IGF1R Inhibitors and Akt Inhibitors for Use in the Treatment of Cancer - Patent application

Abstract

The present invention relates to combination therapy of IGF1R inhibitors with Akt inhibitors for the treatment of cancer, such as colon cancer, ovarian cancer and endometrial cancer.

Description

[Technical field]

[0001] The present invention relates to combination therapies for the treatment of cancer. [Background technology]

[0002] Despite advances in treatment, cancer continues to have a significant impact on societies, families, and individuals worldwide. It is one of the leading causes of death worldwide. According to statistics provided by the National Cancer Institute, there were 18.1 million new cases and 9.5 million cancer-related deaths worldwide in 2018. By 2040, the number of new annual cancer cases is projected to rise to 29.5 million, and the number of cancer-related deaths to 16.4 million. Summary of the Invention [Problem to be solved by the invention]

[0003] Cancer treatment has improved with the use of single-agent targeted therapy in patients with molecularly defined tumors. Nevertheless, many patients still lack effective treatments, and existing or acquired resistance limits the clinical benefit of even our most advanced medicines. Combination therapy using an increasing number of targeted anticancer drugs has the potential to overcome resistance to existing drugs, enhance response, reduce dose-limiting toxicity of single agents, and expand the scope of treatment for patients. [Means for solving the problem]

[0004] The present invention is directed to the use of therapeutic combinations of active ingredients for the treatment of cancer in patients, in particular the combination of IGF1R inhibitor and Akt inhibitor.As described herein, the inventors have observed synergistic effects for the combination of IGF1R inhibitor (e.g., linsitinib) and Akt inhibitor (e.g., MK-2206) in cancer cell lines, particularly colon cancer cell lines.

[0005] In a first aspect, the invention may relate to a combination of an IGF1R inhibitor and an Akt inhibitor for use in a method of treating cancer in a patient, wherein the cancer is selected from colorectal cancer, ovarian cancer and endometrial cancer.

[0006] In some cases, the invention may relate to an IGF1R inhibitor for use in a method for treating cancer in a patient, wherein the cancer is selected from colorectal cancer, ovarian cancer and endometrial cancer, and the IGF1R inhibitor is administered to the patient in combination with an Akt inhibitor.

[0007] In some cases, the invention may relate to an Akt inhibitor for use in a method for treating cancer in a patient, wherein the cancer is selected from colorectal cancer, ovarian cancer and endometrial cancer, and the IGF1R inhibitor is administered to the patient in combination with an IGF1R inhibitor.

[0008] In some cases, the cancer is colon cancer.

[0009] Suitably, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, brigatinib, AXL-1717 and KW-2450, or an IGF1R antibody. The IGF1R antibody may be an IGF1R monoclonal antibody (mAb). The IGF1R antibody may be selected from teprotumumab, AVE-1642, ganitumab, dalotuzumab, lonigutamab ugodotin, A-12, VRDN-002, VRDN-003, ZB-011, BIIB-022, cixutumumab, figitumumab, M-590, robatumumab, XGFR-2, XGFR-4, and istiratumab.

[0010] In some cases, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, brigutinib, AXL-1717, and KW-2450. In some cases, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, brigutinib, and AXL-1717. In some cases, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, and brigutinib. In some cases, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, and BMS-536924. In some cases, the IGF1R inhibitor is selected from linsitinib and GSK1904529A. In some cases, the IGF1R inhibitor is linsitinib.

[0011] Thus, in some cases, the invention may relate to a combination of linsitinib and an Akt inhibitor for use in a method for treating colon, ovarian or endometrial cancer. In some cases, the invention may relate to a combination of AXL-1717 and an Akt inhibitor for use in a method for treating colon, ovarian or endometrial cancer.

[0012] In some cases, the Akt inhibitor is an allosteric Akt inhibitor. In some cases, the Akt inhibitor is an allosteric Akt inhibitor selected from MK-2206, miransertib, and BAY1125976.

[0013] In other cases, the Akt inhibitor is an ATP-competitive Akt inhibitor. In some cases, the Akt inhibitor is an ATP-competitive Akt inhibitor selected from capivasertib, afuresertib, and ipatasertib.

[0014] Preferably, the Akt inhibitor is selected from MK-2206, capivasertib, ipatasertib, afuresertib, milansertib, uprosertib, triciribine, PTX-200, TAS-117, COTI-2, LY-2503029, MK-4440, and BAY1125976. In some cases, the Akt inhibitor is selected from MK-2206, capivasertib, ipatasertib, afuresertib, milansertib, and BAY1125976. In some cases, the Akt inhibitor is selected from MK-2206, capivasertib, milansertib, and BAY1125976. In some cases, the Akt inhibitor is selected from MK-2206, ipatasertib, and afuresertib. In some cases, the Akt inhibitor is MK-2206.

[0015] Thus, the combination for use according to the first aspect may be a combination of linsitinib and MK-2206.

[0016] Alternatively, the combination for use according to the first aspect may be a combination of BMS-754807 and MK-2206. Alternatively, the combination for use according to the first aspect may be a combination of GSK1904529A and MK-2206. Alternatively, the combination for use according to the first aspect may be a combination of XL228 and MK-2206. Alternatively, the combination for use according to the first aspect may be a combination of BMS-536924 and afuresertib. Alternatively, the combination is brigutinib (IGF1R inhibitor) and MK-2206 (Akt inhibitor). Alternatively, the combination is linsitinib (IGF1R inhibitor) and ipatasertib (Akt inhibitor). Alternatively, the combination is linsitinib (IGF1R inhibitor) and BAY1125976 (Akt inhibitor). Alternatively, the combination is linsitinib (IGF1R inhibitor) and capivasertib (Akt inhibitor). Alternatively, the combination is linsitinib (IGF1R inhibitor) and milansertib (Akt inhibitor). Alternatively, the combination is XL228 (IGF1R inhibitor) and ipatasertib (Akt inhibitor). Alternatively, the combination is GSK1904529A (IGF1R inhibitor) and ipatasertib (Akt inhibitor). Alternatively, the combination is GSK1904529A (IGF1R inhibitor) and afuresertib (Akt inhibitor). Alternatively, the combination is linsitinib (IGF1R inhibitor) and afuresertib (Akt inhibitor). Alternatively, the combination is BMS-536924 (IGF1R inhibitor) and MK-2206 (Akt inhibitor). Alternatively, the combination is BMS-536924 (IGF1R inhibitor) and ipatasertib (Akt inhibitor). Alternatively, the combination is BMS-536924 (IGF1R inhibitor) and milansertib (Akt inhibitor). Alternatively, the combination is BMS-536924 (IGF1R inhibitor) and capivasertib (Akt inhibitor). Alternatively, the combination is BMS-536924 (IGF1R inhibitor) and BAY1125976 (Akt inhibitor). Alternatively, the combination is GSK1904529A (IGF1R inhibitor) and milansertib (Akt inhibitor).Alternatively, the combination is GSK1904529A (IGF1R inhibitor) and capivasertib (Akt inhibitor). Alternatively, the combination is GSK1904529A (IGF1R inhibitor) and BAY1125976 (Akt inhibitor). Alternatively, the combination is AXL-1717 (IGF1R inhibitor) and MK-2206 (Akt inhibitor). Alternatively, the combination is AXL-1717 (IGF1R inhibitor) and afuresertib (Akt inhibitor). Alternatively, the combination is AXL-1717 (IGF1R inhibitor) and ipatasertib (Akt inhibitor). Alternatively, the combination is AXL-1717 (IGF1R inhibitor) and milansertib (Akt inhibitor). Alternatively, the combination is AXL-1717 (IGF1R inhibitor) and capivasertib (Akt inhibitor).Alternatively, the combination is AXL-1717 (IGF1R inhibitor) and BAY1125976 (Akt inhibitor).

[0017] In some cases, the cancer is a KRAS mutant cancer.

[0018] In some cases, the cancer is an ARID1A mutated and / or ARID2 mutated cancer. For example, the cancer can be an ARID1A mutated cancer. The cancer can be an ARID2 mutated cancer. The cancer can be an ARID1A mutated and ARID2 mutated cancer.

[0019] In some cases, the cancer is an ARID1A mutated and / or ARID2 mutated cancer and an IRS4 wild type cancer. For example, the cancer can be an ARID1A mutated and an IRS4 wild type cancer. The cancer can be an ARID2 mutated and an IRS4 wild type cancer. The cancer can be an ARID1A mutated, an ARID2 mutated and an IRS4 wild type cancer.

[0020] In some cases, the cancer is ARID1A mutated and / or ARID2 mutated and IRS4 wild-type colorectal cancer. In some cases, the cancer is ARID1A mutated and / or ARID2 mutated and IRS4 wild-type colorectal cancer, the IGF1R inhibitor is linsitinib, and the Akt inhibitor is MK-2206.

[0021] In some cases, the cancer is ARID1A mutant ovarian cancer. In some cases, the cancer is ARID1A mutant ovarian cancer, the IGF1R inhibitor is linsitinib, and the Akt inhibitor is MK-2206.

[0022] In some cases, the cancer is ARID1A mutant endometrial cancer. In some cases, the cancer is ARID1A mutant endometrial cancer, the IGF1R inhibitor is linsitinib, and the Akt inhibitor is MK-2206.

[0023] It is understood that IGF1R inhibitor and Akt inhibitor can be administered together (concurrently) or separately, and can be administered at the same time or at different times.For example, the compounds can be administered on different days as part of a treatment cycle or treatment regimen.Preferably, but not necessarily, IGF1R inhibitor and Akt inhibitor are formulated separately.In a preferred method, both compounds are formulated for oral administration.

[0024] The claimed combination therapy can be used for both curative and symptomatic (palliative) purposes. It may lead to better patient outcomes and / or experiences when compared to other treatment regimens and may additionally or alternatively expand the treatment options available to patients.

[0025] Suitably, the patient may be a human patient.

[0026] The present invention also relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a combination of an effective amount of an IGF1R inhibitor and an effective amount of an Akt inhibitor, wherein the cancer is selected from colorectal cancer, ovarian cancer and endometrial cancer.

[0027] The present invention also relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of an IGF1R inhibitor in combination with an effective amount of an Akt inhibitor, wherein the cancer is selected from colorectal cancer, ovarian cancer and endometrial cancer.

[0028] The present invention also relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of an Akt inhibitor in combination with an effective amount of an IGF1R inhibitor, wherein the cancer is selected from colorectal cancer, ovarian cancer and endometrial cancer.

[0029] The invention also relates to the use of a combination of an IGF1R inhibitor and an Akt inhibitor in the manufacture of a medicament for the treatment of cancer in a patient, wherein the cancer is selected from colon cancer, ovarian cancer and endometrial cancer.

[0030] The invention also relates to the use of an IGF1R inhibitor in combination with an Akt inhibitor in the manufacture of a medicament for the treatment of cancer in a patient, wherein the cancer is selected from colon cancer, ovarian cancer and endometrial cancer.

[0031] The invention also relates to the use of an Akt inhibitor in combination with an IGF1R inhibitor in the manufacture of a medicament for the treatment of cancer in a patient, wherein the cancer is selected from colon cancer, ovarian cancer and endometrial cancer.

[0032] The present invention includes combinations of the described embodiments and preferred features except where such combinations are clearly unacceptable or explicitly avoided.

[0033] BRIEF DESCRIPTION OF THE DRAWINGS Embodiments and experiments illustrating the principles of the present invention will now be discussed with reference to the accompanying drawings. [Brief description of the drawings]

[0034] [Figure 1]Graph of correlation between individual biomarkers and synergy in response to MK-2206 + linsitinib in colon cancer cell lines. Log2ΔIC50 (A) and ΔEmax (B) are plotted against ARID1A mutation status. Each point is the average response of a single cell line. Box and whisker plots show median and interquartile range. WT: wild type, MUT: mutant. Dotted line represents the threshold above which a cell line is defined as synergistic for the combination. See Example 2. [Diagram 2] Graph of correlation between individual biomarkers and synergy in response to MK-2206 + linsitinib in colon cancer cell lines. Log2ΔIC50 (A) and ΔEmax (B) are plotted against ARID2 mutation status. Each point is the average response of a single cell line. Box and whisker plots show median and interquartile range. WT: wild type, MUT: mutant. Dotted line represents the threshold above which a cell line is defined as synergistic for the combination. See Example 2. [Diagram 3] Graph of correlation between individual biomarkers and synergy in response to MK-2206 + linsitinib in colon cancer cell lines. Log2ΔIC50 (A) and ΔEmax (B) are plotted against IRS4 mutation status. Each point is the average response of a single cell line. Box and whisker plots show median and interquartile range. WT: wild type, MUT: mutant. Dotted line represents the threshold above which a cell line is defined as synergistic for the combination. See Example 2. [Figure 4] 1 is a graph of the correlation of biomarker combinations with ARID1A, ARID2, and IRS4 mutation status and sensitivity to MK-2206 (anchor) + linsitinib (library) in colon cancer cell lines. Colon cancer cell lines are arranged by Log2ΔIC50 in boxes below the plot, showing either mutation (dark gray or black) or wild type (light gray) status for the indicated genes. Each point is the average response of a single cell line. See Example 2. [Diagram 5]Graph of correlation of biomarker combinations with ARID1A, ARID2, and IRS4 mutation status and sensitivity to MK-2206 (anchor) + Linsitinib (library) in colon cancer cell lines. Box plots show the effect of the combination of biomarkers ARID1A mutation and ARID2. Box plots labeled "ARID1A or ARID2" show the effect of MK-2206 (anchor) + Linsitinib (library) in colon cancer cell lines with either ARID1A or ARID2 mutations (including colon cancer cell lines with ARID1A and ARID2 mutations). Box plots labeled "Other" show the effect of MK-2206 (anchor) + Linsitinib (library) in all other colon cancer cell lines. Each point is the average response of a single cell line. A two-tailed Welch t-test was performed. Box and whisker plots show the median and interquartile range. The dotted line represents the threshold above which a cell line is defined as synergistic for the combination. See Example 2. [Figure 6] 1 is a graph of the correlation of biomarker combinations with ARID1A, ARID2, and IRS4 mutation status in colon cancer cell lines and sensitivity to MK-2206 (anchor) + Linsitinib (library). Box plots show the combined effect of biomarkers ARID1A mutation, ARID2 mutation, and IRS4 wild type. The box plot labeled "ARID1A / ARID2 / IRS4 wild type" shows the effect of MK-2206 (anchor) + Linsitinib (library) in colon cancer cell lines with either ARID1A mutation or ARID2 mutation in combination with IRS4 wild type status (including colon cancer cell lines with ARID1A mutation and ARID2 mutation). The box plot labeled "Other" shows the effect of MK-2206 (anchor) + Linsitinib (library) in all other colon cancer cell lines. Each point is the average response of a single cell line. Box and whisker plots show the median and interquartile range. The dotted line represents the threshold above which a cell line is defined as synergistic for the combination. See Example 2. [Figure 7-1]Correlation of biomarker combinations with ARID1A, ARID2, and IRS4 mutation status and sensitivity to other IGF1R and Akt inhibitor combinations in colon cancer cell lines. For each combination, one Akt inhibitor was combined with one IGF1R inhibitor across a discrete 1000-fold (7-point) dose range in four colon cancer cell lines. Viability was measured using CellTiter-Glo reagent 72 h after drug treatment. Single agent and combination viability measurements were fitted for each cell line to derive multiple parameters, including range of single agent values ​​and synergy scores. For all measurements of concentration combinations, Bliss excess was calculated by comparing the observed cellular response to the combination with the response predicted from Bliss independence based on monotherapy activity. The "Bliss window" was reported as the maximum Bliss excess value measured in 25 possible 3x3 submatrix or "windows" in the 7x7 dose matrix. The Akt and IGF1R inhibitor combinations shown were: (A) BMS-536924 (IGF1R inhibitor) + afuresertib (Akt inhibitor), (B) GSK1904529A (IGF1R inhibitor) + afuresertib (Akt inhibitor), (C) GSK1904529A (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (D) linsitinib (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (E) XL228 (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (F) XL228 (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (G) XL228 (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (H) XL228 (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (I ... (F) BMS-536924 (IGF1R inhibitor) + MK-2206 (Akt inhibitor), (G) Brigutinib (IGF1R inhibitor) + MK-2206 (Akt inhibitor), (H) GSK1904529A (IGF1R inhibitor) + MK-2206 (Akt inhibitor), (I) Linsitinib (IGF1R inhibitor) + MK-2206 (Akt inhibitor), and (J) XL228 (IGF1R inhibitor) + MK-2206 (Akt inhibitor). Box plots show the combined effect of the biomarkers ARID1A mutation, ARID2 mutation, and IRS4 wild type.The box plots labeled "Biomarker +ve" show the effect of the titled IGF1R and Akt inhibitor combination in colon cancer cell lines with either ARID1A or ARID2 mutations in combination with IRS4 wild type status (including colon cancer cell lines with ARID1A and ARID2 mutations). The box plots labeled "Biomarker -ve" are all other colon cancer cell lines. Each point is a replicate, with 5-8 replicates per cell line. Box and whisker plots show median and interquartile range. See Example 3. [Figure 7-2]Correlation of biomarker combinations with ARID1A, ARID2, and IRS4 mutation status and sensitivity to other IGF1R and Akt inhibitor combinations in colon cancer cell lines. For each combination, one Akt inhibitor was combined with one IGF1R inhibitor across a discrete 1000-fold (7-point) dose range in four colon cancer cell lines. Viability was measured using CellTiter-Glo reagent 72 h after drug treatment. Single agent and combination viability measurements were fitted for each cell line to derive multiple parameters, including range of single agent values ​​and synergy scores. For all measurements of concentration combinations, Bliss excess was calculated by comparing the observed cellular response to the combination with the response predicted from Bliss independence based on monotherapy activity. The "Bliss window" was reported as the maximum Bliss excess value measured in 25 possible 3x3 submatrix or "windows" in the 7x7 dose matrix. The Akt and IGF1R inhibitor combinations shown were: (A) BMS-536924 (IGF1R inhibitor) + afuresertib (Akt inhibitor), (B) GSK1904529A (IGF1R inhibitor) + afuresertib (Akt inhibitor), (C) GSK1904529A (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (D) linsitinib (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (E) XL228 (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (F) XL228 (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (G) XL228 (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (H) XL228 (IGF1R inhibitor) + ipatasertib (Akt inhibitor), (I ... (F) BMS-536924 (IGF1R inhibitor) + MK-2206 (Akt inhibitor), (G) Brigutinib (IGF1R inhibitor) + MK-2206 (Akt inhibitor), (H) GSK1904529A (IGF1R inhibitor) + MK-2206 (Akt inhibitor), (I) Linsitinib (IGF1R inhibitor) + MK-2206 (Akt inhibitor), and (J) XL228 (IGF1R inhibitor) + MK-2206 (Akt inhibitor). Box plots show the combined effect of the biomarkers ARID1A mutation, ARID2 mutation, and IRS4 wild type.The box plots labeled "Biomarker +ve" show the effect of the titled IGF1R and Akt inhibitor combination in colon cancer cell lines with either ARID1A or ARID2 mutations in combination with IRS4 wild type status (including colon cancer cell lines with ARID1A and ARID2 mutations). The box plots labeled "Biomarker -ve" are all other colon cancer cell lines. Each point is a replicate, with 5-8 replicates per cell line. Box and whisker plots show median and interquartile range. See Example 3. [Figure 8] 1 is a graph of the correlation between ARID1A mutation status and sensitivity to MK-2206+linsitinib in ovarian and endometrial cancer cell lines. Selected ovarian cancer (A) or endometrial cancer (B) cell lines were treated with MK-2206+linsitinib. Synergy metrics delta Log2IC50 and delta Emax were generated as described in Example 5. The graph shows two independent replicates for each cell line. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0036] IGF1R inhibitors Insulin-like growth factor 1 receptor (IGF1R or 1GF-1R) is a tyrosine kinase receptor, i.e., it transmits signals by adding phosphate molecules to specific tyrosines. IGF1R consists of two alpha and two beta subunits. The IGF1R signaling pathway has been implicated in several cancers, and IGF1R is overexpressed in cancer cells, stimulating proliferation, enabling oncogenic transformation, and inhibiting apoptosis. IGF1R is believed to have anti-apoptotic properties, which allow cancer cells to resist the cytotoxic properties of chemotherapy drugs or radiation therapy.

[0037] Suitably, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, brigutinib, AXL-1717, and KW-2450, or may be an IGF1R antibody. In some cases, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, brigutinib, AXL-1717, and KW-2450. In some cases, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, brigutinib, and AXL-1717. In some cases, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924 and brigutinib. In some cases, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228 and BMS-536924. In some cases, the IGF1R inhibitor is selected from linsitinib and GSK1904529A. Preferably, the IGF1R inhibitor is linsitinib.

[0038] Linsitinib Linsitinib, also known as OSI-906, is a selective inhibitor of the insulin-like growth factor 1 receptor (IGF-1R or IGF1R) with an IC 50is 35 nM. IGF1R is overexpressed in cancer cells, stimulating proliferation, enabling oncogenic transformation, and inhibiting apoptosis. In other words, linsitinib is an IGF1Ri. Linsitinib has the following structure:

[0039] [ka]

[0040] In IUPAC nomenclature, linsitinib can be referred to as 3-[8-amino-1-(2-phenyl-7-quinolinyl)-3-imidazo[1,5-a]pyrazinyl]-1-methyl-1-cyclobutanol. Linsitinib is commercially available.

[0041] Linsitinib has an IC of 75 nM 50 It is also a potent insulin receptor (IR) inhibitor with a . Without wishing to be bound by any particular theory, the inventors theorize that its activity may be mediated through dual inhibition of these targets.

[0042] GSK1904529A GSK1904529A is also known as GSK4529. GSK1904529A is a selective inhibitor of IGF1R and IR, with an IC 50 are 27 nM and 25 nM, respectively, and are >100-fold selective for IGF1R / IR over Akt1 / 2, Aurora A / B, B-Raf, CDK2 and EGFR. GSK1904529A has the following structure:

[0043] [ka]

[0044] In IUPAC nomenclature, GSK1904529A can be referred to as N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonylpiperazin-1-yl)-1-piperidyl]anilino]pyrimidin-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-methoxy-benzamide.GSK1904529A is commercially available.

[0045] XL228 XL228 is a protein kinase inhibitor with IC50 activity against IGF1R in cell-free assays 50 XL228 also exhibits IC of 5 nM, 1.4 nM, 3.1 nM, 6.1 nM and 2 nM against wild-type ABL kinase, ABL T315I, Aurora A, SRC and LYN, respectively, in cell-free assays. 50 XL228 has the following structure:

[0046] [ka]

[0047] In IUPAC nomenclature, XL228 can be referred to as N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[(3-isopropylisoxazol-5-yl)methyl]-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine. XL228 is commercially available.

[0048] BMS-536924 BMS-536924 is also known as CS-0117. BMS-536924 is an ATP-competitive IGF1R / IR inhibitor and has an IC 50 The IC value of BMS-536924 is 100 nM / 73 nM. 50 ), Fak (IC of 150 nM 50 ) and Lck (IC of 341 nM 50), and very low activity against Akt1 and MAPK1 / 2. BMS-536924 has the following structure:

[0049] [ka]

[0050] In IUPAC nomenclature, BMS-536924 can be referred to as 4-[[2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]-3-(4-methyl-6-morpholino-1H-benzimidazol-2-yl)-1H-pyridin-2-one. BMS-536924 is commercially available.

[0051] BMS-754807 BMS-754807 is a potent and reversible IGF1R / IR inhibitor with IC 50 The IC value for Met (c-Met) is 1.8 nM / 1.7 nM. BMS-754807 has an IC value of 5.6 nM. 50 ), Aurora A / B (IC of 9nM / 25nM 50 ), TrkA / B (IC of 7.4 nM / 4.1 nM) 50 ) and Ron (IC of 44 nM 50 ), and Flt3 (IC of 170 nM). 50 ), and shows little activity against Lck, MK2, PKA, and PKC. BMS-754807 has the following structure:

[0052] [ka]

[0053] In IUPAC nomenclature, BMS-754807 can be referred to as 1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoro-3-pyridyl)-2-methyl-pyrrolidine-2-carboxamide. BMS-754807 is commercially available.

[0054] Brigutinib Brigutinib is also known as AP26113. Brigutinib is a potent and selective ALK inhibitor (IC of 0.6 nM). 50 ) and ROS1 (IC of 0.9 nM 50 Brigutinib is also an inhibitor of IGF1R (IC of 24.9 nM). 50 ), IR (IC of 196 nM 50 ) and FLT3 (IC of 2.1 nM 50 ) also inhibits. Brigutinib has the following structure:

[0055] [ka]

[0056] In IUPAC nomenclature, brigutinib can be referred to as 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]phenyl]pyrimidine-2,4-diamine. Brigutinib is commercially available.

[0057] AXL-1717 AXL-1717 is also known as AXL1717, picropodophyllin, or PPP. AXL-1717 is an IGF-1R inhibitor and is an IC 50 is 1 nM. AXL-1717 exhibits selectivity for IGF-1R, i.e., AXL-1717 is an IGF1Ri. AXL-1717 does not co-inhibit tyrosine phosphorylation of IR or a select panel of receptors less closely related to IGF-IR (e.g., FGF-R, PDGF-R, or EGF-R). AXL-1717 induces apoptosis with antitumor activity. AXL-1717 has the following structure:

[0058] [ka]

[0059] In IUPAC nomenclature, AXL-1717 can be referred to as (5R,5aR,8aS,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one. AXL-1717 is commercially available.

[0060] KW-2450 KW-2450 is an orally active multikinase inhibitor that inhibits both the insulin-like growth factor receptor (IGF-1R) and the insulin receptor (IR), and has been shown to be effective in treating chronic myocardial infarction (CCI). 50 are 7.39 nM and 5.64 nM, respectively. KW-2450 has the following structure:

[0061] [ka]

[0062] In IUPAC nomenclature, KW-2450 can be referred to as N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide. KW-2450 is commercially available.

[0063] IGF1R antibody Suitably, the IGF1R inhibitor may be an IGF1R antibody. The IGF1R antibody may be an IGF1R monoclonal antibody (mAb). IGF1R antibodies include teprotumumab (Horizon Therapeutics USA Inc, Genmab AS, Horizon Therapeutics Plc, F. Hoffmann-La Roche Ltd), AVE-1642 (Viridian Therapeutics Inc, Zenas BioPharma (USA) LLC, ImmunoGen Inc), ganitumab (Amgen Inc, Takeda Pharmaceutical Co. Ltd), dalotuzumab (Merck & Co Inc), lonigtamabu ugodotin (Acelyrin Inc), A-12 (University of Washington), VRDN-002 (Viridian Therapeutics Inc), VRDN-003 (Viridian Therapeutics Inc), ZB-011 (Zenas BioPharma (USA) LLC), BIIB-022 (Biogen Inc), cixutumumab (Eli Lilly and Co), and figitumumab (Pfizer Inc), M-590 (The University of Hong Kong), lobatumumab (Merck & Co Inc), XGFR-2 (F. Hoffmann-La Roche Ltd), XGFR-4 (F. Hoffmann-La Roche Ltd) and istiratumab (Merrimack Pharmaceuticals Inc).

[0064] Akt inhibitors The Akt signaling pathway is involved in inhibiting cellular apoptosis and stimulating cell proliferation following activation of Akt (also known as protein kinase B)-a serine / threonine kinase. Currently, three mammalian isoforms are known: Akt1 / PKB-alpha, Akt2 / PKB-beta and Akt3 / PKB-gamma.

[0065] Akt is targeted both by molecules that block its ATP-binding site and by targeting so-called allosteric (other) sites (Lazaro et al., Biochem Soc Trans. 2020 Jun 30, 48(3):933-943; Kostaras et al., Br J Cancer. 2020 Aug, 123(4):542-555). Whereas ATP-competitive Akt inhibitors (exemplified by compounds such as capivasertib, afuresertib, and ipatasertib) have predictable effects on Akt's ability to phosphorylate target proteins by simply preventing substrate access to the active site, allosteric Akt inhibitors have often diverse and less predictable effects on the function of the enzyme. MK-2206 (and other allosteric Akt inhibitors, such as milansertib and BAY1125976) bind to Akt at a site distinct from its active site, yet still exert an inhibitory effect on Akt kinase activity. This effect is believed to be due to conformational changes induced by the binding of the compound. Such conformational changes have additional effects on the activity of Akt, e.g., altering its ability to bind partner proteins. Thus, allosteric Akt inhibitors exert additional effects on target proteins compared to active site blockade.

[0066] Thus, in some cases, the Akt inhibitor is an allosteric Akt inhibitor, such as MK-2206, milansertib, and BAY1125976.

[0067] In other cases, the Akt inhibitor is an ATP-competitive Akt inhibitor, such as capivasertib, afuresertib, and ipatasertib.

[0068] Suitably, the Akt inhibitor is selected from MK-2206, capivasertib, ipatasertib, afuresertib, milansertib, uprosertib, triciribine, PTX-200, TAS-117, COTI-2, LY-2503029, MK-4440 and BAY1125976. In some cases, the Akt inhibitor is selected from MK-2206, capivasertib, ipatasertib, afuresertib, milansertib and BAY1125976. In some cases, the Akt inhibitor is selected from MK-2206, capivasertib, milansertib and BAY1125976. In some cases, the Akt inhibitor is selected from MK-2206, ipatasertib and afuresertib. Preferably, the Akt inhibitor is MK-2206.

[0069] MK-2206 MK-2206 is also known as UNII-51HZG6MP1K. MK-2206 is a pan-Akt inhibitor with an IC 50 are 8 nM / 12 nM / 65 nM for Akt1 / 2 / 3 respectively and have the following structures:

[0070] [ka]

[0071] In IUPAC nomenclature, MK-2206 can be referred to as 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one. MK-2206 is commercially available and is usually supplied and used as the dihydrochloride salt.

[0072] Capivasertib Capivasertib, also known as AZD5363, potently inhibits all isoforms of Akt (Akt1 / Akt2 / Akt3) with IC 50 is 3nM / 8nM / 8nM for Akt1 / 2 / 3, respectively. Capivasertib has the following structure:

[0073] [ka]

[0074] In IUPAC nomenclature, capivasertib can be referred to as 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxy-propyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide. Capivasertib is commercially available.

[0075] Ipatasertib Ipatasertib is also known as GDC-0068 and RG7440. Ipatasertib is a highly selective pan-Akt inhibitor with IC 50 is 5nM / 18nM / 8nM for Akt1 / 2 / 3, respectively. Ipatasertib has the following structure:

[0076] [ka]

[0077] In IUPAC nomenclature, ipatasertib can be referred to as (2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperazin-1-yl]-3-(isopropylamino)propan-1-one. Ipatasertib is commercially available.

[0078] Afuresertib Afuresertib is also known as GSK2110183 and ASB138. Afuresertib is a potent, orally bioavailable Akt inhibitor that inhibits K i is 0.08 nM / 2 nM / 2.6 nM for Akt1 / 2 / 3, respectively. Afuresertib has the following structure:

[0079] [ka]

[0080] In IUPAC nomenclature, afuresertib can be referred to as N-[(1S)-1-(aminomethyl)-2-(3-fluorophenyl)ethyl]-5-chloro-4-(4-chloro-2-methyl-pyrazol-3-yl)thiophene-2-carboxamide. Afuresertib is commercially available.

[0081] Milansertib Milansertib, also known as ARQ-092, is a potent, selective, orally bioavailable allosteric Akt inhibitor with IC 50 is 2.7 nM / 14 nM / 8.1 nM for Akt1 / 2 / 3, respectively. Miransertib has the following structure:

[0082] [ka]

[0083] In IUPAC nomenclature, milansertib can be referred to as 3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine. Milansertib is commercially available and is usually supplied and used as the hydrochloride salt.

[0084] Uprosertib Uprosertib is also known as GSK2141795, GSK795, and UPB795. Uprosertib is a selective, ATP-competitive, orally bioavailable Akt inhibitor with IC 50 are 180 nM / 328 nM / 38 nM for Akt1 / 2 / 3, respectively. Uprosertib has the following structure:

[0085] [ka]

[0086] In IUPAC nomenclature, uprosertib can be referred to as N-[(2S)-1-amino-3-(3,4-difluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-2-methylpyrazol-3-yl)furan-2-carboxamide. Uprosertib is commercially available.

[0087] Triciribine Triciribine is also known as NSC154020, VD-0002, vqd-002, API-2 and TCN. Triciribine is a DNA synthesis inhibitor, but also inhibits Akt in PC3 cell lines (human prostate cancer cell lines), and has been shown to be effective in treating rheumatoid arthritis. 50 is 130 nM. Triciribine has the following structure:

[0088] [ka]

[0089] In the IUPAC nomenclature, triciribine is (2R,3R,4S,5R)-2-(5-amino-7-methyl-2,6,7,9,11-pentazatricyclo[6.3.1.0 4,12 ]dodeca-1(12),3,5,8,10-pentaen-2-yl)-5-(hydroxymethyl)oxolane-3,4-diol. Triciribine is commercially available and can be supplied and used as the phosphate salt, PTX-200, described below.

[0090] PTX-200 PTX-200 is also known as triciribine phosphate, tricycloside phosphate, and TCN-P. PTX-200 is the phosphate salt of triciribine described above, which inhibits Akt in PC3 cell lines (human prostate cancer cell lines) and increases IC 50 is 130 nM. PTX-200 has the following structure:

[0091] [ka]

[0092] In the IUPAC nomenclature, PTX-200 is [(2R,3S,4R,5R)-5-(5-amino-7-methyl-2,6,7,9,11-pentazatricyclo[6.3.1.0 4,12 [dodeca-1(12),3,5,8,10-pentaen-2-yl)-3,4-dihydroxyoxolan-2-yl]methyl-dihydrogenphosphate. PTX-200 is commercially available and may be supplied and used as the monohydrate, sometimes referred to as TCN-PM.

[0093] TAS-117 TAS-117 is a potent, selective, orally active allosteric Akt inhibitor with IC 50 are 4.8nM / 1.6nM / 44nM for Akt1 / 2 / 3, respectively. TAS-117 induces antimyeloma activity and enhances lethal endoplasmic reticulum (ER) stress induced by proteasome inhibition. TAS-117 induces apoptosis and autophagy. TAS-117 has the following structure:

[0094] [ka]

[0095] In the IUPAC nomenclature, TAS-117 is 3-amino-1-methyl-3-[4-(5-phenyl-8-oxa-3,6,12-triazatricyclo[7.4.0.0 2,6 TAS-117 can be referred to as ]trideca-1(9),2,4,10,12-pentaen-4-yl)phenyl]cyclobutan-1-ol. TAS-117 is commercially available and may be supplied and used as the hydrochloride salt.

[0096] COTI-2 COTI-2, a low-toxicity anticancer drug, is an orally available third-generation thiosemicarbazone that is an activator of a mutant form of the p53 protein and has potential antineoplastic activity. COTI-2 acts by both reactivating mutant p53 and inhibiting the PI3K / Akt / mTOR pathway. COTI-2 induces apoptosis in multiple human tumor cell lines. COTI-2 exhibits antitumor activity in HNSCC through p53-dependent and -independent mechanisms. COTI-2 converts mutant p53 to the wild-type conformation. COTI-2 has the following structure:

[0097] [ka]

[0098] In IUPAC nomenclature, COTI-2 can be referred to as N-[(Z)-6,7-dihydro-5H-quinolin-8-ylideneamino]-4-pyridin-2-ylpiperazine-1-carbothioamide. COTI-2 is commercially available.

[0099] LY-2503029 LY-2503029 (Eli Lilly and Co) is a protein kinase B (Akt) inhibitor. LY-2503029 binds to and inhibits the activity of Akt, resulting in inhibition of the PI3K / Akt signaling pathway leading to tumor cell proliferation and induction of tumor cell apoptosis.

[0100] MK-4440 MK-4440 (Merck & Co Inc) is also known as MK4440, ARQ751 and bevolisertib. MK-4440 is an orally active, potent and selective pan-AKT serine / threonine kinase inhibitor with IC 50are 0.55 nM / 0.81 nM / 1.31 nM for Akt1 / 2 / 3, respectively. MK-4440 is in development for the treatment of cancer. In particular, MK-4440 can be used as a single agent or in combination with other anticancer drugs to study solid tumors with PIK3CA / Akt / PTEN mutations. MK-4440 has the following structure:

[0101] [ka]

[0102] In IUPAC nomenclature, MK-4440 can be referred to as N-[1-[3-[3-[4-(1-aminocyclobutyl)phenyl]-2-(2-aminopyridin-3-yl)imidazo[4,5-b]pyridin-5-yl]phenyl]piperidin-4-yl]-N-methylacetamide. MK-4440 is commercially available.

[0103] BAY1125976 BAY1125976 is a selective allosteric Akt1 / Akt2 inhibitor. BAY1125976 inhibits the activity of Akt1 and Akt2 and has an IC 50 The values ​​are 5.2 nM and 18 nM, respectively, at 10 μM ATP. BAY1125976 has the following structure:

[0104] [ka]

[0105] In IUPAC nomenclature, BAY1125976 can be referred to as 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-imidazo[1,2-b]pyridazine-6-carboxamide. BAY1125976 is commercially available.

[0106] Specific IGF1R and Akt Inhibitor Combinations In some cases, the combination of an IGF1R inhibitor with an Akt inhibitor for use in the treatment methods described herein can be a combination of a specific IGF1R inhibitor and an Akt inhibitor.

[0107] In some cases, the combination is linsitinib (IGF1R inhibitor) and MK-2206 (Akt inhibitor), BMS-754807 (IGF1R inhibitor) and MK-2206 (Akt inhibitor), GSK1904529A (IGF1R inhibitor) and MK-2206 (Akt inhibitor), XL228 (IGF1R inhibitor) and MK-2206 (Akt inhibitor), BMS-536924 (IGF1R inhibitor) and afuresertib (Akt inhibitor), BMS-536924 (IGF1R inhibitor) and MK-2206 (Akt inhibitor), brigutinib (IGF1R inhibitor), F1R inhibitor) and MK-2206 (Akt inhibitor), linsitinib (IGF1R inhibitor) and ipatasertib (Akt inhibitor), linsitinib (IGF1R inhibitor) and BAY1125976 (Akt inhibitor), linsitinib (IGF1R inhibitor) and capivasertib (Akt inhibitor), linsitinib (IGF1R inhibitor) and milansertib (Akt inhibitor), XL228 (IGF1R inhibitor) and ipatasertib (Akt inhibitor), GSK1904529A (IGF1R inhibitor) and ipatasertib (Akt inhibitor), GSK1904 529A (IGF1R inhibitor) and afuresertib (Akt inhibitor), linsitinib (IGF1R inhibitor) and afuresertib (Akt inhibitor), BMS-536924 (IGF1R inhibitor) and ipatasertib (Akt inhibitor), BMS-536924 (IGF1R inhibitor) and milansertib (Akt inhibitor), BMS-536924 (IGF1R inhibitor) and capivasertib (Akt inhibitor), BMS-536924 (IGF1R inhibitor) and BAY1125976 (Akt inhibitor), GSK1904529A (IGF1R inhibitor) and milansertib (Akt inhibitor), GSK1904529A (IGF1R inhibitor) and capivasertib (Akt inhibitor), GSK1904529A (IGF1R inhibitor) and BAY1125976 (Akt inhibitor), AXL-1717 (IGF1R inhibitor) and MK-2206 (Akt inhibitor), AXL-1717 (IGF1R inhibitor) and afuresertib (Akt inhibitor), AXL-1717 (IGF1R inhibitor) and ipatasertib (Akt inhibitor), AXL-1717 (IGF1R inhibitor) and milansertib (Akt inhibitor),The therapeutic agent may be selected from AXL-1717 (IGF1R inhibitor) and capivasertib (Akt inhibitor), and AXL-1717 (IGF1R inhibitor) and BAY1125976 (Akt inhibitor).

[0108] In some cases, the combinations include linsitinib (IGF1R inhibitor) and MK-2206 (Akt inhibitor), BMS-754807 (IGF1R inhibitor) and MK-2206 (Akt inhibitor), GSK1904529A (IGF1R inhibitor) and MK-2206 (Akt inhibitor), XL228 (IGF1R inhibitor) and MK-2206 (Akt inhibitor), BMS-536924 (IGF1R inhibitor) and afuresertib (Akt inhibitor), BMS-536924 (IGF1R inhibitor) and MK-2206 (Akt inhibitor), brigutinib (IGF1R inhibitor) and MK-2206 (Akt inhibitor). , linsitinib (IGF1R inhibitor) and ipatasertib (Akt inhibitor), linsitinib (IGF1R inhibitor) and BAY1125976 (Akt inhibitor), linsitinib (IGF1R inhibitor) and capivasertib (Akt inhibitor), linsitinib (IGF1R inhibitor) and milansertib (Akt inhibitor), XL228 (IGF1R inhibitor) and ipatasertib (Akt inhibitor), GSK1904529A (IGF1R inhibitor) and ipatasertib (Akt inhibitor), and GSK1904529A (IGF1R inhibitor) and afuresertib (Akt inhibitor).

[0109] In some cases, the combinations include linsitinib (IGF1R inhibitor) and MK-2206 (Akt inhibitor), GSK1904529A (IGF1R inhibitor) and MK-2206 (Akt inhibitor), XL228 (IGF1R inhibitor) and MK-2206 (Akt inhibitor), BMS-536924 (IGF1R inhibitor) and MK-2206 (Akt inhibitor), BMS-536924 (IGF1R inhibitor) and afuresertib (Akt inhibitor). , brigutinib (IGF1R inhibitor) and MK-2206 (Akt inhibitor), linsitinib (IGF1R inhibitor) and ipatasertib (Akt inhibitor), XL228 (IGF1R inhibitor) and ipatasertib (Akt inhibitor), GSK1904529A (IGF1R inhibitor) and ipatasertib (Akt inhibitor), and GSK1904529A (IGF1R inhibitor) and afuresertib (Akt inhibitor).

[0110] In some cases, the combination can be selected from linsitinib (an IGF1R inhibitor) and MK-2206 (an Akt inhibitor), BMS-754807 (an IGF1R inhibitor) and MK-2206 (an Akt inhibitor), and GSK1904529A (an IGF1R inhibitor) and MK-2206 (an Akt inhibitor).

[0111] In some cases, the combination can be selected from linsitinib (IGF1R inhibitor) and MK-2206 (Akt inhibitor), linsitinib (IGF1R inhibitor) and BAY1125976 (Akt inhibitor), linsitinib (IGF1R inhibitor) and capivasertib (Akt inhibitor), and linsitinib (IGF1R inhibitor) and milansertib (Akt inhibitor).

[0112] In some cases, the combination is linsitinib (IGF1R inhibitor) and MK-2206 (Akt inhibitor). In some cases, the combination is BMS-754807 (IGF1R inhibitor) and MK-2206 (Akt inhibitor). In some cases, the combination is GSK1904529A (IGF1R inhibitor) and MK-2206 (Akt inhibitor). In some cases, the combination is XL228 (IGF1R inhibitor) and MK-2206 (Akt inhibitor). In some cases, the combination is BMS-536924 (IGF1R inhibitor) and afuresertib (Akt inhibitor). In some cases, the combination is BMS-536924 (IGF1R inhibitor) and MK-2206 (Akt inhibitor). In some cases, the combination is brigutinib (IGF1R inhibitor) and MK-2206 (Akt inhibitor). In some cases, the combination is linsitinib (IGF1R inhibitor) and ipatasertib (Akt inhibitor). In some cases, the combination is linsitinib (IGF1R inhibitor) and BAY1125976 (Akt inhibitor). In some cases, the combination is linsitinib (IGF1R inhibitor) and capivasertib (Akt inhibitor). In some cases, the combination is linsitinib (IGF1R inhibitor) and milansertib (Akt inhibitor). In some cases, the combination is XL228 (IGF1R inhibitor) and ipatasertib (Akt inhibitor). In some cases, the combination is GSK1904529A (IGF1R inhibitor) and ipatasertib (Akt inhibitor). In some cases, the combination is GSK1904529A (IGF1R inhibitor) and afuresertib (Akt inhibitor). In some cases, the combination is linsitinib (IGF1R inhibitor) and afuresertib (Akt inhibitor). In some cases, the combination is BMS-536924 (IGF1R inhibitor) and ipatasertib (Akt inhibitor). In some cases, the combination is BMS-536924 (IGF1R inhibitor) and milansertib (Akt inhibitor). In some cases, the combination is BMS-536924 (IGF1R inhibitor) and capivasertib (Akt inhibitor). In some cases, the combination is BMS-536924 (IGF1R inhibitor) and BAY1125976 (Akt inhibitor).In some cases, the combination is GSK1904529A (IGF1R inhibitor) and milansertib (Akt inhibitor). In some cases, the combination is GSK1904529A (IGF1R inhibitor) and capivasertib (Akt inhibitor). In some cases, the combination is GSK1904529A (IGF1R inhibitor) and BAY1125976 (Akt inhibitor). In some cases, the combination is AXL-1717 (IGF1R inhibitor) and MK-2206 (Akt inhibitor). In some cases, the combination is AXL-1717 (IGF1R inhibitor) and afuresertib (Akt inhibitor). In some cases, the combination is AXL-1717 (IGF1R inhibitor) and ipatasertib (Akt inhibitor). In some cases, the combination is AXL-1717 (IGF1R inhibitor) and milansertib (Akt inhibitor). In some cases, the combination is AXL-1717 (IGF1R inhibitor) and capivasertib (Akt inhibitor). In some cases, the combination is AXL-1717 (IGF1R inhibitor) and BAY1125976 (Akt inhibitor).

[0113] Thus, a combination for use in the treatment methods described herein can be a combination of linsitinib and MK-2206.

[0114] Pharmaceutically acceptable salts As described herein, any compound may be provided as a pharmaceutically acceptable salt, hydrate or solvate (solvate). Suitable pharmaceutically acceptable salts are known in the art and are described, for example, in Berge et al., J Pharm Sci, 1977 66(1) p. 1.

[0115] Administration of the active ingredient The compound used in the method of the present invention can be administered by any suitable route, including oral and intravenous routes.It is understood that oral administration may be preferred.The compound can be provided in a pharmaceutical composition that includes the compound and one or more pharma-ceutically acceptable excipients.The formulation for oral administration can be in the form of a tablet or a capsule that contains powder or liquid.

[0116] Administration is preferably in a "therapeutically effective amount" or "effective amount" (used interchangeably) sufficient to show benefit to an individual. The actual amount administered, as well as the rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment, such as determining dosage, is within the responsibility of general practitioners and other physicians, and typically takes into account the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration, and other factors known to physicians. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins.

[0117] Suitable dosing regimens may be based on those previously used in clinical trials and / or approved regimens.

[0118] For example, linsitinib was previously administered orally to patients as a single agent at a dose of 150 mg twice daily during Phase I clinical trials (Fassnacht et al., Lancet Oncol., April 2015, 16(4):426-435). The recommended dose of linsitinib for Phase II trials was 150 mg twice daily (Puzanov et al., Clin Cancer Res., February 15, 2015, 21(4):701-711). Linsitinib has also been administered at a dose of 400-450 mg daily in combination with irinotecan (a TOP1 inhibitor, Davis et al., Oncologist, December 2018, 23(12):1409-e140), with treatment administered in cycles with linsitinib administered on days 1-3 every 7 days.

[0119] XL228 was administered by 1-hour IV infusion once or twice weekly in patients with Ph+ leukemia harboring the T315I mutation or resistant or intolerant to at least two prior BCR-ABL inhibitor therapies. Dose levels tested to date include 0.45, 0.9, 1.8, 3.6, 7.2, and 10.8 mg / kg once weekly, and 3.6 mg / kg twice weekly (https: / / ir.exelixis.com / news-releases / news-release-details / exelixis-reports-positive-phase-1-data-xl228-ash-annual-meeting). XL228 has also been administered by weekly IV infusion at a maximum tolerated dose (MTD) of 6.5 mg / kg in patients with solid tumors or multiple myeloma (Smith et al., Journal of Clinical Oncology 2010 28:15_suppl, 3105-3105).

[0120] In a phase II study with a 7-day lead-in of 90 mg once daily (QD) in patients with ALK-positive, advanced non-small cell lung cancer, brigutinib was administered at 180 mg QD until patients experienced objective disease progression according to Response Evaluation Criteria in Solid Tumors. Upon radiological progression, patients receiving brigutinib 180 mg QD who experienced grade 2 or less toxicity on treatment had the option to escalate the brigutinib dose to 240 mg QD at the investigator's discretion (Kim et al., Future Oncology 2021 17:14, pp. 1709-1719).

[0121] AXL-1717 was administered as a twice-daily (BID) treatment at a dose of either 300 or 400 mg of AXL-1717 in patients with previously treated, locally advanced or metastatic non-small cell lung cancer (58 patients) (Bergqvist et al., Acta Oncologica, 56:3, pp. 441-447, DOI:10.1080 / 0284186X.2016.1253866).

[0122] KW-2450 was administered in combination with lapatinib (a dual tyrosine kinase inhibitor) and letrozole (an aromatase inhibitor) to patients with advanced / metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in a Phase I study using doses of 25 mg / day KW-2450 plus 1500 mg / day lapatinib and 2.5 mg / day letrozole (Umehara et al., Therapeutic Advances in Medical Oncology. 2018, 10. Doi:10.1177 / 1758835918786858).

[0123] MK-2206 has been administered to patients every other day at doses of 30 mg, 60 mg, 75 mg, and 90 mg (Yap et al., J Clin Oncol., 2011 Dec. 10, 29(35):4688-4695). In another study, patients were given 200 mg of MK-2206 once a week (Xing et al., Breast Cancer Res., 2019 Jul. 5, 21(1):78). MK-2206 has also been administered orally at a dose of 135 mg once a week in combination with selumetinib (a protein kinase inhibitor; Chung et al., JAMA Oncol., 2017 Apr. 1, 3(4), 516-522).

[0124] Capivasertib was administered in a Phase III, double-blind, randomized study evaluating the efficacy of capivasertib and fulvestrant (a hormone therapy drug) in the treatment of patients with locally advanced (inoperable) or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ / HER2-) breast cancer following recurrence or progression during or after aromatase inhibitor (AI) therapy. Capivasertib was administered at 400 mg BID (2 oral tablets) on an intermittent weekly dosing schedule administered on days 1-4 of each week of a 28-day treatment cycle (https: / / clinicaltrials.gov / ct2 / show / NCT04305496). Capivasertib has also been administered orally at 320 mg twice daily on a 4-day-on / 3-day-off schedule starting on day 2 of each 21-day cycle in a phase II study in patients with castration-resistant prostate cancer (Crabb et al., J Clin Oncol. 2021 Jan 20; 39(3): 190-201).

[0125] Ipatasertib has been administered in a Phase II clinical trial at 400 mg once daily on days 1-21 of a 28-day cycle in patients with cancers with a high prevalence of PI3K / Akt pathway activation, including triple-negative breast cancer (TNBC), along with paclitaxel (a chemotherapy drug) (Kim et al., The Lancet Oncology, Volume 18, Issue 10, 2017, pp. 1360-1372 and Oliveira et al., Ann Oncol, 1 Aug 2019, 30(8), pp. 1289-1297. Doi: 10.1093 / annonc / mdz177).

[0126] Afuresertib has been administered with both carboplatin (a chemotherapy drug) and paclitaxel (another chemotherapy drug) in patients with recurrent platinum-resistant ovarian cancer in a Phase IB dose-escalation study, using continuous oral doses of afuresertib of 50-150 mg per day (Blagden et al., Clin Cancer Res (2019) 25 (5), pp. 1472-1478). Afuresertib has also been administered at 25-150 mg per day in patients with multiple myeloma in a Phase I study, evaluating the maximum tolerated dose (MTD), which was observed to be 125 mg per day (Spencer et al., Blood (2014) 124 (14): pp. 2190-2195).

[0127] Milansertib has been administered in combination with anastrozole (hormonal therapy) at either 200 mg QD 5 days on / 9 days off or 150 mg QD 5 days on / 9 days off in patients with PIK3CA and Akt1 mutated ER+ endometrial and ovarian cancer in a phase IB study (Hyman et al., Cancer Res (2018) 78 (13_Supplement): CT035, https: / / doi.org / 10.1158 / 1538-7445.AM2018-CT035). Milansertib has also been administered at 10 mg daily (approximately 5 mg / m2) in patients with Proteus syndrome. 2 / day) orally, and this is increased to 30 mg / day (approximately 15 mg / m 2 / day), then after 3 months of treatment, 50 mg / day (approximately 25 mg / m 2 / day) (Biesecker et al., Cold Spring Harb Mol Case Study, 2020 Feb 3, 6(1):a004549, doi:10.1101 / mcs.a004549). A Phase I study in hematological malignancies also showed that milansertib was administered QD 15 mg / m 2 which is then administered at a maximum dose of 25 mg / m 2(https: / / www.drugdiscoverytrends.com / arqule-reports-positive-phase-i-data-in-haematological-malignancies-study / ).

[0128] Uprosertib has been administered at 50 mg QD in combination with trametinib (a MEK1 / MEK2 inhibitor) in patients with solid tumors deemed sensitive to MEK and / or Akt inhibition in a Phase I dose-escalation study (Tolcher et al., Cancer Chemother Pharmacol, 2020, 85(4), 673-683). Uprosertib has also been administered orally at doses up to 75 mg once daily in combination with dabrafenib (an anticancer drug, a B-Raf inhibitor) and trametinib (a MEK1 / MEK2 inhibitor) in patients with stage IIIC-IV BRAF-mutated cancer (https: / / clinicaltrials.gov / ct2 / show / NCT01902173).

[0129] PTX-200 was administered at 35 mg with 80 mg paclitaxel weekly in patients with locally advanced, HER2-negative breast cancer in a Phase 2a trial (https: / / smallcaps.com.au / prescient-therapeutics-encouraging-efficacy-results-leading-cancer-drug-candidate-ptx-200 / ). PTX-200 has also been administered at 25-55 mg / m2 intravenously over 1 hour in combination with cytarabine in patients with relapsed or refractory acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or chronic myeloid leukemia (CML). 2 dose (15 mg / m2 if necessary) 2 The study was administered at a dose of 10 mg / kg / day (reduced to 10 mg / kg / day) in a randomized controlled trial (https: / / clinicaltrials.gov / ct2 / show / study / NCT02930109).

[0130] COTI-2 is being evaluated in a Phase 1b / 2a trial at 60 mg / m in patients with solid tumors including ovarian, fallopian tube, primary peritoneal, endometrial, cervical, lung, pancreatic or colorectal cancer, or head and neck squamous cell carcinoma. 2 It was administered orally at doses of 0.5–3.5 mg / kg, 5 days per week every 3 weeks in combination with IV doses of cisplatin (https: / / www.globenewswire.com / en / news-release / 2019 / 05 / 08 / 1819580 / 0 / en / Cotinga-Pharmaceuticals-Releases-Early-Interim-Data-of-Phase-1b-2a-Combination-Trial-of-COTI-2-in-Solid-Tumors.html).

[0131] BAY1125976 inhibited AKT1 in a Phase I study E17K It was administered orally at 60 mg BID in patients with hormone receptor-positive metastatic breast cancer, including nine patients with mutations (Schneeweiss et al., Cancers 2019, 11(12), 1987, https: / / doi.org / 10.3390 / cancers11121987).

[0132] Suitable dosing regimens for other IGF1R inhibitors (e.g., GSK1904529A, BMS-536924, and BMS-754807) and Akt inhibitors (e.g., TAS-117, LY-2503029, and MK-4440) are also described in the art.

[0133] Thus, the active ingredients described herein can be administered in a dosage of about 1 mg to about 1000 mg, for example, about 5 mg to about 700 mg, for example, about 10 mg to about 500 mg. The dosage can depend on the administration schedule.

[0134] In some embodiments, each dose of the IGF1R inhibitor may be administered at a dosage of about 1 mg to about 1000 mg, such as about 50 mg to about 600 mg, such as about 100 mg to about 500 mg, such as about 150 mg to about 450 mg. In some embodiments, the IGF1R inhibitor may be administered at a dosage of about 150 mg. The IGF1R inhibitor administered at the above dosages may be selected from linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, AXL-1717 and KW-2450, or an IGF1R antibody, as described herein.

[0135] In some embodiments, each dose of the Akt inhibitor can be administered at a dosage of about 1 mg to about 1000 mg, such as about 10 mg to about 500 mg, such as about 30 mg to about 300 mg, such as about 60 mg to about 200 mg. The Akt inhibitor administered at the dosages above can be selected from MK-2206, capivasertib, ipatasertib, afuresertib, milansertib, uprosertib, triciribine, PTS-200, TAS-117, COTI-2, LY-2503029, MK-4440, and BAY1125976, as described herein.

[0136] When administered in combination, the active ingredients described herein can be administered simultaneously or sequentially.In some embodiments of the combination therapy described herein, the IGF1R inhibitor and the Akt inhibitor are administered sequentially.In some embodiments, the active ingredients are administered in parallel treatment cycles or regimens, so that there are days when only one of the drugs is administered.

[0137] Each of the active ingredients described herein can be administered independently, either orally or parenterally.

[0138] In some embodiments, the IGR1R inhibitor can be administered orally. For example, an IGF1R inhibitor, such as linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, brigutinib, AXL-1717, or KW-2450, can be administered orally.

[0139] In some embodiments, linsitinib can be administered orally. In some embodiments, GSK1904529A inhibitors can be administered orally. In some embodiments, XL228 can be administered orally. In some embodiments, BMS-536924 can be administered orally. In some embodiments, BMS-754807 can be administered orally. In some embodiments, brigutinib can be administered orally. In some embodiments, AXL-1717 can be administered orally. In some embodiments, KW-2450 can be administered orally.

[0140] In some embodiments, the Akt inhibitor can be administered orally. For example, the Akt inhibitor, such as MK-2206, capivasertib, ipatasertib, afuresertib, milansertib, uprosertib, triciribine, PTX-200, TAS-117, COTI-2, LY-2503029, MK-4440, or BAY1125976, can be administered orally.

[0141] In some embodiments, the MK-2206 agent can be administered orally. In some embodiments, capivasertib can be administered orally. In some embodiments, ipatasertib can be administered orally. In some embodiments, afuresertib can be administered orally. In some embodiments, milansertib can be administered orally. In some embodiments, uprosertib can be administered orally. In some embodiments, triciribine can be administered orally. In some embodiments, PTX-200 can be administered orally. In some embodiments, TAS-117 can be administered orally. In some embodiments, COTI-2 can be administered orally. In some embodiments, LY-2503029 can be administered orally. In some embodiments, MK-4440 can be administered orally. In some embodiments, BAY1125976 can be administered orally.

[0142] Each of the active ingredients described herein can be independently administered daily, for example, once a day (QD), twice a day (BID), three times a day (TID), or four times a day (QID), or can be administered less frequently, for example, every other day or on certain days of a 7-day or 21-day cycle. Such treatment cycles are frequently used in chemotherapy treatments.

[0143] Suitably, the patient may be a human patient.

[0144] Cancer type The present invention relates to a method for the treatment of cancer in a patient, in particular the treatment of intestinal (colon) cancer, ovarian cancer and / or endometrial cancer. Thus, in some embodiments, the present invention relates to the treatment of colon cancer (or colorectal cancer) in a patient. Alternatively, in some embodiments, the present invention relates to the treatment of ovarian cancer in a patient. Alternatively, in some embodiments, the present invention relates to the treatment of endometrial cancer in a patient.

[0145] Preferably, the cancer is colon cancer.

[0146] In some aspects of the present invention, the cancer can be KRAS mutant cancer.In the aspect of the present invention, the cancer is colon cancer, the colon cancer can be KRAS mutant colon cancer.In the aspect of the present invention, the cancer is ovarian cancer, the ovarian cancer can be KRAS mutant ovarian cancer.In the aspect of the present invention, the cancer is endometrial cancer, the endometrial cancer can be KRAS mutant endometrial cancer.

[0147] In some aspects of the invention, the cancer may be ARID1A mutated and / or ARID2 mutated cancer, and optionally IRS4 wild type cancer. In aspects of the invention where the cancer is colon cancer, the colon cancer may be ARID1A mutated and / or ARID2 mutated colon cancer, and optionally IRS4 wild type colon cancer. In aspects of the invention where the cancer is ovarian cancer, the ovarian cancer may be ARID1A mutated and / or ARID2 mutated ovarian cancer, and optionally IRS4 wild type ovarian cancer. In aspects of the invention where the cancer is endometrial cancer, the endometrial cancer may be ARID1A mutated and / or ARID2 mutated endometrial cancer, and optionally IRS4 wild type endometrial cancer.

[0148] KRAS mutations Suitably, in some aspects of the present invention, the cancer is a KRAS mutant cancer. In some aspects of the present invention, the cancer is colon cancer, the colon cancer is a KRAS mutant colon cancer. In some aspects of the present invention, the cancer is ovarian cancer, the ovarian cancer is a KRAS mutant ovarian cancer. In some aspects of the present invention, the cancer is endometrial cancer, the endometrial cancer is a KRAS mutant endometrial cancer.

[0149] In other words, tumors are classified as having a KRAS mutation by genomic profiling. The KRAS (Kirsten Rat Sarcoma Virus) gene is an oncogene. The HUGO Human Genome Nomenclature Committee symbol report for KRAS can be found at www.genenames.org, which provides a link to its nucleotide sequence.

[0150] KRAS mutations are thought to be associated with approximately 40% of colorectal cancers and can be determined by tests known in the art. Many methods involve the use of PCR to amplify the appropriate region of the KRAS gene, including exons 2 and 3, and then utilize different methods to distinguish wild-type from mutant sequences at key codons, such as 12, 13, and 61. Detection methods include nucleic acid sequencing, allele-specific PCR, single-strand conformation polymorphism analysis, melting curve analysis, and probe hybridization. Tests for detecting KRAS mutations, such as the Cobas® KRAS Mutation Test (Roche) and Therascreen KRAS RGQ PCR Kit (Qiagen), are FDA approved (https: / / www.fda.gov / medical-devices / in-vitro-diagnostics / list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools).

[0151] In other words, a KRAS mutant cancer is a cancer that contains cells that harbor or contain an activated KRAS mutation. It is understood that patients with colorectal cancer currently routinely undergo KRAS mutation analysis.

[0152] As can be seen from Example 1, the inventors observed favorable potency and efficacy for the claimed combination in colon cancer cells, particularly in the KRAS mutant patient population.

[0153] ARID1A and ARID2 The AT-rich interacting domain (ARID) family is a superfamily that belongs to the switch / sucrose non-fermenting (SWI / SNF) chromatin remodeling complexes, a subfamily of ATP-dependent chromatin remodeling complexes found in eukaryotes (Zhu et al., Cancer Biology & Therapy, 2022, Vol. 23, No. 1, pp. 104-111). The ARID family consists of a set of members that are involved in fundamental processes of cellular function, including modification of chromatin structure and regulation of target gene transcription. All members of the ARID family contain a DNA-binding domain through which they can bind to target DNA and participate in the processes of DNA replication, gene expression, and cell growth, differentiation, and development.

[0154] AT-rich interaction domain 1A (ARID1A, sometimes called BAF250a) is a non-catalytic, DNA-binding subunit of the human SWI / SNF complex (chromatin remodeling complex) (Tessiri et al., Peer J, 2022, 10:e12750; Mullen et al., Cancer Treatment Reviews, 2021, 100, 102287). ARID1A is thought to play an important role in crucial cellular processes including transcription, DNA replication and DNA damage repair. A review by Mittal et al. (Mittal et al., 2020, Nat Rev Clin Oncol., 2020 July 17 (7):435-448) references papers showing that the ATP-dependent chromatin remodeler SMARCA4 (also known as the transcriptional activator BRG1) and ARID1A are recruited to sites of DNA damage and aid in homologous recombination (HR)-mediated DNA repair and non-homologous end joining (NHEJ). ARID1A is also thought to interact with the DNA mismatch repair protein Msh2 (MutS homolog 2 or MSH2).

[0155] Mutations in ARID1A induce changes in the expression of multiple genes (e.g., cyclin-dependent kinase inhibitor 1A (CDKN1A), mother's against decapentaplegic homolog 3 (SMAD family member 3 or SMAD3), DNA mismatch repair protein Mlh1 (MutL protein homolog 1 or MLH1), and phosphoinositide 3 kinase interacting protein 1 (PIK3IP1)) through chromatin remodeling dysfunction, which contributes to cancer development and causes cell transformation associated with the phosphoinositide 3 kinase (PI3K) / protein kinase B (PKB or Akt) pathway (i.e., the PI3K / Akt pathway) (Takeda et al., Oncology Reports, 2016, 35:607-613). Mutations in ARID1A impair DNA mismatch repair and can lead to increased mutational burden (TMB), programmed cell death ligand 1 (PD-L1) expression, cytotoxic T lymphocyte (CTL) infiltration, and increased sensitivity to checkpoint inhibitors. For example, mutations in ARID1A have been associated with poly(ADP-ribose) polymerase (PARP) inhibitors (i.e., PARPi), as well as ataxia telangiectasia and sensitivity to Rad3-related protein (ATR) inhibitors (i.e., ATRi).

[0156] ARID1A is a frequently mutated tumor suppressor. Mutations in ARID1A have been associated with various cancers, such as ovarian clear cell carcinoma (Mittal et al., 2020, Nat Rev Clin Oncol., 2020 July 17 (7): 435-448), endometriosis-associated ovarian cancer (Samartzis et al., Int. J. Mol. Sci., 2013, 14, 188824-18849), endometrial cancer (Takeda et al., Oncology Reports, 2016, 35: 607-613), and cholangiocarcinoma (also known as cholangiocarcinoma, via activation of the PI3K / Akt pathway, Tessiri et al., Peer J, 2022, 10: e12750). In particular, ARID1A is mutated in 9% of colorectal cancers (Mullen et al., Cancer Treatment Reviews, 2021, 100, 102287), and ARID1A is mutated in more than 50% of all ovarian clear cell carcinomas and ovarian endometrial cancers. ARID1A-mutated breast and endometrial cancers are associated with increased PI-3K and Akt signaling and sensitivity to PI-3K and Akt inhibitors (Takeda et al., Oncology Reports, 2016, 35: 607-613). Co-occurrence of ARID1A alterations with PI3K / Akt pathway activation has been reported in ovarian clear cell carcinoma, breast cancer and gastric cancer (Huang et al., Mod Pathol, July 2014; 27(7):983-90; Samartzis et al., Oncotarget. July 30, 2014; 5(14):5295-303; Zhang et al., Oncotarget. July 19, 2016; 7(29):46127-46141; De and Dey, Int J Mol Sci. November 15, 2019; 20(22):5732).

[0157] Loss of ARID1A is associated with activation of the PI-3K / Akt / mTOR pathway (Mullen et al., Cancer Treatment Reviews, 2021, 100, 102287). Loss of ARID1A expression also leads to delayed mitosis and chromosome segregation. Silencing of ARID1A in gastric, ovarian, glioma and colon cancer cells has been shown to activate phosphorylation of Akt and PI3K (Zeng et al., Head & Neck Oncology. 2013;5(1):6; Xie et al., Tumour Biol. 2014 Aug;35(8):7921-7; Takeda et al., Oncology Reports 2016;35: 607-613; Zhang et al., Oncotarget. 2016 Jul. 19;7(29):46127-46141), suggesting a correlation between ARID1A deficiency and PI3K / Akt pathway activation.

[0158] Interestingly, rhabdoid tumors and ARID1A-mutated ovarian cell carcinomas depend on RTK signaling, including platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and Met.

[0159] AT-rich interacting domain 2 (ARID2, sometimes called BAF200) is a homologous subunit of the human SWI / SNF complex and also binds DNA (Mullen et al., Cancer Treatment Reviews, 2021, 100, 102287). ARID2 is a subunit of the PBAF chromatin remodeling complex (part of the SWI / SNF complex family) and promotes ligand-dependent transcriptional activation by nuclear receptors. Mutational studies have revealed that ARID2 is a key tumor suppressor in numerous cancer subtypes. ARID2 mutations have also been associated with various cancers, particularly frequent in hepatocellular carcinoma and melanoma. ARID2 mutations occur in urothelial carcinoma and melanoma, and patients may benefit from immune checkpoint inhibitors.

[0160] Without wishing to be bound by any particular theory, the present inventors have observed that ARID1A mutation and / or ARID2 mutation colon cancer is particularly sensitive to the treatment of IGF1R inhibitor combined with Akt inhibitor.Therefore, the present inventors believe that ARID1A or ARID2 mutation may provide a strong genetic biomarker for efficacy in colon cancer patients.See, for example, Example 2 and Figure 5.

[0161] IRS4 The insulin receptor substrate 4 (IRS4) gene encodes the IRS4 protein in humans. The IRS4 protein is a cytoplasmic protein that contains multiple potential tyrosine and serine / threonine phosphorylation sites. The IRS4 protein is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation.

[0162] Without wishing to be bound by any particular theory, the present inventors have also observed that ARID1A mutant and / or ARID2 mutant colon cancers that are also IRS4 wild-type colon cancers are particularly sensitive to treatment with a combination of an IGF1R inhibitor with an Akt inhibitor. See, for example, Example 2 and Figure 6.

[0163] Thus, in some cases, the present invention relates to methods for treating colon cancer in patients where the colon cancer is ARID1A mutated and / or ARID2 mutated, and IRS4 wild-type colon cancer.

[0164] The features disclosed in the preceding description, or the following claims, or the accompanying drawings, are expressed in their specific form, or in terms of means for performing a disclosed function, or methods or processes for obtaining a disclosed result, and can be utilized, as appropriate, separately or in any combination of such features to realize the invention in various of its forms.

[0165] Although the present invention has been described in conjunction with the example embodiments set forth above, numerous equivalent modifications and variations will be apparent to those skilled in the art given this disclosure. Accordingly, the example embodiments of the present invention set forth above are considered to be illustrative and not limiting. Various modifications can be made to the described embodiments without departing from the spirit and scope of the present invention.

[0166] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purpose of improving the understanding of the reader, and the inventors do not wish to be bound by any of these theoretical explanations.

[0167] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0168] Throughout this specification, including the appended claims, unless the context requires otherwise, the words "comprise" and "include", as well as variations such as "comprises", "comprising" and "including", are understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0169] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. As used herein, ranges may be expressed as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, it is understood that the particular value forms another embodiment by use of the antecedent "about." The term "about" in connection with numerical values ​​is optional and may mean, for example, + / - 10%. EXAMPLES

[0170] [Example] [Example 1] Linsitinib or BMS-754807+MK-2206 in breast, colon and pancreatic cancer cell lines Linsitinib was screened in combination with MK-2206 in 51 breast cancer cell lines, 45 colon cancer cell lines, and 29 pancreatic cancer cell lines. BMS-754807 was screened in combination with MK-2206 in 45 colon cancer cell lines. To screen efficiently, we used a 2x7 concentration matrix, or "anchor" approach. We screened each anchor compound at two optimized concentrations and a discrete 1,000-fold (7-point) dose-response curve of the library compound. Viability was read 72 hours after drug treatment using CellTiter-Glo, and drug responses to single agents and responses to combinations were fitted. Single agent and combination viability measurements were fitted for each cell line to derive multiple parameters, including: 1) the impact of the anchor on viability; 2) the maximum library concentration used for the library and combination (Library E max and combination E max ) and 3) the estimated library drug concentration that results in a 50% reduction in viability (IC 50We compared the observed responses to cell combinations with Bliss independence predicted responses based on monotherapy activity and measured the intensity (ΔIC 50 , i.e., increased sensitivity) or efficacy (ΔE max We classified drug combinations based on a shift in the IC10 of the combination relative to Bliss independence (Bliss, Annals of Applied Biology, 1939, 26(3), pp. 585-615) in the inhibition of cell viability (i.e., decreased cell viability). We calculated the IC10 of the combination relative to Bliss at either anchor concentration. 50 Or E max A combination-cell line pair was classified as synergistic if the IL-16 expression level was reduced by 8-fold or 20% more viability reduction. We observed a high percentage of synergy for linsitinib + MK-2206 in colon cancer cells (see Table 1). Combinations were screened in both anchor and library orientations, with the first listed compound being the anchor compound.

[0171] We observed significantly less synergy and activity with the IGF1Ri BMS-754807 (see Table 2), and synergy rates in the colon were subset in KRAS mutant (n=24) and KRAS wild-type (n=21) cell lines (see Table 3).

[0172] [Table 1]

[0173] [Table 2]

[0174] [Table 3]

[0175] [Example 2] Linsitinib or BMS-754807+MK-2206 in breast, colon and pancreatic cancer cell lines method: Linsitinib was screened in combination with MK-2206 in 51 breast cancer cell lines, 45 colon cancer cell lines, and 29 pancreatic cancer cell lines. BMS-754807 was screened in combination with MK-2206 in 45 colon cancer cell lines. To screen efficiently, we used a 2x7 concentration matrix, or "anchor" approach. We screened each anchor compound at two optimized concentrations and a discrete 1,000-fold (7-point) dose-response curve of the library compound. Viability was read 72 hours after drug treatment using CellTiter-Glo, and drug responses to single agents and responses to combinations were fitted. Single agent and combination viability measurements were fitted for each cell line to derive multiple parameters, including: 1) the impact of the anchor on viability; 2) the maximum library concentration used for the library and combination (Library E max and combination E max ) and 3) the estimated library drug concentration that results in a 50% reduction in viability (IC 50 We compared the observed responses to cell combinations with Bliss independence predicted responses based on monotherapy activity and measured the intensity (ΔIC 50 , i.e., increased sensitivity) or efficacy (ΔE max We classified drug combinations based on a shift in the IC10 of the combination relative to Bliss independence (Bliss, Annals of Applied Biology, 1939, 26(3), pp. 585-615) in the inhibition of cell viability (i.e., decreased cell viability). We calculated the IC10 of the combination relative to Bliss at either anchor concentration. 50 Or E max A combination-cell line pair was classified as synergistic if there was an 8-fold decrease in viability or a greater than 20% decrease in viability.

[0176] result: Mutations in ARID1A (mutated n=10, wild type n=35) sensitize colon cancer cell lines to treatment with MK-2206 + linsitinib. Intensity (ΔIC 50 ) and efficacy (ΔE max A significantly higher shift in expression of ARID2 was observed in ARID1A mutant cell lines compared to ARID1A wild-type cells (see Figures 1A and 1B), which was also observed independently for ARID2 mutants (n=7 mutant, n=38 wild-type) (see Figures 2A and 2B).

[0177] The ARID1A and ARID2 mutant populations did not completely overlap, and combining the two markers as "ARID1A mutant or ARID2 mutant" (n=13) improved the ability to distinguish cell lines with high synergy from those with lower synergy than either biomarker alone (see Figure 5).

[0178] The mutational status of IRS4 alone shows some correlation with the response of colon cancer cell lines to treatment with MK-2206 + linsitinib (see Figures 3A and 3B). IRS4 is directly downstream of the IGF1R, and IRS4 mutant cell lines are significantly less sensitive to the combination. All IRS4 mutant cell lines had a Log of <3 (the cutoff value for defining synergy). 2 ΔIC 50 (See Figures 3A and 4), suggesting the option of combining IRS4 with ARID1A and ARID2 as a biomarker for MK-2206 + linsitinib (See Figure 6). Indeed, the combination of ARID1A or ARID2 mutations and IRS4 wild type improved the ability to distinguish cell lines with high synergy of ARID1A or ARID2 mutations from those with lower synergy (See comparison of Figures 5 and 6).

[0179] [Example 3] Other IGF1R+Akt inhibitor combinations in colon cancer cell lines method: Screens were performed in four colon cancer cell lines (LS-180, HCC2998, SW1417, SW837) using a 7x7 matrix approach generating 49 wells of data per cell line / drug combination. For each combination, one Akt inhibitor was combined with one IGF1R inhibitor across a dose range of 1,000 discrete fractions (7 points). Viability was measured using CellTiter-Glo reagent 72 hours after drug treatment. Single agent and combination viability measurements were fitted for each cell line to derive multiple parameters, including ranges of single agent values ​​and synergy scores.

[0180] For all 49 concentration combination measurements, Bliss excess was calculated by comparing the observed cellular response to the combination with the Bliss-independent predicted response based on single-agent activity. The "Bliss window" was reported as the maximum Bliss excess value measured in 25 possible 3 x 3 submatrices, or "windows," of the 7 x 7 dose matrix.

[0181] In addition, HSA (highest single agent) excess was calculated by comparing the observed cellular response to the combination with the highest best single agent response to either drug A or drug B for all 49 concentration combination measurements. The "HSA window" was reported as the maximum HSA excess value measured in 25 possible 3 x 3 sub-matrices or "windows" within the 7 x 7 dose matrix.

[0182] result: The screen included three Akt inhibitors (MK-2206, ipatasertib, and afuresertib) each in combination with one of five IGF1R inhibitors (BMS-536924, brigutinib, GSK1904529A, linsitinib, and XL228). For the purpose of objectively identifying synergistic combinations, cell lines were deemed to exhibit synergy for a combination if the Bliss window was greater than 0.116. This arbitrary cutoff value was based on calculating the average Bliss window across all samples, plus 1× standard deviation. More generally, a higher Bliss window score indicates greater synergy.

[0183] Ten combinations showed synergy in at least one of the biomarker-positive cell lines (LS-180 or HCC2998) and are shown in Figure 7 (A-J). The biomarkers here are "ARID1A mutant or ARID2 mutant and IRS4 wild type" as previously described. The ten combinations shown in Figure 7 were classified as synergistic according to the above criteria and in all cases showed increased synergy in the biomarker-positive cell lines compared to the biomarker-negative lines.

[0184] [Example 4] Linsitinib + Akt inhibitor combination in colon cancer cell line LS-180 method: Compounds were tested in the colon cancer cell line LS-180 using a 7x7 matrix approach generating 49 wells of data per cell line / drug combination. For each combination, one Akt inhibitor was combined with one IGF1R inhibitor across a dose range of 1,000 discrete fractions (7 points). Viability was measured using CellTiter-Glo reagent 72 hours after drug treatment. Single agent and combination viability measurements were fitted for each cell line to derive multiple parameters including range of single agent values ​​and synergy scores.

[0185] The viability measurements of the single agents and combinations were fitted for each combination to derive several parameters, including: 1) the effect of the single agents on viability; 2) the maximum concentration used (E max ) the effect on survival at 100 mg / kg / day, and 3) the estimated drug concentration resulting in a 50% reduction in survival (IC 50 We compared the observed cellular responses to the combinations with the Bliss Independence predicted responses based on monotherapy activity and measured the intensity (ΔIC 50 , i.e., increased sensitivity) or efficacy (ΔE maxDrug combinations were classified based on a shift in the potency of the β-dependent agonist (i.e., decreased cell viability) beyond Bliss independence (Bliss, Annals of Applied Biology, 1939, 26(3), 585-615).

[0186] result: Four Akt inhibitors (MK-2206, milansertib, capivasertib and BAY1125976) were tested in combination with a single IGF1R inhibitor (linsitinib) in LS-180 cells. Note that this cell line is biomarker positive, the biomarkers being ARID1A or ARID2 mutant and IRS4 wild type. Table 4 below shows the ΔIC obtained for each combination from two independent replicates. 50 and ΔE max All four Akt inhibitors showed consistent synergy with linsitinib in this cell line, with IC 50 demonstrated a minimum of one-fifth change.

[0187] [Table 4]

[0188] [Example 5] Linsitinib and MK-2206 in endometrial and ovarian cancer cell lines method: Screens were performed in three endometrial cancer cell lines (MFE-280, MFE-296, and RL95-2) and three ovarian cancer cell lines (OV-90, A2780, and OAW-42) using a 7x7 matrix approach generating 49 wells of data per cell line / drug combination. MK-2206 was combined with linsitinib over a dose range of 1,000 discrete fractions (7 points). Viability was measured 72 h after drug treatment using CellTiter-Glo reagent. Single agent and combination viability measurements were fitted for each cell line to derive multiple parameters including range of single agent values ​​and synergy scores.

[0189] Single agent and combination viability measurements were fitted for each cell line to derive multiple parameters, including: 1) the effect of anchor on viability; 2) the maximum library concentration used for the library and combination (Library E max and combination E max ) and 3) the estimated library drug concentration that results in a 50% reduction in viability (IC 50 We compared the observed cellular responses to the combinations with the Bliss Independence predicted responses based on monotherapy activity and measured the intensity (ΔIC 50 , i.e., increased sensitivity) or efficacy (ΔE max Drug combinations were classified based on a shift in the potency of the β-dependent agonist (i.e., decreased cell viability) beyond Bliss independence (Bliss, Annals of Applied Biology, 1939, 26(3), 585-615).

[0190] result: For each cancer type, two ARID1A mutant cell lines and one ARID1A wild-type cell line were selected for testing. Although the synergy was less pronounced in these two cancer types than in colorectal cancer, a correlation between ARID1A mutation status and synergy was observed. Delta IC, a metric for synergy, was used to measure the synergy. 50 (i.e., ΔIC 50 ) and Delta E max (i.e. ΔE max ), for both endometrial and ovarian cancer cell lines, linsitinib plus MK-2206 demonstrated greater synergy in ARID1A mutant cell lines compared to ARID1A wild-type cell lines (Figure 8).

[0191] References In order to more fully describe and disclose the present invention and the state of the art to which it pertains, a number of publications are cited above. Full citations for these references are set forth below. Each of these references is incorporated herein in its entirety. Berge et al., J Pharm Sci, 1977 66(1) p 1 Bergqvist et al., Acta Oncologica, 56:3, 441-447, DOI: 10.1080 / 0284186X.2016.1253866 Biesecker et al., Cold Spring Harb Mol Case Study, 2020 Feb 3;6(1):a004549; doi: 10.1101 / mcs.a004549 Blagden et al., Clin Cancer Res (2019) 25 (5): 1472-1478 Bliss, Annals of Applied Biology, 1939, 26(3), 585-615 Chung et al., JAMA Oncol., 2017 Apr 1;3(4):516-522 Crabb et al., J Clin Oncol. 2021 Jan 20; 39(3): 190-201 Davis et al., Oncologist, 2018 Dec;23(12):1409-e140 De and Dey, Int J Mol Sci. 2019 Nov 15;20(22):5732 Fassnacht et al., Lancet Oncol., 2015 Apr;16(4):426-435 Huang et al., Mod Pathol, 2014 Jul;27(7):983-90 Hyman et al., Cancer Res (2018) 78 (13_Supplement): CT035; https: / / doi.org / 10.1158 / 1538-7445.AM2018-CT035 Kim et al., Future Oncology 2021 17:14, 1709-1719 Kim et al., The Lancet Oncology, Volume 18, Issue 10, 2017, Pages 1360-1372 Kostaras et al. Br J Cancer. 2020 Aug;123(4):542-555 Lazaro et al. Biochem Soc Trans. 2020 Jun 30;48(3):933-943 Mittal et al., 2020, Nat Rev Clin Oncol., 2020 July 17(7):435-448 Mullen et al., Cancer Treatment Reviews, 2021, 100, 102287 Oliveira et al., Ann Oncol, 2019 Aug 1;30(8):1289-1297. doi: 10.1093 / annonc / mdz177 Puzanov et al., Clin Cancer Res., 2015 Feb 15;21(4):701-711 Remington’s Pharmaceutical Sciences, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins Samartzis et al., Int. J. Mol. Sci., 2013, 14, 188824-18849 Samartzis et al., Oncotarget. 2014 Jul 30;5(14):5295-303 Schneeweiss et al., Cancers 2019, 11(12), 1987; https: / / doi.org / 10.3390 / cancers11121987 Smith et al., Journal of Clinical Oncology 2010 28:15_suppl, 3105-3105 Spencer et al., Blood (2014) 124 (14): 2190-2195 Takeda et al., Oncology Reports, 2016, 35: 607-613 Tessiri et al., PeerJ, 2022, 10:e12750 Tolcher et al., Cancer Chemother Pharmacol, 2020 Apr;85(4):673-683 Umehara et al.. Therapeutic Advances in Medical Oncology. 2018;10. doi:10.1177 / 1758835918786858 Xie et al., Tumour Biol. 2014 Aug;35(8):7921-7 Xing et al., Breast Cancer Res., 2019 Jul 5;21(1):78 Yap et al., J Clin Oncol., 2011 Dec 10;29(35):4688-4695 Zeng et al., Head & Neck Oncology. 2013;5(1):6 Zhang et al., Oncotarget. 2016 Jul 19;7(29):46127-46141 Zhu et al., Cancer Biology & Therapy, 2022, Vol. 23, No. 1, 104-111 https: / / clinicaltrials.gov / ct2 / show / NCT01902173 https: / / clinicaltrials.gov / ct2 / show / study / NCT02930109 https: / / clinicaltrials.gov / ct2 / show / NCT04305496 https: / / www.drugdiscoverytrends.com / arqule-reports-positive-phase-i-data-in-haematological-malignancies-study / https: / / www.fda.gov / medical-devices / in-vitro-diagnostics / list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools www.genenames.org https: / / ir.exelixis.com / news-releases / news-release-details / exelixis-reports-positive-phase-1-data-xl228-ash-annual-meeting https: / / www.globenewswire.com / en / news-release / 2019 / 05 / 08 / 1819580 / 0 / en / Cotinga-Pharmaceuticals-Releases-Early-Interim-Data-of-Phase-1b-2a-Combination-Trial-of-COTI-2-in-Solid-Tumors.html https: / / smallcaps.com.au / prescient-therapeutics-encouraging-efficacy-results-leading-cancer-drug-candidate-ptx-200 /

[0192] For standard molecular biology techniques, see Sambrook, J., Russell, DW Molecular Cloning, A Laboratory Manual. 3rd ed. 2001, Cold Spring Harbor, New York, Cold Spring Harbor Laboratory Press.

[0193] Prevailing Terms 1. A combination of linsitinib or AXL-1717 with an Akt inhibitor for use in a method for the treatment of colon cancer. 2. A combination for use according to clause 1, which is linsitinib and an Akt inhibitor. 3. The combination for use according to clause 1 or 2, wherein the Akt inhibitor is selected from MK-2206, capivasertib, ipatasertib, afuresertib, milansertib, uprosertib, triciribine, PTX-200, TAS-117, COTI-2, LY-2503029 and MK-4440. 4. The combination for use according to clause 3, wherein the Akt inhibitor is selected from MK-2206, ipatasertib and afuresertib. 5. The combination for use according to clause 3, wherein the Akt inhibitor is MK-2206. 6. The combination for use according to clause 1, which is linsitinib and MK-2206. 7. The combination for use according to any one of the preceding clauses, wherein the cancer is KRAS mutated colorectal cancer. 8. The combination for use according to clause 7, wherein the cancer comprises cells with an alteration in ERCC3. 9. A combination for use according to clause 8, wherein the alteration is a mutation. 10. The combination for use according to clause 8, wherein the alteration is a deletion of ERCC3. 11. The combination for use according to clause 10, wherein the deletion of ERCC3 is a homozygous deletion. 12. The combination for use according to any one of the preceding clauses, wherein linsitinib or AXL-1717 and the Akt inhibitor are administered separately.

Claims

1. 1. A combination of an IGF1R inhibitor and an Akt inhibitor for use in a method for treating cancer, wherein the cancer is selected from colon cancer, ovarian cancer and endometrial cancer.

2. 1. An IGF1R inhibitor for use in a method for treating cancer in a patient, wherein the cancer is selected from colon cancer, ovarian cancer and endometrial cancer, and wherein the IGF1R inhibitor is administered to the patient in combination with an Akt inhibitor.

3. 1. An Akt inhibitor for use in a method for treating cancer in a patient, wherein the cancer is selected from colon cancer, ovarian cancer and endometrial cancer, and wherein the Akt inhibitor is administered to the patient in combination with an IGF1R inhibitor.

4. 10. The combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the cancer is colon cancer.

5. the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, brigutinib, AXL-1717 and KW-2450, or an IGF1R antibody; optionally, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, brigutinib, AXL-1717, and KW-2450; optionally, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, BMS-754807, brigutinib, and AXL-1717; optionally, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, BMS-536924, and brigutinib; optionally, the IGF1R inhibitor is selected from linsitinib, GSK1904529A, XL228, and BMS-536924; optionally, the IGF1R inhibitor is selected from linsitinib and GSK1904529A; Optionally, the combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the IGF1R inhibitor is linsitinib.

6. 10. The combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the Akt inhibitor is an allosteric Akt inhibitor.

7. 10. The combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the Akt inhibitor is an ATP-competitive Akt inhibitor.

8. the Akt inhibitor is selected from MK-2206, capivasertib, ipatasertib, afuresertib, milansertib, uprosertib, triciribine, PTX-200, TAS-117, COTI-2, LY-2503029, MK-4440, and BAY1125976; optionally, the Akt inhibitor is selected from MK-2206, capivasertib, ipatasertib, afuresertib, milansertib, and BAY1125976; optionally, the Akt inhibitor is selected from MK-2206, capivasertib, milansertib, and BAY1125976; optionally, the Akt inhibitor is selected from MK-2206, ipatasertib, and afuresertib; optionally, the Akt inhibitor is selected from MK-2206 and afuresertib; Optionally, the combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the Akt inhibitor is MK-2206.

9. 10. The combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the IGF1R inhibitor is linsitinib and the Akt inhibitor is MK-2206.

10. the cancer is an ARID1A-mutated and / or ARID2-mutated cancer, optionally, the cancer is an ARID1A-mutated cancer; optionally, the cancer is an ARID2-mutated cancer; Optionally, the combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the cancer is an ARID1A-mutated and ARID2-mutated cancer.

11. 10. The combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the cancer is an IRS4 wild-type cancer.

12. the cancer is ARID1A mutated and / or ARID2 mutated and IRS4 wild-type colorectal cancer; Optionally, the combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the IGF1R inhibitor is linsitinib and the Akt inhibitor is MK-2206.

13. the cancer is ARID1A mutant ovarian cancer or ARID1A mutant endometrial cancer, Optionally, the combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the IGF1R inhibitor is linsitinib and the Akt inhibitor is MK-2206.

14. 10. The combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the cancer is a KRAS mutant cancer.

15. 10. The combination for use according to claim 1, the IGF1R inhibitor for use according to claim 2, or the Akt inhibitor for use according to claim 3, wherein the IGF1R inhibitor and the Akt inhibitor are administered separately.

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