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Anti-malarial choloroquine shows repurposing promise

Two new papers, one detailing a trial by University of Kentucky Markey Cancer Center researchers and another case study from Children's Hospital Colorado, shows that chloroquine – a drug currently used to treat malaria – may be useful in treating patients with metastatic cancers.

This follows results earlier this week that linked anticancer and antimalarial pathways in plant pathways.

The trial data, published in Cell Reports, the study showed that chloroquine induced the secretion of the tumor suppressor protein Par-4 in both mouse models and in cancer patients in a clinical trial. Secreted Par-4 is essential for tumor cell death and the inhibition of tumor metastasis.

Chloroquine induces Par-4 secretion via the classical secretory pathway that requires activation of p53 (a mutation of the p53 protein, or disturbances in the pathways that signal to p53, is common in many cancers).

Mechanistically, p53 directly induces Rab8b, a GTPase essential for vesicle transport of Par-4 to the plasma membrane prior to secretion.

The study’s findings indicate that chloroquine induces p53- and Rab8b-dependent Par-4 secretion from normal cells for Par-4-dependent inhibition of metastatic tumour growth.

“Because p53 is often mutated in tumours, it makes the tumours resistant to treatment,” said Vivek M. Rangnekar, the Alfred Cohen endowed chair in oncology research at the UK Markey Cancer Center and a professor in the UK Department of Radiation Medicine, and also the co-leader of the Cancer Cell Biology and Signalling research program and associate director at Markey. “However, this study shows that the relatively safe, FDA-approved drug chloroquine empowered normal cells – which express wild type p53 – to secrete Par-4 and stop metastasis in p53-deficient tumours.”

Meanwhile, a paper published in the journal eLife describes adding chloroquine has stabilised a patients disease and increased both the quantity and quality of her life.

Combining the anti-malaria drug with her treatment stopped an essential process that 26 year-old Lisa Rosendahl's cancer cells had been using to resist therapy, re-sensitizing her cancer to the targeted treatment that had previously stopped working.

Along with Rosendahl, two other brain cancer patients were treated with the combination and both showed similar, dramatic improvement.

After many surgeries, radiation treatments and chemotherapy, Lisa had started the drug vermurafenib, which was originally developed to treat BRAF melanoma and is now being tested in paediatric brain tumours.

Lisa's experience on the drug was typical of patients with BRAF cancers who are treated with BRAF inhibitors such as vemurafenib - after a period of control, cancer develops additional genetic mechanisms to drive its growth and survival and is able to progress past the initial drug.

Knowing that Lisa Rosendahl's tumor was positive for BRAFV600E mutation, and that this marked the tumor as especially dependent on autophagy - and also knowing that traditional options and even clinical trials were nonexistent - the group at CU Cancer Centerworked with Rosendahl and her father, Greg, to add the autophagy-inhibiting drug chloroquine to her treatment.

"We have treated three patients with the combination and all three have had a clinical benefit. It's really exciting - sometimes you don't see that kind of response with an experimental treatment. In addition to Lisa, another patient was on the combination two-and-a-half years. She's in college, excelling, and growing into a wonderful young adult, which wouldn't have happened if we hadn't put her on this combination," says paper first author Jean Mulcahy-Levy, MD, investigator at the University of Colorado Cancer Center and pediatric oncologist at Children's Hospital Colorado.

For more on drug repurposing, read about propanalol being repurposed to treat cancer here.

Source: Cell Reports & eLife

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