Methods for the effective treatment of metastatic cancer
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Publication Number
US-11744842-B2
Publication Date
2023-09-05
Expiration Date
Abstract
The present invention relates to methods for the treatment of metastatic cancer. Methods of treating metastatic cancer by administration of a set of drugs overcome multiple mechanisms of melphalan resistance and hypersensitize cancer cells to melphalan are described. The methods involve the administration of drug(s) that induce oxidative stress in cancer cells, in conjunction with melphalan on a defined schedule.
Core Innovation
The invention relates to cancer therapy drug regimens built around DNA crosslinking combined with redox and repair modulation. It describes use of a redox-cycling agent, including methylene blue or leuco-methylene blue, to deplete glutathione (GSH) and increase oxidative stress, thereby involving ROS species such as superoxide and hydrogen peroxide (H2O2). The regimen embodiments further describe sensitizing cells to DNA crosslinking agents by inhibiting nucleotide excision repair (NER).
The document describes redox-active thiol modification and/or ROS-mediated effects connected with NER components, and it also discusses other redox-sensitive DNA damage repair proteins. The described approach includes regulating the intracellular GSSG/GSH reduction potential to inhibit repair pathways, including NER and homologous recombination (HR).
The document also describes regimen combinations that may include oxidative-stress inducers together with DNA crosslinkers, and optionally proteasome inhibitors. Examples of proteasome inhibitors mentioned include carfilzomib (Kyprolis) and bortezomib (Velcade), and stem cell infusion is referenced in connection with hematopoietic/bone marrow stem cells. The described drug sets include combinations such as BCNU plus an anthracycline or methylene blue plus melphalan.
The invention relates to treating metastatic cancer or refractory metastatic cancer in a subject by administering bizelesin, bone marrow stem cells, and an MDR-1 pgp pump inhibitor. The bizelesin component is defined by an approximately 1 μg/m2 to approximately 20 μg/m2 dose range, and the inhibitor is provided in a milligram to gram dose range to inhibit efflux of bizelesin by the MDR-1 pgp pump. The disclosure further includes refinements that may narrow the target to solid metastatic cancer, and may include purification of bone marrow stem cells to reduce the number of circulating tumor cells.
Claims Coverage
The partial content includes three independent claims. Across these independent claims, the core coverage is a therapeutically effective bizelesin regimen in combination with bone marrow stem cells and an MDR-1 pgp pump inhibitor, with quantitative bizelesin dosing and inhibitor efflux-inhibition functionality.
Bizelesin dose with bone marrow stem cells and MDR-1 pgp inhibition
A combination for therapy for treating metastatic cancer or refractory metastatic cancer in a subject, comprising a therapeutically effective dose of bizelesin or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective dose of bizelesin is approximately 1 μg/m2 to approximately 20 μg/m2, bone marrow stem cells, and an MDR-1 pgp pump inhibitor or a pharmaceutically acceptable salt thereof in a range of a milligram to gram dose that inhibits efflux of bizelesin by the MDR-1 pgp pump.
Delivering bizelesin with bone marrow stem cells and MDR-1 pgp efflux inhibition
A method of treating metastatic cancer or refractory metastatic cancer in a subject in need thereof, comprising delivering an approximately 1 μg/m2 to approximately 20 μg/m2 dose of bizelesin or a pharmaceutically acceptable salt thereof to a treatment site of the subject, in combination with bone marrow stem cells, and an MDR-1 pgp inhibitor or a pharmaceutically acceptable salt thereof in a range of a milligram to gram dose that inhibits efflux of bizelesin from the MDR-1 pgp pump.
Tariquidar-based MDR-1 pgp inhibition in a bizelesin-stem cell combination
A combination for therapy for treating metastatic cancer or refractory metastatic cancer in a subject, comprising a therapeutically effective dose of bizelesin or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective dose of bizelesin is approximately 1 μg/m2 to approximately 20 μg/m2, bone marrow stem cells, and tariquidar or a pharmaceutically acceptable salt thereof in a range of a milligram to gram dose that inhibits efflux of bizelesin by the MDR-1 pgp pump.
Across the independent claims, the claim coverage centers on treating metastatic cancer or refractory metastatic cancer with a defined bizelesin dose range in combination with bone marrow stem cells and an MDR-1 pgp pump inhibitor. The method claim covers delivery of this combination to a treatment site, and the partial content further specifies tariquidar in one independent claim.
Stated Advantages
Depletes glutathione (GSH) and increases oxidative stress.
Involves ROS species such as superoxide and hydrogen peroxide (H2O2).
Sensitizes cells to DNA crosslinking agents by inhibiting nucleotide excision repair (NER).
Regulates the intracellular GSSG/GSH reduction potential to inhibit repair pathways, including NER and homologous recombination (HR).
Inhibits efflux of bizelesin by the MDR-1 pgp pump.
Treats metastatic cancer or refractory metastatic cancer in a subject.
Documented Applications
Cancer therapy drug regimens using a redox-cycling agent together with DNA crosslinking agents.
Cancer therapy regimens that may include oxidative-stress inducers together with DNA crosslinkers, and optionally proteasome inhibitors.
Treating metastatic cancer or refractory metastatic cancer in a subject using a combination of bizelesin, bone marrow stem cells, and an MDR-1 pgp pump inhibitor.
Delivering a combination of bizelesin, bone marrow stem cells, and an MDR-1 pgp pump inhibitor to a treatment site as a method of treating metastatic cancer or refractory metastatic cancer.
Treating metastatic cancer or refractory metastatic cancer in a subject, including solid metastatic cancer.
Method of treating metastatic cancer or refractory metastatic cancer by delivering bizelesin to a treatment site in combination with bone marrow stem cells and an MDR-1 pgp inhibitor.
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