Use of pyruvate or succinate to enhance the efficacy of a hypoxia activated prodrug for the treatment of tumors
Inventors
Matsumoto, Shingo • Gillies, Robert J. • Mitchell, James B. • Cherukuri, Murali K. • Saito, Keita
Assignees
H Lee Moffitt Cancer Center and Research Institute Inc • US Department of Health and Human Services
Publication Number
US-9402820-B2
Publication Date
2016-08-02
Expiration Date
2032-04-20
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Abstract
The identification of pO2 lowering agents as transient hypoxia-inducers is disclosed herein. Provided is a method of enhancing the efficacy of a hypoxia-sensitive agent in a subject, by administering to the subject a therapeutically effective amount of the hypoxia-sensitive agent and a therapeutically effective amount of a pO2 lowering agent. Methods of treating a subject with a tumor, by administering to the subject a therapeutically effective amount of a pO2 lowering agent and a therapeutically effective amount of a hypoxia-sensitive agent are also disclosed.
Core Innovation
This disclosure concerns agents that transiently decrease the partial pressure of oxygen (pO2) in tumors and methods of using these agents to increase the efficacy of hypoxia-sensitive agents for treating tumors in subjects. Specifically, it is disclosed that exogenous administration of a pO2 lowering agent, such as mitochondrial substrates like pyruvate or succinate, can transiently enhance hypoxia in tumor cells, thereby increasing the activity and efficacy of hypoxia-sensitive agents.
The problem being addressed is that hypoxia within solid tumors is associated with resistance to standard treatments, such as radiotherapy, due to the tumor's disordered vasculature leading to poorly perfused regions. Conventional drug therapy is less effective in hypoxic tumors since drugs rely on the bloodstream for delivery. Although hypoxia-activated prodrugs have been developed to target hypoxic tumor regions, there remains a need for innovative methods to improve anticancer therapy.
Claims Coverage
The patent includes one independent claim directed to a method of enhancing the efficacy of a hypoxia activated prodrug in a subject having a tumor by co-administering the prodrug and a specific pO2 lowering agent. The main inventive features focus on the use of pyruvate or its isotopologues to transiently enhance tumor hypoxia to increase prodrug efficacy.
Method for enhancing hypoxia-activated prodrug efficacy using pyruvate or its isotopic variants
A method comprising administering to a subject having a tumor a therapeutically effective amount of a hypoxia activated prodrug and a therapeutically effective amount of CH3COCOO−, 13CH3COCOO−, and/or CH3COCOOH (pyruvate or isotopologues), where the pyruvate amount is sufficient to transiently enhance hypoxia of the tumor, thereby enhancing the prodrug efficacy.
Specific targeting of pancreatic, colon, and squamous cell carcinomas
The method is applied where the tumor is pancreatic cancer, colon cancer, or squamous cell carcinoma, demonstrating therapeutic enhancement in these cancer types.
Administration regimens for pyruvate
The pyruvate or its isotopic variants can be administered as a single dose or multiple doses, and administration can be prior to or concurrent with the hypoxia activated prodrug.
Measurement of oxygen partial pressure to confirm hypoxia enhancement
The method can include measuring the partial pressure of oxygen in the tumor after pyruvate administration and detecting a decrease in oxygen partial pressure as confirmation of transient hypoxia induction.
The independent claim discloses a method of enhancing the efficacy of the hypoxia activated prodrug TH-302 in treating specific tumor types by co-administering pyruvate or its isotopic variants to transiently increase tumor hypoxia, with various dosing and administration sequences, supported by measurement of decreased tumor oxygen partial pressure.
Stated Advantages
The pO2 lowering effect induced by mitochondrial substrates like pyruvate is transient and reversible, providing a controlled hypoxia induction that can be coordinated with administration of hypoxia-sensitive agents, avoiding long-lasting hypoxia detrimental to healthy cells.
Using naturally occurring mitochondrial substrates as pO2 lowering agents offers a relatively safe approach to enhance tumor hypoxia compared to prior anti-angiogenic or vascular disrupting agents that cause prolonged hypoxia.
The invention enables selective cytotoxicity towards hypoxic tumor cells while sparing normoxic normal cells, potentially improving the therapeutic index of hypoxia-sensitive agents.
Documented Applications
Treatment of various solid tumors, including squamous cell carcinoma, pancreatic cancer, colon cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, hepatocellular carcinoma, basal cell carcinoma, and central nervous system tumors, among others.
Co-administration with hypoxia-activated prodrugs such as TH-302 to enhance anti-tumor efficacy.
Use in combination with radiotherapy or other chemotherapeutic agents, with timing to exploit transient hypoxia induced by pyruvate or succinate.
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