WIN Consortium
“Published in Nature Medicine, results of WINTHER, the first study pioneered by the WIN Consortium. The WINTHER study was one of the last projects of our late Chairman Emeritus Dr John Mendelsohn.” WIN Consortium

WINning together

WIN was formed on the premise that we can accomplish more together than each organization can achieve working alone. We aim to improve cancer patients’ survival and quality of life. View WIN's history and unique attributes:

WIN represents a global collaboration of cancer centers, life science and biotech organizations, pharmaceutical and technology companies, health plans, and not-for-profit organizations.
The Worldwide Innovative Networking (WIN) Consortium in personalized cancer medicine was initiated in 2010 with leadership from leading cancer centers worldwide. WIN is a non-profit, non-governmental organization headquartered in Paris.

WIN was created to accelerate the pace and reduce the cost of translating novel cancer treatments to the bedside by developing and applying, through worldwide clinical trials and research projects, the most promising advances in genomic-based cancer research. WIN aims to initiate research projects each year in a global consortium guided by an independent scientific advisory board.

WIN now includes 39 institutional members. These stakeholders have come together from all parts of the world to address the challenge of increasing the efficacy of cancer diagnostics and therapeutics by understanding the genetics and biology of each individual’s tumor and accounting for genetic differences across diverse populations—from North and South America, Europe, Asia, and the Middle East.

Our goal is to significantly improve outcomes for patients around the globe. We aim to increase the number of patients worldwide that have access to innovative, global clinical trials in the area of genomic-based cancer therapeutics. Global diversity and inclusion of all stakeholders is WIN’s most important and differentiating asset.
WIN is comprised of organizations representing all stakeholders in personalized cancer medicine.
WIN enables cross-sector collaborations designed to accelerate the speed and efficacy with which breakthroughs in personalized cancer medicine can be realized and brought to patients worldwide.

Our members include leading academic, pharmaceutical, life science, not-for-profit, health IT, and healthpayer organizations.
Our members include 28 leading academic centers representing 21 countries and four continents, enabling coordinated studies with a global patient population.
The response to a genetically-targeted therapy can vary due to differences in ethnicity and environment. WIN's global studies are designed to identify and account for this variability, enhancing the speed and efficacy with which novel discoveries can be made and brought to patients around the world.

WIN prioritizes cross-sector interaction designed to enhance learning across and between continents and healthcare sectors.
WIN Symposia, held annually in Paris, brings together hundreds of leaders representing all stakeholders from around the world in a forum designed to promote the exchange of ideas and information.

Clinical trials and projects

WIN members collaboratively design and carry out global studies designed to achieve breakthroughs for patients worldwide. Our distinguished Scientific Advisory Board oversees WIN studies. Current trials include:

SPRING 01 (Survival Prolongation by Rationale Innovative Genomics) proof of concept trial is the first trial exploring the tri-therapy strategy in first line of advanced/metastatic non-small cell lung cancer (NSCLC), following the historical success of this approach in AIDS and tuberculosis for which only tri-therapy demonstrated long term efficacy.
The WIN SPRING trial will be conducted in the USA, France, Spain, Luxembourg and Israel in the following cancer centers: University of California - San Diego's Moores Cancer Center, Avera Cancer Institute (Sioux Falls, Arizona), Institut Curie (Paris), Centre Léon Bérard (Lyon), Hôpital Paris Saint-Joseph (Paris), Vall d'Hebron Institute of Oncology (Barcelona), Centre Hospitalier de Luxembourg (Luxembourg), and Chaim Sheba Medical Center (Israel).

The trial is sponsored by the WIN Consortium and funded by ARC Fondation for cancer research (France). The drugs are donated by Pfizer Inc.
Published in Nature Medicine, results of WINTHER, the first study pioneered by the WIN Consortium.
Published in Nature Medicine, results of WINTHER, the first study pioneered by the WIN Consortium.

Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial - shows that RNA profiling together with DNA testing matches more patients with advanced cancer to personalized therapies than DNA profiling for tumor mutations alone.

WIN is currently planning innovative global clinical trials that represent the next generation of studies focused on lung cancer.
European funded trials WINTHER EU FP7 funded and CHEMORES EU FP6 funded established foundations for WIN future global strategy for lung cancer currently under development.

The concept underlying the new strategy is developed in the following publications:
WIN provides a legal and fundraising framework that enables collective fundraising while protecting its members' intellectual property.
The WIN platform enables multiple organizations from different sectors to productively collaborate while providing for the protection of intellectual property. Each project or clinical trial has its own specific contract or funding mechanism.

People leadership

WIN leaders are selected for their contributions and commitment to making effective, personalized cancer medicine a reality for patients around the world. They guide WIN's strategic, operational, and scientific direction.

Richard L. Schilsky Photo
Chairman
Richard L. Schilsky

Senior Vice President and Chief Medical Officer, American Society of Clinical Oncology (ASCO)

Josep Tabernero Photo
Vice Chairman, WIN Consortium; Chair, WIN Scientific Advisory Board
Josep Tabernero

Director and Clinical Research Director, Vall d'Hebron Institute of Oncology, VHIO (Spain); ESMO President (2018 – 2019); Chair, WIN Scientific Advisory Board

Razelle Kurzrock Photo
Chair, Clinical Trials Committee
Razelle Kurzrock

Chief, Division of Hematology & Oncology, Sr. Deputy Center Director for Clinical Science, University of California San Diego Moores Cancer Center (USA)

Vladimir Lazar Photo
Chief Scientific and Operating Officer
Vladimir Lazar

Chief Scientific and Operating Officer, WIN Consortium


Our members

WIN members include 39 leading organizations representing all stakeholders in personalized cancer medicine covering 21 countries and 4 continents. Our shared vision is delivering the promise of effective, personalized cancer medicine to patients worldwide.


WIN Symposia

WIN Symposia, held annually in Paris, gathers leaders representing a breadth of stakeholders from around the world to learn, share, and collaborate. Visit http://www.winsymposium.org for registration and additional information.

WIN 2019 Symposium logotype

WIN 2019 Symposium

June 23, 2019 - June 24, 2019

The 11th edition of the WIN Symposia will take place at the WIN Symposium 2019 in Paris, France on 23-24 June 2019.

Register today! at https://www.winsymposium.org/

WIN 2018 Symposium logotype

WIN 2018 Symposium

June 25, 2018 - June 26, 2018

The 10th year Anniversary edition of the WIN Symposia took place at the WIN Symposium 2018 in Paris, France on 25-26 June 2018.
The WIN Symposium Organizing Committee had chosen “Global Implementation of Precision Oncology: WINning the War against Cancer” as the theme for this celebratory event.

WIN 2017 Symposium logotype

WIN 2017 Symposium

June 26, 2017 - June 27, 2017

The WIN 2017 Symposium with the theme ‘Expediting Global Innovation in Precision Cancer Medicine’ was held in Paris, France, June 26-27, 2017. The overarching goal of our symposium was to share information to promote and accelerate cutting edge investigations and use of personalized, targeted cancer therapy.


What people are saying

What people are saying
"WIN is an unique, global, translational clinical research organization with a bold vision to bring cutting edge science and technology to the cure of cancer worldwide. It is a privilege to help guide the organization as Chairman." Richard L. Schilsky, WIN Chairman
What people are saying
"Achieving much needed major clinical breakthroughs in cancer treatment requires bold thinking and action, a can do attitude and winning spirit, and close collaboration of stakeholders and contributors with diverse background and expertise. All this is epitomized by WIN." Vladimir Lazar, Chief Scientific and Operating Officer

WINTHER Trial Highlights Challenges, Potential of Transcriptomics for Precision Oncology
Apr 22, 2019 Turna Ray
NEW YORK (GenomeWeb) – A newly published study has demonstrated the potential of using transcriptomics to help get cancer patients on treatments they're most likely to benefit from.

The study, called WINTHER, appears today in Nature Medicine and included RNA expression analysis in addition to genetic sequencing to match cancer patients to drugs. Despite demonstrating the promise of the approach, the study did not reach its primary endpoint as it had to deal with the same challenges that have plagued other precision oncology trials.

This is the first trial to match patients with solid tumors to treatments based on transcriptomics, noted Vladimir Lazar, an investigator on WINTHER and chief scientific and operating officer of the WIN Consortium, the body organizing the study. While the trial may not have reached its prespecified endpoint, "the lessons in this trial and results are very important," Lazar said, highlighting a post-hoc analysis that demonstrated the importance of defining the biology driving the tumor and interrogating that biology to "match" patients to treatments.

The study, led by Razelle Kurzrock from the University of California, San Diego Moores Cancer Center, involved 107 evaluable patients with a variety of cancers enrolled at four centers in Spain, Israel, France, and Canada. Of these patients, 69 individuals received treatments based on results following genetic sequencing using Foundation Medicine's FoundationOne test.

In most precision oncology studies, if patients don't match to targeted treatments based on genetic abnormalities, then they don't have any other options. However, in this study, there were 38 such patients who didn't have DNA alterations, but then received microarray-based RNA expression analysis of tumor and normal tissues and received treatments based on that information.

At the time WINTHER was designed "nobody felt that it was reasonable or ethical to start matching by RNA if the patients had a good DNA match," Kurzrock explained. "However — and here is the important thing — if there was no DNA match then we had an additional option."

Researchers evaluated outcomes by using each patient as his or her own control by comparing their progression-free survival in the present trial (PFS2) against the progression-free survival they experienced on the treatment they received prior to entering the trial (PFS1). Because these were heavily pretreated patients, the expectation would be that they would do worse with every subsequent therapy.

WINTHER investigators hoped to show a degree of improvement in patient outcomes in the trial based on matched therapy, and prespecified a PFS2 to PFS1 ratio of greater than 1.5 in 50 percent of patients in the DNA sequencing arm and in 40 percent of patients in the RNA expression analysis arm. The study failed to meet this prespecified endpoint, however, with 20 percent of patients in the DNA sequencing arm and 26 percent of patients in the RNA expression analysis arm exceeding that ratio.

The field of precision oncology, though relatively new, can now boast a number of advances with the recent approval of larotrectinib (Vitrakvi) for patients with NTRK gene fusions, and even a growing list of next-generation treatment options for when patients develop resistance to first generation targeted drugs, as in the case of EGFR inhibitors. "Even though there are many successes in precision oncology ... there are also limitations with some studies showing that many patients don't have durable responses," Kurzrock said. "Then, the question is, why is it that occurs?"

WINTHER, which had aimed to enroll 60 patients in the DNA sequencing arm and 140 patients in the RNA expression analysis arm, faced a number of challenges that may have impacted the results. In fact, the opposite happened, partly due to regulatory delays in the US. Additionally, the prespecified endpoint of PFS2/PFS1 greater than 1.5 was too ambitious, researchers acknowledged during a presentation last year at the American Society of Clinical Oncology's annual meeting.

According to Lazar, a PFS2/PFS1 ratio of greater than 1.3 is accepted in the field and would have pushed the proportion that met the prespecified endpoint in the overall trial from 22 percent to 25 percent. In all 107 patients, 11 percent experienced a complete or partial response, 15 percent had stable disease for six months or longer, and median overall survival was 5.9 months.

In a blinded post-hoc analysis, researchers developed a DNA and RNA matching score and assessed whether patients who received drugs that they were predicted to benefit from based on molecular profiling data fared better than those who didn't. "The matching score ... tries to reflect the degree to which patients were matched," Kurzrock said, noting that the researchers hypothesized that the degree to which a patient is matched to the therapy should make a difference. "And, indeed, that's what the paper shows." Multivariate analysis demonstrated that patients with an ECOG performance status of 0 and a high matching score had the longest overall survival compared to all other subgroups.

"The changes at the DNA level are not all the changes that occur in a cell," Kurzrock explained. "If there is a change at the DNA level but it is not reflected at the RNA level, then you don't have enough information ... The transcriptomics is going to give you more information about the underlying biology that can help you craft an appropriate therapy."

Additionally, tumors are complicated and typically have multiple changes at the DNA and RNA level that are helping them grow and spread. "Therefore, it makes sense that if there are many different drivers of the tumor and you're only addressing a small portion of the drivers then you may not get a great response, because the tumor has alternative mechanisms by which to grow," Kurzrock said.

In the WINTHER trial, patients had very advanced disease, with 26 percent receiving more than five prior treatments. And although around 300 patients consented to partake in the study, many ended up not getting on a treatment because the quality of their biopsies didn't allow for molecular assessments, they dropped out due to poor health status, or died.

"Most precision oncology studies have been plagued by patients enrolling very late ... and [this is] also reflected in WINTHER," Kurzrock said. "Doctors tend to enroll in these studies as a last-ditch [effort] right before hospice, and by that time, the patient is in bad shape and the tumor has evolved tremendously."

Even so, in WINTHER researchers were able to match 35 percent of consented patients to treatments based on DNA sequencing or RNA expression analysis. If the study had relied only on DNA information, the match rate would have been around 23 percent.

Moreover, despite not reaching the primary endpoint in WINTHER, there were suggestions that transcriptomics may better reflect tumor biology in some cases and therefore identify better targeted treatment "matches" than with DNA information. For example, the authors pointed out that the benefit rate in the RNA expression analysis arm was approximately 32 percent compared to 23 percent in the DNA sequencing arm, though this was not statistically significantly higher.

One of the exceptional responders in the study, a patient with refractory gastrointestinal neuroendocrine tumors, did not have any targetable DNA alterations, but transcriptomics revealed she had elevated expression of AKT2 and AKT3. She received the mTOR inhibitor everolimus (Afinitor), and experienced stable disease that's ongoing at nearly three years. The authors wrote this case is particularly notable since when patients are matched to mTOR inhibitors based on DNA alterations they rarely benefit likely due to the existence of other genomic alterations.

The study not only demonstrates the feasibility of incorporating transcriptomics into precision oncology trials, but also highlights the importance of collaboration among researchers across institutions and in different countries. Richard Schilsky, an author on the paper and chief medical officer of ASCO, noted that WINTHER dealt with its share of logistical challenges, for example, ensuring consistent standard operating procedures for tissue collection and handling across multiple centers in different countries and enabling investigators in different time zones to discuss treatment recommendations based on the -omics data.

"Since WINTHER did not test a specific treatment, there were also challenges in patient access to the recommended treatments and collecting consistent patient follow-up data," Schilsky said. In the study, of the 107 who received single or combination treatment with 159 drugs, 115 treatments were given off-label, 22 were prescribed on-label, and 22 were investigational agents.

Despite these challenges, investigators in the WIN Consortium also learned alot from WINTHER, and are now applying those lessons to the SPRING trial, he noted. "The model of global precision medicine trial is absolutely essential to test interventions in molecularly-defined rare patient populations," Schilsky said.
Comprehensive Tumor Profiling Promises New Therapeutic Options for Patients with Advanced Cancer
VILLEJUIF, France--(BUSINESS WIRE)-- Published in Nature Medicine* today, results of WINTHER, the first study pioneered by the WIN Consortium** - - Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial - shows that RNA profiling together with DNA testing matches more patients with advanced cancer to personalized therapies than DNA profiling for tumor mutations alone.

The WINTHER trial***, NCT01856296, led by investigators from Vall d’Hebron Institute of Oncology - VHIO (Spain), Chaim Sheba Medical Center (Israel) (Raanan Berger), Gustave Roussy (France) (Jean-Charles Soria), Centre Léon Bérard (France) (Pierre Saintigny), Segal Cancer Centre, McGill University (Canada) (Wilson H. Miller), UT MD Anderson Cancer Center (USA) (Jordi Rodon and Apostolia-Maria Tsimberidou) and University of California San Diego, Moores Cancer Center (USA) (Razelle Kurzrock), aimed to expand precision oncology to patients with advanced solid tumors that progressed after treatment with standard therapies.

For the first time in the clinic, the WINTHER trial applied transcriptomics (RNA expression testing) to tailor precision medicine in oncology to a greater number of patients based on the increased expression of RNA in tumors compared to normal tissues.

303 patients were enrolled in WINTHER; 107 of whom were ultimately treated according to recommendations made by a committee of cancer experts spanning five countries. These patients had been heavily pretreated, with one quarter having received five or more prior lines of therapy. Of the 107 patients treated, 69 received treatment based on DNA mutation profiling, and 38 based on RNA profiling. Overall, the WINTHER trial succeeded in matching personalized therapy to 35% of patients with advanced cancer.

“The strategy employed in WINTHER resulted in a higher proportion of patients treated than in many precision medicine trials. Previous studies have identified potential treatments for between 5% and 25 % of patients based on DNA profiling alone, our findings represent an important step toward delivering on the true promise of precision medicine in oncology,” said Richard L. Schilsky, Chairman WIN Consortium and Chief Medical Officer of ASCO.

In this trial, patients were first evaluated for targetable alterations in cancer driver genes. Those who were not matched to drugs based on DNA alterations received a treatment tailored to the differences in gene expression between patients’ tumors and normal tissues which were assessed using a patented algorithm developed by the WIN Consortium. Comparisons with normal tissues proved essential due to highly variable RNA expression between patients and across normal tissue types. The WINTHER researchers showed that RNA expression can be used to expand personalized therapy options for patients and that normal tissue biopsy is safe and accepted by patients.

Patients who received therapy optimally tailored to their respective DNA alterations, or consistent with the algorithm recommendation for RNA guided treatment, responded better. Patients with a good performance status and a high degree of matching had a significantly longer median overall survival of 25.8 months versus 4.5 months for others. There was also a correlation between degree of matching and progression-free survival independent of the number of prior therapies. "Importantly, our results show that patients treated with a drug or regimen more closely matched to the molecular profile of their tumor, do better," observed Razelle Kurzrock, co-leader of the WINTHER trial and Director of UCSD Moores Center for Personalized Cancer Therapy.

“Assessing RNA is an important adjunct to DNA profiling for determining precision treatments. WINTHER rings in a new era for personalized medicine in oncology,” concluded Josep Tabernero, Vice-Chairman WIN Consortium, Director VHIO and President ESMO.

* https://www.nature.com/articles/s41591-019-0424-4

** About WIN: WIN Consortium is a non-profit organization based in Paris, France. We are a worldwide network assembling cancer stakeholders from four continents to develop cutting edge concepts and clinical trials that improve survival for cancer patients. WIN members include 28 outstanding cancer centers plus 8 additional leading pharmaceutical, technology companies and patient advocacy organizations representing stakeholders in precision cancer medicine, www.winconsortium.org

*** WINTHER received funding from the European Union Seventh Framework Program (FP7/2007-2013 under grant agreement n°306125), ARC Foundation for cancer research (France), Pfizer Oncology, Lilly France SAS, and Novartis Pharmaceuticals Corporation.

Contacts
Vladimir Lazar
vladimir.lazar@winconsortium.org
33661091522
This is a single remembrance of two singular men, whose distinctive and distinguished lives, interests, and contributions to the field of oncology intersected and intertwined over decades and locales.
Their stories and origins could not have been more different; their key traits, strengths, and ambitions were admirably the same. Both were visionaries and elite thinkers who pushed boundaries and, when pushed back, pushed harder still. They were highly principled, took risks, challenged dogma, shifted paradigms, and led practice-changing advances. They inspired. They were brothers in science, medicine, and life, competitively pursuing common goals in the lab, clinic, and on the tennis court.

Waun Ki Hong, MD and John Mendelsohn, MD were our colleagues and mentors—a claim that could be made proudly by literally hundreds of doctors and researchers around the world. In January of this year, both died. Hong passed away at his home in California on January 2 at the age of 76. Mendelsohn died at his Texas home on January 7 at the age of 82.

Hong and Mendelsohn are perhaps best known in recent years for their extraordinary work and leadership at The University of Texas MD Anderson Cancer Center. Mendelsohn served as MD Anderson president from 1996 to 2011; Hong was head of the Division of Cancer Medicine until 2014. But their influence extended—and continues to be felt—far beyond those hallways in Houston. They positively and profoundly changed the study and practice of oncology and the lives of countless patients.

Hong, or Ki to his friends, was born in Japanese-occupied Korea during World War II. He lived in a small village 30 miles outside Seoul, the sixth of seven children. Those were difficult times, but worse followed with the Korean War. Yet Ki persevered, crediting his oldest brother, the late Suk Ki Hong, MD, PhD, a prominent renal physiologist, for inspiring him to pursue a career in medicine, following his steps to Yonsei University School of Medicine. Ki also served as a South Korean Air Force flight surgeon during the Vietnam War.

In 1970, with his young, pregnant wife Mi Hwa and just $451 in his wallet, Ki immigrated to the United States in search of better career opportunities. With much effort, he managed to get an internship at Bronx-Lebanon Hospital in New York City. It was a grueling experience, on-call every other night for 12 months combined with trying to learn a new culture, language, and the complexities of parenthood.

A 2-year residency at Veterans Affairs (VA) Medical Center in Boston followed, providing the opportunity to care for multiple cancer patients and stimulating Ki’s interest in the field of oncology, particularly in the context of head and neck cancer, among the most debilitating and disfiguring diseases. A prestigious fellowship at Memorial Sloan Kettering (MSK) Cancer Center in New York came next in 1973, following a memorable interview with Irwin Krakoff, MD, then Chief of the Medical Oncology Service, who could discern through the difficult English intense passion and keen insight. Together with his signature work ethic, Ki took full advantage of the opportunity to learn from the likes of Joseph Burchenal, MD, David Karnofsky, MD, and Robert Wittes, MD, who encouraged him to pursue a career in academic oncology. He returned to the Boston VA in 1975, where he became Chief of Medical Oncology and made the first of several research world marks when he tackled the debilitating nature of laryngeal cancer therapy.

Partnering with Gregory Wolf, MD, at the University of Michigan, he formed the VA Cooperative Group for Laryngeal Cancer Study to fund the practice-changing trial showing that a combination of chemotherapy and radiotherapy was an effective alternative to the then-standard of care for patients with advanced laryngeal cancer: total removal of the voice box. His findings allowed patients to retain their ability to speak and swallow, dramatically improved their quality of life, remains the standard of care, and laid the groundwork for preserving organs in other cancer types.

In 1983 he received a call from Krakoff, who had moved to MD Anderson and realized he needed leaders of Ki's caliber to rebuild the Division of Medicine. Ki became Chief of the Section of Head and Neck Medical Oncology, his role expanded over the next 8 years to assume the Thoracic Section; later combined, making the Sections a Department of Thoracic/Head and Neck Medical Oncology for which Ki was the founding Chair. It was an inspired choice because Ki had a knack for inspiring others, bringing together investigators from diverse fields within basic, clinical and population sciences in a new, unified mission.

His next mark introduced unrivaled rigor to the fledgling field of chemoprevention, derided by some as “soft science.” Beginning in Boston, with more passion than funding, he was able to convince Loretta Itri, MD, then at Hoffmann-La Roche to take a risk on him and this nascent discipline. Fueled by early successes, this work took off in 1991 with the award of a Program Project grant, the first of many NCI awards in this space. Early testing of high-dose retinoic acid in head and neck cancer, at the forefront of translational research, provided proof-of-principle that human cancer development could be interrupted and unprecedented understanding of premalignant biology. It was landmark, paving the way for FDA-registration trials of other agents and sites and attracting hard-core basic scientists and many others, inspiring colleagues like Elizabeth Blackburn, PhD, (Nobel Prize, 2009) to develop the cutting-edge concept of “cancer interception,” leading Stand Up To Cancer (SU2C) and innovative leaders in Pharma to invest in this strategy, including William Hait, MD, PhD, at JNJ who established a vanguard cross-sector cancer “interception accelerator” platform involving imaging devices and computational genomic and other technologies to explore, detect, and disrupt early disease-causing processes, increasingly linked to the germline and continually redefined by microbiota and other discoveries.

Ki’s last major research mark was Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination, aptly dubbed BATTLE; setting the bar high and embracing difficult challenges to set new standards, in this case a breakthrough trial design. The biologic plausibility of the BATTLE design was clear and compelling: assess tumor biology and targets at the time of drug selection. The then current standard in this setting, however, used archival diagnostic tissue, not reflecting current tumor biology that evolves with time and prior treatments. The challenge centered on the feasibility of a complex Bayesian adaptive randomization, requiring core-needle re-biopsy and molecular profiling in the second-line setting. It was a daunting, seemingly impossible task. There was much skepticism. But the approach proceeded in spectacular fashion, completed in record time with < 1% incidence of serious complications among patients undergoing lung biopsy, unequivocally establishing the feasibility of a challenging precision medicine design that has become a leading edge in cancer medicine. BATTLE was the culmination of a recurring transdisciplinary theme in his career, and at the opposite end of the disease spectrum.

In similar fashion, Ki was a staunch proponent for development of a new Investigational Cancer Therapeutics department at MD Anderson, with an essential tissue-agnostic, pathway-driven phase-I strategy. It wasn’t a popular idea. The program would be enormously expensive. It would be unprecedented to consider phase-I drugs to be beneficial. But Ki was undeterred. He had the keen intuition that genomics and molecular science could direct and accelerate early drug development. In 2004 he created a phase-I “program” pioneering genomically-driven umbrella protocols, basket trials and molecular tumor boards. With dramatic growth in patient and trial numbers, targeting virtually every aspect of known signaling defects, addressing an unmet clinical need, Ki provided ample, obvious and overt support to help make the program a department (in 2007) and the idea a stunning reality. The clinical benefit of this vanguard approach was recently validated by the first FDA tissue-agnostic approval (of a TRK inhibitor).

John Mendelsohn was born in Cincinnati and earned his bachelor’s degree in biochemical sciences from Harvard College, where he was the first undergraduate student to work in the laboratory of a new assistant professor named James Watson, PhD.

A Fulbright scholar, John attended Harvard Medical School, graduating in 1963. He took residency in internal medicine at Brigham and Women’s Hospital in Boston, where a chance meeting with then NIH chief of cardiology Eugene Braunwald, MD, would turn out to be a pivotal moment of his career. It was clear early on that John had inherent leadership “gifts” of drive, vision, charisma. While completing a hematology-oncology fellowship at Washington University he received a call from Braunwald, who had moved to the University of California San Diego (UCSD) in 1968 as the founding Chair of the Department of Medicine and wanted to build a strong presence in oncology. He thought of John. As a new school, UCSD rapidly garnered national attention with the bold strategy to first recruit the most prominent leaders, who would attract the top junior faculty, while creating a culture of innovative risk taking. A board-certified hematologist studying lymphocytes in the lab, John jumped at this opportunity to build oncology at this 2-year-old university in 1970—always eager to take on a worthy challenge; quickly appointed to lead oncology in a newly configured Division, then founding Director of its cancer center in 1976, quipping to friends “I guess I will have to learn oncology and take the Boards.”

Enthusiastic (“go for it!”) and inclusive (“we can do it”), John began to build a cancer program to match the nationally known basic science and hemopoiesis programs. Recruited in 1973, Helen Ranney, MD (the first woman to chair a Department of Medicine in the United States), who studied hemoglobin variant biochemistry and genetics, an early model for molecular medicine, shared and fully supported his vision.

It was a vibrant time, these were days of utter originality, forging ahead with more imagination than precedent. John studied, in collaboration with Salk Institute's Ian Trowbridge, PhD, effects of a monoclonal antibody that neutralized the transferrin binding function of the transmembrane protein in human lymphocytes. Gordon Sato, PhD, showed that the requirement for serum in cell culture was primarily due to the need for growth factors. “Flying blind” in 1980, the UCSD pair hypothesized they could make an antibody to prevent the growth factor-receptor connection, in this case epidermal growth factor receptor (EGFR), and block cell proliferation. Specifically, they proposed to make a monoclonal antibody to the extracellular domain of the EGF transmembrane receptor to block ligand binding, inhibit tyrosine kinase activation and cancer cell growth. Unprecedented and uncertain, the initial grant proposal to the NCI was not recommended for funding. They were able to find enough funds to complete initial cell culture studies reported in 1983, which supported their hypothesis, and secured NCI funding to expand this work. At the time, hybridoma-based technology was in its earliest stages, and it took 3 years and thousands of antibodies screened to identify 225, later generating the humanized chimeric antibody C225. That fundamental work specifically resulted in development of cetuximab, now FDA approved to treat colorectal and head and neck cancers, and began the era of targeted therapy. (Later, at Sloan Kettering, he extended this lead, driving early development of trastuzumab.)

As founding cancer center Director, John led the rigorous process including a 700-page specialized cancer center core support grant achieving the initial NCI designation in 1978 (Comprehensive in 2001 as the Moores Cancer Center). In the now-faded pages of an early proposal, one can glimpse John’s remarkable vision, inquisitive spirit, and innovation as he brought together different groups and ideas, notably having the foresight to build an immunology cancer research “unit,” including fundamental studies of T cell receptor biology—an unheard-of notion in the early 1980s, decades before CAR-T and immune checkpoint breakthrough T-cell therapies. He also recruited cancer center faculty pioneering disruptive monoclonal technology (including Ivor Royston, MD, co-founder of Hybritech), launching academia-industry partnerships, paving the way for San Diego to become one of the three largest biotech clusters in the US. Activation of what we now call Investigator Initiated Trials was much faster then--monoclonal CD5-specific antibody T101 moved from the research lab to the clinic in less than 3 years. John was legendary at engaging the broader community, forming the UCSD Cancer Foundation (actually preceding the UCSD Foundation), building the Theodore Gildred Cancer Center, which opened its doors in 1983. He also engaged the academic community, foreshadowing the recent creation of the San Diego NCI Cancer Centers Council (C3) on “the mesa.”

In 1985, John left San Diego to become chair of the Department of Medicine at MSK, and in 1996 became only the third president of MD Anderson. At MSK, John extended his 225 work to HER2, shown to be amplified in a poor-prognostic breast-cancer subset by Dennis Slamon, MD, PhD, at UCLA; catalyzing prolific, fast and furious work, which took off with a 1989 Genentech report of their monoclonal antibody 4D5 inhibiting HER2 overexpressing breast tumor cell growth, followed in months by John's mechanistic discovery that 4D5 blocked HER2 phosphorylation, including the tyrosine residue. The close interaction between the two groups during the cell culture studies continued, leading to a key 1993 meeting where John brought his MSK team to south San Francisco, and they charted early steps of the now historic clinical development of 4D5, subsequently humanized as Herceptin; relentlessly driven by visionaries at Genentech, UCLA, MSK and others.

Mendelsohn arrived at MD Anderson at a challenging time. A compelling report from prestigious consultants had pushed for a limited clinical enterprise. Research, they argued, was too expensive. John went around, pen and pad in hand, talking with rank and file faculty and institutional leaders. A few weeks later, he charted the institution’s course. He would not divest of research, but rather invest in it, expand it beyond anything that had been witnessed or imagined before. We were young (relatively) and in awe of his boldness. Research was MD Anderson’s raison d’etre, and John was going to preside over the largest and most stunning growth in the institution’s history. He built a research-driven, patient-focused enterprise that proved wildly successful—doubling the number of employees and patients, tripling the facility space, quadrupling the annual revenue to more than $3 billion, and increasing private philanthropy 10-fold, all while expanding its education programs. It is considered the world’s top cancer center.

Like Ki, John gave generously of his time and expertise. He offered his much-sought advice freely, forever advocating for any effort that would advance the cause of cancer research and help save more lives. In the last decade of his life, John built globally on the possibilities of precision medicine. Ever prescient, he anticipated the importance of big-data technology to the future of the field and wanted to learn more. Our colleague Jill Mesirov, then associate director at the Broad Institute of MIT and Harvard, recalls a day when John, who was on sabbatical after retiring as President of MD Anderson, introduced himself and asked her to teach him everything he should know about computational genomics. With keen foresight, he had a way of asking the right questions, catching on quickly, and appreciating the vast complexities and impact of this technology in making precision therapy an expanding reality. He launched the Institute for Personalized Cancer Therapy at MD Anderson and became the founding Chair of the Worldwide Innovative Networking (WIN) Consortium in Personalized Cancer Medicine.

These men were so different: the Korean immigrant from humble beginnings and the American Ivy Leaguer. Ki breathed Boston sports, often using sports analogies—“put points on the board” reflecting key career steps such as young investigator awards (Ki provided scientific writer support); while “don't drop the ball on the 1 yard line” conveyed quite a different message. John was an avid reader with broad interests, from music to science to political history. He was a patron of community arts, culture, and education and was Chair of the Houston Grand Opera.

But they were one and the same as well. Both men were tireless workers and detailed administrators, in before dawn and the last to leave at night. They were resourceful, fearless, and resilient. They had a way of looking over the horizon, embracing change, anticipating what would or should come next. We will also remember them as individuals who always strove to do the right thing and were indefatigable optimists. Their work is described as innovative and groundbreaking. They were inspirational and supportive, helping both of us refine and improve our science and advance our careers, as they did with so many others. Hong recruited Lippman to MD Anderson where they worked closely on multiple research projects, and with Mendelsohn provided mentorship and support as he succeeded them in various academic leadership positions at MD Anderson and UC San Diego. Conversely, Mendelsohn and Kurzrock were close collaborators, while Hong provided guidance and support as she became founding Chair of the Department of Investigational Cancer Therapeutics at MD Anderson. They continued to guide us; we lost two members of our External Advisory Board during that week in January.

We honor them for what they accomplished in their lives; both accrued many, many awards and tributes, though both often mused that working and training colleagues was far more rewarding. They seamlessly integrated education and training into the fabric of cancer research and care. Avant-garde scientists and practitioners, they shared their sage advice, passion, and vision with their colleagues and trainees, creating a legacy for generations to come. For example, Ki often said his most meaningful honor was the annual American Association for Cancer Research merit award in his name and in perpetuity, given to a young investigator. We will miss them even more as our friends. It is difficult to distill the essence of these special men, Ki and John were complex, intense, caring, inquisitive, intriguing, and charismatic in so many ways.

They were hard-working and competitive, yet always found time for family. Both enjoyed sharing stories involving their children and grandchildren. Ki often recalled how much he relished going to Fenway Park with his two sons when he was a young father during the Boston VA days. Likewise, who wasn't impressed when they heard that John took up the violin in his 70s after listening to his grandson's inspirational lesson? Devoted husbands, Ki was married to Mi Hwa for nearly 50 years and John to Anne for 56.

They were close friends themselves, but regular foes on the tennis court, a sport they both loved and played often. In the months before John died of a glioblastoma—an end he knew was coming—Ki had taken it upon himself to write a tribute. Factual aspects done but the personal sentiments more difficult to articulate; Ki didn’t finish, succumbing to unexpected kidney failure. John passed 5 days later.

Through the tears, a bit of humor circulated among family and friends.
Ki had let John know there were tennis courts in heaven.

Scott M. Lippman and Razelle Kurzrock
Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
Waun Ki Hong and John Mendelsohn were singular forces who combined to change the world of oncology and, in the process, the lives of countless trainees, faculty, patients, and families.
After these giants of cancer research and treatment died last month—they died five days apart—much was said about their careers and awards, of which there were many. All of this was important, but it’s done, and now we can look at some of the timeless and instinctive leadership ingredients that shaped Ki’s and John’s success.

Through the course of many interactions, their approach to life synergized with each other, and they genuinely became the legends that they created. The relationship was not superficial. They were equals, and they took the time to learn from each other. They worked and played (tennis) together, they discussed programs and science, and in the end, they took care of each other. Whether they explicitly discussed leadership principles we may never know, but the closeness of the relationship suggests that they communicated deeply about how to work effectively in the context of complex academic and scientific systems to accomplish their personal goals while promoting institutional objectives and the work and careers of others.

Those of us lucky enough to have been mentees and colleagues of Ki and John experienced the unique dynamism and influence of each. What they did, and their impact, is a matter of public record; how they did it is another matter altogether.

Over the past month, we have deeply reflected on our history and experiences with Ki and John, and found ourselves researching little-known facets of their careers, gaining insights by tracking down students and colleagues who were delighted to reminisce and recall deeply etched, fond memories of these men, reaching as far back as the early 1970s.

We were struck by how Ki’s and John’s approaches, attitudes and outlook, decisions and dispositions made them the leaders they were. Though much is written on the science of leadership, Ki and John, through their individual and joint accomplishments, could have written a fine book on the applied art of leadership, a few of the themes of which are presented below.

While technology and scientific methodology dramatically changed over Ki’s and John’s careers, the leadership ingredients have stood the test of time…

You never know when a routine or chance meeting could become a career-defining moment.

Both men made the most of even seemingly small opportunities when they presented themselves; and created their own breaks—such as when a Harvard undergraduate (John) knocked on the door of a new assistant professor named James Watson. Recognize that each encounter can leave an enduring impression. Cultivate “presence,” and preparation, to make small interactions noteworthy.

For Ki, it was a 1973 fellowship interview at Sloan Kettering, during which Irwin Krakoff, then chief of the Medical Oncology Service, could discern through the difficult English the intense passion, insight and focus that characterized Ki’s early career. Intrigued, Krakoff kept an eye on Ki during his fellowship and beginning of his faculty career at Boston Veterans Affairs; taking note of Ki’s incredible track-record of bringing precision and incisiveness to challenging clinical trials.

Krakoff was also impressed by Ki’s capacity to work (he often said, “I only consider myself of average intelligence, but I can out-work most people”); absorbing everything he could learn during fellowship from the likes of Joseph Burchenal, David Karnofsky, and Robert Wittes, as he embraced very difficult clinical problems. Ki’s early faculty career at the Boston VA, focused on head and neck cancer, developing a series of interrelated and innovative clinical trials designed to interrupt this disease process, ranging from neoadjuvant chemotherapy to chemoprevention, each at the cutting edge of translational research.

Krakoff was recruited to MD Anderson in 1983 to elevate the academic stature of the Division of Medicine; a year later (and 10 years after a memorable fellowship interview), Ki was recruited to bring rigor to the clinical trials program as chief of the Section of Head and Neck Medical Oncology, then Charles A. LeMaistre Distinguished Chair of the Department of Thoracic/Head and Neck Medical Oncology at MD Anderson. On a related note, lasting impressions during his fellowship led Wittes, who had moved to the NCI Cancer Therapy Evaluation Program, to connect him several years later with surgeon Greg Wolf, who led the NCI Head and Neck Contracts Program HNCP-178, which set the stage for the pair to design and lead the landmark VACSP-268 laryngeal cancer preservation trial.

For John, it was during his residency at the Brigham and Women’s Hospital. A chance meeting with a visiting professor from NIH, Eugene Braunwald, would turn out to be a defining moment of his career.

Braunwald recognized early on that John had inherent leadership “gifts”: drive, vision, charisma. Several years later, while completing a hematology-oncology fellowship at Washington University, John received a call from Braunwald, who had moved to the University of California San Diego (UCSD) in 1968 as the founding chair of the Department of Medicine, where he wanted to build a strong presence in oncology.

He thought of John, introduced him to hematology division chief Mickey Goulian, who immediately recognized John’s talents and capabilities. They recruited John to UCSD in 1970, enticing him to break from his established Ivy League roots with the opportunity to literally “build oncology from the ground up” at this exciting, vibrant 2-year-old university.

Foster relationships with colleagues and competitors to build mutual respect and advance the field.

Ki and John were masters at convincing and motivating people to join them and collaborate, using many strategies known to build relationships. John shaped and transformed three major cancer centers while launching and driving the era of targeted therapy.

Yet, we highlight Ki’s approach to this principle because of its uniqueness as a tactic in academic medicine. Though we doubt Ki ever read a leadership book, he clearly understood the techniques embodied in the genius of Abraham Lincoln, as outlined in the Team of Rivals by Doris Kearns Goodwin.

Ki had the innate ability to cultivate relationships with colleagues and competitors by simultaneously competing with and promoting the interests of these individuals. With deep political intuition, Ki built a team of trusted friends, colleagues and even rivals to advance cancer research and care.

He found a way to allow each of his competitors—including detractors—to contribute to cancer medicine, where they could achieve personal success, thereby advancing the field and, intended or not, simultaneously enhancing Ki’s stature. Throughout his career, Ki devoted considerable time and effort to elevating the careers of others—nominating and passionately advocating colleagues and competitors alike for major awards and accolades.

This tactic was simultaneously a selfless act, yet also one with great returns on investment, generating longstanding mutual respect and admiration. The success of this strategy was iterated throughout his career, and with each success became a self-reinforcing aspect of Ki’s highly effective interactions with others. This was a political genius on par with that of Lincoln.

Think broadly, look ahead, recognize and promote talent.

John was recruited to UCSD to build an oncology program, but his expertise was as a hematology physician-scientist with additional fellowship training at the NIH, leading a large basic lab effort.

He knew he needed to bring a national leader in solid tumor clinical trials, so in 1976, the year John became the founding UCSD Cancer Center Director, he recruited the late Mark Green, one of the most highly respected oncologists in the United States, famous for his encyclopedic knowledge of clinical oncology (and memorizing medical record numbers of his patients.)

John was always looking for ways to expand the breadth and depth of the UCSD Cancer Center within his modest budget. He successfully promoted and leveraged academic and academic-industry partnerships, and passionately engaged community leaders.

His broad vision is illustrated by his early years at UCSD, building the cancer program and center to encompass very basic studies of T-cell receptor biology, advancing disruptive monoclonal technology and establishing a nascent effort in community engagement.

In 1981, John recruited Georgia Sadler to be the associate director for administration, also realizing that her doctoral training in public health would be a real asset in helping him to expand the breadth of the center.

He supported her efforts to create public education and awareness programs highlighting the importance of cancer prevention and clinical trial participation. This outreach effort had a strong regional focus on reducing cancer disparities, placing meaningful value on what we now call “catchment area,” making John one of the nation’s first directors of an NCI-designated cancer center to use community-campus partnerships as an effective cancer control strategy.

Embrace difficult challenges that address simple, compelling, and worthy questions.

Ki and John developed groundbreaking, yet straightforward, simple and compelling research hypotheses that addressed meaningful problems.
While simple in retrospect, each breakthrough was incredibly difficult and challenging to operationalize and implement, requiring tenacity, resilience and creativity in the face of opposition and scientific concerns regarding the validity of their research ideas and feasibility.

For example, though the idea behind Ki’s Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study was simple and compelling—base targeted drug selection on current tumor biology—it was unprecedented and prompted vigorous debate, skepticism, and even ethical resistance.

The controversy centered on the risk of the core needle re-biopsy required to base drug selection on current biology in the second line setting, versus the risk of inaccurately selecting drug therapy or pathway targets from archival diagnostic tissue.

Despite the skepticism, BATTLE established the feasibility of a challenging precision therapy protocol design that has become an established approach in cancer medicine.

Related to his principle of simple, straightforward hypotheses, Ki designed trials to answer important questions, contributing valuable information, regardless of the result—this was his “no lose approach” to cancer research.

In 1980, John’s groundbreaking hypothesis that launched the era of targeted therapy was, at its core, quite simple—make an antibody to prevent the growth factor-receptor connection, in this case epidermal growth factor receptor (EGFR) to block cell proliferation.

The hypothesis, however, was based on circumstantial evidence, including basic studies of transferrin- and acetylcholine-receptor biology, but no direct experimental data. In fact, prevailing data revealed that monoclonal antibodies functioned as agonists in this setting. Unprecedented, uncertain, and unfunded, John partnered with Gordon Sato, to push the idea to reality through initially scraping together funds for preliminary hybridoma studies, screening thousands of antibodies over several years to find a lead compound (225) with strong antagonist, blocking activity. John moved to Sloan Kettering in 1985, continuing his 225 work, and led seminal studies driving the development of 4D5 and Herceptin with Rakesh Kumar and José Baselga.

These are but a few examples of the approach to leadership embodied and employed by these two great men. There were many similarly important principles in other aspects of their careers, including seamlessly integrating education and training into the fabric of cancer research and care: creatively designed and funded innovative and transformational training mechanisms such as an advanced scholars program.

Having the incredible fortune to work with them over many years, as well as listening to the stories told by former students and colleagues, was exciting and compelling. Ki and John didn’t write an actual book about their leadership experiences, but they “wrote the book,” figuratively, and that bears noting—and retelling.

Read more: For a more in-depth look at the lives of these two extraordinary and inspirational individuals, please read our tribute in Cancer Cell, publishing on Feb. 11, 2019. (The link will go live on the day of publication.)

Copyright (c) 2018 The Cancer Letter Inc.
The Cancer Letter, 8 February 2019
Guest Editorial: Scott Lippman, Daniel D. Karp & James L. Abbruzzese