MYC – A Critical Target for Pan Cancer Therapy
MYC is one of the first human genes identified as an oncogene. The first findings in the early 1980’s link elevated expression of MYC to the development of diverse cancers (Meyer & Pen).
Intense research over the past 40 years has established MYC as one of the most common oncogenic driver genes in human cancers – overexpressed MYC is a feature of more than two-thirds of all human cancers. MYC promotes cancer development by altering or “reprogramming” many different cell pathways, for example, those that control cell metabolism, cell proliferation, and various forms of cell death. Identifying effective strategies to wipe out the MYC protein from cancer cells has been long considered the holy grail among the developers of tissue agnostic (Pan-Can) cancer therapies.
WHY DO WE NOT HAVE DRUGS TO STOP MYC?
Rational structure-based drug development against a specific protein usually requires protein binding “pockets”, into which drug-like molecules can bind. Unfortunately, the primary sequences of MYC do not identify any active sites or druggable pockets such as in kinases, which makes it difficult to develop selective small-molecule antagonists of MYC function (Duffy et al.). Therefore, the promise of targeting MYC may only be possible through indirect approaches, for example inhibiting those pathways that keep MYC expressed and active in cancer cells. Alternatively, one could re-route the MYC cancer pathways so that they turn against the cancer cells. The strategy of killing cancer cells by exploiting specific vulnerabilities that cancer genes created in these cells is called synthetic lethality.
THE PROMISE OF SYNTHETIC LETHAL CANCER DRUGS
Synthetic lethality (SL) is a powerful concept that describes the selective killing of cancer cells which harbor specific alterations of an oncogenic or tumor suppressor (O’Neil et al.) pathway, with a drug that is much less toxic to normal cells. The first clinically approved drugs to exploit SL include PARP-inhibitors for BRCA1/2 mutant cancers (Lord & Ashworth).
The MYC-directed synthetic lethal (MYC SL) strategies take advantage of the inherent vulnerabilities of cancer cells when the MYC oncogene is overexpressed. MYC-directed synthetic-lethal treatments can selectively kill cancer cells, leaving normal healthy cells unscathed.
Take an example of how the MYC SL concept works: Oncogenic MYC sets cells to multiply in a non-stop fashion. Before each cell division, the cells must be able to increase their cell mass so that every cell division produces two cells of equal size rather than two cells of half of the original size. To ensure that the non-stopping cell division cycles take place without loss of any cell mass, MYC juices up the cells’ metabolism so that it starts to procure carbon (a basic block of biomass) from both glucose and glutamine. While normally growing cells can do with less glutamine, the cells with oncogenic MYC die if not provided enough glutamine. Therefore, cancer cells with MYC could be killed by limiting their access to glutamine. This synthetic lethal strategy has spawn new promising treatments currently being tested in cancer patients.
In the cancer cells’ nuclei, where the DNA is located, MYC controls the expression of thousands and thousands of genes to set up a program that feeds at the same time cell division, cell metabolism, cell growth, and cell death. It is important to understand that the MYC SL concept is not about stopping MYC with drugs (which cannot be done) but instead, using the weaknesses in the MYC program to make MYC harmful for those cancer cells which carry it. Therefore, MYC SL could offer a whole portfolio of new drug development opportunities to boost the cell-killing action of known cancer drugs and to expose drug activities, which would trigger cell death specifically in the cancer cells.
SYNTHETIC LETHAL STRATEGY FOLLOWS THE PRINCIPLES OF JUDO
In essence, the concept of synthetic lethality follows the same principles as one of the most popular martial art Judo – instead of trying to subdue the force of your adversary with even mightier force, you just use the strength of your adversary as a weapon against itself. Powerful oncogenes, such as MYC, are the forces driving cancer and weaponizing those forces against cancer could offer a potent strategy to beat cancer.
COMBINING SYNTHETIC LETHAL DRUGS WITH IMMUNOTHERAPIES
The MYCimmune project is discovering and developing treatment strategies that can be combined with immune therapies. While MYC SL-directed therapies are expected to effectively destroy tumor tissue, only the combination of these drugs with immunotherapies are expected to give long-lasting anti-cancer effects (Haikala et al.).
The reasoning why we develop combination therapies is based on the finding that, on one hand, MYC SL treatments can trigger an “immunogenic cell death”. In other words, the type of cell death that helps the body’s own immune cells to attack tumors. However, while making cancer cells vulnerable to cell death, MYC also protects cancer cells from immunity by making tumor cells invisible to the immune cells (Joyce et al.). For this reason, it is mandatory to develop MYC SL treatments, which kill selectively tumor cells, in combination with immune therapies, which could overcome the MYC-caused immunosuppression.
We believe that combining immune therapies for cancer patients must be improved, and this can be best achieved by understanding how MYC contributes to the processes of tumor immune suppression and which MYC SL-therapies immunogenic cell death. We are actively developing strategies to use leverage anti-tumor immune phenotypes to help patient’s immune system to fight cancer.