Anticancer compounds for B cell cancer therapy targeting cellular stress response

Date:
October 13, 2020
Source:
The Wistar Institute
Summary:
Scientists are developing anticancer compounds targeting a pathway
of the endoplasmic reticulum (ER) stress response implicated in the
development of multiple myeloma (MM), chronic lymphocytic leukemia
(CLL) and lymphoma.



FULL STORY ========================================================================== Researchers at The Wistar Institute and collaborators from the University
of Notre Dame are developing anticancer compounds targeting a pathway
of the endoplasmic reticulum (ER) stress response implicated in the
development of multiple myeloma (MM), chronic lymphocytic leukemia (CLL)
and lymphoma. The study was published online today in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research.


==========================================================================
The ER is an important organelle in our cells that oversees the quality
control of protein folding under normal conditions and responds to the accumulation of misfolded proteins found under stressful conditions
by activating specific mechanisms and signaling pathways such as the IRE-1/XBP-1 pathway that triggers a cascade of events that brings cells
back to normal physiological conditions.

The laboratory of Chih-Chi Andrew Hu, Ph.D., professor in the Immunology, Microenvironment & Metastasis Program at Wistar, and collaborators show
that targeting the ER stress signaling response is an effective strategy against various B cell cancers that rely upon ER stress signaling response
to survive under stressful conditions.

The Wistar Institute and Notre Dame teams are working together to advance
a new class of compounds to inhibit IRE-1 protein and block the function
of the IRE- 1/XBP-1 pathway, which promotes survival of malignant B
cells such as MM and CLL cells. The IRE-1 inhibitors being developed by
Hu and collaborators have shown promising activity in several preclinical cancer models, compared to other commercially available IRE-1 inhibitors
having variable and inconsistent ability to selectively target ER stress signaling in vitro and in vivo.

"We carefully compared many published inhibitors of the IRE-1/XBP-1
pathway with our own inhibitors, showing that our compounds are the
most reliable small molecule inhibitors for targeting this pathway in
malignant B cells and that many of the other published inhibitors we
tested have subpar activity or adverse off-target effects," said Hu.

The team measured the ability of various inhibitors to block the RNase
activity of IRE-1 in test tubes and within the cells. The best-performing molecules were further evaluated for their cytotoxicity against MM,
CLL and mantle cell lymphoma, both as single agents and in combination
with PI3K/AKT pathway inhibitors that are used as targeted therapy for
these malignancies.

Two inhibitors developed by the team, B-I09 and D-F07, showed the highest
and longest-lasting inhibitory activity at lower concentrations.

To improve the tumor specificity of these compounds, Hu and colleagues exploited a feature of tumor cells. Since tumor cells typically produce
higher hydrogen peroxide (H2O2) levels than normal cells, researchers
designed, synthesized and tested novel inhibitors modified with boronate
cages, which require high levels of H2O2 to subsequently turn on their inhibitory activity towards IRE-1.

E-F02, a modified prodrug form of B-I09, could be optimally activated
by H2O2 to inhibit IRE-1 in malignant B cells. Furthermore, its killing activity was further enhanced in combination with a compound that induces
the production of H2O2 in the cells. "E-F02's inhibitory activity can
be controlled spatiotemporally with specificity against cancer cells in
vitro," said co- corresponding author Chih-Hang Anthony Tang, M.D., Ph.D.,
a staff scientist in the Hu lab. "Next step is to further test it in vivo
in our cancer mouse models." "We are interested in collaborating with a biotech partner to complete preclinical testing of our lead candidates
in order to pursue clinical development of our IRE-1/XBP-1s inhibitors
to target human CLL and many other cancers including solid tumors to
one day deliver a new highly specific and effective cancer therapy."

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


========================================================================== Journal Reference:
1. Andong Shao, Qin Xu, Walker T. Spalek, Christopher F. Cain,
Chang Won
Kang, Chih-Hang Anthony Tang, Juan R. Del Valle and Chih-Chi
Andrew Hu.

Development of tumor-targeting IRE-1 inhibitors for B cell
cancer therapy. Molecular Cancer Therapeutics, 2020 DOI:
10.1158/1535-7163.MCT- 20-0127 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201013124153.htm

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