A research team led by scientists at Roswell Park Comprehensive Cancer
Center has discovered a molecule that inhibits the growth and metastasis of
pancreatic cancer cells through the iron metabolism pathway. Their findings,
recently published in Molecular Cancer Therapeutics, pave the way toward the
development of a new drug candidate for the treatment of pancreatic cancer.
The molecule, MMRi62, targets iron metabolism to kill cancer cells and the
harmful proteins that encourage their growth and spread, suggesting that
further development and refinement of this compound could lead to a new type
of pancreatic cancer therapy.
"MMRi62 causes degradation of an iron-storage protein called FTH1, as well
as a protein that is mutated in PDAC, resulting [in] inhibition of
metastasis and ferroptosis, a form of cell death triggered by free cellular
iron," says Xinjiang Wang, Ph.D., Associate Professor in the Department of
Pharmacology and Therapeutics at Roswell Park.
Pancreatic ductal adenocarcinoma (PDAC) cells are predisposed to
ferroptosis, a recently identified type of cell death triggered by iron that
has become a focal point of cancer research. The identification of novel
agents that activate ferroptosis represents a new area of potential
therapies for PDAC, an aggressive and largely incurable disease that
accounts for 90% of all types of pancreatic cancer.
A unique feature of PDAC are mutations in the KRAS and TP53 genes, which
drive the disease and make tumors resistant to chemotherapy. Because drugs
and treatments targeting these mutations are not yet available, therapeutic
options for patients with PDAC are limited, and the disease has a 5-year
survival rate of only 12%.
"We showed through this study that in a preclinical model, MMRi62 is capable
of inducing ferroptosis in PDAC cells harboring either KRAS or TP53
mutations, which in turn inhibited tumor growth and prevented metastasis of
tumors to distant organs," adds Dr. Wang.
"Although no ferroptosis-inducing agents are currently available, our hope
is that our discovery will lead to promising new MMRi62-based treatments for
recalcitrant cancers such as PDAC."
Reference:
Junhui Li et al, Small Molecule MMRi62 Induces Ferroptosis and Inhibits
Metastasis in Pancreatic Cancer via Degradation of Ferritin Heavy Chain and
Mutant p53, Molecular Cancer Therapeutics (2022).
DOI: 10.1158/1535-7163.MCT-21-0728