Nav: Home

A new approach to target an 'undruggable' prostate cancer driver

March 23, 2017

ANN ARBOR, Michigan -- New research suggests a novel strategy to target a genetic anomaly that occurs in half of all prostate cancers.

When the genes TMPRSS2 and ERG relocate on a chromosome and fuse together, it's an on-switch for prostate cancer development. But ERG has proven to be a challenging target for the type of small-molecule inhibitors that have had recent successes in treating cancer.

Now, researchers from the University of Michigan Comprehensive Cancer Center have targeted ERG using large molecule peptides. Studies in cell lines and animal models suggest this approach can effectively target and degrade the ERG fusion with little impact on regular cell function. Their findings are published in Cancer Cell.

"Targeting this gene fusion product has been a major challenge. We had to approach this through a different angle," says senior study author Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine.

The researchers identified a panel of peptides that interacted specifically with the ERG protein. They tested the panel in cell lines harboring the gene fusion and found the peptides disrupted ERG function. In cells without the gene fusion, the peptides had little or no impact on gene expression.

They also looked at how the peptides impacted other biological processes regulated by ERG. These tests suggested that the peptides very specifically target the gene fusion without affecting normal cellular functions.

One problem was that peptides degraded quickly, not lasting long enough to travel to the desired target. So the researchers generated mirror images of the peptides. These peptidomimetics avoid the machinery that causes degradation of normal peptides in the body, leading to longer stability.

Tests in animal models showed the peptidomimetics reduced the growth of prostate tumors that harbored the ERG fusion. After extended treatment, more than a third of the mouse tumors showed no signs of recurrence a month later.

"This is an example of how we can deliver precision therapy for prostate cancer: Only patients who have the ERG gene fusion would be matched with this agent. But it's useful because the ERG fusion is so prevalent," Chinnaiyan says.

One drawback to the peptide approach is that large molecules like this can't slip past the cell membrane. That means that the peptides need to modified in some way or be delivered across the cell membrane. Small molecules are the preferred target for drug development because they can get inside of cells and bind to their target more easily.

Chinnaiyan's team will next work to create a three-dimensional outline of how the peptides bind to ERG in the hopes of turning this into a small molecule to inhibit ERG. In parallel, researchers will focus on making the peptidomimetics work better, with more potency in degrading the target.

"This research will potentially develop a new targeted therapy for prostate cancer while we will simultaneously gain knowledge on the inhibition of a very complex gene that drives cancer," said Dr. Howard R. Soule, executive vice president and chief science officer of the Prostate Cancer Foundation, which funded this work.
Additional authors: Xiaoju Wang, Yuanyuan Qiao, Irfan A. Asangani, Bushra Ateeq, Anton Poliakov, Marcin Cieslik, Sethuramasundaram Pitchiaya, Balabhadrapatruni V.S.K. Chakravarthi, Xuhong Cao, Xiaojun Jing, Cynthia X. Wang, Ingrid J. Apel, Rui Wang, Jean Ching-Yi Tien, Kristin M. Juckette, Wei Yan, Hui Jiang, Shaomeng Wang, Sooryanarayana Varambally

Funding: Prostate Cancer Foundation Challenge Award; National Cancer Institute grants R01 CA132874, P50 CA69568, U01 CA113913, R01 CA157845, R01 CA154980; U.S. Department of Defense; AACR-Bayer Prostate Cancer Research Fellowship

Disclosure: The University of Michigan holds a patent on ETS gene fusions as a diagnostic for prostate cancer, which has been licensed to Hologic, where Chinnaiyan is named as a co-inventor. The university has also filed a patent on peptidomimetic inhibitors of ERG described in this study, in which Chinnaiyan and Xiaoju Wang are named as inventors and the patent has been licensed by OncoFusion Therapeutics. Chinnaiyan and Shaomeng Wang are co-founders of OncoFusion, own stock and serve as consultants.

Reference: Cancer Cell, doi: 10.1016/j.ccell.2017.02.017


University of Michigan Comprehensive Cancer Center,

Michigan Medicine Cancer AnswerLine, 800-865-1125

Michigan Health Lab,

Michigan Medicine - University of Michigan

Related Prostate Cancer Articles:

ASCO and Cancer Care Ontario update guideline on radiation therapy for prostate cancer
The American Society of Clinical Oncology (ASCO) and Cancer Care Ontario today issued a joint clinical practice guideline update on brachytherapy (internal radiation) for patients with prostate cancer.
Patient prostate tissue used to create unique model of prostate cancer biology
For the first time, researchers have been able to grow, in a lab, both normal and primary cancerous prostate cells from a patient, and then implant a million of the cancer cells into a mouse to track how the tumor progresses.
Moffitt Cancer Center awarded $3.2 million grant to study bone metastasis in prostate cancer
Moffitt researchers David Basanta, Ph.D., and Conor Lynch, Ph.D., have been awarded a U01 grant to investigate prostate cancer metastasis.
New findings concerning hereditary prostate cancer
For the first time ever, researchers have differentiated the risks of developing indolent or aggressive prostate cancer in men with a family history of the disease.
Prostate cancer discovery may make it easier to kill cancer cells
A newly discovered connection between two common prostate cancer treatments may soon make prostate cancer cells easier to destroy.
New test for prostate cancer significantly improves prostate cancer screening
A study from Karolinska Institutet in Sweden shows that a new test for prostate cancer is better at detecting aggressive cancer than PSA.
The dilemma of screening for prostate cancer
Primary care providers are put in a difficult position when screening their male patients for prostate cancer -- some guidelines suggest that testing the general population lacks evidence whereas others state that it is appropriate in certain patients.
Risk factors for prostate cancer
New research suggests that age, race and family history are the biggest risk factors for a man to develop prostate cancer, although high blood pressure, high cholesterol, vitamin D deficiency, inflammation of prostate, and vasectomy also add to the risk.
Prostate cancer is 5 different diseases
Cancer Research UK scientists have for the first time identified that there are five distinct types of prostate cancer and found a way to distinguish between them, according to a landmark study published today in EBioMedicine.
UH Seidman Cancer Center performs first-ever prostate cancer treatment
The radiation oncology team at UH Seidman Cancer Center in Cleveland performed the first-ever prostate cancer treatment April 3 using a newly-approved device -- SpaceOAR which enhances the efficacy of radiation treatment by protecting organs surrounding the prostate.

Related Prostate Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...