Combining low doses of several cancer drugs at the same time
might overcome the important problem of resistance, researchers
from the Netherlands Cancer Institute conclude. In the lab this
multiple low dose approach shows promising results, they describe
in the scientific journal Nature Communications today.
Resistance is a major problem in the treatment of cancer
patients. Drugs targeting specific signaling proteins within cancer
cells can work very well initially. In the end though, the tumor
becomes resistant and starts growing again. That's why scientists
and clinicians focus their attention on outsmarting cancer by
combining different drugs. A cocktail of drugs that block several
parts of the same signal route in cancer cells, for example, has
proven effective, but patients can experience severe side
Nothing plus nothing
Researchers of the Netherlands Cancer Institute think they might
have found a way around this problem: multiple low dose therapy.
Combining four carefully selected drugs at very low doses appears
to block cancer signals very well in the lab, without significant
side effects. "Initially, we didn't think it was going to work so
well", says researcher and first author of the publication João
Neto. "Each drug individually has no effect at all when used in
such a low dose. So: nothing plus nothing would be… nothing, right?
But we saw a huge synergy when we combined the four drugs at low
The researchers treated both lung cancer cells and mice with
lung cancer with four medicines carrying the not so appealing names
EGFR, RAF, MEK and ERK inhibitors. Why these? They're all blocking
proteins that are part of the same communication route within the
cell. And the cells of certain lung cancers are addicted to it.
They have a mutation in the EGFR gene, making this signal route
hyperactive and cell division go through the roof. Patients
initially respond well to drugs against EGFR, but once resistant
cells find their way around the blockage there aren't a lot of
treatment options left.
Hence the idea of outsmarting the cancer cells by blocking
several crossroads instead of one.
João and his colleagues found out they could block the signaling
route completely with as little as one fifth of the individual
effective drug dose. The cells stopped dividing and died. No
resistance. "In mice the tumors also shrank", he says. "They didn't
disappear completely, like the cells in the lab, because the mice
degraded some of the drugs very fast. So, one of the challenges
when testing this in human patients will be to sustain the right
level of drug in their bodies."
Multiple low dose treatment
That's right, testing in patients will be the next step.
Researchers and clinicians at the Netherlands Cancer Institute
still have quite some work to do though, such as translating the
current findings in cells and mice to the exact right doses in
humans, securing the drugs to be used in the trial, and convince
funders to support this important step into the clinic.
"The potential of multiple low dose treatment goes beyond lung
cancer", says João. "We tested cells of several other cancer types
and saw the same promising results. In theory it can be applied to
a broad range of tumors, as long as they are addicted to a
communication pathway within their cells."
This research was financially supported by the Dutch Cancer
Foundation and Oncode Institute.
in which Joao neatly summarizes his research
- The publication in Nature Communications
- Recent findings of the same Rene Bernard lab on another
innovative approach to combination therapy: the
Low doses of four medicines
administered simultaneously effectively inhibit this essential
signal route in cancer cells (EGFR-, RAF-, MEK- and
About the research
Treatment: Multiple low dose
Tumor type: Lung cancer (EGFR
Research phase: Preclinical and
Tested in: Cancer cells and mice
Research from: The Netherlands and