Our answer to tumours
A small molecule warhead against the Warburg effect
Watch the video to see how curbing lactate production has an impact on tumor growth and revitalisation of the immune system against cancer.
Metabolism
Lactate reduction in cell culture
Here, we have used our prototypic AWW drug B-010 to reduce Lactate and ATP production while reducing glucose consumption in cell culture. These processes are tightly linked to each other.
The red line shows the proliferation activity of the SARS-CoV2 coronavirus in a lung bronchial cancer cell line which has the receptor for virus entry. The inhibition of virus proliferation coincides with the reduction in ATP and Lactate, simply because viruses use the same “Warburg pathways” for their replication as cancer cells do.
Although we can inhibit the Warburg effect at single digit nM concentrations, real cytotoxicity, i.e. cell killing appears only north of single digit µM concentrations. This gives us the window that allows for therapeutic dosing in animal models.
Effect in Xenografts
B-010 and our related AWWs are so far the only small molecules worldwide that limit lactate production and allow for effective dosing in mouse cancer models. Typically, direct inhibitors of glycolysis are hampered by severe side effects and mechanism-based hemolytic anemia or neurotoxicity because erythrocytes and certain brain cells also heavily employ glycolysis.
We can overcome this limitation because our B-010 has a factor of 1000x between onset of cytostatic effects (that come with reducing lactate) and cytotoxic effects (which kills cells no matter whether they are friend or foe).
Here, we show that by using a dose as low as 10 mg/kg/day, we can reduce intratumoral lactate as well as limit cancer growth in a HeLa Xenograft model (i.e. without a fully functional immune system). Phenformin was used to inhibit the alternative OxPhos pathway of energy generation and has a small effect on tumor growth on its own. B-010 indirectly inhibits glycolysis and lactate production very effectively with a highly significant effect on tumor growth as monotherapy. Both, B-010 and Phenformin combined, have an additive effect on cancer growth.
Immune system
Effects in immune-competent mice
So-called syngeneic mouse models have a fully intact immune system and here one can observe “mouse cancer in a mouse”. We used the very aggressive triple-negative breast cancer model 4T1 to demonstrate the effects of our prototype compound B-010.
4T1 tumors are a kind of “immune desert” and in this sense they represent an extreme version of immune-excluded human tumors. Look at the FACS windows on the right. In each window a certain immune cell type can be detected and each dot represents one immune cell in the tumor. In the “no drug” control group you hardly find any active immune cell type but the cancer allies, the MDSCs, are prominently represented in these tumors.
Upon 5 days of B-010 treatment only, you see that all tumor-aggressive immune cells enter the tumor: M1 macrophages, NK-cells, T-cells and even B-cells. These are so far unprecedented effects of a small molecule lactate inhibitor on the tumor microenvironment. This encourages us to combine our AWW treatment with the immunotherapies currently in clinical use to get these immunotherapies to work in late stage solid cancers where they hardly show any effects on their own so far.
