Search

CN-122028920-A - Method for treating hematological cancer

CN122028920ACN 122028920 ACN122028920 ACN 122028920ACN-122028920-A

Abstract

A method of treating hematological cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a phosphatidylinositol 3-kinase gamma (PI 3 Kg) inhibitor and an antimetabolite, optionally further administering a therapeutically effective amount of a BCL-2 inhibitor. A method of identifying a patient with hematologic cancer who is susceptible to treatment with a PI3Kg inhibitor. A method of treating hematological cancer, the method comprising administering a therapeutically effective amount of a p-21 activated kinase 1 (PAK-1) inhibitor to a patient in need thereof, optionally further administering a therapeutically effective amount of a BCL-2 inhibitor.

Inventors

  • A. A. Ryan
  • LUO QINGYU

Assignees

  • 丹娜-法伯癌症研究院

Dates

Publication Date
20260512
Application Date
20241029
Priority Date
20231101

Claims (20)

  1. 1. A method of treating hematological cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a phosphatidylinositol 3-kinase gamma (PI 3K gamma) inhibitor and an antimetabolite.
  2. 2. A PI3K gamma inhibitor and an antimetabolite for use in the treatment of hematologic cancers.
  3. Use of a pi3kγ inhibitor and an antimetabolite in the manufacture of one or more medicaments for the treatment of hematological cancer.
  4. 4. The method according to claim 1, the PI3K gamma inhibitor and the antimetabolite for use according to claim 2, or the use of the PI3K gamma inhibitor and the antimetabolite according to claim 3, wherein the hematological cancer is selected from the group consisting of leukemia, lymphoma, myeloma, myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN).
  5. 5. The method according to claim 1 or 4, the PI3K gamma inhibitor and the antimetabolite for use according to claim 2 or 4, or the use of the PI3K gamma inhibitor and the antimetabolite according to claim 3 or 4, wherein the blood cancer is resistant to cytarabine monotherapy.
  6. 6. The method according to claim 1, 4 or 5, the PI3K gamma inhibitor and the antimetabolite for use according to claim 2, 4 or 5, or the use of the PI3K gamma inhibitor and the antimetabolite according to claim 3,4 or 5, wherein the PI3K gamma inhibitor has an IC50 of 100 or less.
  7. 7. The method according to claim 1, 4, 5 or 6, the PI3K gamma inhibitor and the antimetabolite for use according to claim 2, 4, 5 or 6, or the PI3K gamma inhibitor and the antimetabolite for use according to claim 3, 4, 5 or 6, wherein the PI3K gamma inhibitor is at least 10 times more selective for PI3K gamma than for PI3K alpha and/or at least 10 times more selective for PI3K gamma than for PI3K beta and/or at least 10 times more selective for PI3K gamma than for PI3K delta.
  8. 8. The method according to claim 1,4, 5,6 or 7, the PI3K gamma inhibitor and the antimetabolite for use according to claim 2,4, 5,6 or 7, or the PI3K gamma inhibitor and the antimetabolite for use according to claim 3,4, 5,6 or 7, wherein the PI3K gamma inhibitor is selected from the group consisting of atoleine, bupropion, dapolimus, dulcitol, elgaritide, ji Dali plug, GSK1059615, o Mi Lisai, paspalide, cetuliplug, tenalide, talariplug, vortalide, wortmannin, AS252424, AS605240, AZD3458, ZX-101a and ZX-4081.
  9. 9. The method according to claim 1, 4, 5, 6,7 or 8, the PI3K gamma inhibitor and the antimetabolite for use according to claim 2,4, 5, 6,7 or 8, or the PI3K gamma inhibitor and the antimetabolite for use according to claim 3, 4, 5, 6,7 or 8, wherein the antimetabolite is selected from the group consisting of 5-FU [ fluorouracil ], azacytidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, fluorouridine, fludarabine phosphate, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, penstin, pralatast, thioguanine and Qu Fu uridine/tepirimidine.
  10. 10. The method according to claim 1, 4, 5, 6, 7, 8 or 9, the PI3K gamma inhibitor and the antimetabolite for use according to claim 2, 4, 5, 6, 7, 8 or 9, or the use of the PI3K gamma inhibitor and the antimetabolite according to claim 3, 4, 5, 6, 7, 8 or 9, wherein the PI3K gamma inhibitor is elgaritide and the antimetabolite is cytarabine.
  11. 11. The method according to claim 1, 4, 5, 6, 7, 8, 9 or 10, the PI3K gamma inhibitor and antimetabolite for use according to claim 2, 4, 5, 6, 7, 8, 9 or 10, or the use of the PI3K gamma inhibitor and antimetabolite according to claim 3, 4, 5, 6, 7, 8, 9 or 10, wherein the patient to be treated has been previously identified as having a low baseline PIK3R5.
  12. 12. A method of identifying a hematologic cancer patient susceptible to treatment with a PI3K gamma inhibitor, the method comprising: (i) Comparing the level of a factor indicative of the expression of the gene PIK3R5 in cancerous blood cells obtained from a patient with blood cancer and the level of a factor indicative of the expression of at least one gene from the group consisting of IRF7、LCP2、CCL5、CXCL9、PLSCR1、LYN、JAK2、IFNGR1、IRF8、CD86、TLR2、FAS、STAT1、TAPBP、B2M、CD74、TAP1、CASP1、LAP3、IL18R1、TNFRSF1B、SELL、IL10RA、TNFSF10、IFITM3、STAT2、IRF9、EIF2AK2、LY6E、BST2 and RTP4 with the level of those same factors in non-cancerous blood cells obtained from said patient, or with the level of those same factors known to be present in non-cancerous blood cells of a healthy individual, or with the level of those same factors known to be present in cancerous blood cells of a patient with blood cancer that is insensitive to treatment with a PI3K gamma inhibitor, and (Ii) The patient is selected for treatment if the level of the factor in the patient's cancerous blood cells is higher than the level of the factor in its non-cancerous blood cells, or is higher than the level of the factor in the non-cancerous blood cells of a healthy individual, or is higher than the level of the factor in the cancerous blood cells of a blood cancer patient that is insensitive to treatment with a PI3K gamma inhibitor.
  13. 13. The method of claim 12, wherein the level of the factor in the cancerous blood cells is considered to be higher than its level in the non-cancerous blood cells when the level of the factor in the cancerous blood cells is at least 110%, preferably at least 120%, more preferably at least 130%, even more preferably at least 150%, most preferably at least 200% of its level in the non-cancerous blood cells.
  14. 14. A method of treating hematological cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a p-21 activated kinase 1 (PAK-1) inhibitor.
  15. 15. A PAK-1 inhibitor for use in the treatment of hematological cancer.
  16. Use of a pak-1 inhibitor in the manufacture of a medicament for the treatment of hematological cancer.
  17. 17. The method according to claim 14, the PAK-1 inhibitor for use according to claim 15 or the use of the PAK-1 inhibitor according to claim 16, wherein the hematological cancer is selected from the group consisting of leukemia, lymphoma, myeloma, MDS and MPN.
  18. 18. The method according to claim 14 or 17, the PAK-1 inhibitor for use according to claim 15 or 17, or the use of the PAK-1 inhibitor according to claim 16 or 17, wherein the PAK-1 inhibitor has an IC50 of 100 or less.
  19. 19. The method according to claim 14, 17 or 18, the PAK-1 inhibitor for use according to claim 15, 17 or 18, or the use of the PAK-1 inhibitor according to claim 16, 17 or 18, wherein the PAK-1 inhibitor is at least 2-fold selective for PAK-1 over PAK-2 and/or at least 2-fold selective for PAK-1 over PAK-3 and/or at least 2-fold selective for PAK-1 over PAK-4 and/or at least 2-fold selective for PAK-1 over PAK-6 and/or at least 2-fold selective for PAK-1 over PAK-5/7.
  20. 20. The method according to claim 14, 17, 18 or 19, the PAK-1 inhibitor for use according to claim 15, 17, 18 or 19, or the use of the PAK-1 inhibitor according to claim 16, 17, 18 or 19, wherein the PAK-1 inhibitor is selected from the group consisting of FRAX597, FRAX1036, G-5555, FL172, PF-3758309, AZ13705339, IPA-3 and NVS-PAK1-1.

Description

Method for treating hematological cancer Federal sponsored statement The invention was carried out with government support under W81XWH-20-1-0684 awarded by the national institutes of health medical research and development (DEFENSE HEALTH AGENCY, MEDICAL RESEARCH AND Development Branch) and CA225191 awarded by the national institutes of health (National Institutes of Health). The government has certain rights in this invention. Technical Field Methods for treating hematological cancers are provided. Background Despite recent advances in the development of targeted therapies for some genetic subpopulations of acute leukemia, many disease subtypes lack mechanical targeted therapies and the long-term outcome for most patients is poor. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) are the most common types of acute leukemias in adults and children, respectively. A blast-like plasmacytoid dendritic cell tumor (BPDCN) is a rare invasive hematological malignancy that originates from the plasmacytoid dendritic cell (pDC) lineage. The mammalian phosphoinositide 3-kinase (PI 3K, also known as phosphatidylinositol 3-kinase) family contains 8 isoforms, which can be divided into several classes. Class I PI3 ks (classified as class IA and class IB) produce inositol 3-phosphate lipids to activate signal transduction pathways, while class II and class III PI3 ks are regulatory factors for membrane transport along endocytic pathways. Class IA PI3 ks contain three catalytic subunits, α, β and δ (encoded by PIK3CA, PIK3CB and PIK3 CD), and regulatory subunits, p85α, p55α, p50α, p85β and p55γ (encoded by PIK3R1, PIK3R2 and PIK3R 3). Class IB PI3 ks have only one catalytic subunit p110γ (encoded by PIK3 CG) and 2 regulatory subunits p101 (encoded by PIK3R 5) and p84/p87 (encoded by PIK3R 6), and are activated by G protein-coupled receptors (GPCRs) via heterotrimeric G proteins. Several cancers carry activated class IA PI3 ks and many pathway inhibitors are approved or under development. In contrast, class IB PI3K components (i.e., enzymatic p110γ and regulatory subunits) are of less interest, and therapeutic focus is limited to reprogramming macrophages with PI3K γ inhibitors for solid tumor immunotherapy. Therefore, the role of pi3kγ as a driving factor for cancer in cells is not clear. WO2021/242859 proposes methods for reducing the viability of cells expressing p 3k gamma, treating myeloid malignancies (e.g. AML) and sensitizing cells (especially cancer cells expressing p 3k gamma) to chemotherapeutic agents. These methods comprise contacting cells with a PI3K inhibitor that inhibits PI3kγ in an isoform-specific manner or administering the PI3K inhibitor to a subject. Examples of such PI3K gamma inhibitors are IPI-549 (elgaritide (eganelisib)), AS252424 and AS605240. However, WO2021/242859 discloses that therapies using PI3K gamma inhibitors in combination with antimetabolites are ineffective. Specifically, no chemotherapy sensitization of IPI-549 mediated by pii 3kγ inhibition was observed with cytarabine, azacytidine, decitabine, methotrexate, glagecloth, docetaxel, and oxaliplatin. Similarly, the inventors have previously discovered a dependence of BPDCN on pi3kγ signaling (see Q. Luo LLS Award Abstract https://www.lls.org/award/defining-pik3r5-related-pi3k-gamma-dependency-novel-therapeutic-target-blood-cancers）. they discovered that BPDCN is uniquely dependent on PIK3R5 and its partner PIK3CG and demonstrated that pi3kγ blocking drugs can suppress BPDCN cells more effectively than AML cells. Hematological cancer therapies that work by inhibiting PI3K gamma are under investigation, and therefore, there is a possibility to discover new therapeutic strategies for hematological cancers, in particular for the treatment of invasive leukemias such as BDPCN. Disclosure of Invention Further research has led to the development of such therapeutic strategies, including targeting the PI3K gamma pathway as a means of treating hematologic cancers. In a first aspect, there is provided a method of treating hematological cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a PI3K gamma inhibitor and an antimetabolite. Additional embodiments of this first aspect include a PI3K gamma inhibitor and an antimetabolite for use in the treatment of hematological cancer and the use of a PI3K gamma inhibitor and an antimetabolite in the manufacture of one or more medicaments for the treatment of hematological cancer. In a further embodiment of the first aspect, there is provided a method of treating hematological cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a PI3K gamma inhibitor, an antimetabolite, and a BCL-2 antagonist. In another embodiment, this includes a PI3K gamma inhibitor, an antimetabolite and a BCL-2 antagonist for use in treating hematological cancers, and the use of a PI3K gamma inhibitor