There were a number of interesting posters at the AACR-NCI-EORTC Molecular Targets meeting today. Specifically, two on metastatic pancreatic cancer caught my eye. You can read about the other one on Millennium/Takeda’s ADC MLN0264 here.
This is an area of high unmet medical need with the fourth highest number of cancer deaths in the US and a median survival of 10 months or less. Even with improvements in the standard of care, it still remains a miserable cancer to get.
Many of you will be aware that KRAS is mutated in 90% of pancreatic cancer cases. As Dr Barry Nelkin (Johns Hopkins) noted today,
“The good news is that we know the target, the bad news is that we haven’t been able to hit it… Yet.”
We do know that KRAS activates three major signaling pathways, namely:
Oddly, we have a plethora of inhibitors for the first two, but not for RAL. Unfortunately, RAL signaling is critically important in pancreatic cancer.
Dr Nelkin observed that it has been shown that inhibition with CDK5 resulted in the loss of RAL activity in pancreatic cancer cells, as well as reduction in their ability to form tumours and metastasize in vivo. Interestingly, addition of PI3K or MEK inhibitors further decreased the cells transformation.
Dinaciclib (Merck), an inhibitor of CDK1,2,5 and 9 was shown to block RAL activity in pancreatic cancer cells as well as inhibiting xenograft growth and metastasis. In other words, RAL is now druggable!
The researchers at Johns Hopkins showed some nice preclinical evidence that tumour size was reduced in pancreatic cell lines when dinaciclib was combined with either an Akt inhibitor (MK-2206) or an ERK inhibitor (SCH772984).
These results therefore provided a solid rationale for combining a CDK5 inhibitor with one from the PI3K/Akt/mTOR or RAF/MEK/ERK pathways in the clinic. A phase I combination trial of dinaciclib plus MK-2206 is currently enrolling at four centres, including three in the US.
I think this is a most interesting trial with a solid rationale that is well worth evaluating in advanced pancreatic cancer. The story though, gets a little interesting. I tweeted to Dr Nelkin’s colleague, Dr Anirban Mitra, who is now Professor of pancreatic cancer research at MD Anderson and learned something rather surprising:
@MaverickNY thanks! Need a company that will push this to clinic, now that MK2206 is dead. We are seeing cytocidal not cytostatic effects.
— Anirban Maitra (@Aiims1742) October 21, 2013
Cytocidal for the uninitiated means they are seeing pancreatic cancer cells being killed. It’s a short word but it means a lot.
At the poster today, Dr Nelkin confirmed that he had heard rumours to this effect, but stated Merck had at least committed to finishing the phase I trial. It’s not immediately obvious why MK-2206 might be discontinued or on the chopping block, but who knows what will happen if the phase I data turns out to be stunning. I for one, sincerely hope that they are.
Other companies with a CDK5 and a PI3K/AKT/mTOR inhibitor in their pipeline would do well to watch out for the readout of these results – they could be very interesting indeed.