Australian scientists have found a new and effective way to treat a particularly aggressive blood cancer in children. Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in kids. Despite dramatic improvements in the survival of children with ALL over past several decades, children who develop ‘high risk’ ALL – subtypes that grow aggressively and are often resistant to standard treatments – often relapse, and many of these children die from their disease. One common type of high-risk ALL for which new therapies are urgently needed is ‘Philadelphia chromosome-like ALL’ (Ph-like ALL), named for its similarity to another type, Ph-positive ALL. Shared genetic characteristics of these two types of high-risk ALL have led scientists to hypothesize that they may respond to similar treatments; specifically, a newer class of drugs known as kinase inhibitors.
However, experiments have shown that cases of Ph-like ALL that contain a genetic mutation known as CRLF2r – about half of all cases of this subtype – respond poorly to kinase inhibitors when used as a single agent. Scientists have since been investigating whether kinase inhibitors are more effective when used in combination with other agents. In new research published a couple of weeks ago in the international journal Leukemia, scientists at Children’s Cancer Institute tested more than 5000 drugs in combination with the Janus kinase (JAK2) inhibitor, ruxolitinib, finding that this drug worked synergistically with several types of commonly used anticancer drugs, the most effective being antimetabolites, glucocorticoids, topoisomerase inhibitors and agents directed against microtubules.
Based on their in vitro findings, the researchers then carried out in vivo testing in living models of disease known as ‘patient-derived xenograft models’ (PDXs) or ‘avatars’: mice specially bred to grow leukemia cells taken from individual patients with CRLF2r Ph-like ALL. Results showed that the addition of ruxolitinib to a common treatment regimen called VXL (standing for vincristine, dexamethasone and L-asparaginase) enhanced treatment efficacy in two out of three avatars, achieving long-term suppression of leukemia growth in one of these. But that’s not all. Another team from the Faculty of Health and Medical Sciences at the University of Copenhagen, is focusing on another aspect of chemoresistance in ALL, by atudying the signal transduction of the Notch1 receptor.
They found the cellular element the induces the drug resistance; the protein kinase C (PKC). The majority of T-ALL patients have mutations in the so-called Notch1 gene. This mutation causes a cell surface receptor to induce cancer cell growth. By using a drug that inhibits this receptor, it is possible to stop the cancer cells from dividing and growing. On the other side, an ihbitor of PKC could be suitable. In the past inhibitors of PKC isoforms have been seen to repress cellular duplication or even indice cancer cell death. Unfortunately, the cancer cells are good at adapting and in many cases develop resistance towards the Notch-inhibitor. The challenge scientists are facing with drug resistance is very hard to overcome as long as they only targeting one protein, in this case the Notch1 receptor, at a time.
That is why researchers have been looking for a therapy option that targets two proteins at the same time, making it much more difficult for the cancer cells to develop resistance. There area couple of known Notch1 inhibitors called crenigacestat, JQ-FT and WC75, which has a dual selectivity including preference for leukemia cells. On the other side, very recent PKC inhibitors are enzastaurin and midostaurin; they are very effective in killing cancer cells. Cellular proteins to use as a target in cancers and leukemia are hundreds; the more specific molecules they are targeted with (in this case in combination), the higher the chance to erase malignant cells once for all.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Franciosa G et al. Nat Commun 2021; 12(1):2507.
Bohm JW, Sia KCS et al. Leukemia 2021 Apr 24.
Karsa M, Kosciolek A et al. Br J Cancer 2021 Apr 9.
Dott. Gianfrancesco Cormaci
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