Treatment of childhood cancer using glycogen synthase kinase type B inhibitors

Abstract

A method for treating cancer in a pediatric patient requiring treatment is provided, comprising administering 9-ING-41 to the patient in combination with an additional therapeutic agent.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 493,909, filed on 3 April 2023, and U.S. Provisional Patent Application No. 63 / 494,858, filed on 7 April 2023. The entirety of each of the aforementioned applications is incorporated herein by reference.

[0002] This disclosure relates to a method for treating cancer in pediatric patients. [Background technology]

[0003] GSK-3 is a serine / threonine kinase originally described as a major regulator of metabolism, particularly glycogen biosynthesis. By regulating numerous substrates, GSK-3 is involved in a diverse range of disease processes, including cancer, immune disorders, metabolic disorders, and neurological disorders. GSK-3 has two widely expressed and highly conserved isoforms: GSK-3α and GSK-3β.

[0004] GSK-3β is particularly effective in controlling tumor progression and the activity of oncogenes (such as β-catenin, cyclin D1, and c-Myc), as well as cell cycle regulatory factors (e.g., p27). Kip1 It is important in regulating epithelial-mesenchymal transition mediators (e.g., zinc finger proteins SNAI1, Snail). Abnormal overexpression of GSK-3β has been shown to promote tumor growth and chemotherapy resistance in various solid tumors, including colorectal cancer, ovarian cancer, pancreatic cancer, and glioblastoma, through different effects on the kappa light chain enhancer (NF-κB) pathway and c-Myc pathway of activated B cells, which are nuclear factors that promote survival, as well as on apoptotic mechanisms mediated by tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) and p53.

[0005] 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indole-7-yl)pyrrole-2,5-dione ("9-ING-41" or "erlaglucib") has the following chemical structure:

[0006] [ka] It is a GSK-3β inhibitor that possesses [the characteristic].

[0007] 9-ING-41 is a groundbreaking new drug, an intravenous (IV) administered, maleimide-based small molecule potent selective GSK-3β inhibitor, exhibiting remarkable preclinical and clinical antitumor activity, including G0-G1 and G2-M phase arrest.

[0008] The synthesis, characterization, and / or biological activity of 9-ING-41 are described in U.S. Patent No. 8,207,216; Gaisina et al., From a Natural Product Lead to the Identification of Potent and Selective Benzofuran-3-yl-(indol-3-yl)maleimides as Glycogen Synthase Kinase 3β Inhibitors That Suppress Proliferation and Survival of Pancreatic Cancer Cells, J. Med. Chem. 2009, 52, 1853-1863; and Hilliard, et al., Glycogen synthase kinase 3β inhibitors induce apoptosis in ovarian cancer cells and inhibit in-vivo tumor growth, Anti-Cancer Drugs 2011, 22:978-985. 9-ING-41 has been reported to be useful in the treatment of certain cancers, including brain tumors, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, and pancreatic cancer, as well as in the treatment of traumatic brain injury. [Overview of the Initiative]

[0009] This disclosure provides a method for treating cancer in a pediatric patient requiring treatment, comprising administering 9-ING-41 to the patient in combination with an additional therapeutic agent.

[0010] In some cases, the cancer is alveolar rhabdomyosarcoma, embryonic central nervous system tumor (NOS), neuroblastoma, osteosarcoma, progressive ependymoma, Ewing's sarcoma, rhabdomyosarcoma, pediatric glioblastoma multiforme (GBM), diffuse interstitial pontine glioma (DIPG) / diffuse central glioma (DMG), Wilms' tumor, recurrent ependymoma, CIC reconstitutional sarcoma, high-grade astrocytoma, adrenocortical carcinoma, embryonic central nervous system (CNS), ependymoma, glioma, astrocytoma, or adrenocortical.

[0011] In some cases, cancer is refractory or recurrent. [Modes for carrying out the invention]

[0012] A deeper understanding of this disclosure can be gained by referring to the following description, which includes the definitions and examples below. Certain features of the disclosed compositions and methods are described herein in the context of separate embodiments, but may also be provided in combination in a single embodiment. Alternatively, various features of the disclosed compositions and methods described in the context of a single embodiment for the sake of brevity may also be provided individually or in any partial combination.

[0013] Unless otherwise specifically defined herein, scientific and technical terms used in connection with this application shall have the meanings that a person skilled in the art would ordinarily understand. Furthermore, unless otherwise specifically required by context, singular terms shall include plural forms and plural terms shall include singular forms.

[0014] As adopted above and throughout this disclosure, the following terms and abbreviations shall be understood to have the following meanings unless otherwise indicated.

[0015] When used in a specification including the attached claims, the singular forms "a," "an," and "the" include the plural forms, and references to specific numbers include at least that specific number unless the context clearly indicates otherwise.

[0016] Where a range of values ​​is expressed, the exemplary embodiments include one specific value and / or the other specific value. All ranges are inclusive and combinable. Furthermore, references to values ​​listed in a range include each and all values ​​within that range. When a value is expressed as an approximation preceded by "approximately," it is understood that the specific value forms another embodiment. As used herein, the term "approximately" when referring to measurable values ​​such as quantity or duration means that it includes a reasonable variation of the value, such as ±10% from a specific value. For example, the phrase "approximately 5-20 mg / kg" could include a range of 4.5 to 22, including ±10% of 5, ±10% of 20, or 5-20.

[0017] For clarity, it should be noted that certain features of the disclosure described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the disclosure described in the context of a single embodiment for the sake of brevity may also be provided individually or in any partial combination.

[0018] As used herein, the term "pediatric patient" refers to a human patient under the age of 23.

[0019] It should be understood that, as used herein, the terms “method of treatment” and “treatment method,” whether used alone or in conjunction with other terms, may be used interchangeably with the phrase “for use in the treatment of a particular disease.”

[0020] As used herein, whether used alone or in combination with other terms, the terms "treat," "treating," "treated," and "treatment" refer to palliative, alleviating, and / or curative uses and results, or any combination thereof, and include the same.

[0021] As used herein, whether used alone or in combination with other terms, a "therapeutic agent" is (a) a compound or composition that treats a specific condition, symptom, disorder, or disease described herein; (b) a compound or composition that attenuates, alleviates, or eliminates one or more symptoms of a specific condition, disorder, or disease described herein; (c) a compound or composition that delays the onset or relapse (reoccurrence) of a specific condition, symptom, disorder, or disease described herein; (d) a compound or composition that prevents the onset of a specific condition, symptom, disorder, or disease described herein. The terms "therapeutic" and "therapeutically effective" are to be understood to encompass any one of the effects (a)-(d) described above, alone or in combination with any of the other effects (a)-(d).

[0022] The term "administering" means directly administering a compound or composition of the present invention or administering a prodrug, derivative, or analog that forms an equivalent amount of an active compound or substance in the body.

[0023] As used herein, the term "refractory cancer" refers to a cancer that is resistant to conventional chemotherapy treatment. Refractory cancers include cancers that were resistant at the start of conventional chemotherapy treatment or that acquired resistance during the course of conventional chemotherapy treatment.

[0024] As used herein, the term "recurrent cancer" generally refers to a cancer that has recurred (come back) after a period during which the cancer could not be detected. The cancer may recur in the same location as the original (primary) tumor or in another location in the body.

[0025] As used herein, the term “CIC reconfiguration sarcoma” refers to a type of small round cell tumor classified as a Ewing sarcoma. Historically, these tumors have been identified with Ewing sarcoma, but they are genetically distinct and, on average, tend to be more metastatic than Ewing sarcoma.

[0026] How to use In some embodiments, the present disclosure provides a method for treating cancer in a pediatric patient requiring treatment, comprising administering 9-ING-41 to the patient in combination with an additional therapeutic agent.

[0027] In some embodiments of the disclosed method, the cancer is alveolar rhabdomyosarcoma, embryonic central nervous system tumor NOS, neuroblastoma, osteosarcoma, progressive ependymoma, Ewing's sarcoma, rhabdomyosarcoma, pediatric glioblastoma multiforme (GBM), diffuse stromal pontine glioma (DIPG) / diffuse central glioma (DMG), Wilms' tumor, recurrent ependymoma, CIC reconstitution sarcoma, high-grade astrocytoma, adrenocortical carcinoma, embryonic central nervous system cancer, ependymoma, glioma, astrocytoma, or adrenocortical carcinoma.

[0028] In some embodiments of the disclosed method, the cancer is a sarcoma.

[0029] In some embodiments of the disclosed method, the sarcoma is alveolar rhabdomyosarcoma, osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, or CIC reconstitution sarcoma.

[0030] In some embodiments of the disclosed method, the sarcoma is alveolar rhabdomyosarcoma.

[0031] In some embodiments of the disclosed method, the sarcoma is rhabdomyosarcoma.

[0032] In some embodiments of the disclosed method, the sarcoma is osteosarcoma.

[0033] In some embodiments of the disclosed method, the sarcoma is Ewing's sarcoma.

[0034] In some embodiments of the disclosed method, the sarcoma is a CIC-reconstructed sarcoma.

[0035] In some embodiments of the disclosed method, the cancer is an embryonic central nervous system tumor NOS (unclassifiable).

[0036] In some embodiments of the disclosed method, the cancer is neuroblastoma.

[0037] In some embodiments of the disclosed method, the cancer is an advanced ependymoma.

[0038] In some embodiments of the disclosed method, the cancer is childhood glioblastoma multiforme (GBM).

[0039] In some embodiments of the disclosed method, the cancer is diffuse stromal pontine glioma (DIPG) / diffuse central glioma (DMG).

[0040] In some embodiments of the disclosed method, the cancer is Wilms' tumor.

[0041] In some embodiments of the disclosed method, the cancer is a recurrent ependymoma.

[0042] In some embodiments of the disclosed method, the cancer is a high-grade astrocytoma.

[0043] In some embodiments of the disclosed method, the cancer is adrenocortical carcinoma.

[0044] In some embodiments of the disclosed method, the cancer is an embryonic central nervous system cancer.

[0045] In some embodiments of the disclosed method, the cancer is an ependymoma.

[0046] In some embodiments of the disclosed method, the cancer is a glioma.

[0047] In some embodiments of the disclosed method, the cancer is an astrocytoma.

[0048] In some embodiments of the disclosed method, the cancer is adrenocortical carcinoma.

[0049] In some embodiments of the disclosed method, the cancer is refractory or recurrent.

[0050] In some embodiments of the disclosed method, the cancer is a refractory cancer.

[0051] In some embodiments of the disclosed method, the cancer is recurrent cancer.

[0052] In some embodiments of the disclosed method, the cancer is both refractory and recurrent.

[0053] In some embodiments, the disclosed method is performed on pediatric patients.

[0054] In some embodiments of the disclosed method, the pediatric patient is between 0 and 23 years of age, for example, one of the following: 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 12 months old, 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, 17 years old, 18 years old, 19 years old, 20 years old, 21 years old, 22 years old, or 23 years old.

[0055] In some embodiments of the disclosed method, the pediatric patient is between 0 and 18 years of age, for example, one of the following: 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 12 months old, 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, 17 years old, or 18 years old.

[0056] In some embodiments of the disclosed method, the pediatric patient is between 0 and 14 years old, for example, one of the following: 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 12 months old, 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, or 14 years old.

[0057] In some embodiments of the disclosed method, 9-ING-41 is administered in amounts of approximately 5 to 20 mg per kg of patient body weight, for example, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, approximately 10 mg / kg, approximately 11 mg / kg, approximately 12 mg / kg, approximately 13 mg / kg, approximately 14 mg / kg, approximately 15 mg / kg, approximately 16 mg / kg, approximately 17 mg / kg, approximately 18 mg / kg, approximately 19 mg / kg, or approximately 20 mg / kg.

[0058] In some embodiments of the disclosed method, 9-ING-41 is administered intravenously.

[0059] In some embodiments of the disclosed method, 9-ING-41 is administered at a dose of approximately 7 mg / kg.

[0060] In some embodiments of the disclosed method, 9-ING-41 is administered in an amount of approximately 9.3 mg / kg.

[0061] In some embodiments of the disclosed method, 9-ING-41 is administered in an amount of approximately 12.4 mg / kg.

[0062] In some embodiments of the disclosed method, 9-ING-41 is administered in an amount of approximately 15 mg / kg.

[0063] In some embodiments of the disclosed method, 9-ING-41 is administered once a week during a 21-day cycle.

[0064] In some embodiments of the disclosed method, 9-ING-41 is administered twice a week during a 21-day cycle.

[0065] In some embodiments of the disclosed method, 9-ING-41 is administered three times per week during a 21-day cycle.

[0066] In some embodiments of the disclosed method, 9-ING-41 is administered four times a week during a 21-day cycle.

[0067] In some embodiments of the disclosed method, 9-ING-41 is administered five times a week during a 21-day cycle.

[0068] In some embodiments of the disclosed method, 9-ING-41 is administered six times a week during a 21-day cycle.

[0069] In some embodiments of the disclosed method, 9-ING-41 is administered seven times a week during a 21-day cycle.

[0070] In some embodiments of the disclosed method, 9-ING-41 is administered at a dose of approximately 7 mg / kg twice a week during a 21-day cycle.

[0071] In some embodiments of the disclosed method, 9-ING-41 is administered at a dose of approximately 9.3 mg / kg twice a week during a 21-day cycle.

[0072] In some embodiments of the disclosed method, 9-ING-41 is administered at a dose of approximately 12.4 mg / kg twice a week during a 21-day cycle.

[0073] In some embodiments of the disclosed method, 9-ING-41 is administered at a dose of approximately 15 mg / kg twice a week during a 21-day cycle.

[0074] In some embodiments of the disclosed method, the additional therapeutic agent includes irinotecan, cyclophosphamide, topotecan, temozolomide, PI3 kinase, protein kinase B (AKT) inhibitor, or mTOR inhibitor.

[0075] In some embodiments of the disclosed method, the additional therapeutic agent includes irinotecan.

[0076] In some embodiments of the disclosed method, irinotecan is administered at a dose of 20-50 mg / m². 2 It is administered in doses of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / m². 2 It is one of the days.

[0077] In some embodiments of the disclosed method, irinotecan is administered intravenously.

[0078] In some embodiments of the disclosed method, irinotecan is administered on days 1 to 5 of each 21-day cycle.

[0079] In some embodiments of the disclosed method, irinotecan is 50 mg / m². 2 It is administered intravenously at a daily dose.

[0080] In some embodiments of the disclosed method, irinotecan is administered at a dose of 50 mg / m² on days 1-5 of each 21-day cycle. 2 It is administered intravenously at a daily dose.

[0081] In some embodiments of the disclosed method, irinotecan is administered at a dose of 50 mg / m² on days 1-5 of each 21-day cycle. 2 It is administered intravenously over 90 minutes at a daily dose.

[0082] In some embodiments of the disclosed method, the additional therapeutic agent includes temozolomide.

[0083] In some embodiments of the disclosed method, temozolomide is administered orally.

[0084] In some embodiments of the disclosed method, temozolomide is administered on days 1 to 5 of each 21-day cycle.

[0085] In some embodiments of the disclosed method, temozolomide is administered orally at a dose of 100 mg / m 2 for patients with a body surface area of at least 0.5 m 2 / dose.

[0086] In some embodiments of the disclosed method, temozolomide is administered orally at a dose of 2.5 mg / kg for patients with a body surface area of less than 0.5 m 2

[0087] In some embodiments of the disclosed method, temozolomide is administered orally at a dose of 100 mg / m 2 / dose on days 1 to 5 of each 21-day cycle.

[0088] In some embodiments of the disclosed method, the additional therapeutic agent includes both irinotecan and temozolomide, and each of irinotecan and temozolomide is administered by the method disclosed herein.

[0089] In some embodiments of the disclosed method, the additional therapeutic agent includes cyclophosphamide.

[0090] In some embodiments of the disclosed method, cyclophosphamide is administered intravenously.

[0091] In some embodiments of the disclosed method, cyclophosphamide is administered on days 1 to 5 of each 21-day cycle.

[0092] In some embodiments of the disclosed method, cyclophosphamide is administered intravenously at a dose of 400 mg / m 2 / dose on days 1 to 5 of each 21-day cycle.

[0093] In some embodiments of the disclosed method, cyclophosphamide is administered at a dose of 400 mg / m​2 It is administered intravenously over 30 minutes at the prescribed dose.

[0094] In some embodiments of the disclosed method, the additional therapeutic agent includes topotecan.

[0095] In some embodiments of the disclosed method, topotecan is administered intravenously.

[0096] In some embodiments of the disclosed method, topotecan is administered on days 1 through 5 of each 21-day cycle.

[0097] In some embodiments of the disclosed method, topotecan is administered at a dose of 1.2 mg / m² on days 1-5 of each 21-day cycle. 2 It is administered intravenously over 30 minutes at the prescribed dose.

[0098] In some embodiments of the disclosed method, topotecan is administered at a dose of 1.2 mg / m² on days 1 to 5. 2 It is administered intravenously over 30 minutes at the prescribed dose.

[0099] In some embodiments of the disclosed method, the additional therapeutic agent comprises both cyclophosphamide and topotecan, and each of cyclophosphamide and topotecan is administered in the manner disclosed herein.

[0100] In some embodiments of the disclosed method, the additional therapeutic agent includes one or more PI3K inhibitors, such as copanlisib, idelalisib, umbralicib, duvelisib, alpelisib, inavolisib, gedatricib, or paxalisib.

[0101] In some embodiments of the disclosed method, the additional therapeutic agent includes, for example, a protein kinase B (AKT) inhibitor such as capivacertib, mirancertib, or ipatasertib.

[0102] In some embodiments of the disclosed method, the additional therapeutic agent includes, for example, an mTor inhibitor such as sirolimus, everolimus, and temsirolimus.

[0103] In some embodiments of the disclosed method, the additional therapeutic agent includes, for example, a PD-L1 inhibitor such as atezolizumab (Tecentriq), avelumab (Bavencio), or durvalumab (Imfinzi).

[0104] In some embodiments of the disclosed method, the additional therapeutic agent includes, for example, a PD-1 inhibitor such as pembrolizumab (Keytruda), nivolumab (Opdivo), or semiprimab (Libtayo).

[0105] In some embodiments of the disclosed method, the additional therapeutic agent includes, for example, CTLA-4 inhibitors such as ipilimumab (Yervoy) and tremelimumab (Imjuno).

[0106] In some embodiments, the disclosed method results in a complete response based on the RECIST 1.1 criteria.

[0107] In some embodiments, the disclosed method results in a partial response based on the RECIST 1.1 criteria.

[0108] In some embodiments, the disclosed method results in a stable disease according to RECIST 1.1 criteria.

[0109] In some embodiments, the methods of this disclosure extend the patient's overall survival (OS). As used herein, the term "overall survival" is defined as the period from the start of treatment to death from any cause.

[0110] In some embodiments, the methods of this disclosure extend the patient's progression-free survival (PFS). As used herein, the term “progression-free survival” is defined as the period from the start of treatment to objective tumor progression or death.

[0111] It will be understood that in the methods of this disclosure, 9-ING-41 may be administered as a pharmaceutical composition comprising 9-ING-41 and at least one pharmaceutically acceptable excipient.

[0112] Similarly, additional therapeutic agents used in the methods of this disclosure may be administered as a pharmaceutical composition comprising a therapeutic agent and at least one pharmaceutically acceptable excipient.

[0113] In this specification, references to methods of treating cancer using the disclosed compounds or compositions should be understood to also be interpreted as references to (i) the disclosed compounds or compositions for use in methods of treating cancer; and / or (ii) the use of the disclosed compounds or compositions in the manufacture of cancer treatment pharmaceuticals. [Examples]

[0114] [Example 1] Human pharmacokinetics of 9-ING-41 from the NCT03678883 study:

[0115] [Table 1]

[0116] [Example 2] Clinical trials

[0117] [Table 2-1]

[0118] [Table 2-2]

[0119] [Table 2-3]

[0120] [Table 2-4]

[0121] [Table 2-5]

[0122] [Table 2-6]

[0123] [Table 2-7]

[0124] [Table 2-8]

[0125] [Table 2-9]

[0126] [Table 2-10]

[0127] [Table 2-11]

[0128] [Table 2-12]

[0129] result: 9-ING-41 demonstrated good tolerability in this pediatric patient population with a severe history of prior treatment. The limited infusion volume and twice-weekly administration schedule highlight the need for an oral dosage form.

[0130] One patient with recurrent Ewing's sarcoma achieved complete radiological and pathological response after three cycles of erlaglucib / cyclophosphamide / topotecan. Six patients (26.1%) had stable disease (2 NBL, 1 aRMS, 1 EP, 1 OS, 1 GBM). Eight patients (35%) continued treatment for more than three months (2 NBL, 2 EP, 1 OS, 1 aRMS, 1 ES, 1 PB). The median treatment duration was 40 days (range 1–126 days).

[0131] [Table 3-1]

[0132] [Table 3-2]

[0133] The 5-year survival rate for newly diagnosed Ewing sarcoma patients is over 70%, but for patients who have relapsed (recurrent), similar to those enrolled in this study, the 5-year survival rate is less than 30%. Patients who experience metastasis or disease progression despite two or more chemotherapy regimens have an extremely short survival period of less than 6 months. There are no treatment regimens that significantly extend survival in patients with metastatic or refractory Ewing sarcoma.

[0134] Clinical data have been obtained from treating refractory pediatric malignancies with 9-ING-41 in combination with cyclophosphamide / topotecan. The patients enrolled in this study were those who had already received standard treatment for their respective diseases but had experienced disease progression. Of the 25 evaluable patients enrolled in this study, 7 were patients with metastatic refractory Ewing's sarcoma or Ewing-like sarcoma.

[0135] All seven Ewing's sarcoma patients enrolled in this study had metastatic disease and, despite a history of chemotherapy and radiation therapy, experienced disease progression before joining the study. Four of the seven patients had previously received two or more chemotherapy regimens. All patients received erlaglucib plus cyclophosphamide / topotecan combination therapy. One patient achieved complete tumor remission at the initial tumor evaluation (two months after the start of treatment) and discontinued all treatment four months later. Almost two years after the end of treatment, the patient remains in remission with no evidence of disease. The second patient showed partial remission with a 52% tumor reduction at the initial tumor evaluation, and the third patient showed partial remission with a 96% tumor reduction at the initial tumor evaluation. Four of the seven patients are still alive, and three are continuing treatment. See Table 2.

[0136] [Table 4]

[0137] [Table 5]

[0138] [Example 3] Immunostimulatory effects of 9-ING-41 on NK cells and T cells in human liposarcoma and osteosarcoma cell lines. Saos-2 osteosarcoma and 93T449 liposarcoma cell lines were treated with the small molecule GSK-3 inhibitor 9-ING-41 (erlaglucib) to achieve an IC50 ratio. 72Cells were pre-treated. 48 hours after treatment, cells were collected and analyzed by Western blot. Furthermore, both cancer cell lines, as well as TALL-104 T cells and NK-92 NK cells, were treated with 0.5 μM 9-ING-41 for 24 hours and collected for Luminex cytokine profiling. Western blotting showed an increase in cPARP, an apoptosis marker, in both cancer cell lines after 9-ING-41 treatment. An increase in PD-L1 expression was also observed. Cytokine analysis showed enhanced 9-ING-41-responsive immune cell activity. Treated T cells showed an increase in CXCL11, which is associated with T cell recruitment, and an increase in IL-18 levels, which has been shown to induce IFN-γ production in Th1 cells. Furthermore, NK-92 cells showed an increase in the IL-8 chemokine and soluble TRAIL (TRAIL / TNFSF10). A uniform increase in the growth factor TGF-α was observed in cancer cell lines, but only the Saos-2 osteosarcoma cell line showed an increase in IL-6. Follow-up cytokine profiling is ongoing. The increase in immunostimulatory cytokines and elevated PD-L1 expression suggests a rationale for the combination of 9-ING-41 and immune checkpoint blockade therapy. The potential synergistic effects of these two therapies are currently being investigated in co-culture experiments of sarcoma cells and immune cells. The treatment cohort in this experiment includes combinations of 9-ING-41 with anti-PD-L1, anti-PD-1, or anti-CTLA-4 immune checkpoint inhibitors. These results suggest a promising combination therapy strategy for soft tissue and osteosarcoma patients, and future research will aim to elucidate the mechanism of efficacy.

Claims

1. A method for treating cancer in pediatric patients requiring treatment, comprising administering 9-ING-41 to the pediatric patient in combination with an additional therapeutic agent.

2. The method according to claim 1, wherein the cancer is alveolar rhabdomyosarcoma, embryonic central nervous system tumor NOS, neuroblastoma, osteosarcoma, progressive ependymoma, Ewing's sarcoma, rhabdomyosarcoma, pediatric glioblastoma multiforme (GBM), diffuse interstitial pontine glioma (DIPG) / diffuse central glioma (DMG), Wilms' tumor, recurrent ependymoma, CIC reconstitution sarcoma, high-grade astrocytoma, adrenocortical carcinoma, embryonic central nervous system, ependymoma, glioma, astrocytoma, or adrenocortex.

3. The method according to claim 1 or claim 2, wherein the cancer is a sarcoma.

4. The method according to claim 3, wherein the sarcoma is alveolar rhabdomyosarcoma, osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, or CIC reconstructed sarcoma.

5. The method according to claim 4, wherein the sarcoma is alveolar rhabdomyosarcoma.

6. The method according to claim 4, wherein the sarcoma is rhabdomyosarcoma.

7. The method according to claim 4, wherein the sarcoma is osteosarcoma.

8. The method according to claim 4, wherein the sarcoma is Ewing's sarcoma.

9. The method according to claim 4, wherein the sarcoma is a CIC-reconstructed sarcoma.

10. The method according to any one of claims 1 to 9, wherein the cancer is refractory or recurrent cancer.

11. The method according to any one of claims 1 to 10, wherein 9-ING-41 is administered in an amount of approximately 5 to 20 mg / kg per body weight of the patient.

12. The method according to claim 11, wherein 9-ING-41 is administered twice a week during a 21-day cycle.

13. The method according to claim 11, wherein 9-ING-41 is administered at a dose of approximately 9.3 mg / kg twice a week during a 21-day cycle.

14. The method according to claim 11, wherein 9-ING-41 is administered at a dose of approximately 12.4 mg / kg twice a week during a 21-day cycle.

15. The method according to claim 11, wherein 9-ING-41 is administered at a dose of approximately 15 mg / kg twice a week during a 21-day cycle.

16. The method according to any one of claims 1 to 15, wherein the additional therapeutic agent comprises irinotecan, cyclophosphamide, topotecan, temozolomide, a PI3 kinase inhibitor, a protein kinase B (AKT) inhibitor, an mTOR inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, or a CTLA-4 inhibitor.

17. The method according to claim 16, wherein the additional therapeutic agent comprises irinotecan.

18. The aforementioned irinotecan is administered at a dose of 50 mg / m² on days 1-5 of each 21-day cycle. ２ The method according to claim 17, wherein the dose is administered intravenously over a period of 90 minutes at a daily dose.

19. The method according to any one of claims 16 to 18, wherein the additional therapeutic agent comprises temozolomide.

20. The aforementioned temozolomide is administered at a dose of 100 mg / m² on days 1-5 of each 21-day cycle. ２ The method according to claim 19, which is administered orally in a specified dose.

21. The method according to claim 16, wherein the additional therapeutic agent comprises cyclophosphamide.

22. The aforementioned cyclophosphamide is administered at a dose of 400 mg / m² on days 1-5 of each 21-day cycle. ２ The method according to claim 21, wherein the dose is administered intravenously over a period of 30 minutes.

23. The method according to any one of claims 16 to 22, wherein the additional therapeutic agent comprises topotecan.

24. The aforementioned topotecan was administered at a dose of 1.2 mg / m² on days 1 to 5. ２ The method according to claim 23, wherein the dose is administered intravenously over a period of 30 minutes.

25. The method according to claim 16, wherein the additional therapeutic agent comprises a PI3 kinase inhibitor.

26. The method according to claim 16, wherein the additional therapeutic agent comprises an mTOR inhibitor.

27. The method according to any one of claims 1 to 26, wherein the patient is 0 to 23 years of age.

28. The method according to claim 27, wherein the patient is between 0 and 18 years of age.

29. The method according to claim 27, wherein the patient is 0 to 14 years of age.

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