by ecancer reporter Clare Sansom

Delegates at the NCRI conference were treated to a tour de force on Tuesday afternoon with two complementary but contrasting keynote lectures on the cell cycle and its inhibitors, by Tim Hunt from the Francis Crick Institute in London and Dennis Slamon from UCLA Jonsson Comprehensive Cancer Center in Los Angeles.

Hunt, joint winner of the 2001 Nobel Prize for Medicine with Paul Nurse and Leland Hartwell for their discoveries of cell cycle regulators, began with an entertaining and engaging account of his research career.

He explained that his work was at the “extreme basic end” of cancer research, and that work on marine invertebrates had led to discoveries that turned out to be relevant to cancer.

It was while studying the fertilisation of sea urchin eggs in the marine biology labs at Woods Hole, Massachusetts, in the late 1970s that he first became interested in the nature of the biological switch that turns on cell division.

In 1982 he discovered a protein in sea urchins that came and went during the cell division cycle, being found at high levels when the cells were in the act of dividing and undetectable the rest of the time; this was later named cyclin.

He became aware of Paul Nurse' work on a gene in yeast that encodes an inactive protein kinase and that prevents cell division if it is mutated.

To cut a long story short, these proteins are found in all organisms including humans, and cyclins binding to, and activating, these cyclin dependent kinases (CDKs) control progression through the cell cycle.

We have now identified a number of pairs of cyclins and CDKs that act as checkpoints at different points in the cell cycle, controlling both cell growth and division.

As cancer is a disease of aberrant cell division, it seemed likely that CDKs would be good targets for anti-cancer drugs, but until recently no CDK inhibitors have shown efficacy in the clinic.

This set the scene for Dennis Slamon's lecture on the therapeutic implications of cancer diversity, which included a description of the first anti-cancer CDK inhibitor to be licensed for clinical use.

Slamon is best known for his discovery of the HER2 receptor that is over-expressed in over 25% of breast cancers and subsequently for the development of Herceptin.

He described UCLA's panel of about 620 human cancer cell lines, which represent 15 different histologies.

Candidate drugs can be tested in all these to investigate which subgroups of which basic tumour types they should be most effective in.

Pfizer had developed a specific inhibitor of CDK4 and CDK6 known as PD-0332991 and tested it in lymphoma, but it had been disappointing in clinical trials.

Slamon and his colleagues selected this compound for testing with the complete UCLA cell line panel, and found – rather to their surprise – that oestrogen receptor positive luminal breast cancer cell lines were exquisitely sensitive to it.

Resistance to this compound could be correlated with loss of the retinoblastoma protein.

The UCLA group ran a Phase I clinical trial with this compound in this breast cancer subtype and showed some efficacy; Pfizer then took it back to run larger trials.

A Phase III study showed that adding the drug – now named palbociclib – to letrozole doubled progression free survival from 10 to 20 months, and it was approved by the FDA for this indication in February 2015.

Other CDK4/CDK6 inhibitors are now in development, and some, including Lilly's abemaciclib, may be even more promising.

Another of the day's keynote lecturers was Uwe Oelfke from the Institute of Cancer Research and Royal Marsden Hospital in London.

Oelfke, who started his career as a nuclear physicist, moved to the Royal Marsden from Heidelberg to set up next-generation radiation therapies in 2012.

His talk focused on novel technological developments in radiotherapy, covering advances in both 'bullets' – high energy photons or protons – and the definition of the target area.

Technological developments in radiotherapy aim to increase the width of the therapeutic window by maximising the difference between doses delivered to the tumour and to normal tissue. 

The main advantage of protons over photons in radiotherapy is that they are dissipated within the body so the exit dose is minimal.

Proton beam therapy was introduced into the UK in 1989 and has been very successful in treating inner ocular tumours, and two state of the art facilities will open there in the next few years.

Diagnostic imaging has been used to define the target area for radiotherapy for many years, but until now this has relied on static images taken some time before the therapy.

This is not ideal because tumours can move within the body over long and short time-scales; one example of the latter is the movement of a lung tumour with breathing.

One solution to this problem is to incorporate real-time 3D magnetic resonance imaging within radiotherapy machines, and several machines of this type are in development or will be installed in the UK very soon.

Full integration of imaging, radiation and clinical decision making tools will, however, require a significant upgrade to existing IT infrastructure.