TARGETED MOLECULAR THERAPIES FOR CANCER
The DNA revolution and the sequencing of the entire human genome always promised that the benefits would result in better medicines. As more and more genes were cloned, it became possible to map the genes that were abnormal in cancer cells compared to normal cells. Once a key gene is identified, it then became possible to design drugs to target the abnormal gene or, more precisely, its associated protein product. One way to target therapies is with antibodies, as described above. The other way, now generating large numbers of new drugs, is to produce chemicals that interfere with the function, either of the abnormal protein itself or of one of the other elements of the same pathway in the cell. The first and probably best example of the first strategy is the leukaemia drug imatinib (Glivec). A form of leukaemia called chronic lymphocytic leukaemia (CLL) has long been known to be characterized by the presence of a so-called ‘Philadelphia chromosome’. This abnormal chromosome is a fusion of two different chromosomes and results in the production of an abnormal protein derived from two different genes – called the bcr-abl fusion protein. Detailed molecular biology studies established that bcr-abl was both necessary and sufficient (the key conditions for a candidate new drug development) to drive the CLL cells, making it an ideal target. The drug imatinib was the first drug to successfully hit the target and it transformed the prognosis for CLL, with prolonged remissions occurring in patients resistant to the chemotherapy drugs previously used. Sadly, however, the remissions, while lengthy, were not permanent – the cancer cells eventually became resistant. This has been a feature of the targeted small molecular therapies – they are often exquisitely effective, with low side effects compared to chemotherapy, but generally do not lead to cures. However, as already noted in the chemotherapy section with leukaemia, initial use of these drugs singly also only produced remissions but not cures, so, hopefully, combination use will prove similarly beneficial. Time will tell.
The second approach to targeted therapy is to aim for the pathway that is linked to the ‘core’ abnormality. The best example of this is the recent transformation of kidney cancer therapy. Until recently, advanced kidney cancer was all but untreatable, with only two drugs licensed, interferon and interleukin-2, both of very limited effectiveness. Most kidney cancers occur ‘spontaneously’, that is to say, no other family members develop the same cancer. It had been observed many years ago that rare families developed the same tumours, often at a very young age. One such inherited syndrome was described by von Hippel and Lindau and now bears their names. Patients with von Hippel Lindau (VHL) syndrome develop multiple early kidney cancers as part of the disease. Microscopically, the VHL cancers resembled the much more common, non-inherited cancers, so it was suspected that abnormalities in the VHL gene may be present in the spontaneous cancers, and this did indeed turn out to be the case. However, the problem in patients with VHL syndrome is that the normal function in the VHL protein is missing; hence targeting the VHL protein itself would only make the problem worse. Study of the VHL pathway revealed that as a result of VHL underactivity, proteins normally suppressed by the VHL protein became overactive. These include proteins driving the cells to divide and a further family of molecules driving the production of new blood vessels. Drugs were developed which targeted members of this pathway, either up- or downstream of the misfiring VHL protein, including three small molecular therapies, sunitinib, sorafenib, and temsirolimus, and a monoclonal antibody called bevacizumab.
Trials of these drugs have resulted in the treatment of advanced kidney cancer being revolutionized, with all four drugs licensed since 2006 and a further raft of additional drugs also heading into the clinic. As with CLL, however, although for the first time large advanced tumours could be made to shrink, the drugs do not result in cures in most cases, and treatment resistance develops with time. Trials are now focusing on adjuvant therapy, sequencing, and combinations in the hope that further survival gains can be made.
As with the Herceptin story above, the drugs have caused huge controversy due to their cost – patients need to be treated continuously rather than with a limited course of treatment, as was previously the norm with treatments such as chemotherapy. The drugs are expensive – around £25,000–£30,000 per year of treatment – with consequent variations in access. Unlike with Herceptin and breast cancer, however, purchasing authorities in a range of countries, including Canada, Australia, Scotland, and England, have been more resistant to funding treatments for a group of predominantly elderly male patients than they were for the very vocal women’s breast cancer lobby.