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CN-122003240-A - Combination therapy and uses thereof

CN122003240ACN 122003240 ACN122003240 ACN 122003240ACN-122003240-A

Abstract

The present disclosure relates to combinations of BH-3 mimetics and STING agonists, and the use of such combinations in combination therapies for the treatment of cancer.

Inventors

  • A.WEI
  • A. Strauser
  • G. Kelly
  • S. Dipstratan
  • A. ROBERTS
  • Y.Yuan
  • F. BROWN
  • B. Moro
  • G. MATTHEWS

Assignees

  • 阿库勒斯治疗私人有限公司

Dates

Publication Date
20260508
Application Date
20240801
Priority Date
20230801

Claims (20)

  1. 1. A method of treating or inhibiting progression of cancer in a subject, the method comprising co-administering to the subject: BH3 mimetic agent, and STING agonists.
  2. 2. A method of inducing an immune response to cancer in a subject, the method comprising: Co-administering a BH3 mimetic and a STING agonist to the subject, thereby eliciting an anti-cancer immune response in the subject.
  3. 3. The method of any one of the preceding claims, wherein the cancer comprises cells expressing STING protein.
  4. 4. A method of treating or inhibiting progression of cancer in a subject, the method comprising: identifying the subject as a candidate for BH3 mimetic drug therapy; Identifying the cancer as comprising cells expressing STING protein, and Administering to the subject both a BH3 mimetic agent and a STING agonist, Wherein said STING agonist is administered sequentially or simultaneously with said BH3 mimetic agent.
  5. 5. The method of any one of the preceding claims, wherein the cancer comprises TP53 wild-type cells and TP53 mutant/defective cells.
  6. 6. The method of any one of the preceding claims, wherein the cancer is refractory or resistant to BH3 mimetic drug monotherapy.
  7. 7. The method of any one of the preceding claims, wherein the co-administration comprises simultaneous administration of the BH3 mimetic and the STING agonist.
  8. 8. The method of any one of the preceding claims, wherein the co-administration comprises sequentially administering the BH3 mimetic agent and the STING agonist.
  9. 9. The method of any one of the preceding claims, wherein the BH3 mimetic agent is administered orally or intravenously.
  10. 10. The method of any one of the preceding claims, wherein the STING agonist is administered intravenously or intratumorally.
  11. 11. The method of any one of the preceding claims, wherein the BH3 mimetic agent and the STING agonist are each administered in therapeutically effective amounts.
  12. 12. The method of any of the preceding claims, wherein the BH3 mimetic agent is selected from BCL-2 selective inhibitors, such as valnemulin (venetoclax), BCL-XL selective inhibitors, such as a-1331852, and MCL-1 selective inhibitors, such as S63845.
  13. 13. The method of any one of the preceding claims, wherein the STING agonist is selected from any one of compounds 1-1 to 1-172, 2-1 to 2-25, 3-1 to 3-24, 4-1 to 4-112, and 5-1 to 5-15.
  14. 14. The method of any one of the preceding claims, wherein the BH3 mimetic agent is administered in an amount of about 50 mg/day to about 600 mg/day.
  15. 15. A method according to any preceding claim, wherein the STING agonist is administered in an amount of from about 10 μg/week to about 6,400 μg/week in an amount of from 1 dose to 1 to 3 doses per week of from 3 weeks.
  16. 16. The method of any one of the preceding claims, wherein the cancer is a hematological cancer.
  17. 17. The method according to any one of the preceding claims, wherein the cancer is a hematological cancer selected from leukemias, such as Acute Myeloid Leukemia (AML), lymphomas, such as T cell lymphomas and Multiple Myeloma (MM), or recurrent/refractory forms of any one of these diseases.
  18. 18. The method of any one of the preceding claims, wherein the cancer is a hematological cancer selected from Acute Myeloid Leukemia (AML), natural killer/T cell lymphoma (NKTL), extranodal NK/T cell lymphoma (ENKTL), and Multiple Myeloma (MM), or a relapsed/refractory form of any of these diseases.
  19. 19. The method according to any one of claims 1 to 16, wherein the cancer is a leukemia selected from Acute Myeloid Leukemia (AML), including promyelocytic leukemia, chronic Myelogenous Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL), or a relapsed/refractory form of any of these diseases.
  20. 20. The method of any one of claims 1 to 16, wherein the cancer is lymphoma.

Description

Combination therapy and uses thereof The present application claims priority from australian provisional patent application 2023902434 (filed on day 1 of 8 at 2023) and 2023903793 (filed on day 24 at 10 at 2023), the entire contents of which are incorporated herein by reference. Technical Field The disclosure herein relates to combination therapies and methods of use thereof in medicine. More particularly, the disclosure herein relates to therapies comprising a combination of BH3 mimetic agents and STING agonists suitable for the treatment and management of proliferative disorders, such as cancer, and medical treatment methods using the therapies. Background The survival rate of many cancers has increased significantly over the past decade due to molecular profiling and improvements in new treatments for these malignancies. However, a mutant disease of tumor suppressor gene TP53 (also referred to as TRP53 in mice or p53 in general) remains a significant clinical challenge for the treatment of cancer. TP53 is the most commonly mutated gene in all cancer types, but TP53 mutant cancers are particularly resistant to cytotoxic drugs that rely on DNA damage to trigger cancer cell death. TP53 mutant cancer cells also often have defects in a wide variety of pathways, including metabolism, genomic stability, and autophagy, which result in reduced sensitivity to a wide variety of anticancer agents. For hematological cancers, such as lymphomas and leukemias, a subset of patients with TP53 mutations in malignant cells are generally considered to be at adverse risk and have poor survival results. TP53 mutations are present in 5% -15% of Acute Myeloid Leukemia (AML) (up to 25% in elderly patients), TP53 mutations are present in 25% of Non-hodgkin lymphomas (Non-Hodgkin lymphomas, NHL), and TP53 mutations are present in up to 60% of natural killer/T (NKT) cell lymphoma cases in some populations. Thus, effective treatments for cancers with mutations in TP53, and in particular hematological cancers with mutations in TP53, are currently still an urgent but not yet fully addressed clinical need. TP53 is activated in response to oncogene activation, DNA damaging cytotoxic drugs, and other stresses such as g-radiation, in which case it transcriptionally upregulates expression of genes encoding pro-apoptotic BH 3-only proteins (e.g., NOXA, PUMA, BIM) and thereby initiates the intrinsic apoptotic pathway. Intrinsic apoptotic signaling is affected by the balance between pro-apoptotic and anti-apoptotic members of the BCL-2 family. Pro-apoptotic BH 3-only proteins bind to and sequester pro-survivin (e.g., MCL-1, BCL-2, BCL-XL), thereby promoting activation of pro-apoptotic effectors BAK and BAX. Activated BAK and BAX result in Mitochondrial Outer Membrane Permeability (MOMP) which releases apoptosis-generating factors into the cytoplasm, thereby catalyzing activation and cell destruction of the caspase cascade. BH3 mimetic agents are small molecule inhibitors that bind directly to and inhibit selected pro-survival members of the BCL-2 family. The identification of the function of different BCL-2 family members, aided by the continued in-depth insight into the structural interactions between pro-apoptotic and pro-surviving family members, has motivated the concept of killing cancer cells by targeting pro-surviving members with small molecules that mimic the function of BH 3-only proteins (now known as BH3 mimetic agents). The development of BH3 mimetic drugs is seen as a major milestone toward the development of a cancer therapy that is not limited to TP53 types (TP 53-diagnostic) as its use would allow activation of apoptosis downstream of TP 53. Unfortunately, although patients may initially respond well to treatment with BH3 mimetics, recent clinical data indicate that most patients will relapse. A series of mechanisms have been identified that allow resistance to BH3 mimetics to propagate, with perhaps most surprising that functional TP53 is necessary to achieve maximum BH3 mimetic-induced leukemia cell apoptosis. Although the underlying mechanism of this TP 53-mediated response to BH3 mimetic agents is currently unknown, recent evidence suggests that patients with TP 53-deficient hematological cancers, such as Chronic Lymphocytic Leukemia (CLL) or AML, have poor results following treatment with the BCL-2 specific BH3 mimetic agent, venezutolg (venetoclax). Accordingly, a treatment for cancer that addresses one or more of the above problems, or at least provides a useful alternative, is desirable. In particular, improved methods of treating cancer or inhibiting progression thereof by killing malignant cells without being restricted by their TP53 status (mutant or wild-type) are desirable. The invention described herein provides a novel combination therapy that overcomes the impediment to successful treatment of otherwise fragile cancers driven by the mutated state of TP53 by BH3 mimetic agents, and possibly other anti-cancer age