Methods of improving cancer chemotherapy
Inventors
Hammock, Bruce D. • Hwang, Sung Hee • De Vere White, Ralph W. • Pan, Chong-xian • Zhang, Hongyong • Henderson, Paul • MA, Ai-Hong • Zimmermann, Maike • WANG, Fuli
Assignees
United States Represented By Department Of Veterans Affairs AS • US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-11426385-B2
Publication Date
2022-08-30
Expiration Date
2038-08-14
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Abstract
Provided are methods and compositions for prolonging survival and/or reducing or inhibiting tumor growth in a cancer subject receiving a regimen of one or more chemotherapeutic agents, an inhibitor of soluble epoxide hydrolase (sEHi) and a non-steroidal anti-inflammatory drug (NSAID) that inhibits one or more enzymes selected from the group consisting of cyclo-oxygenase (“COX”)-1, COX-2, and 5-lipoxygenase (“5-LOX”). The methods and compositions decrease toxicity and/or adverse side effects in subjects receiving a regimen of one or more chemotherapeutic agents.
Core Innovation
Provided are methods and compositions for prolonging survival and/or reducing or inhibiting tumor growth in a cancer subject receiving a regimen of one or more chemotherapeutic agents, an inhibitor of soluble epoxide hydrolase (sEHi) and a non-steroidal anti-inflammatory drug (NSAID) that inhibits one or more enzymes selected from the group consisting of cyclo-oxygenase (COX)-1, COX-2, and 5-lipoxygenase (5-LOX). The methods and compositions decrease toxicity and/or adverse side effects in subjects receiving a regimen of one or more chemotherapeutic agents.
Chemotherapy remains a mainstream treatment for many types of cancers but has significant limitations due to toxicity, which restricts dose levels, dosing range, and duration of treatment. For example, cisplatin, a commonly used chemotherapeutic agent, is only moderately effective in most cancer types and highly toxic. Combination chemotherapy is further limited because accumulated toxicity restricts dosing and treatment duration.
The invention provides compositions and methods to improve the utility and effectiveness of chemotherapy by combining anti-cancer agents that enhance chemotherapy effectiveness without increasing toxicity or side effects. This includes administering one or more chemotherapeutic agents with an inhibitor of soluble epoxide hydrolase (sEHi) and a NSAID inhibiting COX-1, COX-2, and/or 5-LOX. The combination can prolong survival, reduce or inhibit tumor growth, allow longer treatment duration or increased cycles, and potentiate anti-tumor activity without increasing toxicity. In some embodiments, a dual inhibitor of sEH and COX-2, such as PTUPB, is used.
Claims Coverage
The patent includes 2 independent method claims covering treatment regimens for cancer involving chemotherapeutic agents combined with sEH inhibitors and NSAIDs targeting COX-1, COX-2, or 5-LOX.
Method of prolonging survival with combined chemotherapeutic agents, sEH inhibitor, and NSAID
Administering a regimen comprising one or more chemotherapeutic agents (selected from platinum coordination complexes and nucleoside analogs), an inhibitor of soluble epoxide hydrolase (sEHi), and a non-steroidal anti-inflammatory drug (NSAID) that inhibits COX-1, COX-2, and/or 5-LOX, to prolong survival in a subject needing cancer treatment.
Method of reducing or inhibiting tumor growth with combined chemotherapeutic agents, sEH inhibitor, and NSAID
Administering a regimen comprising one or more chemotherapeutic agents (selected from platinum coordination complexes and nucleoside analogs), an sEH inhibitor, and a NSAID inhibiting COX-1, COX-2, and/or 5-LOX, to reduce or inhibit tumor growth more effectively than chemotherapeutic agents alone.
The claims inventively cover methods of cancer treatment that use combined administration of one or more chemotherapeutic agents with an inhibitor of soluble epoxide hydrolase and an NSAID targeting COX and/or 5-LOX enzymes, specifically to prolong survival and reduce tumor growth, with embodiments including specific chemotherapeutic classes and dual inhibitors such as PTUPB.
Stated Advantages
Potentiates anti-tumor activity of chemotherapy without increasing toxicity or adverse side effects.
Allows longer duration or increased cycles of chemotherapy treatment due to decreased toxicity.
Provides synergistic inhibition of tumor growth with combined inhibition of sEH and COX-2 and reduction in proliferation signaling pathways.
Reduces chemotherapy-associated toxicity, including protection of normal tissues and prevention of weight loss and major organ damage.
Documented Applications
Treatment of various cancers including bladder, ovarian, cervical, breast, testicular, prostate, head and neck, oral, esophageal, gastric, lung, pancreatic, skin, leukemia, colon, and colorectal cancer.
Use of platinum coordination complex chemotherapeutic agents such as cisplatin, carboplatin, oxaliplatin in combination with sEH inhibitors and NSAIDs.
Use of nucleoside analog chemotherapeutic agents such as gemcitabine, cytarabine, capecitabine, 5-fluorouracil in combination with sEH inhibitors and NSAIDs.
Potentiation of efficacy and reduction of toxicity during chemotherapy regimens including cisplatin and gemcitabine in bladder cancer patient-derived xenograft (PDX) models.
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