The 24-year-old physician Dr. Laura Hinze
from Hannover Medical School receives the Paul Ehrlich and Ludwig Darmstaedter Prize
for Young Researchers 2022, as announced today by the Scientific Council of the
Paul Ehrlich Foundation. Laura Hinze is being honoured for her significant
contribution to the understanding of signal transduction in cancer cells. She
has discovered how leukaemia cells develop resistance to the chemotherapeutic
agent asparaginase, thereby presenting a novel target for the treatment of
acute lymphoblastic leukaemia (ALL), the most common cancer in children. Her discovery
also derives a new approach for the treatment of colorectal cancer and other
solid tumours.
FRANKFURT. Unlike
normal body cells, leukaemia cells are not able to produce sufficient amounts
of the amino acid asparagine. They have to import asparagine. Because the
enzyme asparaginase catalyses the degradation of asparagine, its injection
drastically reduces the extracellular supply of this amino acid. Consequently,
leukaemia cells die from this depletion, while normal body cells are not
harmed. However, leukaemia cells can learn to evade the effect of asparaginase.
To find out how this happens, Dr. Laura Hinze
and her group used CRISPR/Cas9 gene scissors to systematically switch off
around 19,000 genes in a culture of resistant ALL cells – only one in each cell
– and observed what happened when they treated the cells with asparaginase. A
culture to which only a buffer solution was added served as a control. In the
culture treated with asparaginase, those cells in which one of the two genes
NKD2 or LGR6 had been switched off, died particularly frequently. They had
apparently lost their resistance. Conversely, this indicated that cells in
which these genes function become resistant particularly frequently. Hinze and
her team demonstrated that both genes code for inhibitors of the Wnt signalling
pathway.
In the healthy organism, this signalling
pathway is responsible for embryonic development and later for tissue repair
and maintenance. Its untimely activation favours the development of cancer.
This is mainly due to an excessive amount of the protein ß-catenin, which
carries growth impulses into the cell nucleus. When the Wnt signalling pathway
is inactive, the excess ß-catenin is marked for degradation with ubiquitin
molecules. Central to this labelling work is the enzyme glycogen synthase
kinase 3 (GSK3). It ensures that ß-catenin is fed to the proteasome, where it
is broken down into small fragments and amino acids like all proteins that
could harm the cell or that it does not need. It is from this source that the
leukaemia cell fetches the asparagine of which it has been deprived of by
treatment with asparaginase. Through a partial activation of the Wnt signalling
pathway, which blocks the degradation of ß-catenin without spurring its potentially
oncogenic signals, Hinze and colleagues succeeded in largely drying up this
source of resistance. The same effect they achieved by selective GSK
inhibition. Leukaemia mice that received both asparaginase and GSK3 inhibitors
survived much longer than those treated with asparaginase alone.
Mutations in the Wnt signalling pathway
that led to its overactivation are characteristic for many colorectal cancers.
Hinze therefore examined to what extent her research results could be
transferred to this second most common of all cancers. Her initial hypothesis:
15 percent of all Wnt signalling pathway mutations in colorectal cancer lie
upstream of the enzyme GSK3. In patients with this genetic signature, the
enzyme is thus endogenously inhibited. The proteasome no longer supplies
asparagine. If one depletes asparagine additionally by administering
asparaginase, one could starve the colon cancer cells. Laura Hinze and her
group have now preclinically proven this hypothesis. It could also apply to
other solid tumours that are characterised by a Wnt-induced endogenous
inhibition of GSK3.
The prize will be awarded - together with
the main prize 2022 and the prizes of the year 2021 - on 14 March 2022 at 5
p.m. by the Chairman of the Scientific Council of the Paul Ehrlich Foundation
in Frankfurt's Paulskirche. Due to the pandemic, the number of available seats
is limited. The event will be broadcast via livestream. Please do not hesitate
to contact us if you have any questions.
Please find pictures of
the award winner and a more comprehensive background information for
download under: www.paul-ehrlich-stiftung.de
Further
Information:
Press Office Paul Ehrlich Foundation
Joachim Pietzsch
Phone: +49 (0)69 36007188
j.pietzsch@wissenswort.com
www.paul-ehrlich-stiftung.de