Nanoparticle for overcoming leukemia treatment resistance

Date:
June 18, 2020
Source:
University of Connecticut
Summary:
One of the largest problems with cancer treatment is the development
of resistance to anticancer therapies. A research team found that
repurposing a commonly used chemotherapy drug using a nanoparticle
was more effective than both a solution of the pure drug and other
available treatments.



FULL STORY ========================================================================== UConn associate professor of pharmaceutics Xiuling Lu, along with
professor of chemistry Rajeswari M. Kasi, was part of a team that
recently published a paper in Nature Cell Biology finding a commonly
used chemotherapy drug may be repurposed as a treatment for resurgent
or chemotherapy-resistant leukemia.


==========================================================================
One of the largest problems with cancer treatment is the development of resistance to anticancer therapies. Few FDA-approved products directly
target leukemia stem cells, which cause treatment-resistant relapses. The
only known method to combat their presence is stem cell transplantation.

Leukemia presents unique treatment challenges due to the nature of this
form of cancer. The disease affects bone marrow, which produces blood
cells. Leukemia is a cancer of the early blood-forming cells, or stem
cells. Most often, leukemia is a cancer of the white blood cells. The
first step of treatment is to use chemotherapy to kill the cancerous white blood cells, but if the leukemia stem cells in the bone marrow persist,
the cancer may relapse in a therapy-resistant form.

Fifteen to 20% of child and up to two thirds of adult leukemia patients experience relapse. Adults who relapse face a less-than 30% five-year
survival rate. For children the five-year survival rate after relapse is
around two thirds. When relapse occurs, chemotherapy does not improve the prognosis for these patients. There is a critical need for scientists to develop a therapy that can more effectively target chemotherapy-resistant cells.

There are two cellular pathways, Wnt- b-catenin and PI3K-Akt, which
play a key role in stem cell regulation and tumor regenesis. Cooperative activation of the Wnt- b-catenin and PI3K-Akt pathways drives self-renewal
of cells that results in leukemic transformation, giving rise to cancer relapse. Previous studies have worked on targeting elements of these
pathways individually, which has had limited success and often results
in the growth of chemo-resistant clones.

The researchers screened hundreds of drugs to find one that may inhibit
this interaction. They identified a commonly used chemotherapy drug, doxorubicin as the most viable target. While this drug is highly toxic
and usually used with caution in clinical settings, the team found when
used in multiple, low doses, it disrupts the Wnt- b-catenin and PI3K-Akt pathways' interaction, while potentially reducing toxicity.



==========================================================================
Lu's lab contributed a nanoparticle which allowed the drug to be injected safely and released sustainably over time, a key to the experiment's
success.

The nanoparticle encasing doxorubicin enables slow release of the drug
to the bone marrow to reduce the Akt-activated Wnt- b-catenin levels
in chemo- resistant leukemic stem cells and reduce the tumorigenic
activity. In low doses, doxorubicin stimulated the immune system while
typical clinical doses are immunosuppressive, inhibiting healthy immune
cells.

Lu is the CEO of Nami Therapeutics, a startup which designs nanoparticles
for drug delivery in a variety of clinical contexts including cancer
treatment and vaccine delivery.

Because of its rate of drug release, Lu's patented nanoparticle was
more effective than both a solution of the pure drug and a liposomal doxorubicin, the only commercially available version of a nanoparticle
carrying doxorubicin.

"It's exciting that the whole research team identified this new mechanism
to effectively inhibit leukemia stem cells," Lu says. "We are happy to see
that our proprietary nanoparticle delivery system has such potential to
help patients." By using low, but more sustained, doses of this drug, leukemia-initiating activity of cancerous stem cells was effectively
inhibited.

The researchers demonstrated clinical relevance by transplanting patient leukemic cells into mice and observing that low-dose doxorubicin's
ability to disrupt these cells. Patient sample transplants with therapy-resistant leukemia stem cells rapidly developed leukemia. But
the low-dose doxorubicin nanoparticle treatment improved survival by
reducing the presence of leukemia stem cells.

Lu says the next steps for this research is to further validate the now- patented method and nanoparticle and eventually bring it into clinical
usage.

Lu and her collaborator, Rajeswari Kasi, also have two pending patents
on copolymer-nanoparticles for drug delivery and methods for treating
chemo- resistant cancer-initiating cells.


========================================================================== Story Source: Materials provided by University_of_Connecticut. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. John M. Perry, Fang Tao, Anuradha Roy, Tara Lin, Xi C. He,
Shiyuan Chen,
Xiuling Lu, Jacqelyn Nemechek, Linhao Ruan, Xiazhen Yu, Debra
Dukes, Andrea Moran, Jennifer Pace, Kealan Schroeder, Meng Zhao,
Aparna Venkatraman, Pengxu Qian, Zhenrui Li, Mark Hembree,
Ariel Paulson, Zhiquan He, Dong Xu, Thanh-Huyen Tran, Prashant
Deshmukh, Chi Thanh Nguyen, Rajeswari M. Kasi, Robin Ryan,
Melinda Broward, Sheng Ding, Erin Guest, Keith August, Alan
S. Gamis, Andrew Godwin, G. Sitta Sittampalam, Scott J. Weir,
Linheng Li. Overcoming Wnt-b-catenin dependent anticancer therapy
resistance in leukaemia stem cells. Nature Cell Biology, 2020; 22
(6): 689 DOI: 10.1038/s41556-020-0507-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200618120149.htm

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