Certain molecular drivers of cancer growth are "undruggable" - it's been nearly impossible to develop chemicals that would block their action and prevent cancer growth. Many of these molecules function by passing cancer-promoting information through a gate in the nucleus, where the instructions are carried out. Researchers have found a way to block the nuclear gates used by these molecules, and show that this inhibition can halt aggressive prostate cancer in mice bearing human tumors.
"We found that a particular gatekeeper, the nuclear pore protein called POM121, traffics molecules that boost tumor aggressiveness," said first and co-corresponding author of the paper published in the journal Cell. "Blocking this gatekeeper prevents several molecules from reaching their targets in the nucleus, thus decreasing tumor growth." The researchers also showed that blocking POM121 transport helps restore chemotherapy efficacy in preclinical models of the disease.
This is the first demonstration that nuclear pore proteins may be effective anti-cancer targets for prostate cancer.
Using computational biology techniques that integrate genetic information from prostate cancer patients and experimental models, the investigators dissected the functions of nuclear pore proteins across the course of the disease from early to late stages. They discovered that an abundance of the POM121 component of the nuclear pore was associated with aggressive tumors that continue to grow despite standard therapy.
The researchers then showed that blocking POM121 or disrupting its partner Importin β could block molecules such as MYC, E2F1, and the androgen receptor - three molecules that drive aggressive prostate cancer - from reaching the nucleus to activate tumor growth and spread.
"This study shows that blocking the import machinery may be an effective strategy to target the undruggable," said co-corresponding author. "For example, MYC is an oncogenic transcription factor wherein successful direct blockage does not exist. We provide a remarkable approach to target not only MYC but also E2F1 by impairing their nuclear import, critical for their oncogenic function in prostate cancer."
Although about 85-90 percent of men diagnosed at early stages of prostate cancer are cured after receiving surgery or radiotherapy, the remaining 10-15 percent of men have an aggressive disease course. This advanced disease is characterized by the appearance of tumors in distant organs (metastasis) and the acquisition of resistance to hormone therapy targeting the androgen receptor and anticancer drugs, which precede death in most prostate cancer patients. "Prostate cancer remains a major health challenge, as the second leading cause of cancer death in this country. This study represent a major breakthrough in identifying a new means for targeting advanced prostate cancers," said a co-author on the study.
Researchers also demonstrated that combining inhibitors of the POM121-Importin β axis with standard chemotherapy regimens decreased tumor size in mouse models bearing human prostate cancer tumors.
The researchers plan to continue the work by identifying specific chemical compounds against POM121 and determine their efficacy and toxicity for use in human clinical trials.
https://www.jefferson.edu/university/news/2018/08/09/Blocking-undruggable-cancer-targets.html
https://www.cell.com/cell/fulltext/S0092-8674(18)30909-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867418309097%3Fshowall%3Dtrue
Blocking the nuclear transport to treat cancer
- 1,239 views
- Added
Edited
Latest News
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
How protein synthesis in de…
By newseditor
Posted 22 Apr
Atlas of mRNA variants in d…
By newseditor
Posted 22 Apr
Other Top Stories
Constant traffic noise may boost depression risk
Read more
Brain tangles in an animal model through exposure to environmental…
Read more
Myc is required for early embryo development
Read more
Exposure to air pollution increases the risk of obesity
Read more
Scientists part the clouds on how droplets form
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Structure of antiviral drug…
By newseditor
Posted 23 Apr
Type-I-interferon-responsiv…
By newseditor
Posted 23 Apr
Selenium, diabetes, and the…
By newseditor
Posted 23 Apr
Long-term neuropsychologica…
By newseditor
Posted 23 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar