Scientists from the Walter and Eliza Hall Institute of Medical Research (WEHI) and Murdoch Childrens Research Institute, Melbourne, Australia in collaboration with Sanford Burnham Prebys (SBP) have developed a new strategy to induce cancer cell death to combat acute myeloid leukemia (AML), a type of cancer in which the bone marrow makes abnormal blood cells or platelets.
In cancers, the natural pathway of programmed cell death, apoptosis, is disabled, thereby resulting in uncontrolled cell growth and multiplication. Traditional chemotherapies and available therapeutics target the apoptosis pathway to kill cancer cells and hence are often ineffective, have a high relapse rate within the first five years post-treatment leading to an alarming fatality rate (50%).
In this new study published in Science Translational medicine, these researchers have found a workaround for certain types of cancers, by unleashing an alternate inflammatory cell death process called necroptosis, which was defined recently in immune cells and its bone-marrow precursors.
“It has been speculated that inducing necroptosis might be an effective way to kill cancer cells”, said Professor John Silke of WEHI, who led the team. Contrary to apoptosis, in which cell contents are retained inside ‘blebs’ of plasma membrane, this is a relatively controlled cellular explosion.
“We knew that necroptosis can be induced in vitro by treating cells with two drugs—birinapant, a SMAC (Second mitochondria-derived activator of caspases) mimetic and emricasan, a caspase-8 inhibitor. Our collaborators showed that, while untreated mice had tumor cells basically everywhere, none were detectable in those given both drugs.” said Salvesen, Professor in SBP’s NCI-designated Cancer Center.
The drugs work synergistically; while birinapant kills the AML cells, emricasan augments this effect by sensitizing the AML cells to birinapant. High efficacy and safety of these drugs have been demonstrated and together with the fact that AML will be less likely to develop resistance against this drug combination gives a bright ray of hope for AML patients.
Dr Brumatti added that since cancer cells often acquire resistance to traditional chemotherapy-induced apoptosis, this novel type of chemotherapy had a clinically feasible potential to be used to treat leukemias that have poor scope otherwise.
“These findings are especially exciting since there have been no treatment breakthroughs in AML in decades.” quoted Salvasen.
Clinical trials may have to wait though, since the caspase-8 inhibitor has a very short lifetime in the body and a variant that sustains longer needs to be developed.