Starving cancer cells to death
One of the major issues with patients fighting leukemia or cancer in general is relapse, although chemotherapy helps to get rid of most cancer cells. But these cells come back.
Dr Cedric Tremblay in the Australian Centre for Blood Diseases at Monash University is first author on a recently published Nature Communications study on a novel approach to weakening, then killing, cancer cells.
He said, “What we're trying to find is a new way of getting rid of cancer cells. In general, cancer therapy uses targeted drugs that will block a specific receptor, marker, gene or protein that helps cancer cells to survive.”
However, he said that cancer cells are highly adaptive and they find a way to renew themselves with ‘work arounds’ by finding other proteins, genes, signals or receptors that could compensate for the effect of those drugs, which the cancer cells then add to their adaptive repertoire.
“Cancer cells have a capacity called ‘plasticity’. For example there are some chemotherapy drugs such as Pegaspargase that will deprive cancer cells of circulating asparagine - an essential amino acid for cancer cells - but then they adapt by using another amino acid to survive. So it's a ‘Red Queen’ evolutionary chase where you're trying to block access to things that the cancer cell needs, but it adapts and reacts to the challenge and uses other things instead.”
But what if, instead of trying to employ the cancer cell’s evolutionary mechanisms in order to win that Red Queen race, the problem is approached in a different way?
“We were studying how signals from the cancer cell’s environment sustain or contribute to cancer development in general, and recover from treatment with chemotherapy in particular. We realized that if we found a way to block all the communication we could literally starve the cancer cell to death.”
Dr Tremblay said that cancer cells, unlike normal cells, are more active. They need more material, they are more aggressive, they have different mutations, they recover from damage more quickly. Even the least active cancer cells are still more active than the more dormant normal, healthy cells.
“Our idea was that silencing signals for a short time would affect the highly active, hungry cancer cells much more than the quieter, less active, normal cells. For example normal blood stem cells - that is, the cells of origin of all blood cells - are mostly dormant and in a protective environment so if you hit them for a short period of time with a drug that will shut the whole environment down it won't affect them that much because they're ‘sleeping’.”
The researchers thought the signal blocking might have a large effect on normal cells but the drug they used, Dynole 34-2, has a short 15 minute window of action, and the normal cells were not affected. They discovered that repeating the dose multiple times made a big difference for cancer cells but not for normal cells.
Dynole 34-2 is not a clinical drug. It is used in research as an inhibitor of dynamin, which is important for the uptake of signals by cells from their environment. Dr Tremblay said, “By inhibiting the dynamin molecule we can restrict many functions that are essential for any cells but it will have a greater impact on cancer cells because they rely more on all those functions than normal cells that are less active.
The team first tested the Dynole 34-2 with samples from leukaemia patients in vitro, then in mice to see if it worked in vivo. It successfully blocked the integration of signals from the environment specifically to the relapse-inducing cancer cells and did not negatively affect the normal stem cells which are responsible for recovery after chemotherapy. They found that a 15-minute spell of ‘silencing’ twice a day for two weeks was enough to weaken the cancer cells sufficiently that chemotherapy could kill them all.
“In a patient the treatment could be given for longer. We've done one assay where we did it multiple times over six and eight weeks and it's more effective. We think the repetition has an additive effect.
“Our studies are focused on leukemia but there's one study from our collaborator, who developed that drug, which showed that the drug also worked to prevent the integration of signals in brain cancer and in colon cancer, so that's a clue that the drug might be effective with other really aggressive cancers.”
Another significant clinical advantage of using Dynamin over targeting a specific gene in a specific pathway, or protein as the case may be, is the reduction in possible side effects. Targeting a gene or protein may affect its function in healthy cells, whereas simply targeting activity only affects active cells, which are the cancer cells.
“The drug is not suitable for patients right now but we have established the proof-of-principle. Five to ten years down the track we could be looking at clinical trials.”
Tremblay CS, Chiu SK, Saw J, McCalmont H, Litalien V, Boyle J, Sonderegger SE, Chau N, Evans K, Cerruti L, Salmon JM, McCluskey A, Lock RB, Robinson PJ, Jane SM, Curtis DJ. Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells. Nat Commun. 2021 Feb 19;12(1):1288. doi: 10.1038/s41467-021-21688-1. Erratum for: Nat Commun. 2020 Dec 4;11(1):6211. PMID: 33608527.