Valproic Acid - a potential Histone Deacetylase Inhibitor (HDACi) for HRPC - more evidence needed

Definitions

Gene expression: The process by which a gene's coded information is converted into the structures present and operating in the cell. Expressed genes include those that are transcribed into mRNA and then translated into protein and those that are transcribed into RNA but not translated into protein (e.g., transfer and ribosomal RNAs).

Histones: A type of protein found in chromosomes. Histones bind to DNA, help give chromosomes their shape, and help control the activity of genes.

Acetylation: Process of introducing an acetyl group (CH₃CO) into an organic compound with deacetylation being the removal of he acetyl group. 

HDAC: Histone deacetylase (HDAc) is an enzyme that changes the way histone binds to DNA. HDAc inhibitors are being studied as a treatment for cancer.

Differentiation: The modification of cancerous cells back toward "normal cells."

cytostatic: tending to retard cellular activity and multiplication; as opposed to cytotoxic which kills cancer cells.

MTD: maximum tolerated dose, generally determined during a phase I clinical trial.

PK: pharmacokinetics. The terminal half life of VPA is 8-11 hours.  However, the ER version is designed to release valproic acid over more than 18 hours.

VPA: Valproic Acid.  Depakote ER is a brand name.  ER stands for extended release for once/day dosing.  Also called divalproex sodium.  There is also a delayed-release(DR) formulation.

Introduction

Currently, there are at least three drugs in the HDACi class that are available to patients (with a prescription) -- valproic acid (Depakote), vorinostat (Zolinza, originally it was called SAHA) and phenylbutyrate.  Valproic acid (Depakote) is a used for certain types of seizures and convulsions and for preventing migraine headaches (with the ER form).  Vorinostat has recently been approved for treating cutaneous T-Cell lymphoma and is being studied in HRPC patients. Phenylbutyrate is used to help treat a deficiency of enzymes that aid in the removal of ammonia from the body.  For prostate cancer, these are all used "off label."

This article will only be covering valproic acid and its extended release form of Depakote ER.  Vorinostat has also had a phase II clinical trial for HRPC and that will covered briefly.

HDACI (Histone deacetylase inhibitors): What are they?

A thorough explanation of HDACIs is beyond the scope of this article and the reader is referred to references 1-5 as well as many others listed in PUBMED. Even narrowing a PUBMED search to HDACIs and prostate cancer yields 41 publications.  In brief, histone acetylation results in increased gene expression and this process is regulated by histone acetylation transferases and histone deacetylases.  A number of cancers disrupt these mechanisms.  Inhibiting histone deacetylases, therefore results in greater gene expression which is associated with differentiation and growth arrest. HDACIs thus are thought to target multiple pathways.

A review paper(6) by Morris MJ and Scher HI, while it was focused on research at MSKCC, covers some basic points related to targeted therapies.  Targeting individual pathways is difficult when the pathways have variable expression and with screening methods that are not up to the task of finding appropriate patients for the drug. An example they used was HER2 where the expression of HER2 substantially varied both by clinical state and site of disease. Furthermore, better screening and tumor sampling strategies were needed, but not available - so they discontinued further development of Herceptin for prostate cancer.  Another example is where targeting a single protein involved in a single pathway might be insufficient to achieve a clinically significant response - in this case an antisense oligonucleotide that targeted BCL-2 which ended up producing no significant anti-tumor effects. 

Targeting multiple pathways, then, may be a better approach by maximizing the likelhood of achieving clinical responses and by minimizing the need to identify patients with uncharacteristic expression of a single protein.  Histone deactylase inhibitors target multiple pathways.

Valproic Acid (VPA) (2-propylpentanoic acid).

Brand name: Depakote ER.

 Single Agent Studies

Valproic Acid structurally belongs to the short-chain fatty acid class of HDAC Inhibitors. VPA inhibits cell growth, regulates differentiation, and may have effects on tumor invasion and angiogenesis (reference (7) lists 3 papers relevant to this.) 

Most of the data on VPA comes from pre-clinical models.  Xia Qinghua, et al (7) recently reviewed their results for in vitro and in vivo studies.  Their results suggest that short term (acute) treatment with VPA leads to growth inhibition and cell death in prostate cancer cells -- but, unfortunately, once the treatment is stopped the antiproliferation effect ceases.  However, when administered continuously (chronically - 10-14 days), cell proliferation decreases profoundly in vitro (petri dish cells) and there is a significant reduction in tumor volume at clinically relevant doses in vitro (mouse models.)  Their thought is that VPA would be a good agent for men with rising PSAs when tumor burden is low, perhaps leading to a lengthening of the PSA doubling time.  They also found that the androgen receptor is down-regulated with chronic VPA treatment.

S. Sharma, et al (8) looked at VPA both in pre-clinical studies and in a small group of patients with androgen independent prostate cancer (AIPC). Six cell lines, including prostate cancers were treated to escalating concentrations of VPA over 24-144 hours.  They found that VPA inhibited all solid tumor cells lines in a dose-dependent and time-dependent manner. Longer times and higher dose levels were best (at least 72-96 hours with 2-4mM.)  Patients with AIPC were given oral VPA every week or as tolerated. The doses used were 10, 15, 20, and 25mg/kg). Assuming a 70kg patient, this would correspond to 700mg to 1750mg (it isn't clear from the abstract whether or not this is just once per week or every day.)

There were only 5 patients in this study. Transient decreases in PSA were seen in all 5 when PSA was normalized to the testosterone level taken at the same time as the PSA level. Three of 4 patients had increases in their normalized PSA when they stopped VPA and one patient, re-starting VPA after stopping it had a normalized PSA decline.  Side effects were all grade 1 and were confusion (1 patient), fatigue (3), dizziness (2) and nausea and vomiting (1).

Hopefully, a full paper will be published on this study since only an abstract exists at this time.  So far, this is the only study that seems to be available using single agent VPA in AIPC patients.

Atmaca, et al (9) recently published their results in a phase I trial with VPA and refractory advanced cancer -- 1 patient with prostate cancer was included. The doses used and toxicities are of interest here. There were 26 patients progressing with solid tumors. The starting dose was VPA 30mg/kg/day (Doses: 30, 60, 75, 90, 120mg/kg).  Intravenous VPA was given over 1 hour for 5 consecutive days of a 21 day cycle. The daily dose was divided in half.  The MTD was 60mg/kg/day.  PK study: the 30 and 60mg/kg doses resulted in baseline VPA median concentrations in the range usually achieved during anti-epileptic therapy (50-120mg/l). The median maximum serum concentrations for the 30 and 60mg/kg dose levels of VPA did not exceed 200mg/l. No DLT was observed for these dose levels.  For the 90 and 120mg/kg doses median baseline concentrations often exceeded 120mg/l and median maximum concentrations, in this case, were above 200mg/l with some up to 500mg/l.  They suggested that the high maximum concentrations may contribute to the occurrence of DLTs.   

Atmaca, et al found that neurocognitive impairment was the DLT(grade 3 or 4) for in 8(31%) of 26 patients and 7 of the 8 the DLT was represented by confusion or disorientation. There were no grade 3 or 4 hematological toxicities. Five patients had fatigue, 2 were grade 3 (DLT). 13 patients has grade 1 or 2 nausea and/or vomiting.  Somnolence occurred in 21 patients with 19 of the 21 being grade 1 or 2. The other two had DLT at the 120mg/kg level.

One last HDACi is appropriate here -- Vorinostat (SAHA). A phase II trial is being run (ASCO 2007 Annual meeting, Abstract No. 5132, M. Hussain, et al) as a treatment following failed 1st line chemotherapy.  Patients took oral vorinostat 400mg/day in a 21-day cycle. They found considerable toxicities requiring dose reduction.  At the time of the abstract submittal there were 9 response evaluable patients and 3 of them achieved stable disease (23 of 29 patients had been accrued.)

Summary of Dose, method of delivery for single agent VPA

N/A - not applicable.

Combination Studies with VPA

Cell and/or xenograph level Studies with VPA and Chemotherapy

Unfortunately, there do not seem to be any published studies of VPA and chemotherapy at the in vitro/in vivo level.  There are (10, 11) two cell level studies of depsipeptide (FK228) in combination with gemcitabine (GEM) and/or docetaxel (DOC) in vitro and in vivo against hormone refractory prostate cancer (HRPC).  These are included here as an indication as to what might also be possible with VPA, but whether or not a similar effect occurs with VPA awaits actual data.

The paper by M. Kanzaki, et al (10) used low concentrations of FK228 - no effects on the cell cycle arrest and apoptosis induction were observed at this low concentration level -- however,  pretreatment of cells with low dose enhanced the cytotoxicity of both chemotherapeutic agents and the GEM enhancement was greater than that with DOC. 

The other paper, by Z. Zhang, et al (11), looked at FK228 plus docetaxel and found that "FK228/docetaxel surpassed other FK228-based combinations by
achieving more synergism of cytotoxicity. FK228 enhanced the therapeutic effect of docetaxel against AIPCa by exhibiting markedly enhanced and prolonged inhibitory effects in vitro and better tumor regression in vivo by inducing apoptosis."

FK228 is now called Romidepsin and the results of a phase II trial with it in HRPC men (C. Parker et al, ASCO 2007, abstract # 15507, IV FK228 13mg/m2 3 out of 4 weeks) during which they achieved a PSA RR of 7% and a "disease control rate" of 14%.  They suggested that combining FK228 with something else should be studied.

Clinical Trials with Combination Therapy of VPA and Chemotherapy

Münster PN, et al (12, 13) have published the results of their phase I study of VPA and Epirubicin, a topoisomerase II inhibitor.  Epirubicin is an anthracycline chemotherapy marketed by Pfizer under the trade name Ellence in the US.  This phase I trial had 48 patients enrolled, 44 provided toxicity data and 41 were available for response.  Only 2 patients had prostate cancer (5%).

Previous studies(14, 15) had determined that VPA needed to be given before topoisomerase II inhibitor dosing. Given concurrently with or after the topoisomerase II inhibitor resulted in no beneficial effect.  The present trial initially gave an IV "loading" dose of VPA followed by 5 oral doses of Depakote administered every 12 hours beginning one hour after the loading dose.  Epirubicin was administered on day 3, 4 hours after the last VPA dose. The VPA IV loading dose was changed to an oral loading dose when rapid infusions produced unwanted toxicities. The oral loading dose ranged from 75mg/kg up to 160mg/kg (MTD). The every 12 hour oral dosing ranged from 37.5mg/kg to 80mg/kg. There were 41 patients that could be evaluated for response -- 9(22%) had partial responses and 16(39%) had stable disease for 12 weeks or more. 

One of the prostate cancer patients had liver involvement and he had a partial response (100mg/kg oral loading plus 50mg/kg q12h x 5, 100mg/m2  Epirubicin); the results for the other prostate cancer patient are not mentioned.  There were no dose limiting toxicities, but all 3 patients in this cohort had grade 3/4 neutropenia, 1 had anemia and 1 had hypocalcaemia. 

Valproic Acid Combined With Retinoid Acid (RA (ATRA-IV)) 

D. M. Atieh, et al (16) did a phase I trial of VPA plus RA with 9 patients, 5 of whom could be evaluated for toxicity of both drugs of which one was a prostate cancer patient.  They had not yet reached the MTD of VPA. Oral VPA was dosed starting at 10mg/kg every 8 hours until trough VPA serum concentrations of 50-80; 80-100 and 100-120 μg/ml were reached. One patient had a transient decline in PSA.

Summary of Dose, method of delivery for VPA plus other agents such as chemotherapy or retinoid acid.

Discussion and Conclusions

HDAC inhibitors are a potential treatment for cancer. Whether or not Valproic Acid is an effective, worthwhile treatment for HRPC remains to be seen -- if at least phase II trials are ever done in HRPC men.  There just isn't enough evidence of responses from the limited information currently available to recommend this as a treatment.  Patients and their oncologists will have to make their own assessment as to VPA's appropriateness for a given patient.  Some speculation - could mitoxantrone be used instead of epirubicin?  Is chronic dosing with VPA better than a combination therapy? Answers to these questions will have to await some future clinical trial(s).     

Two Options appear reasonable at this time:

1. Take VPA "chronically" -- Xia et al (7) and Sharma et al (8) provide some guidance on this approach.  Sharma used doses of 10-25mg/kg. Compare this to the therapeutic doses and levels of VPA used for seizure control:

15-60 mg/kg. 

50-130 μg/mL(.3-.8 mmol/L per (13)

For a hypothetical 70kg patient this would be 1050mg to 4200mg, so Sharma's dosing is probably conservative, but starting at 10mg/kg would seem reasonable.

2. Use VPA as a chemotherapy enhancer(synergistic with) per Münster, et al (13).  The responding prostate cancer patient was in the 100mg/kg group, while the phase II dose was chosen to be 140mg/kg for 48 hours.

100mg/kg corresponds to 7000mg for the hypothetical 70kg patient.  But this dose level is only applied for 48 hours and repeated every 3 weeks. 

Combining a HDACi with other anticancer agents may ultimately turn out to be the best approach as stated in the review paper by J. E. Bolden et al (17).

Again, discuss this with your oncologist to see if VPA and if one of these approaches would be appropriate for you.  Consider substituting, for example, mitoxantrone for the epirubicin.

Author: Howard Hansen 11 October, 2007.

References

1. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK., Histone deacetylases and cancer: causes and therapies, Nat Rev Cancer. 2001 Dec;1(3):194-202.
 

2. Marks PA, Richon VM, Miller T, Kelly WK, Histone deacetylase inhibitors,
Adv. Cancer Res. 2004;91:137-68.
 

3. Vigushin DM, Coombes RC, Targeted histone deacetylase inhibition for cancer therapy, Curr Cancer Drug Targets. 2004 Mar;4(2):205-18.
 

4. Dokmanovic M, Marks PA., Prospects: histone deacetylase inhibitors, J Cell Biochem. 2005 Oct 1;96(2):293-304.
 

5. Garcia-Manero G, Issa JP, Histone deacetylase inhibitors: a review of their clinical status as antineoplastic agents, Cancer Invest. 2005;23(7):635-42.

6. Morris MJ, Scher HI, Optimizing targeted therapy and developing novel outcome measures for patients with advanced prostate cancer at Memorial Sloan-Kettering Cancer Center, Crit Rev Oncol Hematol. 2003 Jun 27;46 Suppl:S21-31. 
 

7. Xia Q, Sung J, Chowdhury W, Chen CL, Höti N, Shabbeer S, Carducci M, Rodriguez R, Chronic administration of valproic acid inhibits prostate cancer cell growth in vitro and in vivo, Cancer Res. 2006 Jul 15;66(14):7237-44.
 

8. S. Sharma, N. Vogelzang, B. Wong, C. Adams, P. Manno, K. Welborne, Y. Giraud, Preclinical and clinical investigation of histone deacetylase inhibitor valproic acid given orally in androgen independent prostate cancer, Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 14614. 

9. Atmaca A, Al-Batran SE, Maurer A, Neumann A, Heinzel T, Hentsch B, Schwarz SE, Hövelmann S, Göttlicher M, Knuth A, Jäger E, Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial, Br J Cancer. 2007 Jul 16;97(2):177-82. Epub 2007 Jun 19.

10. Kanzaki M, Kakinuma H, Kumazawa T, Inoue T, Saito M, Narita S, Yuasa T, Tsuchiya N, Habuchi T., Low concentrations of the histone deacetylase inhibitor, depsipeptide, enhance the effects of gemcitabine and docetaxel in hormone refractory prostate cancer cells, Oncol Rep. 2007 Apr;17(4):761-7.
 

11. Zhang Z, Stanfield J, Frenkel E, Kabbani W, Hsieh JT., Enhanced therapeutic effect on androgen-independent prostate cancer by depsipeptide (FK228), a histone deacetylase inhibitor, in combination with docetaxel, Urology. 2007 Aug;70(2):396-401.

12. P. N. Munster, D. C. Marchion, E. Bicaku, P. Sullivan, C. Beam, J. Mahany, R. Lush, D. M. Sullivan, A. Daud, Phase I Trial of the Histone Deacetylase Inhibitor, Valproic Acid and the Topoisomerase II Inhibitor, Epirubicin: A Clinical and Translational Study, Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement) 2005: 3084. 
 

13. Münster P, Marchion D, Bicaku E, Schmitt M, Lee JH, DeConti R, Simon G, Fishman M, Minton S, Garrett C, Chiappori A, Lush R, Sullivan D, Daud A., Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study, J Clin Oncol. 2007 May 20;25(15):1979-85. Comment in:
J Clin Oncol. 2007 May 20;25(15):1955-6.

14. Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F., Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA, Cancer Res. 2003 Nov 1;63(21):7291-300.

15. Marchion DC, Bicaku E, Daud AI, Sullivan DM, Munster PN, In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates, Mol Cancer Ther. 2005 Dec;4(12):1993-2000.

16. D. M. Atieh, M. I. Milowsky, M. Cobham, J. Kaplan, C. Smith, L. J. Gudas, D. M. Nanus, Phase I trial of a histone deacetylase inhibitor (HDACI) and retinoid acid (RA) in patients (pts) with advanced solid tumor malignancies,
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 13114. 

17. Jessica E. Bolden, Melissa J. Peart and Ricky W. Johnstone, Anticancer activities of histone deacetylase inhibitors, Nature Reviews Drug Discovery 5, 769-784 (September 2006) | doi:10.1038/nrd2133.