New study below [1].
"On 23 February 2015 {Panobinostat} received FDA accelerated approval for use in patients with multiple myeloma" [2].
Panobinostat "acts as a non-selective histone deacetylase inhibitor".
It is disappointing that we see so little activity in the area of epigenetics. Many of the changes that occur in prostatic epithelial cells as they progress towards cancer or treatment resistance are epigenetic. This means that genetic mutation is not involved. Instead, genes are silenced indirectly.
One of these silencing methods is via methylation of the promoter regions for tumor suppressor genes. Methylation has legitimate use, but tumor suppressor genes are never silenced in normal cells.
PCa tends to be hypermethylated. We can limit access to methyl via a restrictive diet. The primary methyl donor in the diet is folate / folic acid. Alternatively, we can limit the co-factor vitamin B12, that is essential for the conversion of methyl-depleted homocysteine to methionine & thus to SAM, the universal methyl donor.
In addition, a demethylation agent such as genistein might reverse hypermethylation.
The second common epigenetic silencing mechanism involves histones. These are proteins that DNA is efficiently wrapped around for storage. For DNA to be accessed, histones have to be loosened by acetylization. PCa produces histone deacetylase [HDAC] enzymes to keep key DNA sequences tightly wound. The hope is that a safe histone deacetylase inhibitor [HDACI] will be found, to 'un-silence' anti-tumor DNA.
In the new study, Panobinostat was used in men with CRPC who were resistant to Bicalutamide (Casodex).
"The 40 mg panobinostat/bicalutamide regimen increased {radiographic progression-free} survival in CRPC patients resistant to {second-line antiandrogen therapy}. Panobinostat toxicity was tolerable with dose reductions. Epigenetic HDACI therapy reduces AR-mediated resistance to bicalutamide in CRPC models with clinical benefit in patients."
In theory, Panobinostat would be beneficial with other treatments where resistance has occured due to HDAC. & perhaps it could even be used to prevent resistance.
-Patrick
[1] clincancerres.aacrjournals....
Epigenetic Therapy with Panobinostat Combined with Bicalutamide Rechallenge in Castration-Resistant Prostate Cancer
Anna C. Ferrari, Joshi J. Alumkal, Mark N. Stein, Mary-Ellen Taplin, James Babb, Ethan S. Barnett, Alejandro Gomez-Pinillos, Xiaomei Liu, Dirk Moore, Robert DiPaola and Tomasz M. Beer
DOI: 10.1158/1078-0432.CCR-18-1589
ArticleFigures & DataInfo & Metrics PDF
Abstract
Purpose: This study assesses the action of panobinostat, a histone deacetylase inhibitor (HDACI), in restoring sensitivity to bicalutamide in a castration-resistant prostate cancer (CRPC) model and the efficacy and safety of the panobinostat/bicalutamide combination in CRPC patients resistant to second-line antiandrogen therapy (2ndLAARx).
Patients and Methods: The CWR22PC xenograft and isogenic cell line were tested for drug interactions on tumor cell growth and on the androgen receptor (AR), AR-splice variant7, and AR targets. A phase I trial had a 3 × 3 panobinostat dose-escalation design. The phase II study randomized 55 patients to panobinostat 40 mg (A arm) or 20 mg (B arm) triweekly ×2 weeks with bicalutamide 50 mg/day in 3-week cycles. The primary endpoint was to determine the percentage of radiographic progression-free (rPF) patients at 36 weeks versus historic high-dose bicalutamide.
Results: In the model, panobinostat/bicalutamide demonstrated synergistic antitumor effect while reducing AR activity. The dose-limiting toxicity was not reached. The probability of remaining rPF exceeded protocol-specified 35% in the A arm and 47.5% and 38.5% in the B arm. The probabilities of remaining rPF were 47.5% in the A arm and 38.5% in the B arm, exceeding the protocol-specified threshold of 35%. A arm/B arm: adverse events (AE), 62%/19%; treatment stopped for AEs, 27.5%/11.5%; dose reduction required, 41%/4%; principal A-arm grade ≥3 AEs, thrombocytopenia (31%) and fatigue (14%).
Conclusions: The 40 mg panobinostat/bicalutamide regimen increased rPF survival in CRPC patients resistant to 2ndLAARx. Panobinostat toxicity was tolerable with dose reductions. Epigenetic HDACI therapy reduces AR-mediated resistance to bicalutamide in CRPC models with clinical benefit in patients. The combination merits validation using a second-generation antiandrogen. Clin Cancer Res; 1–12. ©2018 AACR.
Footnotes
Note: Supplementary data for this article are available at Clinical Cancer Research Online (clincancerres.aacrjournals.....
Prior Presentation: Presented at the 51st Annual Meeting American Society of Clinical Oncology (ASCO), Chicago, IL, May 29–June 2, 2015.
Received May 21, 2018.
Revision received August 3, 2018.
Accepted September 10, 2018.
Published first September 17, 2018.
©2018 American Association for Cancer Research.
