While cancer is an incredibly painful disease with no guaranteed cure yet, researchers are constantly conducted studies to determine another step towards the cure. A group of researchers at UConn including Associate Professor of pharmaceuticals Xiuling Lu, recently published a study in Nature Cell Biology regarding a common drug used in chemotherapy. The research explored the possibilities of repurposing the drug to treat the resurgent of chemotherapy-resistant leukemia.
One of the major problems with cancer treatment is the potential resistance to anti-cancer therapies. Not many drugs approved by the FDA, target leukemia stem cells. This gives rise to treatment-resistant relapses. However, stem cell transplantation is the only technique known to battle their presence.
Leukemia raises different struggles with treatments due to its nature. This cancer impacts the bone marrow, which is responsible for the production of blood cells. Frequently, leukemia affects white blood cells.
The primary step of the treatment is to kill all cancerous white blood cells by using chemotherapy. However, if the presence leukemia stem cells in the bone marrow sustain, chances of relapse with resistance to therapy may occur.
15-20% of children and two-thirds of adults suffering from leukemia undergo relapse. Adults experiencing a relapse, generally have a 5-year survival rate. While 30% of relapsing adults face this rate, almost two-thirds of relapsing children do too.
During a relapse, chemotherapy generally proves to be unsuccessful for the improvement of prognosis for the patients. Hence, researchers find it crucial to work on the development of therapy with increased effectiveness to target chemotherapy-resistant cells.
How does cancer relapse happen?
The body has 2 cellular pathways
Both play an essential role in regulating stem cells and is tumor regenesis. The collaborative activation of both pathways accelerates self-renewal of cells, which leads to leukemic transformation. This results in cancer relapse.
Previously, researchers have focused on targeting elements of both pathways individually. This resulted in restricted success and frequently led to an increase of chemo-resistant clones.
The researchers analyzed several drugs to find one that may hinder this interaction. They recognized a common drug used in chemotherapy, called doxorubicin. This drug had high toxicity, causing researchers to maintain cautions while performing clinical experiments. The researchers concluded that in minute doses, the drug inhibits the interaction of the Wnt-ß-catenin and PI3K-Akt pathways. Moreover, it could also possibly decrease toxicity.
Lu’s lab identified a nanoparticle that allowed researchers to safely administer the drug with a sustainable release. This was crucial for the success of the experiment. The nanoparticle enclosed the drug, allowing the slow release of doxorubicin into the bone marrow.
This potentially decreased the Akr-activated Wnt-ß-catenin levels in leukemia stem cells that are resistant to chemotherapy. This also resulted in a decrease in tumorigenic activity. In minute doses, doxorubicin enhanced the immune system, while conventional clinical dosages are generally immunosuppressive which hinders healthy and functioning immune cells.
Owing to the rate of rug release, Lu patented the nanoparticle. It had increased effectiveness than
- A purely concentrated solution of the drug and,
- Liposomal doxorubicin; the only accessible version of a nanoparticle carrying doxorubicin, available commercially.
Minute but sustained doses of the drug, led to effective inhibition of the activity in leukemic stem cells that causes cancer relapse. The researchers concluded clinical results after the transplant of leukemic cells into mice. They observed and analyzed the image of low-dose doxorubicin.
While the mice developed leukemia rapidly, low-dose doxorubicin nanoparticles enhanced the survival rate with the decrease in the presence of leukemic stem cells. Lu explains further steps being the validating of the patented technique. Lu further hopes for the entry of the nanoparticle into clinical experiments and usage.