Search

CN-122003234-A - TPM1.8 and/or TPM1.9 isomer targeted compounds for prevention and/or treatment of cancer

CN122003234ACN 122003234 ACN122003234 ACN 122003234ACN-122003234-A

Abstract

The present invention addresses the problem of providing new and improved therapeutic compounds for the prevention and/or treatment of cancer (e.g. ovarian cancer). The present invention provides compounds targeting TPM1.8 and/or TPM1.9, alternative splice variants of TPM1. The compounds or pharmaceutical compositions comprising at least one compound according to the invention counteract chemotherapy resistance, e.g. to taxane-and/or platinum-based chemotherapeutic agents. Furthermore, the invention includes methods of identifying compounds targeting tpm1.8 and/or tpm1.9 isomers that have therapeutic effects in inhibiting, suppressing, preventing and/or treating cancer.

Inventors

  • Ricardo fortune
  • Peter William Gangning
  • Edna Kristen. Hardman
  • NICOLE SARAH BRYCE

Assignees

  • 鹿特丹伊拉斯姆斯大学医疗中心
  • 新南创新有限公司

Dates

Publication Date
20260508
Application Date
20240724
Priority Date
20230724

Claims (15)

  1. 1. A compound which is an inhibitor of tropomyosin 1 alternative splice isomer tpm1.8 and/or tpm1.9, wherein the compound is selected from the group consisting of -A small molecule inhibitor selected from 3- (2-methyl-indol-1-yl) -propylamine (PubChem CID 6494468) and 1-phenylmethyl-1H-indole-2-methanol (PubChem CID 18973468), and pharmaceutically acceptable salts, hydrates, derivatives, solvates or prodrugs thereof; antisense polynucleotides reducing expression of tropomyosin 1 isomer 1.8 and/or 1.9 (Tpm1.8 or Tpm1.9), and -An antibody that reduces tpm1.8 and/or tpm1.9 polypeptide levels and/or tpm1.8 or tpm1.9 polypeptide activity.
  2. 2. The compound according to claim 1 for use in a method of preventing and/or treating cancer.
  3. 3. The compound for use according to claim 2, wherein the cancer expresses a TPM1 alternative splice isomer, preferably wherein the cancer expresses a TPM1 alternative splice isomer of TPM1 exon 1b, more preferably alternative splice isomers TPM1.8 and/or TPM1.9.
  4. 4. The compound according to any one of the preceding claims, wherein the cancer is selected from Acute Myelogenous Leukemia (AML), adrenocortical carcinoma, bladder urothelial carcinoma, brain low grade carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, lymphoid tumor diffuse large B-cell lymphoma, mesothelioma, ovarian cancer, in particular ovarian serous carcinoma, pancreatic adenocarcinoma, rectal adenocarcinoma, sarcoma, skin melanoma, gastric adenocarcinoma, testicular germ cell tumor, thymoma, thyroid carcinoma, uterine sarcoma, endometrial carcinoma, uveal melanoma, and combinations thereof.
  5. 5. The compound according to any one of the preceding claims, wherein the cancer is ovarian cancer, more preferably high grade serous ovarian cancer.
  6. 6. The compound for use according to any one of claims 2 to 5, wherein the compound is administered in combination with an additional anti-cancer therapy, preferably selected from chemotherapy, targeted therapies such as immunotherapy, stem cell therapy, hormonal therapy, radiation therapy and surgery and combinations thereof, more preferably taxane and/or platinum based chemotherapy.
  7. 7. The compound for use according to any one of claims 2 to 6, wherein the use comprises administering the compound to a subject at a dose of 0.1mg/kg to 100 mg/kg.
  8. 8. A pharmaceutical composition comprising a compound according to claim 1, preferably the composition further comprises a pharmaceutically acceptable carrier.
  9. 9. A method of inhibiting, suppressing, preventing or treating proliferation, motility, invasion, diffusion, migration, metastasis or chemotherapy resistance of cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 8.
  10. 10. The method of claim 9, wherein the cancer expresses a TPM1 alternative splice isomer, preferably wherein the cancer expresses a TPM1 alternative splice isomer of TPM1 exon 1b, more preferably alternative splice isomers TPM1.8 and/or TPM1.9.
  11. 11. The method of claim 9, wherein the cancer is selected from Acute Myelogenous Leukemia (AML), adrenocortical carcinoma, urinary bladder urothelial carcinoma, low grade brain carcinoma, invasive breast carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, lymphoid tumor diffuse large B-cell lymphoma, mesothelioma, ovarian carcinoma, in particular ovarian serous carcinoma, pancreatic adenocarcinoma, rectal adenocarcinoma, sarcoma, skin melanoma, gastric adenocarcinoma, testicular germ cell tumor, thymoma, thyroid carcinoma, uterine sarcoma, endometrial carcinoma, uveal melanoma, and combinations thereof, preferably wherein the cancer is ovarian cancer, more preferably high grade serous ovarian cancer.
  12. 12. The method of claim 10 or 11, wherein the therapeutically effective amount comprises a dose of 0.1mg/kg to 100 mg/kg.
  13. 13. A method of identifying a compound targeting tpm1.8 and/or tpm1.9 isomers for inhibiting, suppressing, preventing and/or treating proliferation, motility, invasion, migration, metastasis and/or chemotherapy resistance of cancer, the method comprising: a) Contacting cancer cells expressing tpm1.8 and/or tpm1.9 isoforms with a test compound, and B) Measuring inhibition of tpm1.8 and/or tpm1.9 expression and/or activity in said cancer cells, Wherein the discovery of inhibition identifies the test compound as a compound for use in a method of inhibiting, suppressing, preventing and/or treating cancer.
  14. 14. The compound of claim 1 for use in a method of inhibiting, suppressing, preventing or treating movement, invasion, diffusion, migration, metastasis or chemoresistance of cancer.
  15. 15. A method for determining the presence of epithelial-to-mesenchymal transition (EMT) in a cancer cell, comprising determining the expression of tpm1.8 and/or tpm1.9 in the cell, whereby an increase in expression relative to control expression is indicative of the presence of EMT in the cell.

Description

TPM1.8 and/or TPM1.9 isomer targeted compounds for prevention and/or treatment of cancer Technical Field The present invention relates to the use of compounds targeting the alternative splice isomer TPM1.8 and/or TPM1.9 of tropomyosin 1 (TPM 1) in a method of preventing and/or treating cancer. Furthermore, the present invention relates to a method for identifying other compounds that target TPM1.8 and/or TPM1.9 isomers and for use in a method for preventing and/or treating cancer. Background Phenotypic plasticity, defined as the ability of individual cells with stable genotypes to exhibit different phenotypes when exposed to specific environmental signals, represents a characteristic feature of cancer cells involved in the process from primary foci to distant organ sites where metastatic colonization occurs. Phenotypic plasticity is driven by a broad range of epigenetic mechanisms that allow reversibility of epithelial-to-mesenchymal transition and mesenchymal-to-epithelial transition (EMT/MET). Epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are believed to underlie the local spread and distant metastasis of most epithelial malignancies, including ovarian cancer, where there is a lack of physical barriers between the primary site and the metastatic site, suggesting that alternative shedding mechanisms may exist. EMT/MET is regulated by a wide range of epigenetic mechanisms involving chromatin remodeling due to histone methylation/acetylation, non-coding RNAs, promoter DNA methylation, and post-transcriptional mechanisms (e.g., alternative Splicing (AS)). Metastasis is the leading cause of the greatest number of cancer deaths. Metastatic disease, or movement of cancer cells from one site to another, is a complex process requiring abrupt remodeling of the cytoskeleton. The various components of the cytoskeleton, actin (microfilaments), microtubules (MT) and intermediate filaments are highly integrated and their functions are well coordinated in normal cells. Ovarian cancer is the most fatal gynaecological cancer, but the early stages of ovarian cancer do not show any noticeable symptoms. Most patients with ovarian cancer present with a diffuse disease at the time of diagnosis, and most patients will be treated for metastatic disease, which is one of the main causes of poor prognosis of ovarian cancer. There is a need for a better understanding of the course of cancer metastasis. Tropomyosin plays an important role as an actin-binding protein in metastatic disease and is often down-regulated in the cellular transformation and dedifferentiation processes of tumor development. Among the various epigenetic mechanisms, tropomyosin AS may play a role in regulating EMT/MET in cancer metastasis. The tropomyosin 1 (TPM 1) gene encodes various AS isoforms. The inventors have undertaken their study on whether the alternative splice isomer of TPM1 can be used as a therapeutic target for the treatment of cancer. The present invention solves the problem of providing novel compounds for the prevention and/or treatment of cancer, such as ovarian cancer. Disclosure of Invention Unexpectedly, the inventors of the present invention have found that the two isoforms TPM1.8 and TPM1.9 of the tropomyosin 1 gene (TPM 1) provide novel and promising targets for the prevention and/or treatment of cancer (e.g. ovarian cancer). Without wishing to be bound by theory, it is believed that tpm1.8 and/or tpm1.9 represent specific isoforms involved in EMT activation through a variety of signaling pathways including Wnt, TGF- β, hedgehog, and Notch. Furthermore, tpm1.8/9 isomers may promote diffusion from primary tumors into the abdominal cavity due to their localization to pseudopodia and functional role in cell movement. The examples and figures below show, inter alia, that tpm1.8/9 isomer is a promising target for the prevention and/or treatment of cancer (e.g. ovarian cancer). Furthermore, compounds of the invention targeting tpm1.8 and/or tpm1.9 isomers are shown to be useful in the prevention and/or treatment of cancer (e.g., ovarian cancer). The inventors further found that RBM4 and ESRP1 were up-and down-regulated, respectively, in CD44 High height EpCAM Low and low cells immortalizing High Grade Serous Ovarian Cancer (HGSOC) cell lines OV90, SKOV3, COV504 and CAOV3 by FACS using CD44 and EpCAM antibodies. Such CD44 High height EpCAM Low and low cells display a mesenchymal-like morphology, in contrast to the epithelial appearance of their corresponding CD44 High height EpCAM High height cells, whereby CD44 High height EpCAM Low and low cells display increased migration and invasion capacity. Furthermore, AS both by RT-qPCR and Western blot analysis, the TPM1 Alternative Splicing (AS) pattern observed in ovarian cancer involved exon 1a/2a and exon 1b, exon 1a/2a marked the up-regulated Tpm1.6/7 isomer in CD44 High height EpCAM High height cells, and exon 1b was characterized by the up-