by Mark A. Rubin1,2
1 Department for BioMedical Research, University of Bern, Bern, Switzerland, 2 Weill Cornell Medical Collage, New York, USA
[*] Name and circumstances have been changed to protect privacy.
Mira Lund[*] was the newly named CEO of a biotechnology company known for innovation and stellar record for their social commitment to improving health care. In 2016 at a New York fundraising event, I was introduced to her, and we managed to exchange a few words despite a time conscious organizer trying to move her along to the podium. Mira’s eyes beamed as I gave her the elevator pitch about the new Englander Institute for Precision Medicine, a burgeoning effort in precision medicine to align the right therapy with the right patient at the right time. Our goal, I explained, is to improve patient care1 by investing in infrastructure and linking hospital clinical patient records (the electronic health record) to large genomic data sets2. She nodded as the event organizer escorted her to the podium. She glanced at her prepared notes and began in a soft, confident, and enthusiastic voice to describe the cause for which the event was raising money. She pleaded with the assembled crowd of New York City social luminaries to donate help and support to cancer research.
In the fall of 2012, precision medicine was an abstract, evolving term in the United States. It came to my attention when I was preparing a grant application for a 10-million-dollar grant from Stand Up to Cancer and the Prostate Cancer Foundation (SU2C-PCF). Charles Sawyers, one of our team leaders and chair of the group that penned a White Paper for the Institute of Medicine on precision medicine3, suggested we focus on the feasibility of a precision medicine trial. And so we wrote an outline for a prospective clinical trial aiming to better understand why anti-androgen therapy often fails with men with advanced prostate cancer. This treatment is standard of care, but we asked whether better results could be achieved — and achieved not necessarily with new drugs but with existing drugs.
…we were going from 1-5 genes to 20,000.
For every patient enrolled in the study, biopsies of prostate cancer metastases would be performed; the intention was not to diagnose their cancer again (we already knew that the patients had advanced prostate cancer) but instead to find out what newly acquired mutations their tumours had developed since the start of therapy.
We proposed performing whole exome sequencing and whole transcript sequencing with the goal of discovering novel mechanisms of resistance. At the time, this was at the least a logarithmic leap compared to what was being done for genomic testing of prostate cancer; we were going from 1-5 genes to 20,000. We would link clinical and pathology data from all six clinical sites (the Fred Hutch Cancer Center, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, Dana Farber Cancer Center, the University of Michigan Cancer Center, and the Royal Marsden in England) with the so-called Big Data — the large genomic datasets generated at the Broad Institute, Weill Cornell Medicine, and the University of Michigan.
Could we do this in real time, so that our findings could play a direct role in patient care?
This was all new at the time. Our first study on prostate cancer had attributes of a clinical trial as well as of genome research. But unlike research, we needed to move the genomics to a clinically relevant level. Could we do this in real time, so that our findings could play a direct role in patient care? Could we meet the regulatory requirements for this study? Over the next five years, we enrolled over 500 men with advanced prostate cancer. At first, obtaining metastatic biopsies from each patient seemed like an unreachable goal due to the requirements of coordinating biopsies with interventional radiologists, oncologists, pathologists, and clinical laboratories. However, after a slow start and rumblings about the costs and the increased time required, and once we developed and established work routines (standard operating procedures)4, we managed more and more to obtain high-quality biopsies and to process the tiny tumour samples for genomic and transcriptomic analyses. We began to see phenomenal results, and not just from one institution; all six sites working together could achieve inclusion rates in the 90 % range. This experience confirmed that patients with advanced cancer and their families participate in research enthusiastically, even if the projects will help to save only few patients and will more likely help improve the treatment methods of the future.
As oncologists and researchers at my former institutions learned about our work, they asked us to apply our methods also to other cancers.
Observations made at all six centres led one of our team members, Johann de Bono at the Royal Marsden, to an important finding: As many as 20 % of our patients with advanced prostate cancer had a mutation in one of the many DNA repair genes. Genes called PARP are responsible for maintaining the integrity of the genome. We became interested in these mutations, because de Bono was already using PARP inhibitors in one of his clinical trials. The PARP inhibitors disarm the alternate way that the tumour cells repair their DNA. This leads to what is called synthetic lethality — basically a one-two punch that results in the death of the tumour cells. When de Bono and his group examined the genomic features of the 30 % of men who had long-term responses to PARP inhibition therapy, there was a preponderance of DNA repair gene mutations in contrast to men who did not respond to the therapy6. The study allowed our group to perform a larger study, which confirmed that 10 % to 20% of men with advanced prostate cancer had a DNA repair gene mutation — often from birth7. These findings will change the treatment of men with advanced prostate cancer. In the future, men will have genetic testing and counselling and will be informed of their genetic risk. This was our first special moment in precision medicine.
As oncologists and researchers at my former institutions learned about our work, they asked us to apply our methods also to other cancers. The same tools and concepts established in the SU2C-PCF funded trial could now be applied more broadly1. Lessons learned about sharing data through genomic sequencing portals also gave our researchers an opportunity to develop hypotheses for new research studies by posting them on cBioportal – a Google-like web-based application for researchers to explore the landscape of cancer mutations and posit new questions.
We can now show which drugs or drug combinations can optimally kill tumour cells and thus predict the best drugs for individual patients. This is precision oncology.
One innovation of our programme was a living tumour bank. We began to culture patients’ tumour cells using methods developed by Hans Clevers’ group in the Netherlands for examining colon cells. Culturing the cells in a three-dimensional scaffold or matrix promotes the formation of tumour cell spheroids or organoids. Could these patient-derived organoids be used as avatars aiding quick selection of available drugs? Could the organoids in this way help to avoid adverse side effects and save valuable time? The precision medicine approach would be to identify the right drug and thus to create a new standard of care. In the lab, we saw success8. We and others9 can now show which drugs or drug combinations can optimally kill tumour cells and thus can predict the best drugs for individual patients. This is precision oncology.
The real challenges of precision medicine hit home for us when Mira Lund’s doctor asked us to help her. Mira, the wiry, energetic entrepreneur — an industry leader — had widespread metastases. She wanted us to try everything and anything. Her consulting oncologists from across the United States told her that there were no more options for her. We organized a biopsy of the metastases and performed all the genomic tests that we had developed in the SU2C-PCF study. We were able to obtain enough tumour cells to culture organoids. A screening of all FDA-approved drugs revealed a combination of therapies that worked astonishingly well on her tumour cells (but not on other tumour cells from the same type of cancer taken from other patients). From this, we knew which two drugs to give her, even though we did not understand why. But Mira’s fight against cancer was now fatiguing her more and more. By the time we were able to do additional testing in xenograft models to confirm our findings, she was too sick for therapy of any sort, and she died shortly after our discovery. What a loss for our community. We grieved for her. We also grieved for our inability to help her in time despite coming to the right conclusion.
We need to find innovative ways to propose new therapies and new trials.
But first it was important to demonstrate that this work added to the quality of clinical care. In precision tumor boards, we discussed all the findings of patients on the trial. However, only anecdotally did we find a better treatment for a patient. Of course, our starting point put us in a challenging position – our patients had already failed the typical therapies or standard of care. Currently, these results are not particular to prostate cancer. In a recent large trial with over 10 000 comprehensively sequenced tumours from the Memorial Sloan Kettering Cancer Center, the investigators were able to find a genomically matched novel therapy at a rate of only 10% of the cases that did not respond to standard of care5. We need to find innovative ways to propose new therapies and new trials. And we need to do this in a timely manner.
Both Mira’s story and the DNA repair mutation story belong to precision medicine reality. As we succeed at becoming better, smarter, and more efficient, we may have the chance to get patients like Mira into the right trial or to treat them with the right drugs — and thus to make a difference. The more studies that we conduct and especially the more data that we share, the better the biomedical community will understand why some patients respond and others do not. Researchers, too, will later benefit from these findings and, it is hoped, the findings will contribute towards development of urgently needed future classes of drugs.
As I now begin working with my new colleagues in Switzerland at the Inselspital and the University of Bern to set up precision medicine for cardiology, neurology, oncology and other areas where help is needed, I am more aware than ever that we have a lot of hard work ahead of us. The findings of our prostate cancer study and experiences with patients like Mira remind me what we need to do. We need to work closely in Switzerland and also at the international level and utilize the chances to improve health care. With its well-functioning health care system, highly educated population, and high availability of technology in the health care system, Switzerland is well positioned to make important advances in precision medicine — and this particularly as there is significant support for the national development of precision medicine from two national programmes.
I think of Mira every day. I shook her hand, looked into her eyes.
This earmarked support from the Swiss Personalized Health Network (SPHN) and Personalized Health and Related Technologies (PHRT) should allow us to ask bold research questions and to dissolve the boundaries between clinical care and basic research. We need to find ways to share data freely, responsibly, and swiftly to gain the knowledge that will save the next Mira that comes to us asking for help. Finally, we need to make this knowledge available to each and every patient, whether the patient is the head of the company that makes trains and buses or the person who drives the number 10 bus in Bern.
I think of Mira every day. I shook her hand, looked into her eyes. We almost had something to offer her — we saw the drugs work on her tumour cells growing in a dish — but we were too late. And that is just not good enough. We must work together for the Swiss Personalized Health Network, so that we can be right on time. And punctuality, as I have learned over the past year, is a very Swiss characteristic.
About the author
Mark Rubin was born in Riverside, California, and studied at Mount Sinai School of Medicine, New York (USA). After completing his clinical training at the Deutsches Herzzentrum Berlin (Germany), Georgetown University Medical Center in Washington, DC, and Johns Hopkins Hospital in Baltimore, he specialized in urology and pathology and worked as an assistant professor at the University of Michigan in Ann Arbor. In 2002, he moved to Brigham and Women’s Hospital in Boston. Rubin joined Weill Cornell Medicine in New York, as a full professor in 2007 and became the director of the Englander Institute for Precision Medicine in 2013. Since February 2017 he is also director of the department of clinical research at Inselspital in Bern.
His research endeavors mainly focus on the genomic changes accompanying and driving the progression of prostate cancer. His research teams in New York and Bern are also developing novel treatment strategies to treat advanced prostate cancer.
About this article
This article has been republished with permission from Cancer Research in Switzerland, the annual review of the Swiss Cancer Research foundation (SCR) and Swiss Cancer League (SCL). Click here to read the full publication.
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