Design drug pairs where resisting one makes you vulnerable to the other
Choose two treatments so that whatever the tumour does to escape the first, it becomes easier to kill with the second. The immune system is a good candidate partner.
An evolutionary double bind pairs therapies with opposing selection pressures. Examples with preclinical support include MAPK inhibition increasing antigen presentation (making escape via MAPK reactivation immune-visible) and antiandrogen resistance via lineage plasticity creating dependence on EZH2. The proposal is to make double-bind logic an explicit design criterion, with a mechanistic screen for pairs in which resistance to A upregulates the target of B.
- Tumour heterogeneity and clonal evolution · A tumour is many tumours. Treatments that kill most cells leave the rest to grow back, changed.
- Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.
- Too many combinations to test · There are thousands of possible drug pairs and sequences. Trials can test a few dozen a year.
Pages like this
not linked directly; found by shared links- IdeaTime immunotherapy to the moment targeted drugs make tumours visible
Shares Too many combinations to test, RAS / RAF / MEK / ERK (MAPK), Acquired resistance to every therapy, Immune checkpoint inhibitors.
- IdeaAdd the second drug on day one when the escape route is predictable
Shares BRAF, Too many combinations to test, RAS / RAF / MEK / ERK (MAPK), Acquired resistance to every therapy.
- IdeaAn open atlas of collateral sensitivity for every approved targeted drug
Shares Tumour heterogeneity and clonal evolution, Too many combinations to test, Acquired resistance to every therapy.
- IdeaBlock the chemical switch that lets cells hide from treatment
Shares EZH2, Acquired resistance to every therapy.
- TrialCOMBI-AD
Shares BRAF, RAS / RAF / MEK / ERK (MAPK).
- IdeaRotate between drugs on a fixed schedule instead of waiting for failure
Shares Too many combinations to test, Acquired resistance to every therapy.
- IdeaFactorial dose finding for drug combinations instead of full dose of everything
Shares Too many combinations to test, Immune checkpoint inhibitors.
- IdeaSlow the tumour's mutation engine with APOBEC inhibitors during targeted therapy
Shares Tumour heterogeneity and clonal evolution, Acquired resistance to every therapy.