Safety concerns raised for neuroblastoma candidate drug

Date:
November 9, 2021
Source:
St. Jude Children's Research Hospital
Summary:
Scientists have identified the primary target of the experimental
cancer drug CX-5164, revealing a possible risk for late effects
of treatment.



FULL STORY ==========================================================================
St. Jude Children's Research Hospital scientists looking for drugs
to improve survival of children with high-risk neuroblastoma found a
promising candidate in CX-5461. Then researchers identified safety
concerns with the experimental drug that have implications for
current clinical trials in adults. The study appears today in Nature Communications.


========================================================================== CX-5461 is a small molecule that has been studied for more than a
decade. It has been widely described as a first-in-human inhibitor of
the enzyme RNA polymerase 1. Phase II clinical trials of CX-5461 are
underway in adults with leukemia, lymphoma and breast cancer.

St. Jude researchers demonstrated in this study that CX-5461 killed neuroblastoma tumor cells primarily by targeting and disrupting the
activity of the enzyme topoisomerase II beta (TOP2b) and not by inhibiting
RNA polymerase 1.

"These new details of CX-5461's mechanism of action in cancer treatment
have potentially important safety implications for patients," said Paul Geeleher, Ph.D., St. Jude Department of Computational Biology. He and
John Easton, Ph.D., St. Jude Computational Biology, are the study's corresponding authors. The first author is Min Pan, Ph.D., a scientist
in the Geeleher lab.

"Decades of study of an existing class of chemotherapy agents have shown
that off-target drug interactions with TOP2bleave patients at risk for
serious and life-threatening side effects such as acute myeloid leukemia
or cardiotoxicity that emerge years later," Geeleher said. "The findings highlight a previously unappreciated safety concern with CX-5461."
Search for new high-risk neuroblastoma drugs took unexpected turn The
study began as a quest to find new treatments for children with high-risk neuroblastoma, whose survival rates have remained about 50% for the last
20 years. Neuroblastoma arises from cells of the developing peripheral
nervous system and is diagnosed in about 800 children annually in the U.S.

CX-5461 showed significant anti-tumor activity in combination therapy
in preclinical studies of pediatric neuroblastoma, but safety concerns
must be addressed before planning clinical trials in children, Geeleher
said. "Patients enrolled in ongoing CX-5461 phase II trials should be
closely monitored for these late-emerging TOP2b-related adverse events,"
the researchers noted.

========================================================================== Story Source: Materials provided by
St._Jude_Children's_Research_Hospital. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Min Pan, William C. Wright, Richard H. Chapple, Asif Zubair, Manbir
Sandhu, Jake E. Batchelder, Brandt C. Huddle, Jonathan Low, Kaley B.

Blankenship, Yingzhe Wang, Brittney Gordon, Payton Archer, Samuel W.

Brady, Sivaraman Natarajan, Matthew J. Posgai, John Schuetz,
Darcie Miller, Ravi Kalathur, Siquan Chen, Jon Patrick Connelly,
M. Madan Babu, Michael A. Dyer, Shondra M. Pruett-Miller, Burgess
B. Freeman, Taosheng Chen, Lucy A. Godley, Scott C. Blanchard,
Elizabeth Stewart, John Easton, Paul Geeleher. The chemotherapeutic
CX-5461 primarily targets TOP2B and exhibits selective activity
in high-risk neuroblastoma. Nature Communications, 2021; 12 (1)
DOI: 10.1038/s41467-021-26640-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211109120314.htm

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