A group of scientists at the Medical College of Georgia's Cancer Center, US, fed tumour cells increasing doses of histone deacetylase (HDAC) inhibitors in similar amounts to patients given the drug. By removing the cells that die, the surviving cell line became resistant to high levels of the drugs. "The ultimate goal is to be able to understand how cancer cells develop resistance and to have forward-thinking strategies about how to combat that resistance," said Dr Warren Fiskus, postdoctoral fellow in the laboratory of Dr Kapil Bhalla, director of the Medical College of Georgia Cancer Center. There are already many cancer cell lines that have been engineered to be resistant to one form of therapy or another. Although they have attracted considerable scientific interest, they have so far proved of limited use in terms of eventual benefits to patients, according to Professor Herbie Newell, director of translational medicine at Cancer Research UK. He went on to explain to DrugResearcher.com that as yet, there are very few patients who are resistant to HDAC inhibitors. "The development of HDAC inhibitors is still at a very early stage. There's only one compound that has proven activity and that is in a relatively rare tumour type," Prof. Newell said. "However, there may be patients intrinsically resistant to HDAC inhibitors," he pointed out. That would widen the scope of people who could benefit from researching the mechanisms of HDAC resistance in this cell line. In the meantime, Dr Bhalla's research is best seen as a kind of pre-emptive strike against future resistance to these drugs. "Resistance is going to emerge, so you need a cellular model to understand mechanisms of resistance and an in vivo model, a mouse model typically, to test new combinations you design based on studies in culture," Dr Bhalla explained. However, Prof. Newell also explained that a mechanism that confers resistance to a drug can also be the same mechanism that protects normal cells from the drug's side effects. Therefore, a drug that bypasses this mechanism may also have more of an effect in normal cells so that overall, the drug's benefit (or therapeutic index) doesn't significantly improve. When examining the resistant cells, the team initially made a disappointing discovery; not only could the cells fight off HDAC inhibitors, they were also resistant to many other therapies including more standard treatment such as chemotherapy. However, happily, the researchers also found that the cells were highly sensitive to heat shock protein 90 (hsp90) inhibitors, another emerging cancer treatment. Heat shock proteins are protein caretakers, activating genes that ultimately make proteins, moving them around cells and helping them fold into the right shape to function. Misfolded proteins can cause a myriad of diseases, including cancer. "As part of their resistance mechanisms, they acquired greater sensitivity to hsp90 inhibitors," said Dr Bhalla. "This creates a potential combination that can be tested in mouse models and ultimately clinical trials." Both hsp90 and HDAC inhibitors are regarded as being most useful as a method of increasing the effectiveness of other anticancer drugs. As such, they are being tested as combination therapies, but not with each other. The team weren't surprised by their results though, given that they have already published work that indicates the two classes of drugs have a synergistic effect. "This particular cell line can be used to really look at newer agents and new combinations in vitro and in vivo and see if they are safe and effective together," said Dr Fiskus. Dr Bhalla added that they have already put the cell line into a mouse model and other scientists have asked if they can use the resistant cell line for their own experiments. The results presented by Dr Fiskus at the American Society of Hematology's recent meeting in Atlanta, US, will prick up the ears of those in the pharma industry developing hsp90 and HDAC inhibitors. There are several firms having a go at finding HDAC blockers:
Merck & Co.'s Zolina (vorinostat). Approved
Miikana Therapeutics (MKC-1704, preclinical)
Nycomed (unnamed preclinical candidates)
Pharmacyclics (PCI-24781, PI)
Tikvah Therapeutics (TIK-201, PI)
Gloucester Pharmaceuticals (romidepsin, PII), licensed from Astellas.
Syndax Pharmaceuticals (SNDX-275, PII)
Curagen and TopoTarget (belinostat, PII)
Celgene (formerly Pharmion) in collaboration with MethylGene (MGCD0103, PII)
Novartis (LBH589, PII).
This last entry is perhaps the most significant as Novartis also have several hsp90 inhibitors in clinical development, most notably Mycograb (efungumab), which is in final stage trials for fungal infections and also in earlier stage trials for cancer. They seem to be the only pharma company with both classes of drug in its pipeline and so are perhaps best placed to take advantage of this new research. In fact, the Medical College of Georgia is participating in a clinical trial of the aforementioned HDAC inhibitor, LBH589. Studies also are underway for some innovative uses of hsp90 inhibitors, including Dr John Catravas' studies of its potential as an anti-angiogenesis agent and Dr Abdullah Kutlar's studies to see if it can reduce morbidity and related lung problems in sickle cell disease by suppressing inflammation.