Cancer Cell Obituary: Waun Ki Hong (1942-2019) John Mendelsohn (1936-2019)

Posted: Monday, February 11, 2019

Cancer Cell Obituary: Waun Ki Hong (1942-2019) John Mendelsohn (1936-2019)

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.

Waun Ki Hong MD

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 MD

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