MONOAMINE OXIDASE INHIBITORS AND METHODS FOR TREATMENT AND DIAGNOSIS OF PROSTATE CANCER

Abstract

A method of treating prostate cancer in a subject with biochemically recurrent prostate cancer is provided. The method includes administering to a subject in need thereof an effective amount of a pharmaceutical composition that includes phenelzine.

Claims

1. A method of treating prostate cancer in a subject with biochemically recurrent prostate cancer comprising: administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising phenelzine.

2. The method of claim 1, wherein the pharmaceutical composition is administered orally.

3. The method of claim 2, wherein the pharmaceutical composition is administered orally twice a day and the amount of phenelzine in each dose is about 30 mg.

4. The method of claim 1, wherein the pharmaceutical composition further comprises an excipient.

5. The method of claim 1, wherein the pharmaceutical composition further comprises a physiologically acceptable carrier.

6. The method of claim 1, wherein a primary endpoint is a proportion of patients who achieve a PSA decline of 50% from baseline.

7. A method of treating prostate cancer in a subject with a post-prostatectomy PSA 0.4 ng/ml or a post-radiation therapy PSA 2 ng/ml above a post-therapy nadir comprising: administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising phenelzine.

8. The method of claim 7, wherein the pharmaceutical composition is administered orally.

9. The method of claim 8, wherein the pharmaceutical composition is administered orally twice a day and the amount of phenelzine in each dose is about 30 mg.

10. The method of claim 7, wherein the pharmaceutical composition further comprises an excipient.

11. The method of claim 7, wherein the pharmaceutical composition further comprises a physiologically acceptable carrier.

12. The method of claim 7, wherein a primary endpoint is a proportion of patients who achieve a PSA decline of 50% from baseline.

13. The method of claim 1, further comprising one or more monoamine oxidase A (MAO-A) inhibitors.

14. The method of claim 13, further comprising a Chinese herb medicine and/or a plant extract.

15. The method of claim 7, further comprising one or more monoamine oxidase A (MAO-A) inhibitors.

16. The method of claim 15, further comprising a Chinese herb medicine and/or a plant extract.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0035] FIG. 1 (A-F). shMAOA knockdown (KD) of MAOA in human LNCaP (A-C) and C4-2 (D-F) PCa cells significantly reduced tumor xenograft growth (A, D), tumor weight (B, E) and tumor incidence (C, F) in athymic nude mice (subcutaneous injection, 6 mice per cell line, 3 tumor inoculation sites per mouse). shCon and shMAOA, WT and MAOA-KD cells. *,p<0.05, **,p<0.01.

[0036] FIG. 1 (G-I). shMAOA KD of MAOA in murine MCP3 (Pten/p53 /) PCa cells eliminated tumor xenograft growth in B6 immune-intact mice (subcutaneous injection, 6 mice per cell line. 3 tumor inoculation sites per mouse).

[0037] FIG. 2. PSA trend over time in a BCRPC patient treated with phenelzine. The data show a 74% decrease maintained for over 1 year.

[0038] FIG. 3. Waterfall plot of PSA decline following phenelzine treatment in patients with recurring prostate cancer.

DETAILED DESCRIPTION

Definition

[0039] Unless otherwise indicated herein, all terms used herein have the meanings that the terms would have to those skilled in the art of the present invention. Practitioners are particularly directed to current textbooks for definitions and terms of the art. It is to be understood, however, that this invention is not limited to the particular methodology, protocols, and reagents described, as these may vary.

[0040] Treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.

[0041] A therapeutically effective amount of a monoamine inhibitor is an amount sufficient to carry out a specifically stated purpose. An effective amount may be determined empirically and in a routine manner in relation to the stated purpose.

[0042] A Carrier or Carriers as used herein include pharmaceutically acceptable, carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. The physiologically acceptable carrier may be a sterile aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants.

[0043] The present invention is directed to a method of treating prostate cancer in a subject with biochemically recurrent prostate cancer. The method includes administering to the subject in need thereof an effective amount of a pharmaceutical composition that includes phenelzine.

[0044] In addition, the present invention is directed to a method of treating prostate cancer in a subject with a post-prostatectomy PSA 0.4 ng/ml or a post-radiation therapy PSA 2 ng/ml above a post-therapy nadir. The method includes administering to the subject in need thereof an effective amount of a pharmaceutical composition that includes phenelzine.

[0045] In a preferred embodiment, the pharmaceutical composition is administered orally.

[0046] In another embodiment, the pharmaceutical composition is administered orally twice a day and the amount of phenelzine in each dose is about 30 mg.

[0047] In another embodiment, the pharmaceutical composition further includes an excipient.

[0048] In another embodiment, the pharmaceutical composition further includes a physiologically acceptable carrier.

[0049] In another embodiment, a primary endpoint is a proportion of patients who achieve a PSA decline of 50% from baseline.

[0050] In another embodiment, the method further includes a monoamine oxidase A (MAO-A) inhibitor or a salt thereof.

[0051] In another embodiment, the method further includes a Chinese herb medicine and/or a plant extract with the MAO-A inhibitor or a salt thereof.

[0052] Another aspect of the present invention is directed to a method of treating prostate cancer in a subject with a post-prostatectomy PSA 0.4 ng/ml or a post-radiation therapy PSA 2 ng/ml above a post-therapy nadir. The method includes administering to the subject in need thereof an effective amount of a pharmaceutical composition that includes phenelzine.

[0053] The following examples are provided in order to demonstrate and further illustrate certain embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof. While such examples are typical of those that might be used, other procedures known to those skilled in the art may alternatively be utilized. Indeed, those of ordinary skill in the art can readily envision and produce further embodiments, based on the teachings herein without undue experimentation.

Knock Down MAO A Specifically Reduces the Tumor Growth

[0054] Data demonstrates that MAO A inhibitors reduce prostate cancer progression and metastasis. The following experiments demonstrate that this effect is due to inhibiting MAO A, not LSD1, (MAO A inhibitors also inhibits enzyme LSD1). In these experiments, the inventor specifically targets and silences tumor MAOA by lentiviral shMAOA. The results demonstrate significant inhibition of the growth of human PCa cells (both androgen-sensitive and androgen-insensitive) in vitro and tumor xenograft in vivo (FIG. 1A-F), further, it eliminates the growth of a murine tumor xenograft in immune-intact mice (FIG. 1G-I).

MAO Inhibitor (Phenelzine) Reduces PSA Level in Prostate Cancer Patients

[0055] Based on data supporting therapeutic potential for targeting of MAOA in prostate cancer, a phase 2 clinical trial was initiated to explore the effect of phenelzine (Nardil, a MAOA/B inhibitor) in patients with biochemically recurrent prostate cancer (BCRPC) (ClinicalTrials.gov Identifier: NCT02217709).

[0056] Eligibility included patients with elevated PSA after primary therapy defined by: post-prostatectomy PSA 0.4 ng/ml or post-radiation therapy PSA 2 ng/ml above a post-therapy nadir, non-castrate levels of circulating testosterone (>50 g/dl), and no evidence of metastatic cancer on standard imaging studies.

[0057] Patients were enrolled in an open-label fashion to receive a target dose of phenelzine 30 mg orally twice daily. The primary endpoint is the proportion of patients who achieve a PSA decline of 50% from baseline.

[0058] A preliminary analysis was performed after twelve evaluable patients were enrolled according to the Simon minimax two-stage design to define the probability of response to phenelzine (P1) as 20% and reject the drug if the response probability (P0) is 5% with power set at 0.8.

[0059] At the interim analysis, two subjects demonstrated 50% maximum decline in PSA level. Maximal PSA declines varying between 1-44% have been observed in six other subjects in the non-castrate group (see FIGS. 2 and 3). The adverse events profile varied greatly across subjects with some subjects reporting no ongoing toxicities while mild toxicities typically associated with MAOAIs were observed in others. Common toxicities reported included fatigue, dizziness, edema, and hypertension which were generally grade 1. The preliminary finding of 50% PSA decrease in 2/12=17% meets pre-specified criteria for continued enrollment towards the goal of 21 evaluable subjects.

[0060] Although the present invention has been described in terms of specific exemplary embodiments and examples, it will be appreciated that the embodiments disclosed herein are for illustrative purposes only and various modifications and alterations might be made by those skilled in the art without departing from the spirit and scope of the invention as set forth in the following claims.

REFERENCES

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