,153Sm,149Pm,149Tb,152Tb,155Tb,161Tb,165Dy,166Ho,169Er,177Lu,188Re,198Au,203Pb,212Pb,211At,212BI,213Bi,223Ra,225Ac, and227Th. In some embodiments, said radionuclide is selected from:43Sc,44Sc,47Sc,61Cu,64Cu,67Cu,68Cu,68Ga,89Sr,89Zr,90Y, "mTc,123I,125I,131I,153Sm,149Pm,149Tb,152Tb,155Tb,161Tb,165Dy,166Ho,169Er,177Lu,188Re,198Au,203Pb,212Pb,211At,212BI,213Bi,223Ra,225Ac, and227Th. In some embodiments, said radionuclide is selected from:161Tb,177LU, and225Ac.

[0172] In some embodiments, said radionuclide is a beta-emitter. In some embodiments, said radionuclide is a long-range beta emitter, e.g., wherein said long-range beta emitter is selected from the group consisting of90Y,32P,186Re / 188Re;166Ho,76As / 77As,89Sr, and153Sm. In some embodiments, said radionuclide is a medium range beta-emitter, e.g., wherein said medium range beta-emitter is selected from the group consisting of13 JI,177Lu,67Cu,161Tb, and105Rh. In some embodiments, said radionuclide is a low-energy beta-emitter, e.g., wherein said low- energy beta-emitter is selected from the group consisting of45Ca and35S. In some embodiments, said radionuclide is a conversion or Auger-emitter, e.g., wherein said conversion or Auger-emitter is selected from the group consisting of51Cr,67Ga, "Tcm,1 1' in.114mIn,123I,125I, and2O1T1. In some embodiments, said radionuclide is an alpha emitter, e.g., wherein said alpha emitter is selected from the group consisting of212Bi,213Bi,223Ac,225Ac,212Pb,255Fm,223Ra,149Tb and221At.

[0173] In some embodiments, said radionuclide is selected from:161Tb, and177Lu.

[0174] In some embodiments, said radionuclide is "C. In some embodiments, said radionuclide is13N. In some embodiments, said radionuclide is15O. In some embodiments, said radionuclide is18F. In some embodiments, said radionuclide is43Sc. In some embodiments, said radionuclide is44Sc. In some embodiments, said radionuclide is47Sc. In some embodiments, said radionuclide is64Cu. In some embodiments, said radionuclide is67Cu. In some embodiments, said radionuclide is68Ga. In some embodiments, said radionuclide is89Sr. In some embodiments, said radionuclide is89Zr. In some embodiments, said radionuclide is90Y. In some embodiments, said radionuclide is "mTc. In some embodiments, said radionuclide is123I. In some embodiments, said radionuclide is131I. In some embodiments, said radionuclide is153Sm. In some embodiments, said radionuclide is149Tb. In some embodiments, said radionuclide is152Tb. In some embodiments, said radionuclide is155Tb. In preferred embodiments, said radionuclide is161Tb. In some embodiments, said radionuclide is165Dy. In some embodiments, said radionuclide is166Ho. In some embodiments, said radionuclide is169Er. In preferred embodiments, said radionuclide is177Lu. In some embodiments, said radionuclide is188Re. In some embodiments, said radionuclide is198Au. In some embodiments, said radionuclide is203Pb. In some embodiments, said radionuclide is212Pb. In some embodiments, said radionuclide is211At. In some embodiments, said radionuclide is212Bi. In some embodiments, said radionuclide is213Bi. In some embodiments, said radionuclide is223Ra. In some embodiments, said radionuclide is225Ac. In some embodiments, said radionuclide is227Th.

[0175] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to a radionuclide, and said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

[0176] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to a radionuclide selected from161Tb and177Lu. In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to161Tb. In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to177Lu. In some preferred embodiments, said PSMA- conjugated radiopharmaceutical is chelated to225Ac.

[0177] In some embodiments, said Compound A is chelated to a radionuclide selected from161Tb and177Lu. In some embodiments, said Compound A is chelated to161Tb. In some embodiments, said Compound A is chelated to177Lu. In some preferred embodiments, said Compound A is chelated to225Ac.

[0178] Inhibitors of PI3K, AKT, and / or mTOR

[0179] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is a dual PI3K / mTOR inhibitor. In some embodiments, the inhibitor of PI3K, AKT, and / or mTOR is selected from: Buparlisib (NVP-BKM120; BKM120), CH5132799 (PA-79), Pilaralisib (XL147; SAR245408), ZSTK474, Sonolisib (PX-866), Pictilisib (GDC-0941; RG7321), Copanlisib (BAY 80-6946; Aliqopa), B591, TG-100-115,RIDR-PI-103, BYL719 (Alpelisib; Piqray), Serabelisib (INK-117; MLN-117; TAK-117), GSK2636771, Idelalisib (GS-1101; CAL-101; Zydelig), Zandelisib (ME-401; PWT-143), AMG 319, YY-20394 (Linperlisib), INCB050465 (Parsaclisib; IBI-376), Umbralisib (TGR-1202; RP5264), Tenalisib (RP6530), Taselisib / GDC-0032 / RG-7604, AZD8186, AZD8835, IPI-145 / Duvelisib / INK1197, Leniolisib (CDZ173), Eganelisib (IPI-549), Dactolisib (BEZ-235; NVP-BEZ235), Apitolisib (GDC-0980, RG7422), Gedatolisib (PF-05212384; PKI-587, SF1126, Omipalisib (GSK458; GSK2126458), Samotolisib (LY3023414), Bimiralisib (PQR309), Paxalisib (GDC-0084; RG7666), XL765 (Voxtalisib; SAR245409), GNE-493, GNE-477, PF-04691502, WJD008, BGT226, MK-2206, miransertib (ARQ 092), ARQ 751, BAY1125976, uprosertib (GSK2141795), GSK690693, LY2780301, ipatasertib (GDC-0068), capivasertib (AZD5363), edelfosine, perifosine (KRX-0401), afuresertib (GSK2110183), rapamycin, temsirolimus (CCI-779), everolimus (RAD001), ridaforolimus (AP23573; deforolimus; MK-8669), 32- deoxorapamycin (SAR943), Zotarolimus (ABT-578), PP242, PP30, WAY-600, WYE-687, WYE-354, KU0063794, AZD8055, OSI-027, AZD2014, INK128, Torin 1, curcumin, resveratrol, epigallocatechin gallate (EGCG), genistein, 3,3-diindolylmethane (DIM), and caffeine; or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the inhibitor of PI3K, AKT, and / or mTOR is an inhibitor of PI3K. In some embodiments, said inhibitor of PI3K is selected from: Buparlisib (NVP- BKM120; BKM120), CH5132799 (PA-79), Pilaralisib (XL147; SAR245408), ZSTK474, Sonolisib (PX-866), Pictilisib (GDC-0941; RG7321), Copanlisib (BAY 80-6946; Aliqopa), B591, TG-100-115,RIDR-PI-103, BYL719 (Alpelisib; Piqray), Serabelisib (INK-117; MLN- 117; TAK-117), GSK2636771, Idelalisib (GS-1101; CAL-101; Zydelig), Zandelisib (ME- 401; PWT-143), AMG 319, YY-20394 (Linperlisib), INCB050465 (Parsaclisib; IBI-376), Umbralisib (TGR-1202; RP5264), Tenalisib (RP6530), Taselisib / GDC-0032 / RG-7604, AZD8186, AZD8835, IPI-145 / Duvelisib / INKl 197, Leniolisib (CDZ173), Eganelisib (IPI- 549), Dactolisib (BEZ-235; NVP-BEZ235), Apitolisib (GDC-0980, RG7422), Gedatolisib (PF-05212384; PKI-587, SF1126, Omipalisib (GSK458; GSK2126458), Samotolisib (LY3023414), Bimiralisib (PQR309), Paxalisib (GDC-0084; RG7666), XL765 (Voxtalisib; SAR245409), GNE-493, GNE-477, PF-04691502, WJD008, and BGT226; or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the inhibitor of PI3K is: a pan-PI3K inhibitor; an isoform- specific PI3K inhibitor; or a dual PI3K / mTOR inhibitor. In some embodiments, the inhibitor of PI3K is a pan-PI3K inhibitor.

[0182] In some embodiments, said pan-PI3K inhibitor is selected from: Buparlisib (NVP- BKM120; BKM120), CH5132799 (PA-79), Pilaralisib (XL147; SAR245408), ZSTK474, Sonolisib (PX-866), Pictilisib (GDC-0941; RG7321), Copanlisib (BAY 80-6946; Aliqopa), B591, TG-100-115, and RIDR-PI-103; or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of PI3K is an isoform-specific PI3K inhibitor. In some embodiments, said isoform-specific PI3K inhibitor is selected from: BYL719 (Alpelisib; Piqray), Serabelisib (INK-117; MLN-117; TAK-117), GSK2636771, Idelalisib (GS-1101; CAL-101; Zydelig), Zandelisib (ME-401; PWT-143),AMG 319, YY-20394 (Linperlisib), INCB050465 (Parsaclisib; IBI-376), Umbralisib (TGR-1202; RP5264), Tenalisib (RP6530), Taselisib / GDC-0032 / RG-7604, AZD8186, AZD8835, IPI-145 / Duvelisib / INK1197,

[0183] Leniolisib (CDZ173), and Eganelisib (IPI-549); or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the inhibitor of PI3K is a dual PI3K / mTOR inhibitor. In some embodiments, said dual PI3K / mTOR inhibitor is selected from: Dactolisib (BEZ-235; NVP- BEZ235), Apitolisib (GDC-0980, RG7422), Gedatolisib (PF-05212384; PKI-587, SF1126, Omipalisib (GSK458; GSK2126458), Samotolisib (LY3023414), Bimiralisib (PQR309), Paxalisib (GDC-0084; RG7666), XL765 (Voxtalisib; SAR245409), GNE-493, GNE-477, PF- 04691502, WJD008, and BGT226; or a pharmaceutically acceptable salt thereof.

[0185] In preferred embodiments, the inhibitor of PI3K, AKT, and / or mTOR is a dual PI3K / mTOR inhibitor. In preferred embodiments, said dual PI3K / mTOR inhibitor is bimiralisib, or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is an inhibitor of AKT. In some embodiments, said inhibitor of AKT is selected from: MK-2206, miransertib (ARQ 092), ARQ 751, BAY1125976, uprosertib (GSK2141795), GSK690693, LY2780301, ipatasertib (GDC-0068), capivasertib (AZD5363), edelfosine, perifosine (KRX-0401), and afuresertib (GSK2110183); or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, said inhibitor of AKT is an allosteric inhibitor of AKT, or an ATP-competitive inhibitor of AKT.

[0188] In some embodiments, said inhibitor of AKT is an allosteric inhibitor of AKT. In some embodiments, said allosteric inhibitor of AKT is selected from: MK-2206, miransertib (ARQ 092), ARQ 751, and BAY1125976; or a pharmaceutically acceptable salt thereof

[0189] In some embodiments, said inhibitor of AKT is an ATP-competitive inhibitor of AKT. In some embodiments, said ATP-competitive inhibitor of AKT is selected from: uprosertib (GSK2141795), GSK690693, LY2780301, ipatasertib (GDC-0068), and capivasertib (AZD5363); or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, said inhibitor of AKT is selected from: edelfosine, perifosine (KRX-0401), and afuresertib (GSK2110183); or a pharmaceutically acceptable salt thereof. In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is an inhibitor of mTOR. In some embodiments, said inhibitor of mTOR is selected from: rapamycin, temsirolimus (CCI-779), everolimus (RAD001), ridaforolimus (AP23573; deforolimus; MK- 8669), 32-deoxorapamycin (SAR943), Zotarolimus (ABT-578), PP242, PP30, WAY-600, WYE-687, WYE-354, KU0063794, AZD8055, OSI-027, AZD2014, INK128, Torin 1, curcumin, resveratrol, epigallocatechin gallate (EGCG), genistein, 3,3-diindolylmethane (DIM), and caffeine; or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Buparlisib (NVP- BKM120; BKM120) or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the inhibitor of PI3K, AKT, and / or mTOR is CH5132799 (PA- 79) or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Pilaralisib (XL147; SAR245408) or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is ZSTK474 or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, said compound capable of inhibiting PI3K, AKT, and / or mTOR is Sonolisib (PX-866) or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Pictilisib (GDC- 0941; RG7321) or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Copanlisib (BAY 80-6946; Aliqopa) or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is B591 or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is TG-100-115 or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is RIDR-PI-103 or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is BYL719 (Alpelisib; Piqray) or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Serabelisib (INK- 117; MLN-117; TAK-117) or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is GSK2636771 or a pharmaceutically acceptable salt thereof. In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Idelalisib (GS- 1101; CAL-101; Zydelig) or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Zandelisib (ME- 401; PWT-143) or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is AMG 319 or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is YY-20394 (Linperlisib) or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is INCB050465 (Parsaclisib; IBI-376) or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Umbralisib (TGR-1202; RP5264) or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Tenalisib (RP6530) or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Taselisib / GDC- 0032 / RG-7604 or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is AZD8186 or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is AZD8835 or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is IPI- 145 / Duvelisib / INKl 197 or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Leniolisib (CDZ173) or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Eganelisib (IPI- 549) or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Dactolisib (BEZ- 235; NVP-BEZ235) or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Apitolisib (GDC- 0980, RG7422) or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Gedatolisib (PF- 05212384; PKI-587 or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is SF1126 or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Omipalisib (GSK458; GSK2126458) or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Samotolisib (LY3023414) or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Bimiralisib (PQR309; also identified herein as Compound 1*) or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Paxalisib (GDC- 0084; RG7666) or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is XL765 (Voxtalisib; SAR245409) or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is GNE-493 or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is GNE-477 or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is PF-04691502 or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is WJD008 or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is BGT226 or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is MK-2206 or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is miransertib (ARQ 092) or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is ARQ 751 or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is BAY1125976 or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is GSK690693 or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is LY2780301 or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is ipatasertib (GDC- 0068) or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is capivasertib (AZD5363) or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is edelfosine or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is perifosine (KRX- 0401) or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is afuresertib (GSK2110183) or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is rapamycin or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is temsirolimus (CCI-779) or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is everolimus (RAD001) or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is ridaforolimus (AP23573; deforolimus; MK-8669) or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is 32- deoxorapamycin (SAR943) or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Zotarolimus (ABT-578) or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is PP242 or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is PP30 or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is WAY-600 or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is WYE-687 or a pharmaceutically acceptable salt thereof. In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is WYE-354 or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is KU0063794 or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is AZD8055 or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is OSI-027 or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is AZD2014 or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is INK128 or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is Torin 1 or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is curcumin or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is resveratrol or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is epigallocatechin gallate (EGCG) or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is genistein or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is 3,3- diindolylmethane (DIM) or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is caffeine or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is FB214, or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is JBL200, or a pharmaceutically acceptable salt thereof.

[0266] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is AF030, or a pharmaceutically acceptable salt thereof. In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is a compound of Formula (I): wherein:

[0267] X1, X2and X3are, independently of each other, N or CH; with the proviso that at least two of X1, X2and X3are N;

[0268] Y is N or CH;

[0269] W is H or F; with the proviso that when W is F, then X1, X2and X3are N;

[0270] R1and R2are independently of each other

[0271] (i) a morpholinyl of formul wherein the arrow denotes the bond in formula (I); and wherein R3and R4are independently of each other H, Ci-Csalkyl optionally substituted with one or two OH, Ci- C2fluoroalkyl, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II); or

[0272] (ii) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R7; wherein R7is independently at each occurrence Ci-Csalkyl optionally substituted with one or two OH, Ci-C2fluoroalkyl, Ci-C2alkoxyCi- Csalkyl. Cs-Cecycloalkyl; or two R7substituents form together a bivalent residue -R8R9- selected from Ci-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CH2CH2- O-; with the proviso that at least one of R1and R2is a morpholinyl of formula II; and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts thereof. In some embodiments of Formula I, R3and R4denote two independent substitutions and substituents, as defined herein, of said morpholinyl of formula (II) which are either both on the same carbon atom of said morpholinyl of formula (II) or on different carbon atoms of said morpholinyl of formula (II), and, hereby further, either on the same carbon-carbon bridge or on different carbon-carbon bridges linking the heteroatoms of said morpholinyl of formula (II).

[0273] Typically and preferably, when R3and R4form together a bivalent residue -R5R6- selected from Ci-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH- CH2-, or any of the structures O , wherein the arrows denote the bonds in formula (II), then said bivalent residue -R5R6- and said bonds denoted by said arrows are linked to carbon atoms located on different carbon-carbon bridges linking the heteroatoms of said morpholinyl of formula (II).

[0274] In a preferred embodiment, (i) said X1and said X2are N, and said X3is CH; (ii) said X1and said X3are N, and said X2is CH; or (iii) said X2and said X3are N, and said X1is CH, and preferably tautomers, solvates and pharmaceutically acceptable salts thereof.

[0275] In some embodiments, (i) said X1and said X2are N, and said X3is CH; or (ii) said X2and said X3are N, and said X1is CH, and preferably tautomers, solvates and pharmaceutically acceptable salts thereof.

[0276] In a preferred embodiment, said X1and said X3are N, and said X2is CH; and preferably tautomers, solvates and pharmaceutically acceptable salts thereof.

[0277] In a preferred embodiment, W is H.

[0278] In a preferred embodiment, W is F.

[0279] In another preferred embodiment, said Y is N, and preferably tautomers, solvates and pharmaceutically acceptable salts thereof. In another preferred embodiment, said Y is CH, and preferably tautomers, solvates and pharmaceutically acceptable salts thereof.

[0280] In another preferred embodiment, said R1and said R2are independently of each other selected from:

[0281] In another preferred embodiment, said R1and said R2are independently of each other selected from:

[0282]

[0283] In another preferred embodiment, said R1and said R2are independently of each other selected from:

[0284] In another preferred embodiment, said R1and said R2are independently of each other selected from:

[0285] In another preferred embodiment, said compound is selected from 1, 1*, 2, 2*, 3, 4, 5,

[0286] 6, 6*, 7, 7*, 8, 8*, 9, 9*, 10, 11, 12, 12*, 13, 13*, 14, 15, 16, 17, 18, 19, 20, 20*, 21, 21*, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 37, 38, 39, 40, 41, 42, 44, 45, 46, 47, 50, 51, 52, 53, 54, 55, 56, 66, 67, 68, 69, 70, 71, 77, 78, 79, 80, 82, 83, 84, 85, 86 and 88, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0287] In another preferred embodiment, said compound is selected from 1, 1*, 2, 2*, 3, 4, 5,

[0288] 6, 6*, 7, 7*, 8, 8*, 9, 9*, 10, 11, 12, 12*, 13, 13*, 14, 15, 16, 17, 18, 19, 20, 20*, 21, 21*, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 37, 38, 39, 40, 41, 42, 44, 45, 46, 47, 82, 83, 84, 85, 86 and 88, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0289] In another preferred embodiment, said compound is selected from 1, 1 *, 2, 2*, 3, 4, 6*,

[0290] 7, 7*, 8, 8*, 9, 9*, 12*, 13, 13*, 20*, 21*, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 82, 83, 84, 85, 86 and 88; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0291] In another preferred embodiment, said compound is selected from 1, 2, 3, 4, 7, 8, 9, 13, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 82, 83, 84, 85, 86 and 88, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0292] In another preferred embodiment, said compound is selected from 1, 1 *, 2, 2*, 3, 4, 6*, 7, 7*, 8, 8*, 9, 9*, 12*, 13, 13*, 20*, 21* and 44, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0293] In another preferred embodiment, said compound is selected from 1, 1 *, 2, 2*, 3, 4, 6*, 7, 7*, 8, 8*, 9, 9*, 12*, 13, 13*, 20*, 21*, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0294] In another preferred embodiment, said compound is selected from 1, 2, 3, 4, 7, 8, 9, 13 and 44, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0295] In another preferred embodiment, said compound is selected from:

[0296] 1 : 4-(difluoromethyl)-5-(4,6-dimorpholino-l ,3,5-triazin-2-yl)pyridin-2-amine;

[0297] 2: 4-(difluoromethyl)-5-(4,6-dimorpholino-l,3,5-triazin-2-yl)pyrimidin-2-amine;

[0298] 3: 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8- yl)-l,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine;

[0299] 4: 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-l,3,5-triazin-2-yl)-4- (difluoromethyl)pyridin-2-amine;

[0300] 7 : 5-(4,6-bis((S)-3-methylmorpholino)-l,3,5-triazin-2-yl)-4- (difluoromethyl)pyrimidin-2-amine;

[0301] 8: (5)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino- 1,3,5 -triazin-2- yl)pyridin-2-amine;

[0302] 9: (5)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino- 1,3, 5 -triazin-2- yl)pyrimidin-2-amine;

[0303] 13: 4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-l-yl)- 1,3,5 -triazin-2- yl)pyrimidin-2-amine; and

[0304] 44: 4-(difhioromethyl)-5-[4-[(37?,5S)-3,5-dimethylmorpholin-4-yl]-6-[(37?)-3- methylmorpholin-4-yl]-l,3,5-triazin-2-yl]pyridin-2-amine.

[0305] In another preferred embodiment, said compound is selected from 1, 2, 3, 4, 7, 8, 9 and 13, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0306] In another preferred embodiment, said compound is selected from 1*, 2*, 6*, 7*, 8*, 9*, 12*, 13*, 20* and 21*, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0307] In another preferred embodiment, said compound is selected from 1*, 2*, 6*, 7*, 8*, 9* and 20*, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0308] In another preferred embodiment, said compound is selected from:

[0309] 1*: 5-(4,6-dimorpholino-l,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine;

[0310] 2*: 5-(4,6-dimorpholino-l,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine;

[0311] 6 * : 5 - [4,6-bis [(3 S)-3-methylmorpholin-4-yl] - 1 ,3 ,5 -triazin-2-yl] -4- (trifluoromethyl)pyridin-2-amine;

[0312] 7 * : 5 - [4,6-bis [(3 S)-3-methylmorpholin-4-yl] - 1 ,3 ,5 -triazin-2-yl] -4- (trifluoromethyl)pyrimidin-2-amine;

[0313] 8*: 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-l,3,5-triazin-2-yl]-4- (trifluoromethyl)pyridin-2-amine;

[0314] 9*: 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-l,3,5-triazin-2-yl]-4- (trifluoromethyl)pyrimidin-2-amine; and

[0315] 20*: 5-(4-morpholino-6-thiomorpholino-l,3,5-triazin-2-yl)-4- (trifluoromethyl)pyridin-2-amine.

[0316] In another preferred embodiment, said compound is selected from 1*, 2; 2*, 3; 6*, 7*, 8; 8*, 9*, 20* and 44, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0317] In another preferred embodiment, said compound is selected from 1*, 2; 2*, 3; 6*, 7*, 8; 8*, 9*, 12*, 13*, 20* and 21*, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0318] In another preferred embodiment, said compound is selected from 2, 3, 8 and 44, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0319] In another preferred embodiment, said compound is selected from 2, 3, and 8, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0320] In another very preferred embodiment, said compound is selected from 3, 8 and 44, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0321] In another very preferred embodiment, said compound is selected from 3 and 8; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0322] In another very preferred embodiment, said compound is selected from 3, 8, 44 and 1 *; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0323] In another very preferred embodiment, said compound is selected from 3, 8, and 1*; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0324] In another very preferred embodiment, said compound is selected from 3, 44 and 1*, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0325] In another very preferred embodiment, said compound is selected from 3 and 1*, and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0326] In another very preferred embodiment, said compound of formula (I) is 2.

[0327] In another very preferred embodiment, said compound of formula (I) is 2; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0328] In another very preferred embodiment, said compound of formula (I) is 3.

[0329] In another very preferred embodiment, said compound of formula (I) is 3; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0330] In another very preferred embodiment, said compound of formula (I) is 8.

[0331] In another very preferred embodiment, said compound of formula (I) is 8; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0332] In another very preferred embodiment, said compound of formula (I) is 44.

[0333] In another very preferred embodiment, said compound of formula (I) is 44; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0334] In another very preferred embodiment, said compound of formula (I) is 1*.

[0335] In another very preferred embodiment, said compound of formula (I) is 1*; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0336] In another preferred embodiment, said R1and R2are independently of each other a morpholinyl of formula (II). In one preferred embodiment, said R1is equal to R2. In another preferred embodiment, said R1is not equal to R2.

[0337] In another preferred embodiment, said W is H, and said R1and R2are independently of each other a morpholinyl of formula (II). In one preferred embodiment, said R1is equal to R2. In another preferred embodiment, said R1is not equal to R2.

[0338] In another preferred embodiment, said W is F, said R1and R2are independently of each other a morpholinyl of formula (II). In one preferred embodiment, said R1is equal to R2. In another preferred embodiment, said R1is not equal to R2.

[0339] In another preferred embodiment, said R1and R2are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z.

[0340] In another preferred embodiment, said W is H, and said R1and R2are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z.

[0341] In another preferred embodiment, said W is F, and said R1and R2are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z.

[0342] In another preferred embodiment, within said morpholinyl of formula (II)

[0343] R3and R4are independently of each other H, Ci-Csalkyl optionally substituted with one or two OH, Ci-C2fluoroalkyl, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci- C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci-Csalkylene optionally substitute Ad with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures O

[0344] ' ; wherein the arrows denote the bonds in formula (II).

[0345] In another preferred embodiment, within said morpholinyl of formula (II)

[0346] R3and R4are independently of each other H, Ci-C2alkyl, preferably methyl, optionally substituted with one or two, preferably one, OH; Ci-C2fluoroalkyl, Ci-C2alkoxy, Ci- C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2- NH-CH2-, or any of the structures ; wherein the arrows denote the bonds in formula (II).

[0347] In the instance that R3 and R4 together form a bivalent residue and are bound to vicinal carbon atoms annulated morpholinyl substituents are formed. In the instance that R3 and R4 together form a bivalent residue and are spanning across the morpholine ring bridged morpholinyl substituents are formed. In the instance that R3 and R4 together form a bivalent residue and are bound to the same carbon atom of the morpholine, spiro morpholinyl substituents are formed.

[0348] In a preferred embodiment, R3and R4form together a bivalent residue -R5R6- selected from Ci-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures and forming a bridged morpholinyl substituent.

[0349] In another preferred embodiment, said R1and R2are independently of each other a morpholinyl of formula (II), wherein R3and R4form together a bivalent residue leading to a bridged morpholinyl, wherein R3and R4form together a bivalent residue -R5R6- selected from Ci-Csalkylene, preferably Ci-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O- CH2-, -CH2-NH-CH2-, or any of the structures

[0350] O ' ; wherein the arrows denote the bonds in formula (II).

[0351] In a further preferred embodiment, said morpholinyl of formula (II) is independently of each other a morpholinyl of said formula (II), wherein R3and R4are independently of each other H, Ci-Csalkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci-Ckalkylene. preferably Ci-C2alkylene, - CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures O ' ; wherein the arrows denote the bonds in formula (II).

[0352] In a further preferred embodiment, said morpholinyl of formula (II) is independently of each other a morpholinyl of said formula (II), wherein R3and R4are independently of each other H, Ci-C2alkyl, preferably methyl; CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci-C3alkylene, preferably Ci-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures

[0353] O ' ; wherein the arrows denote the bonds in formula (II).

[0354] In a further preferred embodiment, said morpholinyl of formula (II) is independently of each other a morpholinyl of said formula (II), wherein R3and R4are independently of each other H or CH3.

[0355] In a further preferred embodiment, said morpholinyl of formula (II) is independently of each other a morpholinyl of said formula (II), wherein R3and R4are independently of each other Ci-C2alkyl, preferably methyl; CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci- C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from -CH2- or C3alkylene, preferably -CH2-, -CH2CF2-, - CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures

[0356] O ; wherein the arrows denote the bonds in formula (II).

[0357] In a further preferred embodiment, said morpholinyl of formula (II) is independently of each other a morpholinyl of said formula (II), wherein R3and R4are independently of each other C2-C3alkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci-C2alkoxy, Ci- C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from -CH2- or C3alkylene, preferably -CH2-, -CH2CF2-, -CHFCHF-, -

[0358] CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures ; wherein the arrows denote the bonds in formula (II).

[0359] In a further preferred embodiment, said morpholinyl of formula (II) is independently of each other selected from

[0360] In a further preferred embodiment, said morpholinyl of formula (II) is independently of each other selected from

[0361] In a further preferred embodiment, said heterocyclic ring Z is a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R7; wherein R7is independently at each occurrence Ci-Csalkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci-C2alkoxyCi-C3alkyl, Cs-Cecycloalkyl; or two R7substituents form together a bivalent residue -R8R9- selected from Ci-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CH2CH2-O-;

[0362] In a further preferred embodiment, said heterocyclic ring Z is selected from

[0363] In another preferred embodiment of the present invention, said R1and said R2are independently of each other a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3and R4are independently of each other H, Ci -Csalkyl optionally substituted with one or two OH, Ci-C2fluoroalkyl, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O- Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II).

[0364] In another preferred embodiment of the present invention, said R1and said R2are independently of each other a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3and R4are independently of each other H, Ci-C2alkyl, preferably methyl, optionally substituted with one or two, preferably one, OH; Ci-C2fluoroalkyl, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from C i -Qalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- , -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II).

[0365] In a further preferred embodiment, said R1is equal to said R2, and said R1and said R2are independently of each other a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3and R4are independently of each other H, Ci -Csalkyl optionally substituted with one or two OH, Ci-C2fluoroalkyl, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O- Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci-Csalkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II).

[0366] In a further preferred embodiment of the present invention, said R1and said R2are independently of each other a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3and R4are independently of each other H, Ch -Chalky I. CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci-C3alkylene, preferably Ci-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-,

[0367] -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II).

[0368] In a further preferred embodiment of the present invention, said R1and said R2are independently of each other a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3and R4are independently of each other H, Ci-Chalkyl, preferably methyl; CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci- C3alkylene, preferably Ci-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-,

[0369] -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II).

[0370] In a further preferred embodiment of the present invention, R1is equal to R2, and said

[0371] R1and said R2are a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3and R4are independently of each other H, Ci-C'salkyl. CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci-C'salkylene. preferably Ci-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-,

[0372] -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II).

[0373] In a further preferred embodiment of the present invention, R1is equal to R2, and said R1and said R2are a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3and R4are independently of each other H, Ci-C2alkyl, preferably methyl; CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci- Csalkylene, preferably Ci-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-,

[0374] -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II).

[0375] In some embodiments, the inhibitor of PI3K, AKT, and / or mTOR is a compound of Formula (I): wherein

[0376] X1, X2and X3are, independently of each other, N or CH; with the proviso that at least two of X1, X2and X3are N; Y is N or CH; and wherein

[0377] R1and R2are independently of each other a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and R1is not equal to R2, and at least one of said R1and said R2are a morpholinyl of formula (II), wherein R3and R4are independently of each other C2-C3alkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from -CH2- or C3alkylene. preferably -CH2-, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures

[0378] O ; wherein the arrows denote the bonds in formula (II).

[0379] In another aspect and preferred embodiment, the inhibitor of PI3K, AKT, and / or mTOR is a compound of Formula (I): wherein

[0380] X1, X2and X3are, independently of each other, N or CH; with the proviso that at least two of X1, X2and X3are N; Y is N or CH; and wherein

[0381] R1and R2are independently of each other a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and R1is not equal to R2, and at least one of said R1and said R2are a morpholinyl of formula (II), wherein R3and R4are independently of each other Ci-C2alkyl, preferably methyl; CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from - CH2- or C3alkylene, preferably -CH2-, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures ; wherein the arrows denote the bonds in formula (II).

[0382] Preferably, said R3and R4form together a bivalent residue -R5R6- selected from -CH2- or C3alkylene. preferably -CH2-, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, any of the structures

[0383] In another preferred embodiment, R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3- methyl-4-morpholinyl, 3,5-dimethyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2- methyl-4-morpholinyl, 3 -methyl -4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4- methylpiperazin-l-yl, or 4-thiomorpholinyl.

[0384] In another preferred embodiment, R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3- methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3- aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl- 4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8- oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4 -methyip ip erazin-l-yl, or 4-thiomorpholinyl.

[0385] In another preferred embodiment, R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3- methyl-4-morpholinyl, 3,5-dimethyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2- methyl-4-morpholinyl, 3 -methyl -4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4- methylpiperazin-l-yl, or 4-thiomorpholinyl, and X1, X2and X3are N; and tautomers, solvates and pharmaceutically acceptable salts thereof. In another preferred embodiment, R1is 4- morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3 -aza-8 -oxabicyclo [3.2.1] oct-3 -yl; and R2is 4- morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4- methylpiperazin-l-yl, or 4-thiomorpholinyl, and X1, X2and X3are N; and tautomers, solvates and pharmaceutically acceptable salts thereof. Preferably Y is N or CH; R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, 3,5-dimethyl-4-morpholinyl, octadeuterio- 4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4- morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4- piperazin-l-yl, 4 -methyip ip erazin-l-yl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof. Preferably Y is N or CH; R1is 4-morpholinyl, 2- methyl-4-morpholinyl, 3 -methyl -4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2- methyl-4-morpholinyl, 3 -methyl -4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4- methylpiperazin-l-yl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0386] In a further preferred embodiment, R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3- methyl-4-morpholinyl, 3,5-dimethyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2- methyl-4-morpholinyl, 3 -methyl -4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4- methylpiperazin-l-yl, or 4-thiomorpholinyl, and X1and X3are N, and X2is CH; and tautomers, solvates and pharmaceutically acceptable salts thereof. In a further preferred embodiment, R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3-aza-8- oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4- morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8- oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl, and X1and X3are N, and X2is CH; and tautomers, solvates and pharmaceutically acceptable salts thereof. Preferably Y is N or CH; R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3- methyl-4-morpholinyl, 3,5-dimethyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2- methyl-4-morpholinyl, 3 -methyl -4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-y, 4- methylpiperazin-l-yl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof. Preferably Y is N or CH; R1is 4-morpholinyl, 2-methyl-4- morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2- methyl-4-morpholinyl, 3 -methyl -4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-y, 4- methylpiperazin-l-yl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0387] In a preferred embodiment, R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4- morpholinyl, 3,5-dimethyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2- methyl-4-morpholinyl, 3 -methyl -4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4- methylpiperazin-l-yl, or 4-thiomorpholinyl, and X1and X2are N, and X3is CH; and tautomers, solvates and pharmaceutically acceptable salts thereof. In a preferred embodiment, R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4- morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4- morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4- piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl, and X1and X2are N, and X3is CH; and tautomers, solvates and pharmaceutically acceptable salts thereof. Preferably, Y is N or CH; R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, 3,5-dimethyl- 4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3-aza-8- oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4- morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8- oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof. Preferably, Y is N or CH; R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4- morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3 -aza-8 -oxabicyclo [3.2.1] oct-3 -yl; and R2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4- morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4- piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0388] In a preferred embodiment, R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4- morpholinyl, 3,5-dimethyl-4-morpholinyl,octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2- methyl-4-morpholinyl, 3 -methyl -4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3- oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4- methylpiperazin-l-yl, or 4-thiomorpholinyl, and X2and X3are N, and X1is CH; and tautomers, solvates and pharmaceutically acceptable salts thereof. In a preferred embodiment, R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4- morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3 -aza-8 -oxabicyclo [3.2.1] oct-3 -yl; and R2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4- morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4- piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl, and X2and X3are N, and X1is CH; and tautomers, solvates and pharmaceutically acceptable salts thereof. Preferably, Y is N or CH; R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, 3,5-dimethyl- 4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3-aza-8- oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4- morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8- oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof. Preferably, Y is N or CH; R1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4- morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl; and R2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4- morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4- piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof.

[0389] In some embodiments, said inhibitor of PI3K, AKT, and / or mTORis selected from the group consisting of Compound 1*, and Compound 2, and Compound 8, and pharmaceutically acceptable salts thereof.

[0390] In some embodiments, said inhibitor of PI3K, AKT, and / or mTORis selected from the group consisting of Compound 1* and Compound 2, and pharmaceutically acceptable salts thereof.

[0391] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib, or a pharmaceutically acceptable salt thereof.

[0392] Most preferred for the present invention are the following compounds with the chemical structures shown below. The names of the corresponding structures were produced using ChemDraw Ultra, version 13.0.1 as well as lower and upper software versions thereof, CambridgeSoft Corp., Cambridge MA.

[0393] In some embodiments, one or more atoms of the PI3K, AKT, and / or mTOR inhibitor can be a radionuclide. In some embodiments, one or more of the F atoms in the PI3K, AKT, and / or mTOR inhibitor (e.g., bimiralisib) can be18F. In some embodiments, one or more of the C atoms in the PI3K, AKT, and / or mTOR inhibitor (e.g., bimiralisib) can benC. In some embodiments, one or more of the N atoms in the PI3K, AKT, and / or mTOR inhibitor (e.g., bimiralisib) can be13N. In some embodiments, one or more of the O atoms in the PI3K, AKT, and / or mTOR inhibitor (e.g., bimiralisib) can be15O.

[0394] Preparation of compounds of the invention

[0395] The compounds of the invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein. Moreover, the synthesis of compounds of the present invention and the intermediates used for said synthesis of compounds of the present invention have already been described in WO 2016 / 075130; in the application PCT / EP2017 / 025137 filed on May 17, 2017 and published as WO / 2017 / 198347 on Nov. 23, 2017; and in the application PCT / EP2018 / 082211 filed on November 22, 2018 and published as WO / 2019 / 101853 on May 31, 2019. The starting materials are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art.

[0396] In preparing compounds of the invention, protection of remote functionality e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include tert-butyloxycarbonyl (BOC), bis-tert-butyloxycarbonyl or dimethylaminomethylenyl. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0397] Methods of separation

[0398] In the methods of preparing the compounds of this invention, it may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; high, medium and low-pressure liquid chromatography methods and apparatus; small scale analytical; and preparative thin or thick layer chromatography, as well as techniques of small-scale thin layer and flash chromatography. Selection of appropriate methods of separation depends on the nature of the materials involved, for example, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation.

[0399] Kits of Parts, Compositions, Combinations, and Methods of Treatment

[0400] As used herein, the term "for use" as used in "composition for use in treatment of a disease” or “combination for use in the treatment of a disease” shall disclose also the corresponding method of treatment of a human subject and the corresponding use of the composition or combination for the manufacture of a medicament for the treatment of a disease. Accordingly, embodiments disclosed herein are understood to related to compositions, kits of parts, combinations, compositions for use, combinations for use, methods of treatment, and the use of a composition or combination as described herein for the manufacture of a medicament.

[0401] In one aspect, the present disclosure provides a kit of parts comprising:

[0402] (i) a PSMA-targeted radiopharmaceutical; and

[0403] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0404] In one aspect, the present invention provides a kit of parts comprising:

[0405] (i) Compound A; and

[0406] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0407] In one aspect, the present invention provides a kit of parts comprising:

[0408] (i) PSMA-11; and

[0409] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0410] In one aspect, the present invention provides a kit of parts comprising:

[0411] (i) PSMA-617; and

[0412] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0413] In preferred embodiments, said kit of parts further comprises instructions for administering said Compound A, said PSMA-11, or said PSMA-617 and said inhibitor of PI3K, AKT, and / or mTOR to treat cancer, preferably prostate cancer, in a subject in need thereof.

[0414] In one aspect, the present disclosure provides a composition comprising:

[0415] (i) a PSMA-targeted radiopharmaceutical; and

[0416] (ii) an inhibitor of PI3K, AKT, and / or mTOR. In one aspect, the present invention provides a composition comprising:

[0417] (i) Compound A; and

[0418] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0419] In one aspect, the present invention provides a composition comprising:

[0420] (i) PSMA-11; and

[0421] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0422] In one aspect, the present invention provides a composition comprising:

[0423] (i) PSMA-617; and

[0424] (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0425] In some embodiments, said kit of parts or said composition comprises said (i) PSMA- targeted radiopharmaceutical and (ii) said inhibitor of PI3K, AKT, and / or mTOR as a combined dosage form. In some embodiments, said kit of parts or said composition comprises said (i) Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR as separate dosage forms.

[0426] In some embodiments, said kit of parts or said composition comprises said (i) Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR as a combined dosage form. In some embodiments, said kit of parts or said composition comprises said (i) Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR as separate dosage forms.

[0427] In some embodiments, said kit of parts or said composition comprises said (i) PSMA- 11 and (ii) said inhibitor of PI3K, AKT, and / or mTOR as a combined dosage form. In some embodiments, said kit of parts or said composition comprises said (i) PSMA-11 and (ii) said inhibitor of PI3K, AKT, and / or mTOR as separate dosage forms.

[0428] In some embodiments, said kit of parts or said composition comprises said (i) PSMA- 617 and (ii) said inhibitor of PI3K, AKT, and / or mTOR as a combined dosage form. In some embodiments, said kit of parts or said composition comprises said (i) PSMA-617 and (ii) said inhibitor of PI3K, AKT, and / or mTOR as separate dosage forms.

[0429] In one aspect, the present invention comprises a combination (e.g., a combination for use) comprising:

[0430] (i) a composition comprising a PSMA-targeted radiopharmaceutical; and

[0431] (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR.

[0432] In one aspect, the present invention provides a combination (e.g., a combination for use) comprising:

[0433] (i) a composition comprising Compound A; and (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR.

[0434] In some embodiments, said combination (e.g., said combination for use) comprises said (i) composition comprising said PSMA-targeted radiopharmaceutical and (ii) said composition comprising an inhibitor of PI3K, AKT, and / or mTOR as a combined dosage form.

[0435] In some embodiments, said combination (e.g., said combination for use) comprises said (i) composition comprising Compound A and (ii) said composition comprising an inhibitor of PI3K, AKT, and / or mTOR as a combined dosage form.

[0436] In some embodiments, said combination (e.g., said combination for use) comprises said (i) composition comprising Compound A and (ii) said composition comprising an inhibitor of PI3K, AKT, and / or mTOR as separate dosage forms.

[0437] In one aspect, the present invention provides a combination (e.g., a combination for use) comprising:

[0438] (i) a composition comprising PSMA-11; and

[0439] (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR.

[0440] In some embodiments, said combination (e.g., said combination for use) comprises said (i) composition comprising PSMA-11 and (ii) said composition comprising an inhibitor of PI3K, AKT, and / or mTOR as a combined dosage form.

[0441] In some embodiments, said combination (e.g., said combination for use) comprises said (i) composition comprising PSMA-11 and (ii) said composition comprising an inhibitor of PI3K, AKT, and / or mTOR as separate dosage forms.

[0442] In one aspect, the present invention provides a combination (e.g., a combination for use) comprising:

[0443] (i) a composition comprising PSMA-617; and

[0444] (ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR.

[0445] In some embodiments, said combination (e.g., said combination for use) comprises said (i) composition comprising PSMA-617 and (ii) said composition comprising an inhibitor of PI3K, AKT, and / or mTOR as a combined dosage form.

[0446] In some embodiments, said combination (e.g., said combination for use) comprises said (i) composition comprising PSMA-617 and (ii) said composition comprising an inhibitor of PI3K, AKT, and / or mTOR as separate dosage forms.

[0447] In some embodiments, said PSMA-targeted radiopharmaceutical comprises a DUPA targeting group. In some embodiments, the PSMA-targeted radiopharmaceutical is selected from the group consisting of PSMA-11, PSMA-617, and PSMA I&T. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA I&T. In some embodiments, the PSMA- targeted radiopharmaceutical is PSMA-11. In some embodiments, the PSMA-targeted radiopharmaceutical is PSMA-617.

[0448] In one aspect, the present invention provides a kit of parts comprising: (i) Compound A; wherein said Compound A is chelated to161Tb; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0449] In one aspect, the present invention provides a kit of parts comprising: (i) Compound A; wherein said Compound A is chelated to177Lu; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0450] In one aspect, the present invention provides a kit of parts comprising: (i) Compound A; wherein said Compound A is chelated to225Ac; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0451] In one aspect, the present invention provides a composition comprising: (i) Compound A; wherein said Compound A is chelated to161Tb; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0452] In one aspect, the present invention provides a composition comprising: (i) Compound A; wherein said Compound A is chelated to177Lu; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0453] In one aspect, the present invention provides a composition comprising: (i) Compound A; wherein said Compound A is chelated to225Ac; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0454] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) Compound A; wherein said Compound A is chelated to161Tb; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0455] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) Compound A; wherein said Compound A is chelated to177Lu; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0456] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) Compound A; wherein said Compound A is chelated to225Ac; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0457] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to161Tb; and said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

[0458] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to177LU; and said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

[0459] In some embodiments, said PSMA-conjugated radiopharmaceutical is chelated to225Ac; and said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

[0460] In one aspect, the present invention provides a kit of parts comprising: (i) Compound A; wherein said Compound A is chelated to161Tb; and (ii) bimiralisib.

[0461] In one aspect, the present invention provides a kit of parts comprising: (i) Compound A; wherein said Compound A is chelated to177Lu; and (ii) bimiralisib.

[0462] In one aspect, the present invention provides a kit of parts comprising: (i) Compound A; wherein said Compound A is chelated to225Ac; and (ii) bimiralisib.

[0463] In one aspect, the present invention provides a composition comprising: (i) Compound A; wherein said Compound A is chelated to161Tb; and (ii) bimiralisib.

[0464] In one aspect, the present invention provides a composition comprising: (i) Compound A; wherein said Compound A is chelated to177Lu; and (ii) bimiralisib.

[0465] In one aspect, the present invention provides a composition comprising: (i) Compound A; wherein said Compound A is chelated to225Ac; and (ii) bimiralisib.

[0466] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) Compound A; wherein said Compound A is chelated to161Tb; and (ii) bimiralisib.

[0467] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) Compound A; wherein said Compound A is chelated to177Lu; and (ii) bimiralisib.

[0468] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) Compound A; wherein said Compound A is chelated to225Ac; and (ii) bimiralisib.

[0469] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to161Tb; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0470] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to177Lu; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0471] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to225Ac; and (ii) an inhibitor of PI3K, AKT, and / or mTOR. In one aspect, the present invention provides a composition comprising: (i) PSMA- 617; wherein said PSMA-617 is chelated to161Tb; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0472] In one aspect, the present invention provides a composition comprising: (i) PSMA- 617; wherein said PSMA-617 is chelated to177Lu; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0473] In one aspect, the present invention provides a composition comprising: (i) PSMA- 617; wherein said PSMA-617 is chelated to225Ac; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0474] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to161Tb; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0475] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to177LU; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0476] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to225Ac; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0477] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to161Tb; and (ii) bimiralisib.

[0478] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to177Lu; and (ii) bimiralisib.

[0479] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to225Ac; and (ii) bimiralisib.

[0480] In one aspect, the present invention provides a composition comprising: (i) PSMA- 617; wherein said PSMA-617 is chelated to161Tb; and (ii) bimiralisib.

[0481] In one aspect, the present invention provides a composition comprising: (i) PSMA- 617; wherein said PSMA-617 is chelated to177Lu; and (ii) bimiralisib.

[0482] In one aspect, the present invention provides a composition comprising: (i) PSMA- 617; wherein said PSMA-617 is chelated to225Ac; and (ii) bimiralisib.

[0483] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to161Tb; and (ii) bimiralisib. In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to177LU; and (ii) bimiralisib.

[0484] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-617; wherein said PSMA-617 is chelated to225Ac; and (ii) bimiralisib.

[0485] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to161Tb; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0486] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to177Lu; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0487] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to225Ac; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0488] In one aspect, the present invention provides a composition comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to161Tb; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0489] In one aspect, the present invention provides a composition comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to177Lu; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0490] In one aspect, the present invention provides a composition comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to225Ac; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0491] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-11 ; wherein said PSMA-11 is chelated to161Tb; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0492] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-11 ; wherein said PSMA-11 is chelated to177LU; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0493] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-11 ; wherein said PSMA-11 is chelated to225Ac; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0494] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to161Tb; and (ii) bimiralisib.

[0495] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to177Lu; and (ii) bimiralisib.

[0496] In one aspect, the present invention provides a kit of parts comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to225Ac; and (ii) bimiralisib. In one aspect, the present invention provides a composition comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to161Tb; and (ii) bimiralisib.

[0497] In one aspect, the present invention provides a composition comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to177Lu; and (ii) bimiralisib.

[0498] In one aspect, the present invention provides a composition comprising: (i) PSMA-11; wherein said PSMA-11 is chelated to225Ac; and (ii) bimiralisib.

[0499] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-11 ; wherein said PSMA-11 is chelated to161Tb; and (ii) bimiralisib.

[0500] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-11 ; wherein said PSMA-11 is chelated to177LU; and (ii) bimiralisib.

[0501] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, comprising: (i) PSMA-11 ; wherein said PSMA-11 is chelated to225Ac; and (ii) bimiralisib.

[0502] In some embodiments, the present invention provides a kit of parts or a composition of as described herein, for use in the treatment of a cancer.

[0503] In one aspect, the present invention provides a method of treating a cancer in a subject in need thereof, the method comprising: administering to said subject a therapeutically effective amount of (i) a PSMA-targeted radiopharmaceutical; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0504] In one aspect, the present invention provides a method of treating a cancer in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of (i) a PSMA-targeted radiopharmaceutical in combination with (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0505] In one aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, said method comprising:

[0506] (i) administering to said subject a therapeutically effective amount of a PSMA-targeted radiopharmaceutical, wherein said subject has previously been treated with an inhibitor of PI3K, AKT, and / or mTOR;

[0507] (ii) administering to said subject a therapeutically effective amount of an inhibitor of PI3K, AKT, and / or mTOR, wherein said subject has previously been treated with a PSMA- targeted radiopharmaceutical; or (iii) administering to said subject a therapeutically effective amount of an inhibitor of PI3K, AKT, and / or mTOR at the same time as administering to said subject a therapeutically effective amount of a PSMA-targeted radiopharmaceutical.

[0508] In one aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, said method comprising: administering to said subject a therapeutically effective amount of a PSMA-targeted radiopharmaceutical, wherein said subject has previously been treated with an inhibitor of PI3K, AKT, and / or mTOR.

[0509] In one aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, said method comprising: administering to said subject a therapeutically effective amount of an inhibitor of PI3K, AKT, and / or mTOR, wherein said subject has previously been treated with a PSMA-targeted radiopharmaceutical.

[0510] In one aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, said method comprising: administering to said subject a therapeutically effective amount of an inhibitor of PI3K, AKT, and / or mTOR at the same time as administering to said subject a therapeutically effective amount of a PSMA-targeted radiopharmaceutical.

[0511] In one aspect, the present disclosure provides an inhibitor of PI3K, AKT, and / or mTOR for use in a method of treating a cancer in a subject; wherein said inhibitor of PI3K, AKT, and / or mTOR is administered in combination with a PSMA-targeted radiopharmaceutical.

[0512] In one aspect, the present disclosure provides a PSMA-targeted radiopharmaceutical for use in a method of treating a cancer in a subject; wherein said PSMA-targeted radiopharmaceutical is administered in combination with an inhibitor of PI3K, AKT, and / or mTOR.

[0513] In one aspect, the present disclosure provides an inhibitor of PI3K, AKT, and / or mTOR for use in a method of treating a cancer in a subject; wherein said inhibitor of PI3K, AKT, and / or mTOR is to be administered in combination with a PSMA-targeted radiopharmaceutical.

[0514] In one aspect, the present disclosure provides a PSMA-targeted radiopharmaceutical for use in a method of treating a cancer; wherein said PSMA-targeted radiopharmaceutical is to be administered in combination with an inhibitor of PI3K, AKT, and / or mTOR.

[0515] In some embodiments of any of the above-aspects, said cancer is prostate cancer. In some embodiments, said prostate cancer is castration-resistant prostate cancer. In some embodiments, said prostate cancer is metastatic castration-resistant prostate cancer. In some embodiments, said prostate cancer is hormone-sensitive prostate cancer. In some embodiments, said prostate cancer is hormone naive prostate cancer (e.g., anti-hormone therapy naive prostate cancer). In some embodiments, said prostate cancer is high-risk localized prostate cancer (HRCaP). In some embodiments, said prostate cancer is nodepositive prostate cancer (N1M0). In some embodiments, said prostate cancer is oligometastatic prostate cancer.

[0516] In some embodiments, said cancer is prostate cancer. In some embodiments, said prostate cancer is PSMA-positive prostate cancer. In some embodiments, said prostate cancer is characterized by overexpression of PSMA.

[0517] In some embodiments, said cancer is prostate cancer, said PSMA-targeted radiopharmaceutical is Compound A, wherein said Compound A is chelated to161Tb; and said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0518] In one aspect, the present invention provides a kit of parts, a composition for use, or a combination for use in the treatment of a prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) Compound A; wherein said Compound A is chelated to161Tb; and (ii) bimiralisib.

[0519] In one aspect, the present invention provides a kit of parts, a composition for use, or a combination for use in the treatment of a prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) Compound A; wherein said Compound A is chelated to177Lu; and (ii) bimiralisib.

[0520] In one aspect, the present invention provides a kit of parts, a composition for use, or a combination for use in the treatment of a prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) Compound A; wherein said Compound A is chelated to225Ac; and (ii) bimiralisib.

[0521] In some embodiments, said cancer is castration-resistant prostate cancer, wherein said Compound A is chelated to161Tb; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0522] In one aspect, the present invention a kit of parts, a composition for use, or a combination for use in the treatment of a castration-resistant prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) Compound A; wherein said Compound A is chelated to161Tb; and (ii) bimiralisib.

[0523] In one aspect, the present invention a kit of parts, a composition for use, or a combination for use in the treatment of a castration-resistant prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) Compound A; wherein said Compound A is chelated to177Lu; and (ii) bimiralisib.

[0524] In one aspect, the present invention a kit of parts, a composition for use, or a combination for use in the treatment of a castration-resistant prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) Compound A; wherein said Compound A is chelated to225Ac; and (ii) bimiralisib.

[0525] In some embodiments, said (i) PSMA-targeted radioligand is Compound A, wherein said Compound A is chelated to161Tb; and (ii) said inhibitor or PI3K, AKT and / or mTOR is bimiralisib.

[0526] In some embodiments, said: (i) PSMA-targeted radioligand is Compound A; wherein said Compound A is chelated to177Lu; and (ii) said inhibitor or PI3K, AKT and / or mTOR is bimiralisib. In some embodiments, said (i) PSMA-targeted radioligand is Compound A, wherein said Compound A is chelated to161Tb; and (ii) said inhibitor or PI3K, AKT and / or mTOR is bimiralisib.

[0527] In some embodiments, said: (i) PSMA-targeted radioligand is Compound A; wherein said Compound A is chelated to225Ac; and (ii) said inhibitor or PI3K, AKT and / or mTOR is bimiralisib.

[0528] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A and (ii) said an inhibitor of PI3K, AKT, and / or mTOR are administered sequentially.

[0529] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR are administered simultaneously.

[0530] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR are administered as a combined dosage form.

[0531] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR are administered simultaneously as a combined dosage form.

[0532] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms.

[0533] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms, wherein said separate dosage forms comprise separate packaging.

[0534] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms, and are administered simultaneously.

[0535] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms, and are administered sequentially.

[0536] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is administered prior to said (ii) inhibitor of PI3K, AKT, and / or mTOR.

[0537] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 1 minute. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 15 minutes. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 30 minutes. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 60 minutes. In some embodiments, said (i) PSMA- targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 2 hours. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 6 hours. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 12 hours. In some embodiments, said (i) PSMA- targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 24 hours. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 2 days. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 5 days. In some embodiments, said (i) PSMA- targeted radiopharmaceutical, preferably Compound A is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 7 days.

[0538] In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered prior to said (i) PSMA-targeted radiopharmaceutical, preferably Compound A. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is administered within about 1 minute. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is administered within about 15 minutes. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA- targeted radiopharmaceutical, preferably Compound A is administered within about 30 minutes. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is administered within about 60 minutes. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA- targeted radiopharmaceutical, preferably Compound A is administered within about 2 hours. PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is administered within about 6 hours. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is administered within about 12 hours. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is administered within about 24 hours. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is administered within about 2 days. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is administered within about 5 days. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably Compound A is administered within about 7 days.

[0539] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, preferably a prostate cancer, wherein said combination comprises: (i) a PSMA-targeted radiopharmaceutical; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0540] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, preferably a prostate cancer, wherein said combination comprises: (i) Compound A; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0541] In one aspect, the present invention provides a method of treating a cancer, preferably a prostate cancer, in a subject in need thereof, the method comprising: administering to said subject a combination comprising (i) a PSMA-targeted radiopharmaceutical; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0542] In one aspect, the present invention provides a method of treating a cancer, preferably a prostate cancer, in a subject in need thereof, the method comprising: administering to said subject a combination comprising (i) Compound A; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0543] In preferred embodiments, as used herein the steps of administering to said subject (i) a PSMA-targeted radiopharmaceutical; and / or (ii) an inhibitor of PI3K, AKT, and / or mTOR preferably comprises administering to said subject a therapeutically effective amount of said (i) a PSMA-targeted radiopharmaceutical; and / or (ii) said inhibitor of PI3K, AKT, and / or mTOR.

[0544] In one aspect, the present invention provides the use of a combination in the manufacture of a medicament for treating a cancer, preferably a prostate cancer, wherein said combination comprises: (i) a PSMA-targeted radiopharmaceutical; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0545] In one aspect, the present invention provides the use of a combination in the manufacture of a medicament for treating a cancer, preferably a prostate cancer, wherein said combination comprises: (i) Compound A; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0546] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is any of those described herein. Preferably said inhibitor of PI3K, AKT, and / or mTOR is a dual PI3K / mTOR inhibitor. More preferably, said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

[0547] In some embodiments, said Compound A is chelated to a radionuclide as described herein. In some preferred embodiments, said Compound A is chelated to161Tb. In some preferred embodiments, said Compound A is chelated to177Lu. In some preferred embodiments, said Compound A is chelated to225Ac.

[0548] In some embodiments, said cancer is prostate cancer, wherein said PSMA-11 is chelated to161Tb,177Lu, or225Ac; and said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0549] In one aspect, the present invention provides a kit of parts, a composition for use, or a combination for use in the treatment of a prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-11 ; wherein said PSMA-11 is chelated to161Tb; and (ii) bimiralisib.

[0550] In one aspect, the present invention provides a kit of parts, a composition for use, or a combination for use in the treatment of a prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-11 ; wherein said PSMA-11 is chelated to177Lu; and (ii) bimiralisib.

[0551] In one aspect, the present invention provides a kit of parts, a composition for use, or a combination for use in the treatment of a prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-11 ; wherein said PSMA-11 is chelated to225Ac; and (ii) bimiralisib.

[0552] In some embodiments, said cancer is castration-resistant prostate cancer, wherein said PSMA-11 is chelated to161Tb; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0553] In some embodiments, said cancer is castration-resistant prostate cancer, wherein said PSMA-11 is chelated to177Lu; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0554] In some embodiments, said cancer is castration-resistant prostate cancer, wherein said PSMA-11 is chelated to225Ac; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0555] In one aspect, the present invention a kit of parts, a composition for use, or a combination for use in the treatment of a castration-resistant prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-11; wherein said PSMA- 11 is chelated to161Tb; and (ii) bimiralisib.

[0556] In one aspect, the present invention a kit of parts, a composition for use, or a combination for use in the treatment of a castration-resistant prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-11; wherein said PSMA- 11 is chelated to177Lu; and (ii) bimiralisib.

[0557] In one aspect, the present invention a kit of parts, a composition for use, or a combination for use in the treatment of a castration-resistant prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-11; wherein said PSMA- 11 is chelated to225Ac; and (ii) bimiralisib.

[0558] In some embodiments, said (i) PSMA-targeted radioligand is PSMA-11, wherein said Compound A is chelated to161Tb; and (ii) said inhibitor or PI3K, AKT and / or mTOR is bimiralisib.

[0559] In some embodiments, said: (i) PSMA-targeted radioligand is PSMA-11; wherein said Compound A is chelated to177Lu; and (ii) said inhibitor or PI3K, AKT and / or mTOR is bimiralisib.

[0560] In some embodiments, said: (i) PSMA-targeted radioligand is PSMA-11; wherein said Compound A is chelated to225Ac; and (ii) said inhibitor or PI3K, AKT and / or mTOR is bimiralisib.

[0561] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 and (ii) said an inhibitor of PI3K, AKT, and / or mTOR are administered sequentially.

[0562] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are administered simultaneously.

[0563] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are administered as a combined dosage form.

[0564] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are administered simultaneously as a combined dosage form.

[0565] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms.

[0566] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms, wherein said separate dosage forms comprise separate packaging.

[0567] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms, and are administered simultaneously.

[0568] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms, and are administered sequentially.

[0569] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is administered prior to said (ii) inhibitor of PI3K, AKT, and / or mTOR.

[0570] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 1 minute. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 15 minutes. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 30 minutes. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 60 minutes. In some embodiments, said (i) PSMA- targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 2 hours. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 6 hours. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 12 hours. In some embodiments, said (i) PSMA- targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 24 hours. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 2 days. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 5 days. In some embodiments, said (i) PSMA- targeted radiopharmaceutical, preferably PSMA-11 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 7 days.

[0571] In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered prior to said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is administered within about 1 minute. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA- 11 is administered within about 15 minutes. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is administered within about 30 minutes. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is administered within about 60 minutes. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is administered within about 2 hours. PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA- 11 is administered within about 6 hours. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is administered within about 12 hours. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is administered within about 24 hours. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA- 11 is administered within about 2 days. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is administered within about 5 days. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-11 is administered within about 7 days.

[0572] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, preferably a prostate cancer, wherein said combination comprises: (i) PSMA-11; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0573] In one aspect, the present invention provides a method of treating a cancer, preferably a prostate cancer, in a subject in need thereof, the method comprising: administering to said subject a combination comprising (i) PSMA-11; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0574] In one aspect, the present invention provides the use of a combination in the manufacture of a medicament for treating a cancer, preferably a prostate cancer, wherein said combination comprises: (i) PSMA-11; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0575] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is any of those described herein. Preferably said inhibitor of PI3K, AKT, and / or mTOR is a dual PI3K / mTOR inhibitor. More preferably, said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

[0576] In some embodiments, said PSMA-11 is chelated to a radionuclide as described herein. In some preferred embodiments, said PSMA-11 is chelated to161Tb. In some preferred embodiments, said PSMA-11 is chelated to177Lu. In some preferred embodiments, said PSMA-11 is chelated to225Ac.

[0577] In some embodiments, said cancer is prostate cancer, wherein said PSMA-617 is chelated to161Tb,177Lu, or225Ac; and said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0578] In one aspect, the present invention provides a kit of parts, a composition for use, or a combination for use in the treatment of a prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-617; wherein said PSMA-617 is chelated to161Tb; and (ii) bimiralisib.

[0579] In one aspect, the present invention provides a kit of parts, a composition for use, or a combination for use in the treatment of a prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-617; wherein said PSMA-617 is chelated to177Lu; and (ii) bimiralisib.

[0580] In one aspect, the present invention provides a kit of parts, a composition for use, or a combination for use in the treatment of a prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-617; wherein said PSMA-617 is chelated to225Ac; and (ii) bimiralisib.

[0581] In some embodiments, said cancer is castration-resistant prostate cancer, wherein said PSMA-617 is chelated to161Tb; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0582] In some embodiments, said cancer is castration-resistant prostate cancer, wherein said PSMA-617 is chelated to177Lu; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

[0583] In some embodiments, said cancer is castration-resistant prostate cancer, wherein said PSMA-617 is chelated to225Ac; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib. In one aspect, the present invention a kit of parts, a composition for use, or a combination for use in the treatment of a castration-resistant prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-617; wherein said PSMA- 617 is chelated to161Tb; and (ii) bimiralisib.

[0584] In one aspect, the present invention a kit of parts, a composition for use, or a combination for use in the treatment of a castration-resistant prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-617; wherein said PSMA- 617 is chelated to177Lu; and (ii) bimiralisib.

[0585] In one aspect, the present invention a kit of parts, a composition for use, or a combination for use in the treatment of a castration-resistant prostate cancer, wherein said kit of parts, composition, or combination for use comprises: (i) PSMA-617; wherein said PSMA- 617 is chelated to225Ac; and (ii) bimiralisib.

[0586] In some embodiments, said (i) PSMA-targeted radioligand is PSMA-617, wherein said Compound A is chelated to161Tb; and (ii) said inhibitor or PI3K, AKT and / or mTOR is bimiralisib.

[0587] In some embodiments, said: (i) PSMA-targeted radioligand is PSMA-617; wherein said Compound A is chelated to177Lu; and (ii) said inhibitor or PI3K, AKT and / or mTOR is bimiralisib.

[0588] In some embodiments, said: (i) PSMA-targeted radioligand is PSMA-617; wherein said Compound A is chelated to225Ac; and (ii) said inhibitor or PI3K, AKT and / or mTOR is bimiralisib.

[0589] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 and (ii) said an inhibitor of PI3K, AKT, and / or mTOR are administered sequentially.

[0590] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are administered simultaneously.

[0591] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are administered as a combined dosage form.

[0592] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are administered simultaneously as a combined dosage form. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms.

[0593] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms, wherein said separate dosage forms comprise separate packaging.

[0594] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms, and are administered simultaneously.

[0595] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 and (ii) said inhibitor of PI3K, AKT, and / or mTOR are provided in separate dosage forms, and are administered sequentially.

[0596] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered prior to said (ii) inhibitor of PI3K, AKT, and / or mTOR.

[0597] In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 1 minute. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 15 minutes. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 30 minutes. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 60 minutes. In some embodiments, said (i) PSMA- targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 2 hours. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 6 hours. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 12 hours. In some embodiments, said (i) PSMA- targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 24 hours. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 2 days. In some embodiments, said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 5 days. In some embodiments, said (i) PSMA- targeted radiopharmaceutical, preferably PSMA-617 is first administered to a subject, and said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered within about 7 days.

[0598] In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is administered prior to said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered within about 1 minute. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered within about 15 minutes. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered within about 30 minutes. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered within about 60 minutes. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered within about 2 hours. PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA- 617 is administered within about 6 hours. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered within about 12 hours. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered within about 24 hours. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered within about 2 days. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered within about 5 days. In some embodiments, said (ii) inhibitor of PI3K, AKT, and / or mTOR is first administered to a subject, and said (i) PSMA-targeted radiopharmaceutical, preferably PSMA-617 is administered within about 7 days.

[0599] In one aspect, the present invention provides a combination for use in a method of treating a cancer in a subject, preferably a prostate cancer, wherein said combination comprises: (i) PSMA-617; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0600] In one aspect, the present invention provides a method of treating a cancer, preferably a prostate cancer, in a subject in need thereof, the method comprising: administering to said subject a combination comprising (i) PSMA-617; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0601] In one aspect, the present invention provides the use of a combination in the manufacture of a medicament for treating a cancer, preferably a prostate cancer, wherein said combination comprises: (i) PSMA-617; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

[0602] In some embodiments, said inhibitor of PI3K, AKT, and / or mTOR is any of those described herein. Preferably said inhibitor of PI3K, AKT, and / or mTOR is a dual PI3K / mT0R inhibitor. More preferably, said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

[0603] In some embodiments, said PSMA-617 is chelated to a radionuclide as described herein. In some preferred embodiments, said PSMA-617 is chelated to161Tb. In some preferred embodiments, said PSMA-617 is chelated to177Lu. In some preferred embodiments, said PSMA-617 is chelated to225Ac.

[0604] EXAMPLES

[0605] The invention will now be illustrated by way of the following non-limiting examples. While particular embodiments of the invention are described below, a skilled person will appreciate that various changes and modifications can be made. References to preparations carried out in a similar manner to, or by the general method of, other preparations, may encompass variations in routine parameters such as time, temperature, workup conditions, minor changes in reagents amounts, and the like.

[0606] EXAMPLE 1 : CO-TREATMENT OF177LU-PSMA-617 AND COMPOUND 1* (PQR309; BIMIRALISIB) OR COMPOUND 2 IN 22RV1 HUMAN PROSTATE CANCER CELLS

[0607] This study determined the anti-proliferative effects of177Lu-PSMA-617 in combination with Compound 1* (PQR309; bimiralisib) and Compound 2 (see, e.g., Borsari et al., Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl-Pyrimidine Moiety, ACS Med. Chem. Lett., 10(10): 1473-1497 (2019)) on cell survival in the human prostate cancer cell line 22Rvl.

[0608] Cell culture: 22Rvl cells (Sigma Aldrich) were cultured according to standard procedures (growth medium: RPMI-160 ATCC modified supplemented with 10% (v / v) FBS, 2 mM L-glutamine, and 1% (v / v) Pen / Strep; growth at 37 °C with 5 % CO2) and harvested when cells were between 70-90 % confluent.

[0609] Determination of IC50 of Compound 1* (PQR309; bimiralisib) and Compound 2, in 22Ryl cells: 9,000 22Rvl cells per well were seeded in opaque-walled clear bottom 96-well plates in growth medium and incubated overnight prior to treatment. Triplicates were seeded for each condition. The next day, medium was replaced with warm medium containing Compound 1* or Compound 2 at different concentrations (10, 3, 1. 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, and 0 pM) and cells were incubated for 7 days. After 7 days, a CellTiter-Glo assay was performed as per manufacturer’s instructions. Luminescence was measured on a Spectramax i3x multi-mode microplate reader and the dose-response curves were determined by non-linear regression analysis in GraphPad Prism, including calculation of the IC50. A plot of percent survival of 22Rvl cells as a function of concentration of Compound 1* or Compound 2 is shown in FIG 1, and the IC50S are given in Table 1, below. Table 1: IC50S of Compound 1* and Compound 2. in 22Ryl Cells (uM)

[0610] Compound 1* and Compound 2 dose-dependently inhibited survival of 22Rvl cells.

[0611] Cell survival of 22Ryl cells treated with177Lu-PSMA-617. Compound 1, or Compound 2. as single agents or treated with combinations of177Lu-PSMA-617 and Compound 1* or Compound 2: Different doses of177Lu-PSMA-617 (0 (vehicle), 0.5, 1, 2.5, 5, 10, and 20 MBq / mL; Table 2) were added to tubes containing 22Rvl cells (final volume of 2.5 mL) and then incubated under constant agitation at 37 °C with 5 % CO2 for 4 hours. After incubation, the cells were washed twice with PBS and cells were seeded in opaque-walled clear bottom 96-well plate with 9 000 cells per well. Triplicates (3 wells) were seeded for each treatment (Table 2). Compound 1* and Compound 2 were added at the concentrations indicated in Table 2 (i.e., these concentrations corresponded to the ICso, ICso, IC50, IC40, IC30, IC20 determined in the previous experiment above). Cells were incubated at 37 °C with 5 % CO2 for 7 days. After incubation, CellTiter-Glo was added to all wells as per the manufacturer’s instructions. The plates were placed on a shaker to induce cell lysis and incubated at room temperature to stabilize the signal. Luminescence was measured on a Spectramax i3x multi-mode microplate reader and the dose-response curve was determined by non-linear regression analysis.

[0612] Table 2: Dosage Combinations for Survival Assay with Compound 1* or Compound 2 and

[0613] 177LU-PSMA-617

[0614] Cell survival decreased with increasing concentrations of Compound 1* (PQR309) or Compound 2 (FIG 2A). Treatment of cells with177Lu-PSMA-617 in combination with Compound 1* (PQR309) or Compound 2 further decreased survival (FIG 2A). To assess the effect of the combination of177Lu-PSMA-617 with Compound 1* (PQR309) or Compound 2, the Bliss synergy score was calculated using SynergyFinder (https : / / synergyfinder.fimm, fi / synergy / 20241025144228237071 / ). A Bliss synergy score above 10 indicates synergy between two drugs. Combination of177Lu-PSMA-617 with both Compound 1* (PQR309) or Compound 2 was synergistic as evidenced by a Bliss synergy score of 11.145 (FIG 2B) and 12.158 (FIG 2C), respectively.

[0615] EXAMPLE 2: CO-ADMINISTRATION OF161Tb-PSMA-I&T OR177Lu-PSMA-617 AND COMPOUND 1* (PQR309; BIMIRALISIB) IN NUDE MICE BEARING 22RV1 TUMORS

[0616] This study evaluated and compared the anti-tumor efficacy of161Tb-PSMA-I&T and177LU-PSMA-617 as single treatment and in combination with Compound 1* in female NMRI nude mice bearing subcutaneous human prostate carcinoma established with the cell line 22Rvl.

[0617] Study outline and procedures: 8-week-old female NMRI nude mice (80 mice required for the experiment plus extra mice in reserve) from Janvier (France) were implanted with 3x10622Rvl cells (Sigma Aldrich; cultured as described in Example 1) in PBS:Matrigel (1: 1) by subcutaneous injection using a 27G needle and a total injection volume of 100 pL at the flank above the right limb on day -16 (relative to start of treatment, defined as study day 0). On day -1 (i.e., 15 days post-implantation), the mice were randomized based on tumor size and body weight to ensure similar average and variation of the groups. Mice were distributed to the treatment and control groups (8 mice per group). FIG 3A is a plot of average body weight of mice at day -1, and FIG 3B is a plot of tumor volume of mice at day -1. Average body weight was 29 g (range from 25.5 to 33.4 g; FIG 3A) and average tumor volume was 175 mm3(range from 76 to 347 mm3; FIG 3B) for all groups.

[0618] Treatments with radioligands (161Tb-PSMA-I&T and177Lu-PSMA-617) and Compound 1* were initiated on study day 0. Study groups and treatment details are outlined in Table 3.

[0619] 161Tb-PSMA-I&T was intravenously (IV) administered once at a target dose of 21.8 MBq or at a target dose of 43.7 MBq.177Lu-PSMA-617 was intravenously administered once at a target dose of 30 MBq or at a target dose of 60 MBq. The doses of 21.8 MBq and 43.7 MBq161Tb-PSMA-I&T correspond to the same dose (in Gy) of 30 MBq and 60 MBq177Lu- PSMA-617. IV injections were carried out at an injection volume of 100-200 pL at the lateral tail vein. Compound 1* was intraperitoneally (IP) administered at 7 mg / kg daily (QD) for 45 days or until mice reached a humane endpoint (see below). Control mice were IV administered with vehicle once. All injections were performed at a dosing volume of 5 mL / kg. Compound 1* was formulated weekly in 7.5% (v / v) SBECD at pH 7. Table 3, Study Groups and Treatment Details

[0620] Mice were checked daily and adverse clinical reactions noted. Animal body weight and tumor size were assessed twice a week. Animals were euthanized at the end of the experiment or upon reaching humane endpoints as listed in Table 4. Euthanasia was performed by cervical dislocation.

[0621] Table 4, Humane endpoints

[0622] Tumor size was measured by caliper 2x every week and on the day of stratification.

[0623] All treatments were tolerated well and no mice had to be sacrificed before reaching the endpoint of the tumor volume being as big as or bigger than 1500 mm3. Treatment with (a) Compound 1* alone; (b) 21.8 MBq161Tb-PSMA-I&T alone; and

[0624] (c) both 30 and 60 MBq of177Lu-PSMA-617 alone did not reduce tumor growth as single agents up to study day 15 (i.e., the last day on which all mice were still alive, allowing all conditions to be compared directly) compared to treatment with vehicle (FIG 4A, 4C, 4D). All mice that were treated with vehicle alone or Compound 1 * alone reached a tumor volume of 1500 mm3by or shortly after day 15 and thus were euthanized on or shortly after day 15.

[0625] In contrast, the combination of Compound 1* with either 21.8 MBq161Tb-PSMA-I&T (FIG 4A) or 30 or 60 MBq177Lu-PSMA-617 (FIG 4C and FIG 4D respectively) reduced tumor growth compared to treatment with vehicle or single agents alone. Treatment with 43.7 MBq161Tb-PSMA-I&T alone reduced tumor growth (FIG 4B) compared to vehicle or monotherapy with Compound 1*. Moreover, the combination of 43.7 MBq161Tb-PSMA-I&T with Compound 1* led to a greater reduction in tumor growth after study day 15 compared to treatment with161Tb-PSMA-I&T alone (FIG 4B).

[0626] Some of the mice treated with161Tb-PSMA-I&T or177Lu-PSMA-617 alone reached the endpoint of tumor volume >1500 mm3after study day 15 (i.e., the day on which most mice in the vehicle group and Compound 1 * monotherapy treatment group reached a tumor volume of >1500 mm3) and several mice treated with Compound 1* in combination with161Tb-PSMA- I&T or177LU-PSMA-617 did not exhibit a tumor volume > 1500 mm3until on or after study day 20. Individual tumor volumes are shown in Figure 5. Based on these individual tumor data, the number of days-until-endpoint was calculated for each mouse (i.e., the number of days from treatment start to reaching a tumor volume of >1500 mm3) (FIG 6). Tumors of mice treated with a combination of161Tb-PSMA-I&T or177Lu-PSMA-617 and Compound 1* reached the endpoint significantly later than mice treated with vehicle, Compoundl*,161Tb- PSMA-I&T or177LU-PSMA-617 alone (p<0.05).

[0627] EXAMPLE 3: CO-ADMINISTRATION OF225AC-PSMA OR212PB-PSMA AND COMPOUND 1* (PQR309; BIMIRALISIB) OR COMPOUND 2 IN NUDE MICE BEARING 22RV1 TUMORS

[0628] The purpose of this study will be to evaluate and compare the anti-tumor efficacy of225AC-PSMA- and212Pb-PSMA-targeting radioligand therapy (RLT; e.g., PSMA-617 or PSMA-I&T), as single treatment and in combination with dual PI3K / mTOR inhibitors (such as Compound 1* (PQR309; bimiralisib) or Compound 2 in mice (e.g., female NMRI nude mice) bearing subcutaneous human prostate carcinoma (established with cell lines such as 22Rvl, LNCaP, or PC3-PIP).

[0629] Mice (e.g., 8-week-old female NMRI nude mice) will be implanted with cells (e.g., 3x10622Rvl cells in PBS:Matrigel (1: 1)) by subcutaneous injection (e.g., using a 27G needle and a total injection volume of 100 pL, e.g., at the flank above the right limb). A sufficient number of mice per treatment group will be implanted (e.g., 8 mice per group plus extra mice as described in Example 2). When subcutaneous tumors reach a certain volume (e.g., 100, 150, or 200 mm3), the mice will be randomized based on tumor size and body weight to ensure similar average and variation of the groups. Mice will be distributed to the treatment and control groups (e.g., 8 mice per group).

[0630] In a first experiment, sub-optimal doses of225Ac-PSMA- and212Pb-PSMA-targeting RLT will be determined by treating tumor-bearing mice with different target doses (e.g., 50, 75, 150, 200, and 300 kBq).225Ac-PSMA- and212Pb-PSMA-targeting RLT or vehicle will be administered once by IV. In parallel, sub-optimal doses of dual PI3K / mTOR inhibitors (such as Compound 1 * or Compound 2) will be determined by treating tumor-bearing mice with different target doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg). The dual PI3K / mTOR inhibitors will be administered (e.g., by IP injection) multiple times (e.g., daily, every 2ndday, or every 3rdday). Mice will be checked daily and adverse clinical reactions will be noted. Animal body weight and tumor size will be assessed twice a week. Animals will be euthanized (e.g., by cervical dislocation) at the end of the experiment or upon reaching humane endpoints (e.g., as listed above in Table 4). Tumor size will be measured by caliper (e.g., 2x every week and on the day of stratification). The tumor volume will be estimated with a formula such as: 0.52(length x width2). Tumor volumes over time (i.e., study days) will be displayed and used to estimate sub-optimal treatment doses for each agent. A sub-optimal dose of225Ac-PSMA- and212Pb-PSMA-targeting RLT and dual PI3K / mTOR inhibitors (such as Compound 1* or Compound 2) is defined as a dose which is not capable of inhibiting or only capable of moderately inhibiting tumor growth (e.g., a dose leading to an inhibition of 10, 20, 30, 40, 50, or 60% compared to vehicle).

[0631] In a second experiment, sub-optimal doses of225Ac-PSMA- and212Pb-PSMA-targeting RLT will be combined with sub-optimal doses of dual PI3K / mTOR inhibitors (such as Compound 1 * or Compound 2).225Ac-PSMA- and212Pb-PSMA-targeting RLT or vehicle will be administered once by IV. Dual PI3K / mTOR inhibitors will be administered (e.g., by IP injections) multiple times (e.g., daily, every 2ndday, or every 3rdday). Mice will be checked and tumor volumes will be measured and analyzed (e.g., as described in Example 2). Additive or synergistic effects of225Ac-PSMA- and212Pb-PSMA-targeting RLT with dual PI3K / mTOR inhibitors (such as Compound 1* or Compound 2) will be calculated using methods described in the art, such as SynergyFinder

[0632] (htps: / / synergyfinder.fimm.fi / synergy / 20241025144228237071 / ).

Claims

CLAIMS1. A combination for use in a method of treating a cancer in a subject, said combination comprising:(i) a composition comprising a PSMA-targeted radiopharmaceutical; and(ii) a composition comprising an inhibitor of PI3K, AKT, and / or mTOR.

2. A method of treating a cancer in a subject in need thereof, the method comprising: administering to said subject a therapeutically effective amount of (i) a PSMA-targeted radiopharmaceutical; and (ii) an inhibitor of PI3K, AKT, and / or mTOR.

3. The method or combination for use of claim 1 or claim 2, wherein said PSMA-targeted radiopharmaceutical comprises a DUPA targeting group.

4. The method or combination for useof any of the preceding claims, wherein said inhibitor of PI3K, AKT, and / or mTOR is a dual PI3K / mT0R inhibitor.

5. The method or combination for use of any of the preceding claims, wherein said inhibitor of PI3K, AKT, and / or mTOR is a compound of Formula (I):wherein:X1, X2and X3are, independently of each other, N or CH; with the proviso that at least two of X1, X2and X3are N;Y is N or CH;W is H or F; with the proviso that when W is F, then X1, X2and X3are N;R1and R2are independently of each other(i) a morpholinyl of formula (II)wherein the arrow denotes the bond in formula (I); and wherein R3and R4are independently of each other H, Ci-Csalkyl optionally substituted with one or two OH, Ci-C2fluoroalkyl, Ci-C2alkoxy, Ci-C2alkoxyCi-C3alkyl, CN, or C(O)O-Ci-C2alkyl; or R3and R4form together a bivalent residue -R5R6- selected from Ci-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structureswherein the arrows denote the bonds in formula (II); or(ii) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R7; wherein R7is independently at each occurrence Ci-C3alkyl optionally substituted with one or two OH, Ci- C2fluoroalkyl, Ci-C2alkoxyCi-C3alkyl, Cs-Cecycloalkyl; or two R7substituents form together a bivalent residue -R8R9- selected from Ci-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CH2CH2-O-; with the proviso that at least one of R1and R2is a morpholinyl of formula II; and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts thereof.

6. The method or combination for use of any of the preceding claims, wherein said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib, or a pharmaceutically acceptable salt thereof.

7. The method or combination for use of any of the preceding claims, wherein said PSMA-conjugated radiopharmaceutical is chelated to a radionuclide.

8. The method or combination for use of any of the preceding claims, wherein said PSMA-conjugated radiopharmaceutical is chelated to161Tb or177Lu.

9. The method or combination for use according to any of the preceding claims, wherein said PSMA-conjugated radiopharmaceutical is chelated to161Tb or177Lu; and wherein said inhibitor of PI3K, AKT, and / or mTOR is bimiralisib.

10. The method or combination for use according to any of the preceding claims, wherein said cancer is prostate cancer.

11. The method or combination for use of any the preceding claims, wherein said cancer is prostate cancer, said PSMA-targeted radiopharmaceutical is Compound A, wherein said Compound A is chelated to161Tb or177Lu; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

12. The method or combination for use of any of the preceding claims, wherein said cancer is castration-resistant prostate cancer, wherein said PSMA-targeted radiopharmaceutical is Compound A, wherein said Compound A is chelated to161Tb or177LU; and wherein said compound capable of inhibiting PI3K, AKT, and / or mTOR is bimiralisib.

13. The method or combination for use of any of the preceding claims, wherein said (i) PSMA-targeted radiopharmaceutical is Compound A, wherein said Compound A and (ii) said an inhibitor of PI3K, AKT, and / or mTOR are administered sequentially.

14. A combination for use in a method of treating a cancer in a subject, preferably a prostate cancer, wherein said combination comprises:(i) Compound A:Compound A; and(ii) an inhibitor of PI3K, AKT, and / or mTOR.

15. A composition or a kit of parts comprising:(i) a PSMA-targeted radiopharmaceutical; and(ii) an inhibitor of PI3K, AKT, and / or mTOR.

Images