PCF-Funded Transformative Research: Changing the Course of Advanced Prostate Cancer

In 2012, PCF funded two “Dream Teams” – groups of top scientists from institutions in the U.S., the UK, and Canada – whose research findings transformed our knowledge of metastatic prostate cancer and ushered in the era of precision medicine in treating prostate cancer.

How did this come about?  PCF didn’t just decide one day to finance large, ambitious projects.  This was simply the next step in the team science culture that has been intrinsic to PCF from its very beginning.  

“We were already funding precision medicine research,” says Howard Soule, Ph.D., PCF’s Executive Vice President and Chief Science Officer.  In fact, shortly before this, PCF and the University of Michigan had recently co-funded an innovative program called MI-ONCOSEQ, led by pathologist and investigator Arul Chinnaiyan, M.D., Ph.D.  “This was quite revolutionary at the time,” says Soule, “because it involved genomic sequencing of prostate cancer patients,” looking at the DNA in each patient’s entire set of genes (called the genome). “The program also had a multidisciplinary tumor board that included medical oncologists, urologists, pathologists, radiologists and nurses,” in addition to basic scientists with expertise in molecular genetics.  “The goal was to look at individual patients’ own genetic information and decide what was actionable.  MI-ONCOSEQ created a system where physicians could then use that data to drive treatments and patient care.”  But that was at only one institution.  

Scaling Up Through Collaboration: The International Dream Team

Then PCF had an opportunity to go much bigger:  to combine resources with Stand Up 2 Cancer and its scientific partner, the American Association for Cancer Research (AACR) to fund a large-scale, collaborative project involving scientists at multiple institutions.  “It was a team science program that, quite honestly, would not have been funded by a government agency or our foundation alone,” says Soule.  

Soule and former PCF CEO medical oncologist and molecular biologist Jonathan Simons, M.D., talked for hours about this. “We wanted a seat at the table,” a part in selecting the winning proposal.  They got it.  “I was that seat at the table for the whole review process.  We were looking for proposals that could change the course of advanced metastatic prostate cancer,” and they hit paydirt.  “All the proposals were excellent,” says Soule.  “We narrowed it down to the four most promising teams and brought them in for interviews.”

They chose a team led by Chinnaiyan, of the University of Michigan, and Charles Sawyers, M.D., of Memorial Sloan Kettering Cancer Center.  Its members were a “Who’s Who” of cancer researchers, including Philip Kantoff, M.D., of Dana-Farber Cancer Institute, Levi Garraway, M.D., Ph.D., of the Broad Institute in Cambridge, Mass., Peter Nelson, M.D., of the Fred Hutchinson Cancer Research Center/University of Washington in Seattle, Mark Rubin, M.D., of Weill Cornell Medical Center, and Johann de Bono, M.D., Ph.D., of the University of London and the Royal Marsden Hospital.  It was dubbed the “International Dream Team.”

“The goal was to create a genomic landscape of alterations in metastatic prostate cancer,” says Soule, “by sequencing as many prostate cancer genomes as they could from metastatic tumor biopsies.  Up to this time, genetic alterations had only been studied on cancer within the prostate.  But nobody has ever died of cancer within the prostate!  Tens of thousands die from cancer that has spread outside the prostate.”  

PCF’s Gamble Pays Off: The West Coast Dream Team

  The reviewers “put a big gold star on that dream team,” says Soule.  “But unbeknownst to them, I came with a check for a second dream team!”  This had been somewhat of a gamble, he reflects.  “We didn’t know at the time, whether a second team would actually flow to the top.”  One did:  the West Coast Dream Team. “I held up the second check, and said, ‘Okay, we want to do two dream teams!”  In another collaboration with funding groups including Stand Up 2 Cancer, the Movember Foundation, and the Coalition to Cure Prostate Cancer, the West Coast Dream Team was soon under way.  

This Dream Team was led by hematologist-oncologist Eric Small, M.D., of UCSF, and Owen Witte, M.D., professor of microbiology, immunology, and molecular genetics at UCLA.  It, too, had an impressive roster that included investigators from four California campuses: UCSF, UCLA, UC Davis, and UC Santa Cruz; along with Oregon Health & Science University and the University of British Columbia in Vancouver, Canada. 

The West Coast Dream Team’s goal, as Witte described it, was “to observe the changes that occur in an individual’s prostate cancer following therapy with certain classes of anti-androgens (hormonal therapy drugs).  What we’re hoping to discover are new ways that the cancer responds (adapts) to the therapy that we can interrupt, and prevent the cancer from regrowing.”  Their plan was to take biopsies from patients with advanced prostate cancer, scrutinize them using a combination of technologies “to define what genes have changed, what pathways are activated, and to use a new class of inhibitors that might be able to treat that individual patient’s tumor.”   

At this time, two drugs in this class – androgen receptor (AR) blockers – were very new:  abiraterone and enzalutamide.  This was a Dream Team designed around treatment resistance.”  As Small said, “The importance of this research is that it begins to individualize patient care: to identify the causes of resistance in an individual patient, and help us tailor therapy for that patient.  Our expectations are that within three years, we will not only understand the process of resistance, but we will be actively treating it.”

Overcoming a Hurdle:  Tricky Biopsies 

The West Coast team planned on taking two sets of metastatic tumor biopsies from each patient, “one before the patient received one of these new treatments, and one after he progressed on the same treatment,” says Soule.  Studying these “before” and “after” tissue snapshots, the researchers would then try to understand exactly how the tumor cells changed to become resistant to the therapy.   

But there was a hurdle.  Capturing cells from a site of metastatic prostate cancer is far trickier than taking tissue samples from within the prostate itself.  It requires an interventional radiologist to reach this isolated patch of cancer.  “Many of these metastatic lesions are in bone,” Soule explains.  “It was difficult to get one good biopsy, let alone two!  The needles would come out, the radiologists would give the tissue to the pathologist, and 60 to 70 percent of these biopsies turned out to have no cancer cells.  We thought, ‘Oh, no, we’ve already funded this! Maybe this can’t be done!  What are we going to do?’”  It was a UCSF medical oncologist who saved the day.  “Phil Febbo, one of the great geneticists, figured out how to train radiologists to do these biopsies, and all of a sudden, the yield of cancer went up to 70 percent or more!  What he contributed to this project was huge.” 

Game-Changing Discoveries:  The Genetic “Map” of Advanced Prostate Cancer

In 2015, the International Dream Team published a landmark paper in the prestigious journal Cell – with a figure that quickly became, among prostate cancer scientists, “the most frequently projected slide anywhere you go where there are people sharing data,” says Soule.  It showed the genomic landscape of metastatic prostate cancer: genetic variations, mutations, copy numbers, and deletions found by sequencing tumors from 500 patients.  This was the largest cancer precision medicine study at that time, and its goal was to match each patient with medicines that target his tumor’s unique mutations.  They found “actionable” tumor mutations, in pathways that can be targeted by available standard or experimental therapies, in more than 90 percent of the patients.  

Chinnaiyan discussed the genomic analysis of the first 150 patients from this cohort at the 2015 annual meeting of the American Association for Cancer Research (AACR).  In the majority – 63 percent – of the samples, they found alterations in the AR pathway.  Until this study, says Soule, “not everybody believed that AR was still active in metastatic prostate cancer.”  Within just a few years, AR-targeting drugs such as abiraterone and enzalutamide became the standard second-line hormonal therapy, given when PSA started to rise on traditional androgen deprivation therapy – sometimes with exceptional results.   Today, these drugs are being given even earlier in the course of prostate cancer.    

The team produced another practice-changing paper a year later, this time in the New England Journal of Medicine, with Pete Nelson as the lead author.   What the team found can be summed up this way:  There are 16 bad genes that we now know to look for; and if you have a mutation in one of these genes, your sons and daughters, and their children need to know about it, because they are more likely to develop cancer, too.

In 692 men with metastatic prostate cancer at institutions in the U.S. and the UK, Nelson and colleagues looked at inherited mutations in 20 “DNA-repair” genes, which serve as minuscule “spell checkers,” looking for and fixing genetic errors.   Sixteen of these genes turned out to be very important, and some were quite unexpected, like BRCA1 and BRCA2.  For years, these genes had been linked to breast, ovarian, and other cancers – but the link to prostate cancer was not clear.  This study proved that the same types of mutations that can cause breast and ovarian cancer in women can cause lethal prostate cancer in men.  

These mutations – other faulty DNA-repair genes they found include ATM, CHEK2, PALB2, strongly involved in pancreatic and breast cancer – are rare in the general population.  But because of this work, we now know that they are more common in men with metastatic prostate cancer.  The team estimated that one in nine – 12 percent – of men with metastatic cancer have them, even if they have no known family history of prostate, breast, or ovarian cancer.  

Moreover, Simons noted at the time, “Prostate cancer isn’t just about men anymore: it’s also about the women who descend from them.  Prostate cancer is now a disease of understanding the genes running in families, which will give us massive clues on new ways to treat it.  It wasn’t that disease before.”

Because of these findings and the results of other work funded in part by PCF, new precision drugs, PARP inhibitors, were being developed for advanced prostate cancer.  “You can connect the dots,” says Soule.  These drugs had shown promise in treating breast cancer in women with BRCA1 and BRCA2 mutations.  “All of a sudden, because of these findings, PARP inhibitors (including olaparib, funded early on with seed money from PCF, rucaparib, and now talazoparib) were being developed for advanced prostate cancer.”

West Coast Dream Team Sheds Light on a Deadly Prostate Cancer

Meanwhile, in California, Felix Feng, M.D., a radiation oncologist and expert in translational research, relocated from the University of Michigan to UCSF and joined the West Coast Dream Team.  “We helped Felix get the key to the kingdom – the key to the lock on the freezer for all those biopsies,” says Soule.  Right away, “Felix used those specimens to figure out a lot of things:  his team published the epigenomic landscape of advanced prostate cancer.  He also showed that the mechanisms of prostate cancer resistance to PARP inhibition was similar to what’s seen in breast and ovarian cancer.”  

Feng was on fire, with idea after idea.  “I probably logged 100 hours with him on the phone, just thinking about all the things that could be done.  There’s nothing more tragic than an underused biobank,” and there was no chance of that happening with Feng.  “When Felix got there, oh, brother, did it get used!”

 The West Coast team’s research shed light on another important subgroup:  men with treatment-resistant metastatic prostate cancer (mCRPC) who have a highly aggressive subtype called small-cell neuroendocrine prostate cancer.  “Previously, it was thought that these cancers made up less than 1 percent of all prostate cancers,” says Soule.  The team suggested that this subtype of cancer might be more successfully treated with drugs that were already developed or being tested in clinical trials for other forms of small-cell neuroendocrine cancer.  

In research published in Cell in 2018, the team published a comprehensive genetic analysis of metastatic prostate cancer that showed widespread structural changes – abnormal duplications, insertions, or deletions of genetic sequences.  In more than 80 percent of patients, the team found numerous extra copies of AR-amplifying sequences.  “This study has provided a tremendous resource that will be publicly available to the prostate cancer research community,” said Feng, co-senior author along with Eric Small.   Feng and colleagues also began a huge effort to characterize the genomic and epigenomic landscape of mCRPC, looking for mechanisms by which the cancer evolves and becomes more resistant to treatment.

Dream Teams 2.0

Feng and Nelson are joining forces as part of the PCF’s next large team science initiative:  the TACTICAL Program.  “They are going to take everything we’ve learned in both of the Dream Teams to date,” says Soule, “and refine it to the level of the single cell.  They will study single cells of advanced prostate cancer using cutting-edge technology to find out what’s going on from one cell to the next.  It’s the next step in resolution:   open the aperture, adjust the focus, and you can see deeper into space.  I’m very proud of the foundational research that was funded through the original Dream Teams, and of what Felix and Pete plan on doing to take it to the next step.  I really believe single-cell biology is the technology worth paying attention to.  Watch this space!”

It is likely that one prostate cancer cell, when examined intimately, will turn out to be very different from a cell right next to it.  “We throw around the term, ‘plasticity,’” says Soule.  “It really means we don’t have a clue.  It means that there is variability on the cellular level.  Understanding that requires machines; the human brain can’t do it.  Let’s say you have 10,000 cells, and each cell is expressing 10,000 genes, and the 10,000 genes are being expressed at different levels in every cell.  But bioinformatics may reveal patterns – understanding that variability, what causes it, what it results in, how it participates in treatment resistance – that may be actionable.”

The TACTICAL Awards are the Dream Teams 2.0. Three large awards have been given so far,  “and all of the data – from the original Dream Teams, as well as the data generated by these new ones – will become accessible to scientists all over the world.”