Invented by Matthew I. Gross, Susanne M. Steggerda, Weiqun Li, Calithera Biosciences Inc
The Calithera Biosciences Inc invention works as follows
The invention is a method of treating cancer with an arginase inhibitor and a chemotherapeutic drug. The invention also relates to methods for assessing the efficacy of cancer treatments by measuring arginine in a tumour.Background for Compositions for inhibiting arginase Activity
Cancer is the uncontrolled proliferation of cells within the body that leads to invasion of vital organs and, often, death. In the beginning, pharmacological cancer treatment used non-specific cytotoxic drugs that attacked all rapidly dividing cell types, including normal ones. The non-specific cytotoxic drugs have anti-tumor properties, but are often restricted in their use due to severe side effects. “As our understanding of the proteins, pathways and other factors that allow cancer cells to flourish has developed, more targeted agents that block specific proteins in cancer cells have been developed.
Immuno-oncology is a new field that has emerged to address the challenges of treating cancers. It’s also known as tumor immunology. Certain tumors have developed mechanisms that allow them to avoid destruction by the immune system. Tumor immunology is the field of medicine that focuses on activating your body’s immune system in order to kill and attack tumors. In tumor immunology, the naturally occurring amino acids arginine and lysine are important because they promote growth, survival, and activation of the body’s cancer fighting cytotoxic T cells. Arginase is an enzyme secreted and produced by myeloid-derived suppressor cells that accumulate among cancer patients with multiple histotypes. Arginase levels were elevated in plasma from patients with renal cell carcinoma, breast, chronic myelogenous, lung, esophageal, prostate, glioblastoma and acute myeloid cancer. There is a requirement to develop arginase inhibitors that restore arginine in the tumor microenvironment and promote the tumor-killing ability of cytotoxic cells.
The invention, in certain aspects, provides methods to identify a therapeutic agent that is effective at increasing the level of arginine within a tumor.
a) measuring the first level of arginine within a tumor
b) Contacting the tumor with a therapy agent; and
c) measuring the second level of arginine within the tumor
The therapeutic agent can increase the amount of arginine within the tumor when the second level is higher than the initial level.
In certain aspects, this invention provides methods for identifying a drug that is effective in increasing the level of arginine within a tumor of a subject.
a) measuring the first level of arginine within a tumor in a subject
b) administering a therapeutic agent to the subject; and
c) measuring the second level of arginine within the tumor of the patient;
The therapeutic agent can increase the amount of arginine within the tumor when the second level is higher than the initial level.
In another aspect, the present invention provides a method of assessing a tumor’s response to an agent of therapy arginine, which comprises:
a) measuring the first level of arginine within a tumor from a cancer patient
b) administering an agent of arginine treatment to the patient; and
c) measuring the second level of arginase in the tumor, and assessing the response to the arginine treatment.
The invention also provides methods to assess the anti-cancer efficacy an agent of arginine treatment, which include:
a) measuring the first level of arginine within a tumor from a cancer patient
b) administering an agent of arginine treatment to the patient; and
c) measuring the second level of arginine within the tumor, and thereby assessing anti-cancer efficacy for an agent of arginine treatment.
The invention also provides methods for treating cancer or preventing it, which include administering to the subject a therapeutically-effective amount of an agent of arginase therapy. The arginase inhibitor can be a compound from Formulae I or II. In some embodiments, these methods also include administering additional chemotherapeutic drugs.
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