100 years ago, Otto Warburg discovered that cancer cells have a dramatically increased rate of glycolysis, consuming huge amounts of glucose to turn it into lactate without the use of oxygen. The deeper sense of cancers “overusing” this pathways lies in the fact that several biosynthetic pathways branch of from glycolysis to provide construction material and building blocks for the unlimited cell growth. Amongst other pathways, the so-called pentose phosphate shunt is employed for this which also creates NADPH to support an antioxidative defense, urgently needed in the stressed cancer cells.
The more advanced the cancer stage, the more the tumors and metastases, in particular, adopt this Warburg metabolism. The huge lactate production and the acidification in the tumor microenvironment that comes with it shield the tumor against hostile attack from the immune system.
Immune system & cancer
Cancer “seeds”, i.e. normal cells that are mutated to adopt a cancer cell genotype and appearance are created in the body every day. The immune system typically detects these early cancer seeds and eliminates them. The immune system is composed of myeloid cells, these is the evolutionary older part of the system that detect abnormal antigens on derailed cells. A particular cell type, the antigen-presenting cells, act as scouts to inform cells of the so-called lymphoid system about their cancer cell findings. Once this lymphoid cells are alarmed to send out specialized CD8 T-cells and Natural Killer cells to find the tumor seeds and to “shoot” them by their biochemical weapons.
Cancer cells have learned to abuse a special immune dampening mechanism that muscles typically employ. Work overloaded musle also produce significant amounts of lactate that is felt as “sore muscle” the next morning. At the cellular level the lactate protects the muscle from beeing overly attacked by these immune cells. This mechanism is highjacked by late-stage cancers that adopt the Warburg effect, not only for providing energy and construction material, but at the same time also to prevent the immune system to attack the tumor.
Our Anti Warburg Warhead
Our goal is it to defeat late-stage cancers, such as metastasizing breast, ovarial cell, pancreatic, colorectal, lung, kidney or liver carcinomas by inhibiting the Warburg metabolism. Lactate is the key visible hallmark of “Warburgish” cancers and reducing the tumors´ lactate production through small-molecule Anti Warburg Warheads is our approach. We achieve this in two major ways: A) by indirectly inhibiting glycolysis at the transcriptional / translational level and B) by directly inhibiting glycolysis through prodrugs that are only converted into the “active weapon” in the environment of a late-stage cancer.
Klick below to view some data how our AWWs (Approach A) perform in cell culture and in vivo. Please note the dual effect on cancer growth as such (by curbing lactate production and “clogging the exhaust pipe” of tumors) and on the tumor immune microenvironment.