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HDAC inhibitors work great in the lab. Why not better in patients?

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HDAC inhibitors work great in the lab. Why not better in patients?

This weekend I shared how I was becoming anxious and frazzled with the added responsibility and concern for my dying father.  The mental and emotional health of myeloma patients and caregivers is an under-served and rarely addressed part of our lives.  You know me; I’m not going to let this go.  I will get back to the “touchy/feely” side of multiple myeloma tomorrow.

In the meantime, I have been sitting on post I recently wrote about HDAC (histone deacetylase) inhibitors.  This promising–yet frustratingly disappointing– new pathway for attacking myeloma isn’t really all that new; researchers have been working on it for the better part of a decade.

Vorinostat, panobinostat and others work on paper and in the lab.  But for some reason results in human subjects has been weak at best so far–and these same researchers aren’t exactly sure why.

Here’s a link to the National Cancer Institute’s site that provides in-depth background information about how the process works, featuring colorful pictures and charts that can bring those of you that are interested up-to-speed about how this pathway works:

Inhibition of Histone Deacetylases (HDACs)

http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/multiplemyeloma_htmlcourse/page4

HDAC

Now check-out the abstract from a study that touts why HDACs should work:

Histone Deacetylase Inhibitors in Multiple Myeloma: Rationale and Evidence for Their Use in Combination Therapy

Source

Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA. Electronic address: jlkaufm@emory.edu.

Abstract

Multiple myeloma (MM) arises from abnormal proliferation and survival (ie, a high proliferative index and a low apoptotic index) of mature immunoglobulin-producing plasma cells in the bone marrow. Development of novel therapeutic options, such as proteasome inhibitors and immunomodulatory agents (IMiDs), has improved treatment outcomes. However, patients often develop relapsed and refractory MM, thus requiring alternative treatment approaches. Histone acetyltransferases and histone deacetylases (HDACs) control the acetylation status of proteins and affect a broad array of physiologic processes (eg, cell cycle, apoptosis, and protein folding) involved in cell growth and survival. The discovery that HDACs might have a role in various hematologic malignancies, including MM, has led to the development of HDAC inhibitors as potential antitumor agents. Preclinical evidence from studies of HDAC inhibitors in combination with proteasome inhibitors (eg, bortezomib and carfilzomib), other antimyeloma agents, including IMiDs (eg, lenalidomide), and cytotoxic agents (eg, melphalan, pegylated liposomal doxorubicin), provides a strong scientific rationale for the evaluation of these regimens. Results from early stage clinical trials further support the use of HDAC inhibitors as a therapeutic option for MM, in combination with current and emerging antimyeloma agents. In this review, we examine the role of protein acetylation that underlies the antimyeloma effects of HDAC inhibitors, discuss the preclinical rationale for the use of HDAC inhibitors in combination with other antimyeloma agents, and provide an overview of the current clinical evidence supporting the use of HDAC inhibitors as a therapeutic option in MM.

Dr JagNext, here’s a YouTube video of Dr. Sundar Jagannath, Director of the Multiple Myeloma Program at the Tisch Cancer Institute at Mount Sinai Medical Center in New York City, discussing HDAC inhibitors late last year:

http://www.youtube.com/watch?v=eXsv9xwQQT0

While his conclusions are positive, my interpretation of data so far is at best mixed.

Finally, here’s what Dana Farber’s Dr. Paul Richardson had to say about this class of drugs following the European meetings this spring on a site called Value-Based Care in Myeloma:

HDAC Inhibitors Show Promise in Myeloma

Interview with Paul G. Richardson, MD
Caroline Helwick

Histone deacetylase (HDAC) inhibitors are among the emerging classes of drugs for the treatment of multiple myeloma. Value-Based Care in Myeloma (VBCM) asked Paul G. Richardson, MD, Director, Jerome Lipper Center for Multiple Myeloma, Dana-Farber Cancer Center, and Associate Professor of Medicine, Harvard Medical School, who has led clinical studies with some of these agents, to describe where the research in this area is heading.

VBCM: Why are HDAC inhibitors of interest in multiple myeloma?

Dr Richardson: Gene expression and epigenetic changes, such as acetylation of histone or nonhistone proteins, are recognized as important factors in cancer development. Aggresome upregulation is a mechanism by which myeloma cells can bypass the antimyeloma effect of proteasome inhibition. When the proteasome pathway is blocked by drugs such as bortezomib, HDAC inhibitors can potentially inhibit the aggresome pathway that is compensating for this.

Therefore, when we combine an HDAC inhibitor with a proteasome inhibitor such as bortezomib, this produces a very potent and toxic proapoptotic signal for tumor cells, at least in the laboratory. This is why we are so interested in combining HDAC inhibitors with proteasome inhibitors as a treatment strategy.

VBCM: Vorinostat and panobinostat are being studied for the treatment of myeloma. How are these drugs different?

Dr Richardson: Vorinostat and panobinostat are in the same drug class, but they have important pharmacokinetic differences and different tolerability profiles. Vorinostat is dosed daily, whereas panobinostat is dosed more intermittently. They are both pan inhibitors, at least in theory, but panobinostat appears to be more potent at targeting HDAC-6, which is a particularly important target.

Another drug is romidepsin, which is used in cutaneous T-cell lymphoma and is approved by the US Food and Drug Administration for this indication. Romidepsin hits different HDACs and appears very promising in preclinical studies of myeloma in the laboratory and in an early, dose-finding trial of patients with advanced myeloma. Specifically, in a recent study of 25 patients with relapsed and refractory myeloma, romidepsin, in combination with bortezomib, produced a 72% response rate, including complete remissions in 8% of patients (Harrison SJ, et al. Blood. 2011;118:6274-6283).

VBCM: How well do these agents partner with other important antimyeloma drugs?

Dr Richardson: Panobinostat and bortezomib partner well together. Conversely, vorinostat and lenalidomide partner well together. Vorinostat and bortezomib can also be combined; however, in phase 3 trials, the benefit of this combination was not as impressive as we had hoped, perhaps because of schedule and dosing issues.

In VANTAGE 088, patients receiving the combination had a median progression-free survival of 7.6 months versus 6.8 months with placebo for an overall difference of <1 month (Dimopoulos MA, et al. Blood. 2011;18:Abstract 811). This was a statistically significant difference, but it was not as clinically meaningful as one would have expected. The intense dosing led to higher response rates (56% vs 41%, respectively), but toxicity was excessive. Therefore, dose and schedule changes may improve the ability to tolerate this drug combination, which is why many of us feel that vorinostat still has considerable promise for the treatment of myeloma. The issue is that the dose and schedule will need careful thought; for example, the combination of lenalidomide and vorinostat (with the latter given 1 week on and 1 week off, and lenalidomide with dexamethasone given according to the classic schedule) has been especially successful. However, at present the overall direction of vorinostat in myeloma is still unclear.

VBCM: Are the outcomes more encouraging with panobinostat?

Dr Richardson: It seems that some of the problems facing the VANTAGE trials have not been seen in the panobinostat trials. The dose and schedule of panobinostat, in combination with bortezomib, was carefully developed as part of a phase 1 program led by Jésus F. San Miguel, MD, PhD. In the phase 2 PANORAMA 2 study, we gave oral panobinostat 20 mg on days 1, 3, and 5 for 2 weeks, with 1 week off, for the first 8 cycles (Richardson PG, et al. Blood. 2011;118:Abstract 814). Responders could continue to receive the drug for another 6 weeks.

The reality seems to be that this particular schedule, with intermittent dosing, is proved more feasible. We do see thrombocytopenia, but with dose reduction it is manageable. Moreover, for a study in patients with relapsed/refractory myeloma, a 49% clinical benefit rate is impressive. I say this carefully, but I am hopeful that the panobinostat trials will be successful.

What these doctors know, but aren’t saying, is there are a number of other more promising HDACs in the early stages of the myeloma therapy pipeline.  Regardless, this disconnect between how well this class of drugs should work, and disappointing clinical trial results–remains an unsolved mystery.

Just what we don’t need: more unsolved questions having to do with multiple myeloma therapy!  But like I often argue, you can never have too many options!  But it is becoming clear the the HDAC inhibitor route is not going to be the be-all or end-all in myeloma therapy.  Unless there is an unexpected bombshell-type breakthrough, this pathway and class of drugs is most likely going to be relegated to a minor niche role; used in patients that either can’t tolerate more powerful drugs options, or need to try and overcome resistance to them.

Feel good and keep smiling!  Pat