The 'Molecular Targets and Cancer Therapeutics' event attracted thousands of scientists and clinicians alike, but mirroring the pharma industry itself, only a small proportion of the drugs discussed are truly innovative.
New drug targets can provide enticing new techniques to combat this deadly disease and researchers are using everything from small molecules to new types of antibody, through tumour-eating virus' and gene therapy as ammunition.
A team of researchers from University College London (UCL) unveiled their preclinical small molecule protein kinase D (PKD) inhibitor called CRT0059359. This target is a key part of a chemical signalling pathway that is disrupted in a variety of cancers, including pancreatic cancer, and is involved cell division and programmed cell death (apoptosis).
"We think this is the first viable protein kinase D inhibitor that has come to light - and our studies using this molecule validate protein kinase D as an anti-cancer target," said lead researcher Dr Lloyd Kelland.
To find an effective inhibitor for PKD, the researchers initially screened over 65,000 molecules to determine if any of them blocked the function of the protein. The hits were then refined and CRT0059359 was the single result. However, the team aren't finished yet:
"We are refining its [CRT0059359's] chemical structure to improve bioavailability and increase potency," Kelland said.
A group at the Memorial Sloan-Kettering Cancer Center, New York, have found that a herpes virus is - for reasons they don't entirely understand - deadly to cancer tumours, despite the fact that it is genetically altered to be harmless to normal cells.
The virus is naturally attracted to nerve cells, where tumours often spread, especially in prostate, head and neck, and pancreatic cancer. Treatment for neurally invasive cancer includes the physical removal of the cancer cells through surgery, which often damages the nerve.
"The invasion of cancer cells along nerves is generally linked with poor outcomes for patients, and can have awful consequences for patients even when it is successfully treated," said Dr Ziv Gil, a researcher at the centre.
"By modifying a virus that is naturally attracted to nerves, it can serve to target and kill cancer and prevent healthy nerves from being damaged."
NV1023 is currently in Phase I clinical trials.
Meanwhile, Canadian biotech firm Arius Research touted their eccentrically monikered anticancer antibody, AR36A36.11.1. Tumours often evade the immune system's wrath and one of the way's they do this is by producing an excess of CD59. This, in turn, prevents the assembly of certain immune system components on the outside of tumour cells.
AR36A36.11.1 effectively 'uncloaks them' by sticking to and blocking the effects of CD59.
One of the researchers at the company, Dr Maldwin Mak, said: "We can disrupt a cancer cell's ability to keep the immune system from poking holes in its membrane."
The monoclonal antibody (MAb), which will soon enter first-in-man clinical trials, has so far been effective in treating prostate, lung, colon and especially breast cancer tumours in mice. This latter result is especially encouraging as it is observed in a breast cancer model that represents a patient population that cannot be treated by Genentech & Roche's Herceptin (trastuzumab), the only therapeutic antibody currently approved for breast cancer treatment.
Arius is also at the preclinical stage of development for a MAb against Trop-2, a protein found on the surfaces of cells and thought to be a key part of the expansive and highly researched mitogen-activated protein kinase (MAPK) pathway.
Micromet, a Munich-based biotech company, is hoping its novel antibodies can take a bite out of tumour cells by effectively gluing them to immune system molecules. The so-called bispecific T-cell engager (BiTE) molecules are constructed by stitching together the binding regions to two antibodies.
At the conference, the company showed off one of their potential drugs that binds both to an activating receptor on the surface of killer T cells, called CD3, and to a protein generally found on the surfaces of skin cancers, called melanoma-associated chondroitin sulfate proteoglycan (MCSP).
"The T cell will briefly attach to the BiTE-decorated cancer cell and inject its deadly cocktail of killer proteins into the tumor cell," said Dr Roman Kischel, director of immunotherapy at Micromet.
"This event gears up the T cell to produce more killer proteins and to go into melanoma serial killing mode."
As well as academic and biotech researchers, the pharma heavyweights also attended the event to showcase their wares. GlaxoSmithKline (GSK) presented data on their first-in-class small molecule drug, GSK923295A, which was developed in partnership with Cytokinetics and is currently in Phase I trials.
The drug inhibits the mitotic kinesin centromere-associated protein E (CENP-E), which is required during mitosis - the process by which a cell duplicates its genetic information in order to generate two, identical, daughter cells.
The study's lead investigator, David Sutton, explained that although CENP-E is expressed in all dividing cells, GSK923925A is more likely to affect rapidly dividing cancer cells.
Thallion Pharmaceuticals, Canada, revealed positive data from a Phase I/II clinical trial of their dual-acting anticancer drug.
Firstly, ECO-4601 inhibits the RAS/MAPK intracellular signalling pathway, which is mutated in many cancer types, and is the target of several approved cancer drugs. However, this drug is thought to differentiate it from the others by inhibiting RAS directly.
"Because RAS sits at a crossroad of multiple signalling pathways, targeting RAS may avoid some of the redundancies inherent in intracellular signalling," said Dr Pierre Falardeau, CEO at Thallion.
The drug also binds to the peripheral benzodiazepine receptor (PBR), which is over-expressed in multiple cancers. This may allow the drug to accumulate within tumour cells, providing a more efficient way to inhibit the RAS/MAPK pathway.
Drug screening techniques on show
Others at the expo concentrated on how they develop drugs, specifically the screening techniques they used. Researchers at St. Jude Children's Research Hospital in Memphis, Tennessee have developed a biochemical assay to help them identify a new strategy for stopping two key regulators of tumour suppressor gene p53, called MDMX and MDM2.
"We now have an understanding of how MDMX and MDM2 target functional p53, but the real challenge has been to find a means of controlling both [of them]," said Dr Damon Reed, a researcher at St. Jude's.
"We are looking for a single therapeutic that will knock out both proteins, thereby allowing p53 to do its job, that is, to kill cancerous cells."
To do this, Reed adapted two biochemical assays, fine tuning them to test over 6,000 biologically active compounds for those that could, ideally, bind to both MDM2 and MDMX. In the first test, the researchers linked fluorescent tracers to a p53-like molecule. If a candidate molecule binds to the MDMX protein it prevents the p53 binding, and, therefore, changes the signal of the fluorescent light.
The second assay was a PerkinElmer AlphaScreen test, and involved attaching small beads to both the p53-like molecule and either MDM2 or MDMX. If the tested compound binds to MDMX or MDM2, it blocks a chain between the two beads, which decreases the amount of light emitted by the beads.
The St. Jude researchers ran the 6,000 compounds through both the AlphaScreen and the fluorescence polarization assay and discovered two small molecules which bound MDMX and MDM2. Both are now being tested in cell culture while the assay search has been expanded to 350,000 compounds.
Finally, Gemin X Pharmaceuticals is looking to disrupt the unusually long lifespan of cancer cells. This property is determined by portions of DNA called telomeres, which prevent the ends of chromosomes from 'fraying' and thus stabilises them. The team at this Canadian firm have developed a combined computer-lab system in order to screen millions of compounds for the ability to disrupt telomere maintenance. Through this process, they have found two potential drugs that inhibit A1 and A2, proteins that help sustain telomeres.
"We are seeking to halt tumour growth by taking the immortality out of cancer cells," said Dr Richard Marcellus, a scientist at the firm.
"Since the A1 and A2 proteins bind directly to DNA, we were looking to find a molecule that could block this specific protein/DNA interaction. However, the chemistry involved in building small molecules that are able to inhibit protein/DNA binding is daunting, so most drug developers have looked elsewhere for easier targets."
To get around this problem, the researchers generated a model of the area that both A1 and A2 bind to on the DNA and began virtually screening two million compounds.
Once that number was whittled down to around 2,000, the ream moved onto move traditional techniques and ran the molecules through a gauntlet of six different assays.
Any molecules that made it through those assays were met with one final test: cytotoxicity - could the candidate, in fact, kill cancer cells? The researchers uncovered five classes of compounds that could halt growth and induce death in skin and lymphoma cancer cells. From those five, Marcellus said, they have identified two classes that would be suitable candidates for further refinement.
