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.
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.).
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.
