Translational research and proteasome inhibitors in multiple myeloma

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Published: 14 Dec 2011
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Prof Kenneth Anderson - Dana-Farber Cancer Institute, Boston, USA

Dr Anderson sits down to discuss the progress made in multiple myeloma with at the ASH 2011 Annual Meeting. There have been major advances in both the clinical and laboratory setting, especially in regards to proteasome inhibitors.  A number of completed clinical trials presented data at this year’s ASH meeting showing improvements in overall survival and complete remission.


Dr Anderson notes that it is a very exciting as the next generation of proteasome inhibitors; bortezomib, and immuno-modulators such as lenalidomide, will lead to more developments in translational research and improved survival rates. Dr Anderson states that protein homeostasis will remain a key target for novel therapeutics and targeted treatment. Data on immunomodulatory drugs is also being presented in combination therapy, as well as immune approaches and monoclonal antibodies to target. Dr Anderson concludes with explaining how translational research has been a catalyst for new drug developments.

2011 ASH Annual Meeting, December 10-13, San Diego, USA

Translational research and proteasome inhibitors in multiple myeloma


Prof Kenneth Anderson - Dana-Farber Cancer Institute, Boston, USA

Once again at ASH this year the progress in multiple myeloma is literally palpable, both in the laboratory but most importantly in bench-to-bedside translation of the new advances to new diagnostic, prognostic and treatment options in myeloma. So we’ve been blessed over the last decade with the development of proteasome inhibitors like bortezomib and immunomodulatory drugs like lenalidomide and what this year’s ASH is all about are the next generation of agents. So we have second generation proteasome inhibitors including carfilzomib, a chymotryptic inhibitor, and marizomib which is a more broad inhibitor of the proteasome, caspase like chymotryptic and tryptic activities all being blocked. We have oral proteasome inhibitors such as MLN9708 that are showing promise, and it’s clear that targeting the proteasome in multiple myeloma is here to stay and that protein homeostasis is a good target for novel therapeutics.


Also the second generation immunomodulatory drugs are here. Thalidomide and lenalidomide have wonderful efficacy, but pomolidomide, the more potent next generation immunomodulatory drug, is being presented here in advanced disease and then in multiple combinations where in fact enhanced activity can be demonstrated. So second generation of agents that we, together in a collaborative way, advanced over the last decade.


Then there are a variety of other new approaches. So in the area of immune approaches we’ve been looking for many, many years for monoclonal antibodies to target multiple myeloma. At this meeting there are a couple of examples I’ll mention that look very promising in this area.


So, the monoclonal antibody alemtuzumab targets the CS1 antigen. It’s present at a gene and a protein level on all patients’ cells, that is all myeloma cells. That observation led from the beside to the bench; to science that showed that targeting CS1 manifested or induced cytotoxicity in myeloma, and in turn, from the bench to the bedside, came a trial of a humanised monoclonal antibody alemtuzumab in myeloma. And although it achieved stable disease in patients whose myeloma was growing, there really weren’t responses that were sufficient to warrant further development. However, it went from the clinic back to the bedside, where the immunomodulatory drug lenalidomide was shown in our and other groups to augment antibody-dependent cellular cytotoxicity by alemtuzumab, and then back to the clinic where 80-90% of people are responding. So as we’re sitting here we have a clinical phase III trial now, hopefully for one of our first antibodies.


There are immunotoxins being presented here, one I’ll just mention, CD138, which reacts with syndecan, universally expressed on myeloma, has been conjugated to a maytansinoid immunotoxin and there is a clinical trial here of that immunotoxin showing promising results. And in the immune area, I’ll mention there are at least two vaccine approaches that look to be promising. The first uses patients’ own myeloma cells fused with their own dendritic cells, and the concept here is to vaccinate the patients against their own myeloma. Because in pre-clinical mirroring models, and now in patients, if you do so, if you vaccinate the patient with his or her own dendritic cells fused to their myeloma cells, you can in so doing induce tumoral and cellular responses against their own myeloma. So that’s translating. And a very exciting vaccine approach is a peptide-based approach. Three targets on myeloma that are universally expressed include CD138 syndecan that I just mentioned; CS1 that I also mentioned, the target of alemtuzumab; and the third target is XBP1, which is a transcription factor universally expressed and required for B-cells to move towards plasma cells.


The strategy here, which is quite clever, is to take these same targets but to break them down in peptides that would be recognised by particular patients in the context of their HLA. So the vaccine targets are the same but the cocktail of peptides may differ, dependent upon the HLA type of the host, and predicated upon their ability to respond. So there’s immune promising therapies in addition to the second generation proteasome inhibitors and immunomodulatory agents. But what also is wonderfully new at ASH this year are phase III combination clinical trials. So we have very exciting data here from bortezomib combined with, on the one hand, AKT inhibitor perifosene. The premise here is that you can block the AKT activation triggered by the proteasome inhibitor bortezomib, and in so doing sensitise or overcome resistance. Clinical trial being updated here shows great promise. The histone deacetylase inhibitors have been added to bortezomib, the proteasome inhibitor. The appeal there is that the proteasome inhibitors block the proteasome degradation of protein but the alternative pathway, so-called agrezomal pathway for breakdown for ubiquinated protein, can be blocked by histone deacetylase inhibitors. So here at ASH we have clinical trials now completed showing that the broad acting histone deacetylase inhibitors, either vorinostat or panobinostat, can block agrezomal degradation, and when combined with the proteasome inhibitor bortezomib, can induce responses in significant fractions of patients whose myeloma is resistant to the proteasome inhibitor bortezomib. And we have a new selective H-DAC inhibitor, H-DAC 6 Selective which just targets that agrezomal pathway, which is now translating from the bench to the beside as well, and we hope will be more potent and avoid some of the side effects of the more broad inhibitors.


But the last comment, an area that I think is very exciting in every cancer, that’s being featured at this year’s ASH, but particularly in myeloma as well, are the genomic advances. So we have very exciting data in our and other institutes that starting to use analyses of DNA whether it be raCGH snip array, mutational analysis, RNA profiling, micro-RNA profiling, splice RNA profiling, all the way up to and including proteomics. And what’s evolving is a very complex genetic signature of multiple myeloma, and the inevitable conclusion is that we are going to need to integrate these various levels of analysis and genomic data in order to finally get an integrated picture of what a particular patient’s tumour is like at a particular time. And that’s the second important feature, because there are studies being presented here that show that there is evolution of the genomic changes over time, not unsurprisingly, but in a very complex fashion. They correlate with progression of disease or relapse of disease. And so that promise of individualised medicine in myeloma is getting more and more realistic but it’s also getting very, very complicated.


Exciting new studies from the United Kingdom, from the United States, from France and other sites, are working to unravel this complexity and there’s a great attempt now internationally in myeloma to collaborate. And that might be the one theme that I would try to stress: in myeloma, we have had remarkable progress over the last decade. We’ve had six new treatment approvals; the survival of our patients has doubled, has probably tripled now; but why has this happened? It’s happened because science such as that being presented at ASH, scientists, whether they be in industry, pharma or in academia, are collaborating with biotech and pharma to do a clinical trial, are collaborating with the regulatory agencies to help them understand what is a meaningful result in clinical myeloma. We’re collaborating with our funding agencies around the world and most importantly we’re collaborating with our patients and our advocacy groups. When those five constituencies are together on the same team, bench to bedside translation can be very rapid and what this year’s ASH represents is the wonderful outcome, the very rewarding outcome for all, that comes from that very collaborative international effort.