Methods for modulating chemotherapeutic cytotoxicity
Inventors
Roberts, David D. • Soto Pantoja, David R.
Assignees
US Department of Health and Human Services
Publication Number
US-11285169-B2
Publication Date
2022-03-29
Expiration Date
2034-03-13
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Abstract
Methods of reducing cytotoxicity of a chemotherapeutic agent to non-cancer cells by administering to a subject with cancer an effective amount of an agent that inhibits CD47 signaling and a DNA damaging agent, such as an anthracycline, topoisomerase inhibitor, or nucleotide synthesis inhibitor, are provided. Example disclosed methods reduce cardiotoxicity. In one example, the methods include administering to a subject with cancer an effective amount of a CD47 antisense morpholino oligonucleotide and an anthracycline such as doxorubicin. Methods of increasing cytotoxicity of a chemotherapeutic agent in cancer cells by administering to a subject with a tumor an effective amount of an agent that inhibits CD47 signaling and a DNA damaging agent such as an anthracycline, topoisomerase inhibitor, or nucleotide synthesis inhibitor, are also provided. In some embodiments, the inhibitor of CD47 signaling is administered to the subject before, during, or after the administration of the DNA damaging agent.
Core Innovation
The invention provides methods of modulating cytotoxicity of chemotherapeutic agents by administering to a subject with cancer an effective amount of an agent that inhibits CD47 signaling in combination with a DNA damaging chemotherapeutic agent. The methods reduce cytotoxicity of chemotherapeutic agents to non-cancer cells while increasing cytotoxicity of the agents to cancer cells. A particular focus is on reducing cardiotoxicity of chemotherapeutic agents such as anthracyclines (for example, doxorubicin) and increasing their cancer cell cytotoxicity concurrently.
The problem being addressed is the detrimental side effects associated with traditional chemotherapeutic agents, which kill rapidly dividing cells including non-cancer cells. The background describes that many chemotherapeutic agents damage DNA and are effective against cancers, but their use is limited by side effects, especially cardiotoxicity. Attempts to modify chemotherapeutics to reduce cardiotoxicity have either decreased efficacy or failed to improve side effects, highlighting the need for alternative approaches to improve chemotherapy safety and effectiveness.
The invention unexpectedly discovers that inhibition of CD47 signaling can differentially modulate chemotherapeutic cytotoxicity: it decreases damage to non-cancer cells and tissues, including the heart, and increases anti-tumor efficacy by making cancer cells more sensitive to chemotherapy. This effect can be obtained by administering agents that inhibit CD47 signaling, including antisense oligonucleotides (such as CD47 morpholinos), antibodies, peptides, or small molecules, either before, during, or after administration of DNA damaging chemotherapeutic agents.
Claims Coverage
The patent contains one independent claim that comprehensively covers the main inventive concept of reducing cytotoxicity of chemotherapeutic agents to non-cancer cells using CD47 inhibition with an antisense morpholino.
Use of an antisense CD47 morpholino oligonucleotide to reduce chemotherapeutic cytotoxicity
A method of reducing cytotoxicity of an anthracycline, a topoisomerase inhibitor, or a nucleotide synthesis inhibitor to non-cancer cells in a subject by administering an effective amount of an antisense CD47 morpholino oligonucleotide in combination with the chemotherapeutic agent, wherein the morpholino is administered before, during, or after administration of the chemotherapeutic agent.
The claims focus on the combination of an antisense CD47 morpholino oligonucleotide with specific classes of DNA damaging chemotherapeutic agents to reduce cytotoxicity to non-cancer cells, with details regarding timing of administration, selection of agents, and target cancer types. This defines the inventive coverage as methods of modulating chemotherapy side effects through CD47 inhibition by antisense agents.
Stated Advantages
Inhibition of CD47 signaling dramatically decreases cytotoxicity of chemotherapeutic agents to non-cancer cells, particularly reducing cardiotoxicity associated with anthracycline chemotherapy.
Inhibition of CD47 signaling increases cytotoxicity of chemotherapeutic agents to cancer cells, thereby enhancing anti-tumor efficacy.
The methods allow administration of chemotherapeutic agents in safer dosages and treatment regimens by protecting normal tissues while effectively targeting tumors.
Documented Applications
Reducing cardiotoxicity of anthracycline chemotherapeutic agents such as doxorubicin in subjects with cancers including breast cancer, lung cancer, ovarian cancer, prostate cancer, and hematological malignancies.
Increasing the efficacy of anthracycline and other DNA damaging chemotherapeutic agents in the treatment of solid tumors and metastatic cancers by co-administering agents that inhibit CD47 signaling.
Protecting non-cancer cells from side effects such as nephrotoxicity, hepatotoxicity, myelosuppression, alopecia, gastrointestinal distress, and peripheral neuropathy caused by chemotherapy.
Using antisense CD47 morpholino oligonucleotides and other agents blocking CD47 signaling to modulate cancer therapy outcomes in humans and animal models.
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