Breaking the prostate cancer supply chain

Common hormone therapies for prostate cancer they include surgical and chemical castration, a term used by clinicians to mean that they have blocked the supply chain of testosterone, a type of androgen, at its source.

But in some patients, the cancer adapts to restore the supply chain by other means, including boosting smaller amounts of testosterone produced in the adrenal glands or replacing other androgen-like molecules.

A class of powerful drugs has emerged since 2012 that targets a link further down the supply chain, a key molecule in the tumor cell called the androgen receptor.

AR binds androgens and delivers them to the nucleus, where AR then binds to DNA and activates genes that promote tumor growth.

These drugs, tested in pivotal phase 3 trials at the ICR under de Bono’s leadership, target various features of RA to disrupt its function.

But the most aggressive forms of the disease created a solution for those drugs that changed the biology of the tumor cell.

In 2017, Peter Nelson, MD, vice president of precision oncology at Fred Hutch, published a study showing that the cancer had rewired its molecular pathways to somehow grow without androgens in these patients. Nelson holds the Stuart and Molly Sloan Precision Oncology Institute Endowed Chair.

This resistance has created an urgent need to find new weak links in the supply chain that could be targeted with new drugs.

Building on research Hsieh began when he won the same challenge grant from the Prostate Cancer Foundation in 2016, his lab found a good place to look for those weak links—at the end of the supply chain, where RNA messenger is translated into protein blocks. .

No more getting lost in translation

Messenger RNA is an intermediary molecule that copies the DNA codes for building proteins stored in the cell’s nucleus and then delivers them outside the nucleus to the cell’s many protein factories, which are called ribosomes.

In ribosomes, genetic sequences of mRNA are translated into amino acid sequences, which are then used to make proteins, the complex molecules that do most of the cell’s work.

Hsieh wants to know specifically how that translation process works in prostate and bladder cancers and how it affects tumor growth.

“There aren’t that many people in the world studying mRNA and cancer,” Hsieh said. “When I first moved here in 2014, no one was studying mRNA translation in cancer at Fred Hutch.”

In a study published in 2019, Hsieh described how the same supply chain that used AR to activate growth genes simultaneously harbored an alternative way to promote growth using muted mRNA translation.

This alternative route acts as a backup that only activates when the main AR supply chain has failed.

Cancer that survives the loss of the AR supply chain becomes highly dependent on mRNA translation to continue to grow.

And that new addiction exposes a new vulnerability in a tumor cell that has evolved to grow without androgens, a weak link that can be broken with drugs.

The weak link is a complex of molecules that regulates the initiation of mRNA translation when the main supply chain is blocked.

Building a team

The two principal contributors to the PCF Challenge grant, Hsieh and Sharp, met at a previous PCF science retreat and began a collaboration that brought Sharp to Seattle for the summer of 2023.

Both are physicians who split their time between the clinic and the laboratory, although Sharp works exclusively with patients in drug trials.

Sharp has a postdoctoral student, Joe Taylor, PhD, who is also interested in mRNA translation, and they found a way through various funding mechanisms for both Sharp and Hsieh to serve as Taylor’s mentor.

“When we started that feedback process, we started thinking that maybe we should work together on a project,” Hsieh said.

They brought in other collaborators, including Steve Blinka, MD, PhD, a postdoc in Hsieh’s lab who won an ASCO Young Investigator Award this year, and created a proposal to discover and develop new drug therapies targeting mRNA translation in lethal prostate cancer.

“It was really through that overseas interaction that we came up with this particular proposal, which will now be funded,” Hsieh said. “It is a clear example of team science at its best.”

Going for high risk, high reward

The team Hsieh and Sharp assembled embarked on a high-risk, high-reward adventure.

It’s high stakes because mRNA translation represents a promising but relatively new frontier of cancer biology.

But the payoff is high, too, because their research could reveal new therapeutic strategies that are sorely needed when advanced prostate cancer inevitably becomes drug-resistant.

“Advanced disease still leads to death,” Hsieh said.

First, the team will study tumor samples to find molecular predictors of which cancers are likely to become dependent on back-up mRNA translation when the usual AR feed is blocked.

This will help them identify patients who might benefit from drugs that target mRNA translation.

The problem is that even if they find the right group of patients, there aren’t many drugs that will do the job.

So the team also wants to figure out how and why the few therapies they have maybe they’re actually testing translation blocking, which will help them identify the drugs most likely to work on different tumor subtypes.

One such therapy is a drug already approved by the US Food and Drug Administration called homoharringtonine. They will also test a drug currently in clinical trial development, as well as a compound Hsieh created in his lab that has drug-like qualities, such as the ability to hit its target in -a dose that is not toxic to healthy tissue. .

They will also test these therapies in preclinical models and cell models alone or in combination with other drugs that can kill anticipated sources of resistance in the bud.

Ultimately, they want to use the biology they discover to inform a clinical trial that provides detailed information about the effect of drugs on different aspects of mRNA translation.

The project aims to find new therapies for advanced prostate cancer that meet the grant’s requirements, but the team’s findings could be more broadly applicable.

“This biology could be transferable, not just to prostate cancer, but to other cancers; and not just late prostate cancer, but early prostate cancer,” Sharp said.