Nuclear gatekeeper could block undruggable prostate cancer targets

August 9, 2018, Thomas Jefferson University
Micrograph showing prostatic acinar adenocarcinoma (the most common form of prostate cancer) Credit: Wikipedia

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 at the Sidney Kimmel Cancer Center—Jefferson Health 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.

The research, co-led by Veronica Rodriguez-Bravo, Ph.D., and Josep Domingo-Domenech, MD, Ph.D., published in Cell August 9, 2018.

"We found that a particular gatekeeper, the nuclear pore protein called POM121, traffics molecules that boost tumor aggressiveness," said first and co-corresponding author Dr. Rodriguez-Bravo, Assistant Professor of Cancer Biology at Jefferson (Philadelphia University + Thomas Jefferson University). "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 .

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 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 Dr. Domingo-Domenech Associate Professor of Medical Oncology at the Sidney Kimmel Medical College at Jefferson. "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 Karen Knudsen, Ph.D., Director of the NCI-designated Sidney Kimmel Cancer Center—Jefferson Health, and a co-author on the study. Jefferson is one of eight NCI-designated cancer centers nationally with a Prostate Cancer Program of Excellence.

Drs. Rodriguez-Bravo and Domingo-Domenech and colleagues also demonstrated that combining inhibitors of the POM121-Importin β axis with standard chemotherapy regimens decreased size in mouse models bearing human 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.

Explore further: When one drug fails, a new door opens for cancer treatment

More information: Veronica Rodriguez-Bravo, Raffaella Pippa, Won-Min Song, Marc Carceles-Cordon, Ana Dominguez-Andres, Naoto Fujiwara, Jungreem Woo, Anna P. Koh, Adam Ertel, Ravi K. Lokareddy, Alvaro Cuesta-Dominguez, Rosa S. Kim, Irene Rodriguez-Fernandez, Peiyao Li, Ronald Gordon, Hadassa Hirschfield, Josep M. Prats, E. Premkumar Reddy, Alessandro Fatatis, Daniel P. Petrylak, Leonard Gomella, W. Kevin Kelly, Scott W. Lowe, Karen E. Knudsen, Matthew D. Galsky, Gino Cingolani, Amaia Lujambio, Yujin Hoshida, Josep Domingo-Domenech, "Nuclear pores promote lethal prostate cancer by increasing POM121 driven E2F1, MYC and AR nuclear import," Cell, DOI: 10.1016/j.cell.2018.07.015, 2018.

Related Stories

When one drug fails, a new door opens for cancer treatment

June 26, 2018
A new class of cancer drugs—called CDK4/6 inhibitors—recently approved to treat breast cancer can stunt the cancer's growth and replication. It is also being explored for a number of other cancers. Unfortunately, patients ...

Analysis of prostate tumors reveals clues to cancer's aggressiveness

July 19, 2018
Using genetic sequencing, scientists have revealed the complete DNA makeup of more than 100 aggressive prostate tumors, pinpointing important genetic errors these deadly tumors have in common. The study lays the foundation ...

Genome's dark matter offers clues to major challenge in prostate cancer

May 28, 2018
The dark matter of the human genome may shed light on how the hormone androgen impacts prostate cancer.

Breakthroughs in understanding the genetic basis of aggressive prostate cancer

December 6, 2017
The retinoblastoma (RB) susceptibility gene was the first gatekeeper gene discovered for cancer. When it was removed, or damaged, cancers thrived. Over the years, researchers discovered many methods to experimentally remove ...

Compound shows promise as next-generation prostate cancer therapy

August 8, 2016
In the search for new ways to attack recurrent prostate cancer, researchers at Duke Health report that a novel compound appears to have a unique way of blocking testosterone from fueling the tumors in mice.

Recommended for you

Student develops microfluidics device to help scientists identify early genetic markers of cancer

October 16, 2018
As anyone who has played "Where's Waldo" knows, searching for a single item in a landscape filled with a mélange of characters and objects can be a challenge. Chrissy O'Keefe, a Ph.D. student in the Department of Biomedical ...

A bad influence—the interplay between tumor cells and immune cells

October 16, 2018
Research at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) yielded new insights into the environment surrounding different types of lung tumors, and described how these complex cell ecosystems may in turn ...

Technique to 'listen' to a patient's brain during tumour surgery

October 16, 2018
Surgeons could soon eavesdrop on a patient's brain activity during surgery to remove their brain tumour, helping improve the accuracy of the operation and reduce the risk of impairing brain function.

Researchers elucidate roles of TP63 and SOX2 in squamous cell cancer progression

October 16, 2018
Squamous cell carcinomas (SCCs) are aggressive malignancies arising from the squamous epithelium of various organs, such as the esophagus, head and neck, lungs, and skin. Previous studies have demonstrated that two master ...

Function of neutrophils during tumor progression unraveled

October 15, 2018
Researchers at The Wistar Institute have characterized the function of neutrophils, a type of white blood cells, during early stages of tumor progression, showing that they migrate from the bone marrow to distant sites and ...

Delving where few others have gone, leukemia researchers open new path

October 15, 2018
A Wilmot Cancer Institute study uncovers how a single gene could be at fault in acute myeloid leukemia (AML), one of the deadliest cancers. The breakthrough gives researchers renewed hope that a gene-targeted therapy could ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.