Finding a new way to break the supply chain fueling advanced prostate cancer

Dr. Andrew Hsieh, professor (Hematology and Oncology) won a $1M grant from the Prostate Cancer Foundation for a collaboration with the Institute of Cancer Research in London to find new therapies for drug-resistant prostate cancer.

The vast majority of people diagnosed with prostate cancer can expect to live long, full lives thanks to improved screening that catches the disease in its early and most treatable stages.

But advanced prostate cancer, which has spread beyond the prostate to other parts of the body, remains notoriously elusive and resourceful when it’s attacked, resisting surgery and drugs that interrupt a vital hormonal supply chain that tumors need to grow.

When treatments block the flow of testosterone, the cancer inevitably finds molecular workarounds that re-establish the supply chain, triggering more runaway tumor growth that hastens death.

Therapies have mostly targeted the beginning and middle of the supply chain with initial success for patients. However, resistance is inevitable within the most lethal forms of the disease.

But researchers at Fred Hutch Cancer Center and the Institute of Cancer Research in London just received a $1 million grant from the Prostate Cancer Foundation to focus on the last links of the supply chain, a process called mRNA translation.

That’s the stage in the tumor cell where genetic instructions get translated into amino acids to make the actual proteins fueling tumor growth.

Preliminary evidence suggests those last links could be broken with a better understanding of how they work when the main hormone supply is cut off. And that could lead to new, more effective, more precise and more tolerable drugs.

Fred Hutch prostate cancer expert and medical oncologist Andrew C. Hsieh, MD and Adam Sharp, MD, PhD, a physician-scientist who leads the Translational Therapeutics Team at the ICR, accepted the two-year PCF Challenge Award at the foundation’s annual scientific retreat last weekend in Carlsbad, California.

The project brings together key leaders in the fields of cancer biology, mouse modelling, drug discovery and development, and advanced prostate cancer medicine from Fred Hutch and ICR.

The ICR team is co-led by Marco Bezzi, PhD who specializes in making pre-clinical mouse models of human disease and Sharp’s long term mentor at ICR, Johann de Bono, MD, who has driven the development of several prostate cancer drugs.

Breaking the supply chain of prostate cancer

Common hormonal therapies for prostate cancer include surgical and chemical castration, a phrase used by clinicians that means they've blocked the supply chain of testosterone, a type of androgen, at the source.

But in some patients, the cancer adapts to re-establish the supply chain by other means, including amplifying smaller amounts of testosterone made in the adrenal glands or substituting other androgens-like molecules.

A class of potent drugs emerged beginning in 2012 that target a link further down the supply chain, a key molecule within the tumor cell called the androgen receptor.

The AR binds androgens and delivers them into the nucleus where AR then binds to DNA and turns on the genes that promote tumor growth.

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

But the most aggressive forms of the disease created a workaround to 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 androgen 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 figured out a good place to look for those weak links — at the end of the supply chain where messenger RNA is translated into protein building blocks.

No longer lost in translation

Messenger RNA is a go-between molecule that copies DNA codes for building proteins stored within the cell’s nucleus and then delivers them outside of the nucleus to the cell’s many protein factories, which are called ribosomes.

In the ribosomes, the mRNA’s genetic sequences 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 cancers of the prostate and bladder and how it affects runaway tumor growth.

“There are not that many people in the world who study mRNA and cancer,” Hsieh said. “When I first moved here in 2014, nobody 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 turn on growth genes simultaneously kept an alternative way to promote growth using mRNA translation turned off.

That alternative pathway acts like a back-up that only kicks in when the main AR supply chain failed.

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

And that new dependence exposes a new vulnerability in a tumor cell that has evolved to grow without androgen, a weak link that potentially 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 main collaborators in the PCF Challenge grant, Hsieh and Sharp, met at a previous PCF scientific retreat and began a collaboration that brought Sharp to Seattle for the summer of 2023.

They are both medical doctors who split their time between the clinic and the lab, though Sharp works exclusively with patients in drug trials.

Sharp has a postdoctoral student, Joe Taylor, PhD, who also is 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 co-mentorship process, we started thinking 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 put together a proposal to discover and develop new drug therapies aimed at mRNA translation in lethal prostate cancer.

“It was really through that across-the-sea interaction that we came upon this particular proposal, which is now going to get funded,” Hsieh said. “It’s a clear example of team science at its best.”

Going for high risk, high reward

The team Hsieh and Sharp have assembled has embarked on a high-risk, high-reward venture.

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

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

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

That will help them identify which patients could benefit from drugs targeting mRNA translation.

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

So, the team also wants to figure out how and why the few therapies they can test actually block translation, which will help them identify the drugs most likely to work on different subtypes of tumors.

One of those therapies is a drug already approved by the U.S. Food and Drug Administration called homoharringtonine. They also will test a drug currently being developed in clinical trials, as well as a compound that Hsieh has created in his lab that has drug-like qualities such as the ability to reach its target in a dosage that isn’t toxic to healthy tissue.

They will also test those therapies in pre-clinical models and cell models separately or in combination with other drugs that can nip anticipated sources of resistance in the bud.

Finally, 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 is aimed at finding new therapies for advanced prostate cancer to fulfill the requirements of the grant, but the team’s discoveries might be more broadly applicable.

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