A new set of drugs exploit a\u00a0recently-revealed\u00a0weakness in\u00a0‘zombie-like’ \u2013 or\u00a0senescent\u00a0\u2013\u00a0cells\u00a0that could lead to\u00a0new\u00a0treatments\u00a0for\u00a0cancer and age-associated diseases.\u00a0The\u00a0study from the MRC Laboratory of Medical Sciences\u00a0(LMS)\u00a0and\u00a0Imperial\u00a0College\u00a0London\u00a0shows\u00a0that senescent\u00a0cells walk a tightrope, risking cell death with\u00a0high\u00a0levels\u00a0of iron\u00a0and other damaging\u00a0agents\u00a0but compensating for this\u00a0by overproducing\u00a0a protective protein that staves off death.\u00a0Targeting this\u00a0defence mechanism\u00a0removes their\u00a0shield\u00a0and\u00a0could\u00a0be used to treat senescence-associated diseases, including cancer. This\u00a0approach\u00a0could complement existing treatments to bring much-needed improvements for cancer patients.<\/p>\n
Cancers grow\u00a0as a result of\u00a0unconstrained cell division. But within most tumors, there is a\u00a0portion\u00a0that does not divide at all: senescent cells.\u00a0Chemotherapy often\u00a0increases\u00a0the proportion of senescent cells\u00a0in a tumor\u00a0as\u00a0it\u00a0aims\u00a0to stem the rapid proliferation, but although these cells\u00a0don’t\u00a0directly increase the size of a tumor, they wreak havoc in their own way. Senescent cells, which are also a defining feature of aging conditions such as fibrosis, influence neighbouring cells by secreting molecules that increase proliferation, the spread of the cancer, and unwanted immune system activity. There is therefore an increasing interest in developing drugs that directly target and kill senescent cells, in cancer and beyond.\u00a0<\/p>\n
Mariantonietta\u00a0D’Ambrosio,\u00a0a\u00a0postdoctoral researcher at the\u00a0LMS, is\u00a0lead author of\u00a0the\u00a0study published\u00a0in\u00a0Nature Cell Biology\u00a0which\u00a0reveals\u00a0a new approach\u00a0to\u00a0killing\u00a0senescent cells in cancer.\u00a0<\/p>\n
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Senescence was considered for a long time to be positive, because senescent cells\u00a0don’t\u00a0proliferate, which is the core feature of cancer. Normal chemotherapy induces\u00a0senescence\u00a0blocking\u00a0the proliferation of cancer cells,\u00a0so the tumor\u00a0doesn’t\u00a0get bigger. But with time you also see the negative side of the senescent cells, because they secrete a lot of factors that influence neighbouring cells and induce even more proliferation, metastasis<\/a>, and recruitment of bad parts of the immune system that will provoke even more aggressiveness in the tumor.\u00a0For this reason, we tried to find some drugs that were able to kill the senescent cells.”\u00a0<\/p>\n
Mariantonietta\u00a0D’Ambrosio,\u00a0postdoctoral researcher, LMS<\/p>\n
<\/p>\n Testing 10,000\u00a0possible drugs\u00a0<\/p>\n The researchers cast a broad net in their search for new drugs that might kill senescent cells. Together with collaborators at the Department of\u00a0Medicinal\u00a0Chemistry at Imperial, they decided to examine a class\u00a0of\u00a0inhibitors\u00a0usually referred\u00a0to\u00a0as ‘covalent\u00a0compounds’. These compounds can form a\u00a0covalent bond\u00a0with their target, which can result in the inhibition of proteins previously considered undruggable. They\u00a0introduced 10,000 different\u00a0covalent\u00a0compounds to both senescent cells and normal cells,\u00a0looking\u00a0for\u00a0the\u00a0ones\u00a0that\u00a0preferentially killed senescent cells\u00a0and\u00a0classing\u00a0the drug as ‘senolytic’, or\u00a0senescent-killing.\u00a0<\/p>\n They narrowed their results down to\u00a0just\u00a0four\u00a0promising\u00a0compounds\u00a0and\u00a0found that three of them\u00a0affected a particular protein: GPX4. GPX4 has a protective role in cells, helping stave off ferroptosis, a type of cell death associated with\u00a0high levels\u00a0of iron and destructive ‘reactive oxygen\u00a0species’. Ferroptosis had\u00a0only recently been revealed as a potential weakness of senescent cells.\u00a0<\/p>\n Mariantonietta\u00a0says, “recent papers have shown this predisposition of senescent cells to ferroptosis, but\u00a0it’s\u00a0a new senescence vulnerability. That creates an opportunity for us to exploit. So now there is research to find\u00a0senolytic\u00a0drugs to kill cells through ferroptosis.”\u00a0<\/p>\n To protect themselves against the\u00a0high levels\u00a0of iron and other ferroptosis-causing\u00a0agents, senescent cells have\u00a0high levels\u00a0of GPX4.\u00a0It’s\u00a0like proactively taking a painkiller so you can keep running on an ankle; the damage and danger\u00a0remains, but the immediate risks are bypassed. Removing the painkiller makes the pain unbearable. And blocking the activity of GPX4, as the drugs\u00a0identified\u00a0by the screening process do,\u00a0removes the shield, making fatal ferroptosis unavoidable.\u00a0<\/p>\n Improved\u00a0outcomes\u00a0in three cancer models\u00a0<\/p>\n The team tested their drugs with three different mouse models of cancer\u00a0and saw improved outcomes\u00a0as a result of\u00a0senescent cell death in each case. Translating this to patients could be a huge asset to cancer treatments.\u00a0<\/p>\n “In mouse models we saw that these drugs reduced tumor size, and improved survival. Now we need to see the effect on the immune system. Is the improvement\u00a0also\u00a0awakening\u00a0the ‘good side’ of the immune system (T cells, natural killer cells) that helps to kill the tumor?” says Professor Jesus Gil,\u00a0senior author and\u00a0Head of the Senescence group at the LMS,\u00a0“Once we know more,\u00a0the next step is\u00a0to\u00a0understand which cancer cell types or specific patients might better respond to this treatment.\u00a0For example,\u00a0if\u00a0a patient undergoing\u00a0chemotherapy\u00a0overexpressed\u00a0GPX4\u00a0then\u00a0you\u00a0could\u00a0use this approach in combination with existing drugs to improve efficacy<\/a>.”\u00a0<\/p>\n This approach offers a much-needed new perspective on cancer therapy, pinpointing senescent cells as an underexploited target.\u00a0Mariantonietta\u00a0says it has potential to transform treatment: “Targeting senescence is a huge opportunity for cancer treatments, and ultimately it can play a supporting role in addition to chemotherapy and immunotherapy<\/a>.”\u00a0<\/p>\n Researchers at several institutions, including the\u00a0Institute of Oncology Research (IOR) in\u00a0Bellinzona,\u00a0Switzerland\u00a0and the M3 Research Centre\u00a0at the University of T\u00fcbingen in\u00a0Germany also contributed to this study.<\/p>\n Source:<\/p>\n Medical Research Council (MRC) Laboratory of Medical Sciences<\/a><\/p>\n Journal reference:<\/p>\n
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