Treatment of metastatic prostate cancer
Inventors
GAO, ALLEN C. • Liu, Chengfei • Lou, Wei • Pan, Chong-xian
Assignees
US Department of Veterans Affairs
Publication Number
US-11215617-B2
Publication Date
2022-01-04
Expiration Date
2034-10-27
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Abstract
The present invention provides new compositions and methods for treating prostate cancer, e.g., drug-resistant prostate cancer, such as anti-androgen drug (e.g., enzalutamide) resistant and/or castration resistant prostate cancer (CRPC). These new compositions include, but are not limited to, pharmaceutical compositions that include an AR-V7 inhibitor, such as niclosamide. Alternatively, these new compositions can include, but are not limited to, pharmaceutical compositions that include an AKR1C3 inhibitor, such as indomethacin. These new methods include, but are not limited to, methods of administering an AR-V7 inhibitor, such as niclosamide, and/or an AKR1C3 inhibitor, such as indomethacin, to treat patients having prostate cancer. The present invention also provides methods of inhibiting androgen receptor variant expression, e.g. AR-V7, and methods of killing cells expressing AR-V7. The present invention further provides methods of inhibiting AKR1C3 expression or activity, and methods of killing cells that express AKR1C3.
Core Innovation
The present invention provides novel compositions and methods for treating prostate cancer, particularly drug-resistant forms such as anti-androgen drug resistant prostate cancer and castration-resistant prostate cancer (CRPC). The invention includes pharmaceutical compositions comprising AR-V7 inhibitors, such as niclosamide, and/or AKR1C3 inhibitors, such as indomethacin, which can be administered to patients to inhibit prostate cancer cell growth and survival. These methods also encompass inhibiting androgen receptor variant expression (e.g., AR-V7) and AKR1C3 expression or activity, resulting in killing cells expressing these proteins.
The problem addressed is the failure of current treatments for prostate cancer once patients progress to castration-resistant prostate cancer or develop resistance to drugs such as enzalutamide and abiraterone. AR splice variants like AR-V7, which lack the ligand binding domain targeted by these drugs, drive androgen-independent cancer growth and confer drug resistance. Additionally, elevated expression of AKR1C3 enzyme, which is involved in intracrine androgen synthesis, contributes to drug resistance in advanced prostate cancer. Existing therapies are ineffective against these resistant cancers, highlighting the need for new treatments targeting these mechanisms.
The invention overcomes these challenges by utilizing AR-V7 inhibitors and AKR1C3 inhibitors to block variant androgen receptor signaling and intracrine androgen production, respectively. Niclosamide inhibits AR-V7 protein expression through enhanced proteasomal degradation and reduces AR-V7 transactivation activity and recruitment to PSA promoter, thereby inhibiting prostate cancer cell growth, migration, invasion, and resistance. Indomethacin inhibits AKR1C3 activity, reversing enzalutamide resistance by suppressing intracrine androgen synthesis. These inhibitors can be used alone or synergistically with anti-androgen drugs and chemotherapeutics to enhance therapeutic outcomes in advanced and drug-resistant prostate cancer.
Claims Coverage
The patent contains one independent claim that covers a method of enhancing the therapeutic effects of prostate cancer drugs using AR-V7 inhibitors.
Method of enhancing therapeutic effect of prostate cancer drugs with AR-V7 inhibition
A method comprising administering to a patient a prostate cancer drug selected from enzalutamide, abiraterone, bicalutamide, or combinations thereof, together with an AR-V7 inhibitor that synergistically increases the therapeutic activity of the drug by reversing or reducing prostate cancer cell resistance to the drug.
Oral administration of AR-V7 inhibitor niclosamide
The AR-V7 inhibitor can be niclosamide administered orally in effective doses, including daily doses of about 500 mg or more, divided into multiple doses per day if desired.
Combination therapy with AKR1C3 inhibitor
The method can further comprise co-administration of an effective amount of an AKR1C3 inhibitor, such as indomethacin, alongside the AR-V7 inhibitor and prostate cancer drug to enhance therapeutic effect.
The claims cover methods of enhancing prostate cancer drug efficacy by administering AR-V7 inhibitors, notably niclosamide, alone or with AKR1C3 inhibitors such as indomethacin, focusing on overcoming drug resistance in advanced prostate cancer through combination therapies with known anti-androgen drugs.
Stated Advantages
AR-V7 inhibitors such as niclosamide inhibit prostate cancer cell growth, induce apoptosis, and overcome resistance to anti-androgen therapies like enzalutamide and abiraterone.
AKR1C3 inhibitors such as indomethacin reduce intracrine androgen synthesis, reverse enzalutamide resistance, and enhance the efficacy of prostate cancer therapies.
Combination of AR-V7 and AKR1C3 inhibitors with current prostate cancer therapies produces synergistic or additive therapeutic effects, improving treatment outcomes in advanced or drug-resistant prostate cancer.
The pharmaceutical compositions including niclosamide and indomethacin are orally bioavailable and well tolerated, enabling convenient administration.
Documented Applications
Treatment of drug-resistant prostate cancer including anti-androgen resistant prostate cancer, castration-resistant prostate cancer, and metastatic castration-resistant prostate cancer.
Use in overcoming resistance or resensitizing prostate cancer cells to anti-androgen drugs such as enzalutamide, abiraterone, bicalutamide, and chemotherapeutic agent docetaxel.
Inhibition of androgen receptor variants, particularly AR-V7, to reduce prostate cancer progression.
Inhibition of intracrine androgen synthesis in prostate cancer cells by targeting AKR1C3.
Combination therapies comprising AR-V7 inhibitors and AKR1C3 inhibitors to enhance therapeutic efficacy of existing prostate cancer drugs.
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