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CN-122028919-A - Compositions and methods for treating cancer by affecting cancer cell membrane receptors and exosomes derived therefrom

CN122028919ACN 122028919 ACN122028919 ACN 122028919ACN-122028919-A

Abstract

The present invention relates to the use of prochlorperazine (prochlorperazine, PCP) or an analogue thereof to treat cancer in an individual by modulating cancer cell membrane proteins and receptors and inducing alterations in the expression of cancer cells and extracellular surface markers produced thereby. The methods of the invention provide novel methods for the treatment and diagnosis of cancer and cancer metastasis. Specific surface markers can be potential candidates for cancer-associated exosomes (extracellular vesicles, EVs) and have utility in diagnosis, prognosis, and therapeutic targets.

Inventors

  • HUANG QIYING
  • LUO YINING
  • Cai Weini
  • Keira Solomon
  • ZHENG DASHAN
  • ZHUANG MINGXI
  • LI LI
  • ZHANG MUXIN
  • HUANG YUTANG
  • Ruan Shixiangling

Assignees

  • 黄奇英

Dates

Publication Date
20260512
Application Date
20240731
Priority Date
20230731

Claims (20)

  1. 1. Use of prochlorperazine (prochlorperazine, PCP) or an analog thereof in the manufacture of a medicament for treating cancer in a subject, wherein the cancer exhibits a high degree of specificity marker on cancer cells or exosomes (extracellular vesicles, EVs) thereof in the subject, wherein the specificity marker is selected from the group consisting of ERBB family members, CD9 and integrins.
  2. 2. The use of claim 1, wherein the ERBB family member is selected from the group consisting of HER1 (epidermal growth factor receptor (EPIDERMAL GROWTH FACTOR RECEPTOR, EGFR)), HER2, and HER 3.
  3. 3. The use of claim 1, wherein the integrin is selected from the group consisting of integrin α6 subunit and integrin β4 subunit.
  4. 4. The use of claim 1, wherein the specific marker is selected from the group consisting of EGFR, p-EGFR, glypican 1, gpc1, epCAM, CD9, integrin, alpha enolase (Enolase, ENOl), HER2, and MET.
  5. 5. The use of claim 1, wherein the cancer is a chemotherapeutic drug resistant cancer.
  6. 6. The use of claim 1, wherein the cancer is a metastatic cancer.
  7. 7. The use of claim 1, wherein the chemotherapeutic agent is an Epidermal Growth Factor Receptor (EGFR) -tyrosine kinase inhibitor.
  8. 8. The use of claim 7, wherein the EGFR-tyrosine kinase inhibitor is afatinib.
  9. 9. The use of claim 1, wherein the chemotherapeutic agent is gemcitabine.
  10. 10. The use of claim 1, wherein the PCP analog is selected from the group consisting of trifluoperazine, fluphenazine, chlorpromazine, thioridazine, and perphenazine.
  11. 11. The use of claim 10, wherein the PCP analog is thioridazine.
  12. 12. The use of claim 1, wherein the cancer is pancreatic cancer, head and neck cancer, or lung cancer.
  13. 13. The use of claim 12, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PANCREATIC ADENOCARCINOMA, PDAC).
  14. 14. The use of claim 12, wherein the head and neck cancer is head and neck squamous cell carcinoma (HEAD AND NECK squamous cell carcinoma, HNSCC).
  15. 15. The use of claim 12, wherein the lung cancer is non-small cell lung cancer (NSCLC).
  16. 16. The use of claim 13, wherein the specific marker on Exosomes (EVs) produced by Pancreatic Ductal Adenocarcinoma (PDAC) is selected from the group consisting of EGFR, p-EGFR, glypican 1 (GPC 1), epCAM, CD9, integrins, alpha enolase (ENO 1), HER2, and MET.
  17. 17. Use of a pharmaceutical composition of prochlorperazine (prochlorperazine, PCP) or an analog thereof in the manufacture of a medicament for treating cancer in a subject, wherein the cancer exhibits a high degree of specificity marker on cancer cells or exosomes (extracellular vesicles, EVs) thereof in the subject, wherein the specificity marker is selected from the group consisting of ERBB family members, CD9, and integrins.
  18. 18. The use of claim 17, wherein the ERBB family member is selected from the group consisting of HER1 (epidermal growth factor receptor (EPIDERMAL GROWTH FACTOR RECEPTOR, EGFR)), HER2, and HER 3.
  19. 19. The use of claim 17, wherein the integrin is selected from the group consisting of integrin α6 subunit and integrin β4 subunit.
  20. 20. The use of claim 17, wherein the specific marker is selected from the group consisting of EGFR, p-EGFR, glypican 1, gpc1, epCAM, CD9, integrin, alpha enolase (Enolase, ENOl), HER2, and MET.

Description

Compositions and methods for treating cancer by affecting cancer cell membrane receptors and exosomes derived therefrom Technical Field The present application claims priority from U.S. provisional patent application No. 63/516,722, filed on 7/31 at 2023, the contents of which are incorporated by reference in their entirety. The present invention relates to compositions and methods for treating cancer by affecting membrane proteins and receptors that result in alterations in surface markers on cancer cells and their derived exosomes. Background Surface markers in cancer refer to proteins or molecules that are present on the surface of cancer cells. These markers may be specific markers for certain cancers, or more commonly are manifested in multiple types of cancers. Surface markers play a vital role in the identification, diagnosis and targeted therapy of cancer. Surface markers on exosomes (extracellular vesicles, EVs) are of interest as potential drug targets for cancer treatment. EVs are bilayer lipid vesicles released by cells into the extracellular space, which play a vital role in intercellular communication by transferring bioactive molecules (e.g., proteins, nucleic acids, and lipids) between cells. The ERBB family, also known as the HER family, is composed of a group of receptor tyrosine kinases that play a critical role in cell growth, survival and proliferation. This family includes four members HER1 (EGFR, ERBB 1), HER2 (ERBB 2), HER3 (ERBB 3), and HER4 (ERBB 4). The hypermanifestations of the ERBB family are often closely related to advanced progression and poor prognosis of various cancers, including pancreatic, head and neck, and lung cancers. A variety of EGFR inhibitors have been investigated as potential methods of treating these cancers in combination with chemotherapeutic agents. However, deregulation of the ERBB family, including oncogenic dimerization of EGFR with other ERBB members, can trigger cancer stem cell characteristics as well as drug resistance. Thus, research into the mechanism of chemotherapy or anti-EGFR drug resistance has driven the development of new combination strategies to overcome these resistance challenges. Integrins are a family of transmembrane proteins that regulate cell-to-cell and cell-to-extracellular matrix interactions. Integrin α6 and integrin β4 are highly expressed in pancreatic cancer and are associated with more aggressive behavior of cancer and poor prognosis. They form integrin α6 (ITGA 6)/integrin β4 (ITGB 4) dimers that bind to extracellular matrix (ECM) ligand layer mucins, promoting cell adhesion, migration, invasion and metastasis. These integrins promote invasiveness of pancreatic cancer cells, particularly in tumor microenvironments rich in fibrotic stroma. CD9 proteins are members of the four transmembrane protein family and are involved in a variety of physiological processes such as cell motility, adhesion, invasion, etc. Previous studies have shown that CD9 recognizes cancer stem cells that are capable of restarting tumor formation and reproducing the heterogeneity of primary pancreatic ductal adenocarcinoma (PANCREATIC ADENOCARCINOMA, PDAC) cells. In addition, CD9 regulates the information transfer of stromal cells that promote PDAC progression [1, 2]. Phenothiazine derivatives are a group of older drugs, which have been studied recently for their potent anticancer effects. Prochlorlazine (prochlorperazine, PCP) acts primarily as an antiemetic with less impact on the central nervous system. Thus, there is a need to develop a new method of treating cancer by affecting membrane receptors to induce alterations in surface markers (including ERBB family and integrins) on cancer cells and their derived exosomes. In addition, surface markers expressed on EVs can be used as biomarkers for selecting patients, and thus guide prochlorperazine therapy to achieve the goals of accurate medical treatment. Disclosure of Invention The inventors have unexpectedly found that prochlorperazine (PCP) has anti-tumor and anti-tumor metastasis efficacy, particularly in the treatment of cancer. In one aspect, the present invention provides a method of treating cancer highly expressed by a specific marker in an individual, comprising the steps of: Collecting a cancer cell sample from the individual; determining whether the specific marker is overexpressed on cancer cells or their Exosomes (EVs), and If the specific marker is overexpressed on the cancer cells or Exosomes (EVs) thereof in the subject, administering to the subject a therapeutically effective amount of prochlorperazine (PCP) or an analog thereof, in combination with a chemotherapeutic agent; Wherein the specific marker is selected from the group consisting of ERBB family members, CD9, and integrins. In another aspect, the invention provides a use of prochlorperazine (PCP) or an analog thereof in the manufacture of a medicament for treating cancer in an individual, said cancer exhibiting a high degree